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Is this the most controversial issue in early breast cancer treatment?
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.
The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.
, as the other expert countered?
The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.
The controversy had arisen the previous year over results from the RxPONDER trial.
Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.
However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).
The results were immediately controversial.
Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.
Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.
“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.
“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.
But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.
Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”
For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”
“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”
But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
Debate rages on
The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”
At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.
Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.
Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”
The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?
Yes, argued Michael Gnant, MD, from the Medical University of Vienna.
Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.
Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.
“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”
The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”
So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.
But the real question is: “What does it mean for clinical practice?”
Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.
Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.
On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.
“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.
Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”
She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.
The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.
Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.
“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.
“I think both are needed in young premenopausal patients,” she added.
Audience responses
After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.
However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.
When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.
A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.
From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.
In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”
Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”
Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”
Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.
Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.
Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.
He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.
Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”
A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.
Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.
He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
Treating individual patients
When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”
For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.
For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.
“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”
“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”
This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.
The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”
“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.
Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”
These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.
Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.
A version of this article first appeared on Medscape.com.
False-positive breast cancer screening likely over 10-year period
Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.
Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.
By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.
The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.
Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.
Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”
The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”
The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.
Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”
The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.
Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.
Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.
By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.
The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.
Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.
Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”
The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”
The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.
Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”
The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.
Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.
Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.
By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.
The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.
Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.
Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”
The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”
The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.
Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”
The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.
JAMA NETWORK OPEN
Brain implant allows fully paralyzed patient to communicate
Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.
The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.
“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.
Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
Mechanism a ‘mystery’
Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.
Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.
In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.
The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.
Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.
A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.
Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.
Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
Controversial history
In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.
Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).
The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.
Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.
“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
Results ‘not stunningly good’
The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.
Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.
Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.
“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”
Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.
“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.
Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”
“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”
The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.
A version of this article first appeared on Medscape.com.
Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.
The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.
“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.
Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
Mechanism a ‘mystery’
Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.
Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.
In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.
The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.
Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.
A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.
Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.
Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
Controversial history
In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.
Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).
The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.
Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.
“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
Results ‘not stunningly good’
The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.
Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.
Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.
“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”
Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.
“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.
Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”
“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”
The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.
A version of this article first appeared on Medscape.com.
Using a commercially available implant and newly designed software, the patient, who was in the advanced stages of Lou Gehrig’s disease and unable to move his eyes, was able to interact with researchers and caregivers, requesting goulash, beer, and music from the band Tool, thanking the researchers who developed the technology and inviting his 4-year-old son to watch a Disney film.
The investigators note the study shows for the first time that communication is possible in patients in a completely locked-in state (CLIS) and offers hope for a better quality of life in this population.
“It should encourage them to live after artificial respiration and to ask for brain-computer interfaces before they become CLIS,” study investigator Niels Birbaumer, PhD, a professor emeritus of the University of Tübingen, Germany, said in an interview. The study was published online March 22 in Nature Communications.
Although the findings appear promising, they build on previous research that was the subject of a 2019 investigation by the largest grant-funding agency in Germany. This controversy prompted the institute that led the current research to appoint an independent expert to audit and monitor the new study.
Mechanism a ‘mystery’
Use of brain-computer interface (BCI) technology to allow ALS patients to communicate has increased in recent years. BCIs capture brain signals, transmit them to a computer, and convert them into a command that the computer carries out.
Previous research shows patients with ALS who retain eye movement and control have been able to use BCIs to communicate. However, until now, the technology has not worked as well in CLIS patients, who have full-body paralysis.
In 2019, German and Swiss researchers implanted two 64-microde arrays in the brain of a 34-year-old patient who was diagnosed with ALS in 2015.
The electrodes measure neuronal activity while an amplifier located on the outside of the patient’s skull amplifies the signals to a computer. Software created by the research team decodes the signals and translates them into commands.
Using an auditory feedback system, the patient was able to use his mind to modulate the pitch of a tone to either high (meaning “yes”) or low (meaning “no.”) Just how the brain does this is a mystery, Dr. Birbaumer said.
A speller program reads letters aloud, first in groups and then individually. When a group contained letters the patient needed to spell a word, he used auditory feedback to select the high-pitch tone.
Initially, the patient was able to correctly spell his name. Ultimately, he was able to form complete sentences. The patient correctly spelled words on 44 of the 107 days in that phase of the experiment, spelling an average of just one character per minute.
Still, the researchers note he was able to interact with his caretakers, family, and researchers, even offering input on changes to make the device more effective.
Controversial history
In 2017, Dr. Birbaumer and Ujwal Chaudhary, PhD, who is the lead author on this current study, published a study in PLOS Biology. That research analyzed a brain-monitoring technique that the scientists claimed enabled patients with ALS who were completely locked in to answer yes or no questions correctly.
Allegations from a whistleblower at the University of Tübingen, where Dr. Birbaumer was a senior professor and Dr. Chaudhary was a postdoctoral researcher, prompted an investigation by the Deutsche Forschungsgemeinschaft, or German Research Foundation (DFG).
The whistleblower claimed that the 2017 paper and a second study published in 2019 contained incomplete data and misrepresented the findings. The DFG investigation found evidence of scientific misconduct and required that Dr. Birbaumer return the grant he had received for the research. The agency also banned Dr. Birbaumer from applying for grants or serving as a grant reviewer for 5 years. Dr. Chaudhary was banned for 3 years. PLOS Biology later retracted the papers.
Both researchers have refuted the allegations and have reportedly sued the German Research Foundation.
“We have no information about the status of our lawsuit against the DFG; it’s still pending,” Dr. Birbaumer told this news organization. “I hope they investigate our present study because the study of 2017 they did not investigate carefully enough.”
Results ‘not stunningly good’
The controversial history prompted the Wyss Center, Geneva, which led this new study, to seek out at an independent BCI expert to audit and monitor the study.
Nick Ramsey, PhD, a professor of cognitive neuroscience at the Brain Center of the University Medical Center Utrecht, the Netherlands, agreed to take on the assignment in March 2020.
Dr. Ramsey has also conducted research on BCI in patients with ALS, but his work has not included patients in CLIS.
“I judged the study to be compliant with universal standards of scientific integrity,” Dr. Ramsey told this news organization. “I am confident that the data and results presented in the paper are valid and will withstand academic and medical scrutiny.”
Commenting on the new findings, Dr. Ramsey noted that the results of the study are “not stunningly good, as the user could only communicate during a limited number of days, and even then with considerable slowness,” Dr. Ramsey said. However, he added that the study does provide proof of principle that communication is possible in CLIS patients.
“The question remains whether a BCI implant continues to work well in these patients, as there are some indications that people in such a state may lose their mental capabilities within months or a few years as a result of the disease and can thus no longer generate a wish to communicate,” Dr. Ramsey said.
Responding to a query from this news organization, a spokesperson for Nature Communications declined to comment on the new study but said that journal editors are “are alert to controversies within each field and take care when considering submissions during the peer-review process.”
“We have rigorous policies to safeguard the integrity of the research we publish,” the spokesperson continued, “including to ensure that research has been conducted to a high ethical standard and is reported transparently.”
The research was funded by Wyss Center for Bio and Neuroengineering, Geneva and Deutsche Forschungsgemeinschaft. The authors have disclosed no relevant financial relationships. Dr. Ramsey received payment from the Wyss Center for his advisory role in this project.
A version of this article first appeared on Medscape.com.
FROM NATURE COMMUNICATIONS
Artificial sweeteners: A modifiable cancer risk?
People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.
Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*
These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.
“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.
“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.
Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.
“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
Important analysis, interpret with caution
“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.
“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”
Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”
His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022.
“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
Conflicting results
Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.
They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.
“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.
According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.
The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.
The current cohort included 102,865 adults who enrolled in 2009-2021.
Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.
At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.
Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).
Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%).
During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.
Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.
Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables.
Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.
Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).
The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.
The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.
Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer.
A version of this article first appeared on Medscape.com.
People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.
Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*
These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.
“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.
“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.
Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.
“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
Important analysis, interpret with caution
“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.
“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”
Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”
His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022.
“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
Conflicting results
Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.
They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.
“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.
According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.
The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.
The current cohort included 102,865 adults who enrolled in 2009-2021.
Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.
At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.
Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).
Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%).
During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.
Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.
Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables.
Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.
Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).
The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.
The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.
Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer.
A version of this article first appeared on Medscape.com.
People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.
Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*
These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.
“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.
“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.
Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.
“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
Important analysis, interpret with caution
“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.
“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”
Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”
His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022.
“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
Conflicting results
Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.
They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.
“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.
According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.
The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.
The current cohort included 102,865 adults who enrolled in 2009-2021.
Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.
At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.
Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).
Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%).
During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.
Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.
Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables.
Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.
Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).
The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.
The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.
Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer.
A version of this article first appeared on Medscape.com.
FROM PLOS MEDICINE
Clinical Edge Journal Scan Commentary: Breast Cancer April 2022
Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.
The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.
The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.
Recommended Additional Reading:
Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090
Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856
Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001
Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.
The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.
The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.
Recommended Additional Reading:
Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090
Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856
Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001
Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.
The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.
The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.
Recommended Additional Reading:
Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090
Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856
Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001
Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0
Breast density linked to familial breast cancer risk
observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.
“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.
Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.
In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.
In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.
The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.
“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.
The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.
The study was funded by the National Institutes of Health.
observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.
“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.
Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.
In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.
In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.
The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.
“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.
The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.
The study was funded by the National Institutes of Health.
observed during mammography, according to a new study of two retrospective cohorts published online Feb. 17 in JAMA Network Open. The findings suggest that breast density measured during mammography may have a genetic component, and suggest the importance of initiating early mammography in premenopausal women with a family history of breast cancer.
“We know that mammographic breast density is a very strong risk factor for breast cancer, probably one of the strongest risk factors, and it’s also a surrogate marker for breast cancer development, especially in premenopausal women. We also know that family history of breast cancer is a strong risk factor for breast cancer as well. Surprisingly, we have very limited information on how these risk factors are related to each other. There have been only two studies that have been done in this field in premenopausal women, and the studies are conflicting. So, we felt that we need to really understand how these two factors are related to each other and whether that would have an impact on modifying or refining mammographic screening in high-risk women,” Adetunji T. Toriola, MD, PhD, MPH, said in an interview. Dr. Toriola is professor of surgery at Washington University, St. Louis.
Previous research identified risk factors for dense breast tissue. A genome-wide association study found 31 genetic loci associated with dense breast tissue, and 17 had a known association with breast cancer risk.
In the JAMA Network Open study, the researchers included data from women who were treated at Washington University’s Joanne Knight Breast Health Center and Siteman Cancer Center. The discovery group included 375 premenopausal women who received annual mammography screening in 2016 and had dense volume and non-dense volume measured during each screen. The validation set drew from 14,040 premenopausal women seen at the centers between 2010 and 2015.
In the discovery group, women with a family history of breast cancer had greater volumetric percent density (odds ratio [OR], 1.25; P < .001). The validation set produced a similar result (OR, 1.30; 95% confidence interval, 1.17-1.45). Subanalyses revealed similar associations in non-Hispanic White and Black or African American women.
The current study included a higher percentage of women with a family history of breast cancer than previous studies, and also controlled for more variables. This may have removed confounding variables that could have affected previous studies.
“It reinforces the need to start mammogram screening early in women who have a family history of breast cancer,” Dr. Toriola said.
The study had some limitations, including a higher percentage of women with a family history of breast cancer than the National Health Interview Survey (23.2% and 15.3%, versus 8.4%), explained by the fact that women with a family history of breast cancer are more likely to seek out screening. The average age of women was on average 47 years, making them closer to perimenopausal than premenopausal.
The study was funded by the National Institutes of Health.
FROM JAMA NETWORK OPEN
Few new cancer drugs replace current standards of care
, a new analysis shows.
Of more than 200 agents evaluated, most (42%) received approval as second-, third-, or later-line therapies.
“While there is justified enthusiasm for the high volume of new cancer drug approvals in oncology and malignant hematology, these approvals must be evaluated in the context of their use,” the authors note in a report published online March 15 in JAMA Network Open. Later-line drugs may, for instance, “benefit patients with few alternatives but also add to cost of care and further delay palliative and comfort services” compared to first-line therapies, which may alter “the treatment paradigm for a certain indication.”
The U.S. Food and Drug Administration approves several new cancer drugs each month, but it’s not clear how many transform the treatment landscape.
To investigate, David Benjamin, MD, with the Division of Hematology and Oncology, University of California, Irvine, and colleagues evaluated all 207 cancer drugs approved in the U.S. between May 1, 2016 and May 31, 2021.
The researchers found that only 28 drugs (14%) displaced the prior first-line standard of care for an indication.
Examples of these cancer drugs include alectinib for anaplastic lymphoma kinase rearrangement–positive metastatic non–small cell lung cancer (NSCLC), osimertinib for epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution NSCLC, atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma, and cabozantinib for advanced kidney cancer.
A total of 32 drugs (15%) were approved as first-line alternatives or new drugs. These drugs were approved for use in the first-line setting but did not necessarily replace the standard of care at the time of approval or were first-of-their-class therapies.
Examples of these drug approvals include apalutamide for nonmetastatic castrate-resistant prostate cancer, tepotinib for metastatic MET exon 14-skipping NSCLC, and avapritinib for unresectable or metastatic gastrointestinal stromal tumor with platelet-derived growth factor receptor alpha exon 18 variant, including D842V variant.
A total of 61 drugs (29%) were approved as add-on therapies for use in combination with a previously approved therapy or in the adjuvant or maintenance settings. These drugs “can only increase the cost of care,” the study team says.
Most new approvals (n = 86) were for use in second-, third- or later-line settings, often for patients for whom other treatment options had been exhausted.
The authors highlight disparities among approvals based on tumor type. Lung-related tumors received the most approvals (n = 37), followed by genitourinary tumors (n = 28), leukemia (n = 25), lymphoma (n = 22), breast cancer (n = 19), and gastrointestinal cancers (n = 14).
The authors note that cancer drugs considered new standards of care or approved as first-line setting alternatives could “provide market competition and work to lower cancer drug prices.”
The study was funded by a grant from Arnold Ventures.
A version of this article first appeared on Medscape.com.
, a new analysis shows.
Of more than 200 agents evaluated, most (42%) received approval as second-, third-, or later-line therapies.
“While there is justified enthusiasm for the high volume of new cancer drug approvals in oncology and malignant hematology, these approvals must be evaluated in the context of their use,” the authors note in a report published online March 15 in JAMA Network Open. Later-line drugs may, for instance, “benefit patients with few alternatives but also add to cost of care and further delay palliative and comfort services” compared to first-line therapies, which may alter “the treatment paradigm for a certain indication.”
The U.S. Food and Drug Administration approves several new cancer drugs each month, but it’s not clear how many transform the treatment landscape.
To investigate, David Benjamin, MD, with the Division of Hematology and Oncology, University of California, Irvine, and colleagues evaluated all 207 cancer drugs approved in the U.S. between May 1, 2016 and May 31, 2021.
The researchers found that only 28 drugs (14%) displaced the prior first-line standard of care for an indication.
Examples of these cancer drugs include alectinib for anaplastic lymphoma kinase rearrangement–positive metastatic non–small cell lung cancer (NSCLC), osimertinib for epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution NSCLC, atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma, and cabozantinib for advanced kidney cancer.
A total of 32 drugs (15%) were approved as first-line alternatives or new drugs. These drugs were approved for use in the first-line setting but did not necessarily replace the standard of care at the time of approval or were first-of-their-class therapies.
Examples of these drug approvals include apalutamide for nonmetastatic castrate-resistant prostate cancer, tepotinib for metastatic MET exon 14-skipping NSCLC, and avapritinib for unresectable or metastatic gastrointestinal stromal tumor with platelet-derived growth factor receptor alpha exon 18 variant, including D842V variant.
A total of 61 drugs (29%) were approved as add-on therapies for use in combination with a previously approved therapy or in the adjuvant or maintenance settings. These drugs “can only increase the cost of care,” the study team says.
Most new approvals (n = 86) were for use in second-, third- or later-line settings, often for patients for whom other treatment options had been exhausted.
The authors highlight disparities among approvals based on tumor type. Lung-related tumors received the most approvals (n = 37), followed by genitourinary tumors (n = 28), leukemia (n = 25), lymphoma (n = 22), breast cancer (n = 19), and gastrointestinal cancers (n = 14).
The authors note that cancer drugs considered new standards of care or approved as first-line setting alternatives could “provide market competition and work to lower cancer drug prices.”
The study was funded by a grant from Arnold Ventures.
A version of this article first appeared on Medscape.com.
, a new analysis shows.
Of more than 200 agents evaluated, most (42%) received approval as second-, third-, or later-line therapies.
“While there is justified enthusiasm for the high volume of new cancer drug approvals in oncology and malignant hematology, these approvals must be evaluated in the context of their use,” the authors note in a report published online March 15 in JAMA Network Open. Later-line drugs may, for instance, “benefit patients with few alternatives but also add to cost of care and further delay palliative and comfort services” compared to first-line therapies, which may alter “the treatment paradigm for a certain indication.”
The U.S. Food and Drug Administration approves several new cancer drugs each month, but it’s not clear how many transform the treatment landscape.
To investigate, David Benjamin, MD, with the Division of Hematology and Oncology, University of California, Irvine, and colleagues evaluated all 207 cancer drugs approved in the U.S. between May 1, 2016 and May 31, 2021.
The researchers found that only 28 drugs (14%) displaced the prior first-line standard of care for an indication.
Examples of these cancer drugs include alectinib for anaplastic lymphoma kinase rearrangement–positive metastatic non–small cell lung cancer (NSCLC), osimertinib for epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution NSCLC, atezolizumab plus bevacizumab for unresectable or metastatic hepatocellular carcinoma, and cabozantinib for advanced kidney cancer.
A total of 32 drugs (15%) were approved as first-line alternatives or new drugs. These drugs were approved for use in the first-line setting but did not necessarily replace the standard of care at the time of approval or were first-of-their-class therapies.
Examples of these drug approvals include apalutamide for nonmetastatic castrate-resistant prostate cancer, tepotinib for metastatic MET exon 14-skipping NSCLC, and avapritinib for unresectable or metastatic gastrointestinal stromal tumor with platelet-derived growth factor receptor alpha exon 18 variant, including D842V variant.
A total of 61 drugs (29%) were approved as add-on therapies for use in combination with a previously approved therapy or in the adjuvant or maintenance settings. These drugs “can only increase the cost of care,” the study team says.
Most new approvals (n = 86) were for use in second-, third- or later-line settings, often for patients for whom other treatment options had been exhausted.
The authors highlight disparities among approvals based on tumor type. Lung-related tumors received the most approvals (n = 37), followed by genitourinary tumors (n = 28), leukemia (n = 25), lymphoma (n = 22), breast cancer (n = 19), and gastrointestinal cancers (n = 14).
The authors note that cancer drugs considered new standards of care or approved as first-line setting alternatives could “provide market competition and work to lower cancer drug prices.”
The study was funded by a grant from Arnold Ventures.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Moderna reports positive COVID-19 vaccine response in kids down to 6 months
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
New guidance on cannabis use for treatment-resistant epilepsy
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
FROM THE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Avoiding delay in AHT may improve survival in HR-positive, ERBB2-negative early BC
Key clinical point: A delay in initiation of adjuvant hormone therapy (AHT) beyond 150 days was significantly associated with poor survival in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer (BC) not receiving chemotherapy.
Major finding: Time to AHT (TTH) >150 days vs. ≤150 days was associated with an increased risk for death in the overall population (hazard ratio 1.31; P < .001).
Study details: Findings are from a population-based retrospective study including 144,103 patients with HR-positive/ERBB2-negative early BC who received AHT without chemotherapy, of which 6.4% of patients experienced a delay in AHT initiation (TTH >150 days) and 93.6% initiated AHT on time (TTH ≤150 days).
Disclosures: This study was supported by the Natural Science Foundation of Fujian Province and the Fujian Provincial Health Technology Project. The authors declared no conflicts of interest.
Source: Fu F et al. Association of adjuvant hormone therapy timing with overall survival among patients with hormone receptor–positive human epidermal growth factor receptor-2–negative early breast cancer without chemotherapy. JAMA Netw Open. 2022;5(2):e2145934 (Feb 15). Doi: 10.1001/jamanetworkopen.2021.45934
Key clinical point: A delay in initiation of adjuvant hormone therapy (AHT) beyond 150 days was significantly associated with poor survival in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer (BC) not receiving chemotherapy.
Major finding: Time to AHT (TTH) >150 days vs. ≤150 days was associated with an increased risk for death in the overall population (hazard ratio 1.31; P < .001).
Study details: Findings are from a population-based retrospective study including 144,103 patients with HR-positive/ERBB2-negative early BC who received AHT without chemotherapy, of which 6.4% of patients experienced a delay in AHT initiation (TTH >150 days) and 93.6% initiated AHT on time (TTH ≤150 days).
Disclosures: This study was supported by the Natural Science Foundation of Fujian Province and the Fujian Provincial Health Technology Project. The authors declared no conflicts of interest.
Source: Fu F et al. Association of adjuvant hormone therapy timing with overall survival among patients with hormone receptor–positive human epidermal growth factor receptor-2–negative early breast cancer without chemotherapy. JAMA Netw Open. 2022;5(2):e2145934 (Feb 15). Doi: 10.1001/jamanetworkopen.2021.45934
Key clinical point: A delay in initiation of adjuvant hormone therapy (AHT) beyond 150 days was significantly associated with poor survival in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (ERBB2)-negative breast cancer (BC) not receiving chemotherapy.
Major finding: Time to AHT (TTH) >150 days vs. ≤150 days was associated with an increased risk for death in the overall population (hazard ratio 1.31; P < .001).
Study details: Findings are from a population-based retrospective study including 144,103 patients with HR-positive/ERBB2-negative early BC who received AHT without chemotherapy, of which 6.4% of patients experienced a delay in AHT initiation (TTH >150 days) and 93.6% initiated AHT on time (TTH ≤150 days).
Disclosures: This study was supported by the Natural Science Foundation of Fujian Province and the Fujian Provincial Health Technology Project. The authors declared no conflicts of interest.
Source: Fu F et al. Association of adjuvant hormone therapy timing with overall survival among patients with hormone receptor–positive human epidermal growth factor receptor-2–negative early breast cancer without chemotherapy. JAMA Netw Open. 2022;5(2):e2145934 (Feb 15). Doi: 10.1001/jamanetworkopen.2021.45934