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Study supports add-on therapy for germline and wildtype BRCA mutations
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The initial improvement that was seen in pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel and standard neoadjuvant chemotherapy translated into improved event-free survival (EFS) rates in patients with resectable TNBC more than 4 years after surgery.
The benefits of adding carboplatin to paclitaxel, followed by four cycles of AC (doxorubicin and cyclophosphamide) chemotherapy, were seen both in patients with germline BRCA mutations and those with wildtype BRCA.
The trial results also demonstrated, however, that there were no short- or long-term benefits to adding veliparib (ABT-888), a poly (ADP-ribose) polymerase (PARP) inhibitor, to the mix.
Although pCR and EFS rates were significantly improved with the combination of paclitaxel and carboplatin compared with paclitaxel alone, there were no significant differences when veliparib was added in either pCR, EFS, or overall survival (OS).
“These findings overall support the inclusion of carboplatin into neoadjuvant chemotherapy for stage 2 and 3 triple-negative breast cancer patients, regardless of germline BRCA status,” concluded lead author Sibylle Loibl, MD, PhD, chief executive officer and chair of the German Breast Group.
She presented the new data during an oral session at the virtual European Society for Medical Oncology (ESMO) Congress 2021.
The BrighTNess results show that “neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pCR rates and benefit of event-free survival rates with manageable toxicity and no safety signals,” commented invited discussant Monica Arnedos, MD, PhD, head of the breast cancer research program at the Institut Bergonié in Bordeaux, France.
The findings also put to rest the notion that patients with germline BRCA mutations would not benefit from carboplatin treatment because of extreme sensitivity to standard neoadjuvant chemotherapy.
“The BrighTNess study says otherwise,” Dr. Arnedos said. “Today we’ve seen that the pCR improved event-free survival regardless of the germline BRCA mutated status, so BRCA-mutated germline patients require neoadjuvant carboplatin.”
The new data may lead to changes in breast cancer guidelines, she suggested.
Prior to these results, the evidence was that “platinum salts as neoadjuvant chemotherapy increased pCR rates in triple-negative breast cancer patients, but this was associated with more toxicity, and with higher rates of treatment discontinuation and dose reduction, without strong evidence of long-term benefit. This led to a lack of consensus to recommend platinum salts in this setting between the different breast cancer guidelines.”
The new BrighTNess data showed that the improved pCR rates translated into an EFS benefit in both platinum-containing groups of the trial, a finding that is consistent with the KEYNOTE-522 trial, which showed that adding pembrolizumab (Keytruda) to chemotherapy improved pCR in patients with early TNBC.
The BrighTNess results suggest that patients with high- or moderate-risk TNBC could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib (Lynparza) for patients with germline BRCA mutations, or capecitabine for patients without mutations, Dr. Arnedos proposed.
BrighTNess study details
The BrighTNess trial involved 634 patients with previously untreated histologically or cytologically confirmed stage 2-3 TNBC who were candidates for potentially curative surgery and had a good performance status. They were randomly assigned to receive either paclitaxel plus carboplatin and veliparib, paclitaxel plus carboplatin only, or paclitaxel alone prior to four cycles of chemotherapy with doxorubicin and cyclophosphamide (AC).
Initial results, published in 2018 in The Lancet Oncology, showed that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone but not paclitaxel plus carboplatin. The trial data supported the addition of carboplatin to standard neoadjuvant chemotherapy but not veliparib, the investigators stated at the time.
Now at the ESMO meeting, Dr. Loibl presented longer follow-up results.
After a median follow-up of 4.5 years, the hazard ratio (HR) for event-free survival with the paclitaxel/carboplatin/veliparib combination compared with paclitaxel alone was 0.63 (P = .016). In a post-hoc analysis, the adjusted HR was 0.57 (P = .018).
In a subgroup of 309 patients who had initial pCRs, the HR for EFS compared with patients without a pCR was 0.26 (P < .0001). Among patients with germline BRCA mutation, the HR for EFS for those who had a pCR was 0.14 (P = .0004), and among those with germline wildtype BRCA and a pCR the HR was 0.29 (P < .0001).
However, there were no significant differences in OS a median of 4.5 years after surgery.
An analysis of the frequency of myelodysplastic syndrome, acute myeloid leukemia, or other second primary malignancies also showed no significant differences between the groups, Dr. Loibl noted.
Although there were higher rates of hematologic malignancies with the addition of carboplatin, with or without veliparib, these adverse events did not compromise either treatment delivery of the benefits of carboplatin on the primary pCR endpoint, she added.
The BrighTNess trial was supported by AbbVie. Dr. Loibl has reported receiving grants and honoraria from AbbVie and others, including Medscape. Dr. Arnedos has reported receiving honoraria, travel grants, and/or research grants from AstraZeneca, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
‘New first-line standard of care’ in cervical cancer
That declaration was made by Raza Mirza, MD, chief oncologist at Copenhagen University Hospital in Denmark, who was invited to discuss the pros and cons of the KEYNOTE-826 trial at the European Society for Medical Oncology (ESMO) Congress 2021.
The trial showed that adding the checkpoint inhibitor pembrolizumab (Keytruda) to standard chemotherapy — with or without bevacizumab — resulted in about a one third reduction in the risk for both disease progression and death compared with chemotherapy alone.
The benefit of adding pembrolizumab was seen both in the overall study population and in patients with higher levels of programmed death ligand-1 (PD-L1), but not in those with biomarker-negative tumors, reported investigator Nicoletta Colombo, MD, PhD, from the University of Milan-Bicocca, Italy.
“Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care,” she said in a late-breaking oral abstract presentation. The study was also simultaneously published online in The New England Journal of Medicine.
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, plus bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors have shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but until now no data about the addition of these agents to chemotherapy were available, Dr. Colombo noted.
Dr. Mirza noted that there is sound rationale for using checkpoint inhibitors targeted against PD-1 in patients with cervical cancer, because PD-L1 has been shown to be a consistent biomarker for infection of the cervix with human papillomavirus (HPV), which is responsible for more than 90% of cervical cancers.
“PD-L1 is significantly upregulated in cervical cancer and detectable by immunohistochemistry,” he said. “PD-L1 expression reduces the immune response since it is able to bind to PD-1 on T-cell lymphocytes, thereby inhibiting their function. These findings suggest that targeting the PD-1/PD-L1 pathway may be therapeutically effective and should be considered in the treatment of cervical cancer.”
KEYNOTE-826 details
This was a double-blind trial conducted in 617 patients stratified by metastatic disease status at diagnosis; PD-L1 combined positive score (CPS) either < 1, 1 to < 10, or ≥ 10. They were randomized in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion.
The dual primary endpoints of progression-free survival (PFS) and overall survival (OS) were each tested sequentially in patients with a PD-L1 CPS ≥ 1 in both the intention-to-treat (ITT) or “all-comers” population, and in patients with a PD-L1 CPS ≥ 10.
Patient characteristics were generally well balanced between the treatment groups, except for a slightly higher proportion of patients with squamous cell histology in the pembrolizumab versus the placebo group (76.3% vs 68.3%).
PFS and OS results
The addition of pembrolizumab was associated with improved PFS across most protocol-specified subgroups, Dr. Colombo and colleagues noted.
After a median follow-up of 22 months, the 12-month PFS rate in the biomarker-selected population (all patients with a PD-L1 CPS ≥ 1) was 45.5% for patients in the pembrolizumab group versus 34.1% in the placebo group. This translated into a hazard ratio (HR) for progression on pembrolizumab of 0.62 (P < .001).
The respective PFS rates in the ITT population were 44.7% and 33.5%, with an HR for progression of 0.65 (P < .001) with the checkpoint inhibitor.
In patients with PD-L1 CPS ≥ 10, the respective rates of PFS and the HR were 44.6%, 33.5%, and 0.58 (P < .001).
OS rates were also significantly improved, he noted.
The 12-month and 24-month OS rates in all patients with PD-L1 CPS ≥ 1 were 75.3% and 53%, respectively, for patients assigned to pembrolizumab versus 63.1% and 41.7% in patients assigned to placebo, translating to an HR for death with pembrolizumab in this group of 0.64 (P < .001).
In the all-comers (ITT) population, respective 12- and 24-month OS rates were 74.8% and 50.4% with pembrolizumab versus 63.6% and 40.4% with placebo. This difference translated into an HR for death with anti-PD-1 of 0.67 (P < .001).
Among patients with the higher PD-L1 levels (≥ CPS 10), the respective OS rates were 75.7% and 54.4% with pembrolizumab versus 61.5% and 44.6% with placebo (HR 0.61, P < .001).
Dr. Mirza emphasized that “we did not see any efficacy of pembrolizumab in the biomarker-negative population,” with an HR for PFS of 0.94 and HR for OS of 1.0 in this subgroup.
The most common grade ≥ 3 adverse events were anemia, which occurred in 30.3% of patients assigned to pembrolizumab compared with 26.9% in the placebo group, and neutropenias, which occurred in 12.4% and 9.7% of patients, respectively. One patient in the pembrolizumab group died from an immune-related event, encephalitis.
Despite his enthusiasm for the regimen, Dr. Mirza tempered it by pointing out that there was an imbalance in the sample sizes regarding histology, and a potential bias introduced by the failure to stratify by tumor histology.
He noted that in other studies checkpoint inhibitors have had only modest activity against adenocarcinomas, which were more frequent in the placebo group in KEYNOTE-826, resulting in a potential positive bias in favor of pembrolizumab.
KEYNOTE-826 is funded by MSD. Dr. Colombo has disclosed consultant, research, and promotional speaking activities for multiple companies. Dr. Mirza has disclosed personal financial interests with Merck and other companies.
A version of this article was first published on Medscape.com.
That declaration was made by Raza Mirza, MD, chief oncologist at Copenhagen University Hospital in Denmark, who was invited to discuss the pros and cons of the KEYNOTE-826 trial at the European Society for Medical Oncology (ESMO) Congress 2021.
The trial showed that adding the checkpoint inhibitor pembrolizumab (Keytruda) to standard chemotherapy — with or without bevacizumab — resulted in about a one third reduction in the risk for both disease progression and death compared with chemotherapy alone.
The benefit of adding pembrolizumab was seen both in the overall study population and in patients with higher levels of programmed death ligand-1 (PD-L1), but not in those with biomarker-negative tumors, reported investigator Nicoletta Colombo, MD, PhD, from the University of Milan-Bicocca, Italy.
“Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care,” she said in a late-breaking oral abstract presentation. The study was also simultaneously published online in The New England Journal of Medicine.
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, plus bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors have shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but until now no data about the addition of these agents to chemotherapy were available, Dr. Colombo noted.
Dr. Mirza noted that there is sound rationale for using checkpoint inhibitors targeted against PD-1 in patients with cervical cancer, because PD-L1 has been shown to be a consistent biomarker for infection of the cervix with human papillomavirus (HPV), which is responsible for more than 90% of cervical cancers.
“PD-L1 is significantly upregulated in cervical cancer and detectable by immunohistochemistry,” he said. “PD-L1 expression reduces the immune response since it is able to bind to PD-1 on T-cell lymphocytes, thereby inhibiting their function. These findings suggest that targeting the PD-1/PD-L1 pathway may be therapeutically effective and should be considered in the treatment of cervical cancer.”
KEYNOTE-826 details
This was a double-blind trial conducted in 617 patients stratified by metastatic disease status at diagnosis; PD-L1 combined positive score (CPS) either < 1, 1 to < 10, or ≥ 10. They were randomized in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion.
The dual primary endpoints of progression-free survival (PFS) and overall survival (OS) were each tested sequentially in patients with a PD-L1 CPS ≥ 1 in both the intention-to-treat (ITT) or “all-comers” population, and in patients with a PD-L1 CPS ≥ 10.
Patient characteristics were generally well balanced between the treatment groups, except for a slightly higher proportion of patients with squamous cell histology in the pembrolizumab versus the placebo group (76.3% vs 68.3%).
PFS and OS results
The addition of pembrolizumab was associated with improved PFS across most protocol-specified subgroups, Dr. Colombo and colleagues noted.
After a median follow-up of 22 months, the 12-month PFS rate in the biomarker-selected population (all patients with a PD-L1 CPS ≥ 1) was 45.5% for patients in the pembrolizumab group versus 34.1% in the placebo group. This translated into a hazard ratio (HR) for progression on pembrolizumab of 0.62 (P < .001).
The respective PFS rates in the ITT population were 44.7% and 33.5%, with an HR for progression of 0.65 (P < .001) with the checkpoint inhibitor.
In patients with PD-L1 CPS ≥ 10, the respective rates of PFS and the HR were 44.6%, 33.5%, and 0.58 (P < .001).
OS rates were also significantly improved, he noted.
The 12-month and 24-month OS rates in all patients with PD-L1 CPS ≥ 1 were 75.3% and 53%, respectively, for patients assigned to pembrolizumab versus 63.1% and 41.7% in patients assigned to placebo, translating to an HR for death with pembrolizumab in this group of 0.64 (P < .001).
In the all-comers (ITT) population, respective 12- and 24-month OS rates were 74.8% and 50.4% with pembrolizumab versus 63.6% and 40.4% with placebo. This difference translated into an HR for death with anti-PD-1 of 0.67 (P < .001).
Among patients with the higher PD-L1 levels (≥ CPS 10), the respective OS rates were 75.7% and 54.4% with pembrolizumab versus 61.5% and 44.6% with placebo (HR 0.61, P < .001).
Dr. Mirza emphasized that “we did not see any efficacy of pembrolizumab in the biomarker-negative population,” with an HR for PFS of 0.94 and HR for OS of 1.0 in this subgroup.
The most common grade ≥ 3 adverse events were anemia, which occurred in 30.3% of patients assigned to pembrolizumab compared with 26.9% in the placebo group, and neutropenias, which occurred in 12.4% and 9.7% of patients, respectively. One patient in the pembrolizumab group died from an immune-related event, encephalitis.
Despite his enthusiasm for the regimen, Dr. Mirza tempered it by pointing out that there was an imbalance in the sample sizes regarding histology, and a potential bias introduced by the failure to stratify by tumor histology.
He noted that in other studies checkpoint inhibitors have had only modest activity against adenocarcinomas, which were more frequent in the placebo group in KEYNOTE-826, resulting in a potential positive bias in favor of pembrolizumab.
KEYNOTE-826 is funded by MSD. Dr. Colombo has disclosed consultant, research, and promotional speaking activities for multiple companies. Dr. Mirza has disclosed personal financial interests with Merck and other companies.
A version of this article was first published on Medscape.com.
That declaration was made by Raza Mirza, MD, chief oncologist at Copenhagen University Hospital in Denmark, who was invited to discuss the pros and cons of the KEYNOTE-826 trial at the European Society for Medical Oncology (ESMO) Congress 2021.
The trial showed that adding the checkpoint inhibitor pembrolizumab (Keytruda) to standard chemotherapy — with or without bevacizumab — resulted in about a one third reduction in the risk for both disease progression and death compared with chemotherapy alone.
The benefit of adding pembrolizumab was seen both in the overall study population and in patients with higher levels of programmed death ligand-1 (PD-L1), but not in those with biomarker-negative tumors, reported investigator Nicoletta Colombo, MD, PhD, from the University of Milan-Bicocca, Italy.
“Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care,” she said in a late-breaking oral abstract presentation. The study was also simultaneously published online in The New England Journal of Medicine.
Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, plus bevacizumab, based on the results of the GOG 240 study.
Immunotherapy with PD-1 inhibitors have shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but until now no data about the addition of these agents to chemotherapy were available, Dr. Colombo noted.
Dr. Mirza noted that there is sound rationale for using checkpoint inhibitors targeted against PD-1 in patients with cervical cancer, because PD-L1 has been shown to be a consistent biomarker for infection of the cervix with human papillomavirus (HPV), which is responsible for more than 90% of cervical cancers.
“PD-L1 is significantly upregulated in cervical cancer and detectable by immunohistochemistry,” he said. “PD-L1 expression reduces the immune response since it is able to bind to PD-1 on T-cell lymphocytes, thereby inhibiting their function. These findings suggest that targeting the PD-1/PD-L1 pathway may be therapeutically effective and should be considered in the treatment of cervical cancer.”
KEYNOTE-826 details
This was a double-blind trial conducted in 617 patients stratified by metastatic disease status at diagnosis; PD-L1 combined positive score (CPS) either < 1, 1 to < 10, or ≥ 10. They were randomized in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion.
The dual primary endpoints of progression-free survival (PFS) and overall survival (OS) were each tested sequentially in patients with a PD-L1 CPS ≥ 1 in both the intention-to-treat (ITT) or “all-comers” population, and in patients with a PD-L1 CPS ≥ 10.
Patient characteristics were generally well balanced between the treatment groups, except for a slightly higher proportion of patients with squamous cell histology in the pembrolizumab versus the placebo group (76.3% vs 68.3%).
PFS and OS results
The addition of pembrolizumab was associated with improved PFS across most protocol-specified subgroups, Dr. Colombo and colleagues noted.
After a median follow-up of 22 months, the 12-month PFS rate in the biomarker-selected population (all patients with a PD-L1 CPS ≥ 1) was 45.5% for patients in the pembrolizumab group versus 34.1% in the placebo group. This translated into a hazard ratio (HR) for progression on pembrolizumab of 0.62 (P < .001).
The respective PFS rates in the ITT population were 44.7% and 33.5%, with an HR for progression of 0.65 (P < .001) with the checkpoint inhibitor.
In patients with PD-L1 CPS ≥ 10, the respective rates of PFS and the HR were 44.6%, 33.5%, and 0.58 (P < .001).
OS rates were also significantly improved, he noted.
The 12-month and 24-month OS rates in all patients with PD-L1 CPS ≥ 1 were 75.3% and 53%, respectively, for patients assigned to pembrolizumab versus 63.1% and 41.7% in patients assigned to placebo, translating to an HR for death with pembrolizumab in this group of 0.64 (P < .001).
In the all-comers (ITT) population, respective 12- and 24-month OS rates were 74.8% and 50.4% with pembrolizumab versus 63.6% and 40.4% with placebo. This difference translated into an HR for death with anti-PD-1 of 0.67 (P < .001).
Among patients with the higher PD-L1 levels (≥ CPS 10), the respective OS rates were 75.7% and 54.4% with pembrolizumab versus 61.5% and 44.6% with placebo (HR 0.61, P < .001).
Dr. Mirza emphasized that “we did not see any efficacy of pembrolizumab in the biomarker-negative population,” with an HR for PFS of 0.94 and HR for OS of 1.0 in this subgroup.
The most common grade ≥ 3 adverse events were anemia, which occurred in 30.3% of patients assigned to pembrolizumab compared with 26.9% in the placebo group, and neutropenias, which occurred in 12.4% and 9.7% of patients, respectively. One patient in the pembrolizumab group died from an immune-related event, encephalitis.
Despite his enthusiasm for the regimen, Dr. Mirza tempered it by pointing out that there was an imbalance in the sample sizes regarding histology, and a potential bias introduced by the failure to stratify by tumor histology.
He noted that in other studies checkpoint inhibitors have had only modest activity against adenocarcinomas, which were more frequent in the placebo group in KEYNOTE-826, resulting in a potential positive bias in favor of pembrolizumab.
KEYNOTE-826 is funded by MSD. Dr. Colombo has disclosed consultant, research, and promotional speaking activities for multiple companies. Dr. Mirza has disclosed personal financial interests with Merck and other companies.
A version of this article was first published on Medscape.com.
Earliest 9/11 responders have higher COPD rates
The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.
The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.
“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.
“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.
“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
Inconsistent findings
Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.
“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.
There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.
They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.
To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.
The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
Earliest arrivals paid the highest penalty
Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.
The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.
In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).
There was no significant interaction between early site arrival and smoking status.
The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.
“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.
In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.
The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.
The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.
“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.
“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.
“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
Inconsistent findings
Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.
“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.
There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.
They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.
To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.
The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
Earliest arrivals paid the highest penalty
Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.
The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.
In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).
There was no significant interaction between early site arrival and smoking status.
The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.
“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.
In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.
The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.
The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.
“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.
“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.
“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
Inconsistent findings
Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.
“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.
There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.
They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.
To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.
The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
Earliest arrivals paid the highest penalty
Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.
The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.
In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).
There was no significant interaction between early site arrival and smoking status.
The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.
“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.
In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.
The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Poor lung function linked to risk for sudden cardiac death
Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.
Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV1) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.
“Our main findings and subsequent conclusions are that low FEV1 is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.
“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.
Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.
“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
Fatal vs. nonfatal events
It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.
To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.
The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.
Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.
Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV1 was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV1 was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).
The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).
“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.
The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.
Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV1) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.
“Our main findings and subsequent conclusions are that low FEV1 is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.
“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.
Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.
“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
Fatal vs. nonfatal events
It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.
To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.
The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.
Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.
Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV1 was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV1 was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).
The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).
“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.
The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.
Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV1) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.
“Our main findings and subsequent conclusions are that low FEV1 is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.
“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.
Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.
“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
Fatal vs. nonfatal events
It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.
To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.
The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.
Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.
Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV1 was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV1 was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).
The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).
“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.
The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fibrosis progression flies below the radar in subclinical ILD
Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.
Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.
“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.
“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.
“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.
He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.
Observational study
Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.
They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.
Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.
They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.
In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.
As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.
“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.
The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.
Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.
Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.
“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.
“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.
“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.
He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.
Observational study
Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.
They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.
Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.
They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.
In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.
As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.
“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.
The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.
Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.
Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.
“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.
“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.
“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.
He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.
Observational study
Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.
They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.
Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.
They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.
In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.
As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.
“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.
The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.
FROM ERS 2021
Obese children with asthma are resistant to ICS
Obese or overweight children with asthma could be using inhaled corticosteroids (ICS) to no avail, combined results from observational studies suggest.
Using Mendelian randomization, a method for reducing bias in observational studies, investigators from the University of Amsterdam Medical Center performed an analysis of data from four cross-sectional studies and one cohort study on a total of 1,511 children with asthma.
They showed that every 1-unit increase in the body mass index (BMI) z score was associated with a more than twofold higher odds ratio for exacerbation, reported Cristina Longo, PhD, a former postdoctoral fellow at AMC, and assistant professor of medicine at the University of Montreal.
“In this large, multicenter Mendelian randomization study, our findings support current evidence that children with higher BMI status respond inadequately to inhaled corticosteroids, and that this association is likely not explained by measured confounding or reverse causation,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Unmeasured confounding
The obese-asthma phenotype in children is characterized by reduced lung function, high symptom expression, poor response to ICS, and high health care utilization.
“While most observational studies suggest that weight status is associated with asthma exacerbations, despite using inhaled corticosteroids, it’s unclear whether these associations may be due to unmeasured confounding or reverse causation, which captures the idea that perhaps obesity is a consequence rather than a cause of uncontrolled severe asthma,” she said.
Traditional observational studies of the obesity-asthma link rely on comparing data on asthma in a target population and comparing nonobese patients with obese patients. The problem with this method, Dr. Longo contended, is that the exposure assignment – weight status – is not random, and could lead to bias from potential imbalance of confounders, leading to unintentionally biased results.
In contrast, Mendelian randomization uses genetic data to approximate random assignment of exposures, using a risk score for BMI based on genetic susceptibility. The score is based on the accumulation of genetic variants (single-nucleotide polymorphisms, or SNPs) that predispose individuals to obesity, with higher numbers of variants results in a higher risk score.
The scores are then used to determine the comparison groups for evaluating the obesity-asthma association.
Alphabet soup
Dr. Longo and colleagues analyzed data on a total 1,511 children enrolled in four observational studies (PACMAN, PAGES, HPR, CLARA) and one cohort study (ALSPAC).
They included children with an asthma diagnosis who used ICS and had available information on both BMI and genetics.
The Mendelian randomization analysis was based on a weighted allele score based on 97 SNPs predictive of BMI based on large-scale genomewide association studies. The exposure for the analysis was age- and sex-adjusted BMI z scores based on World Health Organization growth charts for children.
They found that using the Mendelian randomization approach, for each standard deviation increase in BMI, the OR for any parent-reported asthma exacerbations, including urgent care visits or use of oral corticosteroids, was 2.31 (95% confidence interval, 1.26-4.25).
In contrast, if the traditional observational model had been used, the OR would be a nonsignificant 1.10 (95% CI, 0.99-1.22).
“Treatment guidelines recommend steroids for children with asthma who have a higher-than-normal BMI,” Dr. Longo said in a statement. “Our research group felt that the one-size fits-all approach to treating children with asthma with inhaled steroids as their first-line treatment, particularly those with excess weight, warrants revision. At the very least, research identifying potential alternative treatments should be encouraged and prioritized, especially since 30% of children with asthma are also obese. With the childhood obesity epidemic rising, we expect this percentage to increase meaning this problem of poor control will be seen more frequently in routine clinical practice.”
Christopher E. Brightling, PhD, professor of respiratory medicine at the University of Leicester (England), commented that “this is very good and fascinating research with findings that are important and novel.
“It sheds light on the complex interplay between genes, weight, and response to inhaled corticosteroids, underscoring the need to combine drug treatments with lifestyle and diet modifications. Policy makers, health care providers and families need to do much more to tackle the growing obesity epidemic in young people,” he said.
Dr. Brightling was not involved in the study.
The study was supported by the ERS and the European Union’s H2020 research and innovation program. Dr. Longo was a Horizon 2020 Marie-Sklodowska Cure Respire-3 fellow. Dr. Brightling reported no relevant disclosures.
Obese or overweight children with asthma could be using inhaled corticosteroids (ICS) to no avail, combined results from observational studies suggest.
Using Mendelian randomization, a method for reducing bias in observational studies, investigators from the University of Amsterdam Medical Center performed an analysis of data from four cross-sectional studies and one cohort study on a total of 1,511 children with asthma.
They showed that every 1-unit increase in the body mass index (BMI) z score was associated with a more than twofold higher odds ratio for exacerbation, reported Cristina Longo, PhD, a former postdoctoral fellow at AMC, and assistant professor of medicine at the University of Montreal.
“In this large, multicenter Mendelian randomization study, our findings support current evidence that children with higher BMI status respond inadequately to inhaled corticosteroids, and that this association is likely not explained by measured confounding or reverse causation,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Unmeasured confounding
The obese-asthma phenotype in children is characterized by reduced lung function, high symptom expression, poor response to ICS, and high health care utilization.
“While most observational studies suggest that weight status is associated with asthma exacerbations, despite using inhaled corticosteroids, it’s unclear whether these associations may be due to unmeasured confounding or reverse causation, which captures the idea that perhaps obesity is a consequence rather than a cause of uncontrolled severe asthma,” she said.
Traditional observational studies of the obesity-asthma link rely on comparing data on asthma in a target population and comparing nonobese patients with obese patients. The problem with this method, Dr. Longo contended, is that the exposure assignment – weight status – is not random, and could lead to bias from potential imbalance of confounders, leading to unintentionally biased results.
In contrast, Mendelian randomization uses genetic data to approximate random assignment of exposures, using a risk score for BMI based on genetic susceptibility. The score is based on the accumulation of genetic variants (single-nucleotide polymorphisms, or SNPs) that predispose individuals to obesity, with higher numbers of variants results in a higher risk score.
The scores are then used to determine the comparison groups for evaluating the obesity-asthma association.
Alphabet soup
Dr. Longo and colleagues analyzed data on a total 1,511 children enrolled in four observational studies (PACMAN, PAGES, HPR, CLARA) and one cohort study (ALSPAC).
They included children with an asthma diagnosis who used ICS and had available information on both BMI and genetics.
The Mendelian randomization analysis was based on a weighted allele score based on 97 SNPs predictive of BMI based on large-scale genomewide association studies. The exposure for the analysis was age- and sex-adjusted BMI z scores based on World Health Organization growth charts for children.
They found that using the Mendelian randomization approach, for each standard deviation increase in BMI, the OR for any parent-reported asthma exacerbations, including urgent care visits or use of oral corticosteroids, was 2.31 (95% confidence interval, 1.26-4.25).
In contrast, if the traditional observational model had been used, the OR would be a nonsignificant 1.10 (95% CI, 0.99-1.22).
“Treatment guidelines recommend steroids for children with asthma who have a higher-than-normal BMI,” Dr. Longo said in a statement. “Our research group felt that the one-size fits-all approach to treating children with asthma with inhaled steroids as their first-line treatment, particularly those with excess weight, warrants revision. At the very least, research identifying potential alternative treatments should be encouraged and prioritized, especially since 30% of children with asthma are also obese. With the childhood obesity epidemic rising, we expect this percentage to increase meaning this problem of poor control will be seen more frequently in routine clinical practice.”
Christopher E. Brightling, PhD, professor of respiratory medicine at the University of Leicester (England), commented that “this is very good and fascinating research with findings that are important and novel.
“It sheds light on the complex interplay between genes, weight, and response to inhaled corticosteroids, underscoring the need to combine drug treatments with lifestyle and diet modifications. Policy makers, health care providers and families need to do much more to tackle the growing obesity epidemic in young people,” he said.
Dr. Brightling was not involved in the study.
The study was supported by the ERS and the European Union’s H2020 research and innovation program. Dr. Longo was a Horizon 2020 Marie-Sklodowska Cure Respire-3 fellow. Dr. Brightling reported no relevant disclosures.
Obese or overweight children with asthma could be using inhaled corticosteroids (ICS) to no avail, combined results from observational studies suggest.
Using Mendelian randomization, a method for reducing bias in observational studies, investigators from the University of Amsterdam Medical Center performed an analysis of data from four cross-sectional studies and one cohort study on a total of 1,511 children with asthma.
They showed that every 1-unit increase in the body mass index (BMI) z score was associated with a more than twofold higher odds ratio for exacerbation, reported Cristina Longo, PhD, a former postdoctoral fellow at AMC, and assistant professor of medicine at the University of Montreal.
“In this large, multicenter Mendelian randomization study, our findings support current evidence that children with higher BMI status respond inadequately to inhaled corticosteroids, and that this association is likely not explained by measured confounding or reverse causation,” she said in an oral abstract presentation during the European Respiratory Society International Congress.
Unmeasured confounding
The obese-asthma phenotype in children is characterized by reduced lung function, high symptom expression, poor response to ICS, and high health care utilization.
“While most observational studies suggest that weight status is associated with asthma exacerbations, despite using inhaled corticosteroids, it’s unclear whether these associations may be due to unmeasured confounding or reverse causation, which captures the idea that perhaps obesity is a consequence rather than a cause of uncontrolled severe asthma,” she said.
Traditional observational studies of the obesity-asthma link rely on comparing data on asthma in a target population and comparing nonobese patients with obese patients. The problem with this method, Dr. Longo contended, is that the exposure assignment – weight status – is not random, and could lead to bias from potential imbalance of confounders, leading to unintentionally biased results.
In contrast, Mendelian randomization uses genetic data to approximate random assignment of exposures, using a risk score for BMI based on genetic susceptibility. The score is based on the accumulation of genetic variants (single-nucleotide polymorphisms, or SNPs) that predispose individuals to obesity, with higher numbers of variants results in a higher risk score.
The scores are then used to determine the comparison groups for evaluating the obesity-asthma association.
Alphabet soup
Dr. Longo and colleagues analyzed data on a total 1,511 children enrolled in four observational studies (PACMAN, PAGES, HPR, CLARA) and one cohort study (ALSPAC).
They included children with an asthma diagnosis who used ICS and had available information on both BMI and genetics.
The Mendelian randomization analysis was based on a weighted allele score based on 97 SNPs predictive of BMI based on large-scale genomewide association studies. The exposure for the analysis was age- and sex-adjusted BMI z scores based on World Health Organization growth charts for children.
They found that using the Mendelian randomization approach, for each standard deviation increase in BMI, the OR for any parent-reported asthma exacerbations, including urgent care visits or use of oral corticosteroids, was 2.31 (95% confidence interval, 1.26-4.25).
In contrast, if the traditional observational model had been used, the OR would be a nonsignificant 1.10 (95% CI, 0.99-1.22).
“Treatment guidelines recommend steroids for children with asthma who have a higher-than-normal BMI,” Dr. Longo said in a statement. “Our research group felt that the one-size fits-all approach to treating children with asthma with inhaled steroids as their first-line treatment, particularly those with excess weight, warrants revision. At the very least, research identifying potential alternative treatments should be encouraged and prioritized, especially since 30% of children with asthma are also obese. With the childhood obesity epidemic rising, we expect this percentage to increase meaning this problem of poor control will be seen more frequently in routine clinical practice.”
Christopher E. Brightling, PhD, professor of respiratory medicine at the University of Leicester (England), commented that “this is very good and fascinating research with findings that are important and novel.
“It sheds light on the complex interplay between genes, weight, and response to inhaled corticosteroids, underscoring the need to combine drug treatments with lifestyle and diet modifications. Policy makers, health care providers and families need to do much more to tackle the growing obesity epidemic in young people,” he said.
Dr. Brightling was not involved in the study.
The study was supported by the ERS and the European Union’s H2020 research and innovation program. Dr. Longo was a Horizon 2020 Marie-Sklodowska Cure Respire-3 fellow. Dr. Brightling reported no relevant disclosures.
FROM ERS 2021
Infants breathe better when pregnant moms exercise
Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.
Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.
“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.
Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”
Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.
Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.
To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.
A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.
The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.
The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.
Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).
In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).
“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.
Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”
The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.
Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.
“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.
Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”
Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.
Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.
To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.
A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.
The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.
The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.
Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).
In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).
“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.
Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”
The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.
Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.
“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.
Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”
Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.
Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.
To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.
A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.
The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.
The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.
Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).
In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).
“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.
Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”
The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
COVID-19 spares lung function in young adults
Here’s some encouraging news for once regarding SARS-CoV-2 infections: A study of young adults for whom prepandemic spirometry data were available showed that COVID-19 did not have a significant impact on lung function, even among patients with asthma.
Among 853 Swedish men and women (mean age, 22 years) who were part of a birth cohort study, there were no significant differences in either forced expiratory volume in 1 second (FEV1) or in the ratio of FEV1 to forced vital capacity, reported Ida Mogensen, MD, PhD, a postdoctoral fellow at the Karolinska Institute in Stockholm.
“We found no effect of COVID-19 on spirometric lung function in generally healthy adults,” she said in an oral abstract presented at the European Respiratory Society 2021 International Congress.
The findings echo those of a small study that involved 73 children and adolescents with COVID-19 and 45 uninfected control persons. The investigators in that study, which was also presented at ERS 2021, found that there were no significant differences in the frequency of abnormal pulmonary function measures between case patients and control patients (abstract OA1303).
“The findings from these two studies provide important reassurance about the impact of COVID infection on lung function in children and young adults,” commented Anita Simonds, MD, an honorary consultant in respiratory and sleep medicine at the Royal Brompton Hospital, London.
“We know already that this group is less likely to suffer severe illness if they contract the virus, and these studies, which importantly include comparator groups without COVID-19, show that they are also less likely to suffer long-term consequences with respect to lung function,” she said. Dr. Simonds was not involved in either study.
Young adult study
Dr. Mogenson and colleagues assessed data on 853 participants in the BAMSE Project, a prospective birth cohort study that included 4,089 children born in Stockholm from 1994 to 1996. Of the participants, 147 had asthma. They have been regularly followed with questionnaires on respiratory symptoms and medications. In addition, at 8 and 16 years’ follow-up, spirometry measures and fractional exhaled nitric oxide (FeNO) levels were assessed, allergic sensitization tests were administered, and blood eosinophil levels were measured.
In 2020 and 2021, during the pandemic, the participants underwent spirometry testing and were assessed for antibodies against SARS-CoV-2, and they self-reported use of inhaled corticosteroids.
The investigators defined asthma as any physician diagnosis and asthma symptoms and/or asthma medication use within the previous year. Participants were determined to be COVID-19 seropositive if they had IgG antibodies to the SARS-CoV-2 spike greater than 25.09 AU/mL, IgM antibodies greater than 14.42 AU/mL, or IgA antibodies greater than 2.61 AU/mL, as measured with enzyme-linked immunosorbent assay.
Participants who had been vaccinated against COVID-19 were excluded.
No significant decreases
A total of 243 participants, including 38 with asthma, were seropositive for SARS-CoV-2 antibodies. The mean change in lung function from before the pandemic to the study end date during the pandemic were not significantly different between seropositive participants and seronegative participants or IgM-positive participants and seronegative participants.
Similarly, there were no significant differences in lung function between seropositive and seronegative participants in an analysis that was adjusted for sex, body mass index, smoking status, or prepandemic lung function.
Although there was a trend toward slightly lower function among seropositive participants with asthma in comparison with seronegative patients with asthma, it was not statistically significant, Dr. Mogenson said.
There were also no significant decreases in lung function from the prepandemic measure to the present in any of the inflammatory parameters, including blood eosinophil levels, FeNO, allergic sensitization, or inhaled corticosteroid use.
Potential misclassification
In the question-and-answer period that followed the presentation, session comoderator Sam Bayat, MD, PhD, from the University of Grenoble (France), who was not involved in the study, noted that “some subjects can have positive serology without any symptoms, while others can have symptomatic disease and a couple of months later they have negative serology.”
He asked Dr. Mogenson whether they had included in their study participants with symptomatic COVID-19 and whether that would change the findings.
“We did not have access to RNA testing, so we only had serology, and of course some participants could be wrongly classified to have disease – probably around 15%,” she acknowledged.
She noted that there were no significant changes in lung function among patients who reported having respiratory symptoms.
The study was funded by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Research Council for Health, Working Life and Welfare, the Karolinska Institutet, Formas, the European Research Council, and Region Stockholm. Dr. Mogenson, Dr. Simonds, and Dr. Bayat disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Here’s some encouraging news for once regarding SARS-CoV-2 infections: A study of young adults for whom prepandemic spirometry data were available showed that COVID-19 did not have a significant impact on lung function, even among patients with asthma.
Among 853 Swedish men and women (mean age, 22 years) who were part of a birth cohort study, there were no significant differences in either forced expiratory volume in 1 second (FEV1) or in the ratio of FEV1 to forced vital capacity, reported Ida Mogensen, MD, PhD, a postdoctoral fellow at the Karolinska Institute in Stockholm.
“We found no effect of COVID-19 on spirometric lung function in generally healthy adults,” she said in an oral abstract presented at the European Respiratory Society 2021 International Congress.
The findings echo those of a small study that involved 73 children and adolescents with COVID-19 and 45 uninfected control persons. The investigators in that study, which was also presented at ERS 2021, found that there were no significant differences in the frequency of abnormal pulmonary function measures between case patients and control patients (abstract OA1303).
“The findings from these two studies provide important reassurance about the impact of COVID infection on lung function in children and young adults,” commented Anita Simonds, MD, an honorary consultant in respiratory and sleep medicine at the Royal Brompton Hospital, London.
“We know already that this group is less likely to suffer severe illness if they contract the virus, and these studies, which importantly include comparator groups without COVID-19, show that they are also less likely to suffer long-term consequences with respect to lung function,” she said. Dr. Simonds was not involved in either study.
Young adult study
Dr. Mogenson and colleagues assessed data on 853 participants in the BAMSE Project, a prospective birth cohort study that included 4,089 children born in Stockholm from 1994 to 1996. Of the participants, 147 had asthma. They have been regularly followed with questionnaires on respiratory symptoms and medications. In addition, at 8 and 16 years’ follow-up, spirometry measures and fractional exhaled nitric oxide (FeNO) levels were assessed, allergic sensitization tests were administered, and blood eosinophil levels were measured.
In 2020 and 2021, during the pandemic, the participants underwent spirometry testing and were assessed for antibodies against SARS-CoV-2, and they self-reported use of inhaled corticosteroids.
The investigators defined asthma as any physician diagnosis and asthma symptoms and/or asthma medication use within the previous year. Participants were determined to be COVID-19 seropositive if they had IgG antibodies to the SARS-CoV-2 spike greater than 25.09 AU/mL, IgM antibodies greater than 14.42 AU/mL, or IgA antibodies greater than 2.61 AU/mL, as measured with enzyme-linked immunosorbent assay.
Participants who had been vaccinated against COVID-19 were excluded.
No significant decreases
A total of 243 participants, including 38 with asthma, were seropositive for SARS-CoV-2 antibodies. The mean change in lung function from before the pandemic to the study end date during the pandemic were not significantly different between seropositive participants and seronegative participants or IgM-positive participants and seronegative participants.
Similarly, there were no significant differences in lung function between seropositive and seronegative participants in an analysis that was adjusted for sex, body mass index, smoking status, or prepandemic lung function.
Although there was a trend toward slightly lower function among seropositive participants with asthma in comparison with seronegative patients with asthma, it was not statistically significant, Dr. Mogenson said.
There were also no significant decreases in lung function from the prepandemic measure to the present in any of the inflammatory parameters, including blood eosinophil levels, FeNO, allergic sensitization, or inhaled corticosteroid use.
Potential misclassification
In the question-and-answer period that followed the presentation, session comoderator Sam Bayat, MD, PhD, from the University of Grenoble (France), who was not involved in the study, noted that “some subjects can have positive serology without any symptoms, while others can have symptomatic disease and a couple of months later they have negative serology.”
He asked Dr. Mogenson whether they had included in their study participants with symptomatic COVID-19 and whether that would change the findings.
“We did not have access to RNA testing, so we only had serology, and of course some participants could be wrongly classified to have disease – probably around 15%,” she acknowledged.
She noted that there were no significant changes in lung function among patients who reported having respiratory symptoms.
The study was funded by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Research Council for Health, Working Life and Welfare, the Karolinska Institutet, Formas, the European Research Council, and Region Stockholm. Dr. Mogenson, Dr. Simonds, and Dr. Bayat disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Here’s some encouraging news for once regarding SARS-CoV-2 infections: A study of young adults for whom prepandemic spirometry data were available showed that COVID-19 did not have a significant impact on lung function, even among patients with asthma.
Among 853 Swedish men and women (mean age, 22 years) who were part of a birth cohort study, there were no significant differences in either forced expiratory volume in 1 second (FEV1) or in the ratio of FEV1 to forced vital capacity, reported Ida Mogensen, MD, PhD, a postdoctoral fellow at the Karolinska Institute in Stockholm.
“We found no effect of COVID-19 on spirometric lung function in generally healthy adults,” she said in an oral abstract presented at the European Respiratory Society 2021 International Congress.
The findings echo those of a small study that involved 73 children and adolescents with COVID-19 and 45 uninfected control persons. The investigators in that study, which was also presented at ERS 2021, found that there were no significant differences in the frequency of abnormal pulmonary function measures between case patients and control patients (abstract OA1303).
“The findings from these two studies provide important reassurance about the impact of COVID infection on lung function in children and young adults,” commented Anita Simonds, MD, an honorary consultant in respiratory and sleep medicine at the Royal Brompton Hospital, London.
“We know already that this group is less likely to suffer severe illness if they contract the virus, and these studies, which importantly include comparator groups without COVID-19, show that they are also less likely to suffer long-term consequences with respect to lung function,” she said. Dr. Simonds was not involved in either study.
Young adult study
Dr. Mogenson and colleagues assessed data on 853 participants in the BAMSE Project, a prospective birth cohort study that included 4,089 children born in Stockholm from 1994 to 1996. Of the participants, 147 had asthma. They have been regularly followed with questionnaires on respiratory symptoms and medications. In addition, at 8 and 16 years’ follow-up, spirometry measures and fractional exhaled nitric oxide (FeNO) levels were assessed, allergic sensitization tests were administered, and blood eosinophil levels were measured.
In 2020 and 2021, during the pandemic, the participants underwent spirometry testing and were assessed for antibodies against SARS-CoV-2, and they self-reported use of inhaled corticosteroids.
The investigators defined asthma as any physician diagnosis and asthma symptoms and/or asthma medication use within the previous year. Participants were determined to be COVID-19 seropositive if they had IgG antibodies to the SARS-CoV-2 spike greater than 25.09 AU/mL, IgM antibodies greater than 14.42 AU/mL, or IgA antibodies greater than 2.61 AU/mL, as measured with enzyme-linked immunosorbent assay.
Participants who had been vaccinated against COVID-19 were excluded.
No significant decreases
A total of 243 participants, including 38 with asthma, were seropositive for SARS-CoV-2 antibodies. The mean change in lung function from before the pandemic to the study end date during the pandemic were not significantly different between seropositive participants and seronegative participants or IgM-positive participants and seronegative participants.
Similarly, there were no significant differences in lung function between seropositive and seronegative participants in an analysis that was adjusted for sex, body mass index, smoking status, or prepandemic lung function.
Although there was a trend toward slightly lower function among seropositive participants with asthma in comparison with seronegative patients with asthma, it was not statistically significant, Dr. Mogenson said.
There were also no significant decreases in lung function from the prepandemic measure to the present in any of the inflammatory parameters, including blood eosinophil levels, FeNO, allergic sensitization, or inhaled corticosteroid use.
Potential misclassification
In the question-and-answer period that followed the presentation, session comoderator Sam Bayat, MD, PhD, from the University of Grenoble (France), who was not involved in the study, noted that “some subjects can have positive serology without any symptoms, while others can have symptomatic disease and a couple of months later they have negative serology.”
He asked Dr. Mogenson whether they had included in their study participants with symptomatic COVID-19 and whether that would change the findings.
“We did not have access to RNA testing, so we only had serology, and of course some participants could be wrongly classified to have disease – probably around 15%,” she acknowledged.
She noted that there were no significant changes in lung function among patients who reported having respiratory symptoms.
The study was funded by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Research Council for Health, Working Life and Welfare, the Karolinska Institutet, Formas, the European Research Council, and Region Stockholm. Dr. Mogenson, Dr. Simonds, and Dr. Bayat disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CAR T-cell therapy drives refractory SLE into remission
Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.
A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.
“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.
Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.
“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
Not just for cancer anymore
CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.
There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.
For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.
The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.
One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.
Those investigators generated CD19-targeted CAR T constructs and demonstrated that in mouse models of lupus, CD8-positive T cells from two different lupus strains could be successfully transfected, and that transfer of the CD19-targeting CAR T cells ablated both autoantibodies and CD19-positive cells.
“In both models, survival was remarkably extended, and target organs were spared. These exciting results could pave the way for using CD19-targeted T cells to treat patients with lupus,” they wrote.
Now, that prediction has come to fruition.
“It’s brilliant that the first case report has now been accomplished. I am fully convinced that this method will rid therapy refractory patients of their symptoms,” Dr. Radic said in an interview.
Anti-CD20 failures
B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.
“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.
In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
Case details
As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.
Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.
The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.
Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.
“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.
The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.
The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.
Unanswered questions
Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.
In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.
The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.
Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.
A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.
“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.
Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.
“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
Not just for cancer anymore
CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.
There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.
For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.
The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.
One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.
Those investigators generated CD19-targeted CAR T constructs and demonstrated that in mouse models of lupus, CD8-positive T cells from two different lupus strains could be successfully transfected, and that transfer of the CD19-targeting CAR T cells ablated both autoantibodies and CD19-positive cells.
“In both models, survival was remarkably extended, and target organs were spared. These exciting results could pave the way for using CD19-targeted T cells to treat patients with lupus,” they wrote.
Now, that prediction has come to fruition.
“It’s brilliant that the first case report has now been accomplished. I am fully convinced that this method will rid therapy refractory patients of their symptoms,” Dr. Radic said in an interview.
Anti-CD20 failures
B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.
“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.
In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
Case details
As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.
Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.
The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.
Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.
“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.
The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.
The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.
Unanswered questions
Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.
In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.
The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.
Chimeric antigen receptor T-cell (CAR T) therapy, a life-extending treatment for patients with advanced B-cell malignancies and multiple myeloma, has now been shown to be effective for treating refractory systemic lupus erythematosus (SLE) in at least one patient.
A 20-year-old woman with severe, refractory SLE, active lupus nephritis, pericarditis, and other serious symptoms had both serologic and clinical remission follow the infusion of a CAR T cell product directed against the B-cell surface antigen CD19, reported Georg Schett, MD, and colleagues from the German Center for Immunotherapy at Friedrich Alexander University Erlangen-Nuremberg in Erlangen, Germany.
“Given the role of B cells in a variety of severe autoimmune diseases, CAR T-cell therapy that targets B-cell antigens may have wider application,” they wrote in a letter to the editor of The New England Journal of Medicine.
Dr. Schett said in an email response to an interview request that the patient has remained healthy and asymptomatic without further treatment after 6 months of follow-up.
“The key question will be whether B cells return and whether these B cells will carry on to make antibodies against double-stranded DNA,” he said. “We think that the loss of B cells could be sustained given that CAR T cells are still present in the patient. The main question will be how long CAR T cells will be there and how long they deplete the B cells.”
Not just for cancer anymore
CAR T therapy involves harvesting autologous T cells and transducing them with a lentiviral vector to recognize CD19 or other B-cell surface antigens. The transduced cells are then expanded and reinfused into the patient following a lymphodepletion regimen.
There are currently five CAR T constructs approved by the Food and Drug Administration for the treatment of diffuse large B-cell lymphoma and other B-lineage lymphomas, acute lymphoblastic leukemia, multiple myeloma, and other hematologic malignancies.
For this patient, however, Dr. Schett and colleagues created their own CAR T construct rather than adapting an off-the-shelf product.
The use of this groundbreaking therapy to treat an autoimmune condition is novel, the investigators noted: “This technological breakthrough, together with recent convincing data on the role of B cells in disease pathogenesis derived from preclinical lupus models, provides a rationale for the use of CAR T-cell therapies in patients with SLE,” they wrote.
One such preclinical study was reported in Science Translational Medicine in 2019 by Marko Z. Radic, PhD, of the University of Tennessee Health Science Center in Memphis, and colleagues.
Those investigators generated CD19-targeted CAR T constructs and demonstrated that in mouse models of lupus, CD8-positive T cells from two different lupus strains could be successfully transfected, and that transfer of the CD19-targeting CAR T cells ablated both autoantibodies and CD19-positive cells.
“In both models, survival was remarkably extended, and target organs were spared. These exciting results could pave the way for using CD19-targeted T cells to treat patients with lupus,” they wrote.
Now, that prediction has come to fruition.
“It’s brilliant that the first case report has now been accomplished. I am fully convinced that this method will rid therapy refractory patients of their symptoms,” Dr. Radic said in an interview.
Anti-CD20 failures
B-cell depletion with the anti-CD20 monoclonal antibody rituximab has been shown to be an effective therapeutic strategy for patients with rheumatoid arthritis and multiple sclerosis, but was ineffective in two separate clinical trials for SLE.
“Incomplete B-cell depletion of tissue-resident B cells, or the transient nature of the treatment, may have contributed to the failure of the initial rituximab trials to attain satisfactory outcomes,” Dr. Radic and coauthors wrote.
In patients with severe lupus, autoreactive B cells may lurk in lymphatic organs and/or inflamed tissues. Alternatively, CD20-negative plasma cells, which are unaffected by rituximab, could also be a source of SLE autoantibodies, Dr. Schett and coinvestigators said.
Case details
As noted before, the 20-year-old patient described by Dr. Schett and colleagues presented with World Health Organization class IIIA active lupus nephritis, indicating focal proliferative disease. In addition, she also had nephritic syndrome, pericarditis, pleurisy, rash, and arthritis, and had a history of Libman-Sacks endocarditis.
Her disease was refractory to treatment with all the usual suspects, including hydroxychloroquine, high-dose glucocorticoids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab, and belimumab, another B-cell targeted agent.
The T cell collection, transduction, expansion, and infusion were all successfully performed. By day 9 following infusion, CAR T cells comprised nearly one-third of her total circulating T cells, and then began to decrease, but remained detectable in circulation for the ensuing 7 weeks.
Levels of anti–double-stranded DNA decreased from above 5,000 U/mL to 4 U/mL within 5 weeks, and her complement levels (C3 and C4) normalized.
“These signs of serologic remission were paralleled by clinical remission with proteinuria decreasing from above 2,000 mg of protein per gram of creatinine to less than 250 mg of protein per gram of creatinine,” the investigators wrote.
The patient’s SLE Disease Activity Index score with SELENA (Safety of Estrogens in Lupus National Assessment) modification dropped from 16 at baseline to 0 at follow-up.
The patient did not experience any of the adverse events that are commonly seen in patients treated with CAR T therapy, such as the cytokine release syndrome, neurotoxic adverse events, or prolonged cytopenias.
Unanswered questions
Dr. Radic said that it was unclear from the brief case report whether Dr. Schett and colleagues considered including a “kill switch” in their CAR T construct, which could be activated in the case of serious toxicities.
In addition, their use of both CD4-positive T cells in addition to CD8-positive cells in their construct raises some concern, because in patients with SLE there is evidence that CD4-positive helper T cells can be autoreactive, he noted.
The work by Dr. Schett and colleagues was supported by grants from the German government, European Union, and the Innovative Medicines Initiative. Dr. Schett reported having no conflicts of interest to disclose. Dr. Radic is listed as inventor on a patent for anti-CD19 CAR T cells in lupus.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
How many years of aromatase inhibitor therapy in breast cancer?
That’s a question that has been vexing oncologists for more than a decade, but final results from a large study now suggest that, after an initial 5 years of adjuvant endocrine therapy with tamoxifen and/or an AI, an additional 5 years of AI therapy offer no clinical benefits, compared with an additional 2 years of therapy.
What’s more, 5 years of additional treatment were associated with a significantly increased risk for fractures, compared with 2 years of therapy, Michael Gnant, MD, from the Medical University of Vienna, and colleagues reported in the phase 3 Austrian Breast and Colorectal Cancer Study Group Trial 16 (ABCSG-16).
“Thus, in postmenopausal women with hormone receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, the extension of aromatase inhibitor therapy for 2 years rather than 5 years was sufficient to maximize the benefits of such therapy in most patients without extending the exposure to toxic effects,” they concluded.
The study was published online on July 28, 2021, in the New England Journal of Medicine.
The new results “in patients with hormone-receptor–positive breast cancer who are at low or average risk underscore the importance of avoiding iatrogenic complications when making these decisions,” Pamela J. Goodwin, MD, from the Lunenfeld–Tanenbaum Research Institute at the University of Toronto, wrote in an accompanying editorial.
She noted that these latest results echo those of two earlier studies: the DATA trial and the optimistically named IDEAL trial, both of which showed no benefit of short-term versus longer-term adjuvant endocrine therapy with regard to either disease-free survival (DFS) or overall survival (OS).
“These results provide strong evidence against the routine use of more than 2 years of extended aromatase inhibitor therapy in women who are at low or average risk, similar to those who were included in this trial,” Dr. Goodwin commented.
ABCSG-16 details
Dr. Gnant and colleagues enrolled 3,484 women aged 80 years or younger with HR-positive stage I, II, or III breast cancer for whom there was no evidence of recurrence at baseline. The patients had all received adjuvant tamoxifen or an AI for 5 years; for some patients, the two drugs were administered in sequence until 12 months before randomization.
The patients were randomly assigned to receive oral anastrozole 1 mg daily for either 2 or 5 additional years.
Among all patients, 3,208 had experienced no recurrence 2 years after randomization. These patients were included in the primary DFS analysis. Of this group, 1,635 (51%) had received tamoxifen alone for 5 years, 235 (7.3%) had received an AI alone, and 41.7% had received sequential AIs and tamoxifen.
At a median follow-up of 118 months after randomization, disease progression or death occurred in 670 women – 335 in each trial arm.
The rate of DFS 10 years after randomization was 73.6% in the 2-year additional-therapy group and 73.9% in the 5-year group. The hazard ratio for disease recurrence or death was 0.99 and was not significant. After adjustment for potential confounding factors, the HR remained essentially unchanged (HR, 1.0).
Overall survival at 8 years, a secondary endpoint, was virtually identical between the groups, at 87.5% in the 2-year group and 87.3% in the 5-year group. The HR for death from any cause was 1.02 and was not significant.
The HR for contralateral breast cancer was 1.15, and the HR for a second primary cancer was 1.06; neither was statistically significant.
Although the use of bone-targeted medication was similar between the groups, among patients in the 2-year group, the incidence of clinical bone fractures 5 years after randomization was lower, at 4.7% versus 6.3%, which translates to an HR for fracture with 5 additional years of AI therapy of 1.35 (95% confidence interval, 1.00-1.84).
Adverse events with anastrozole were consistent with its known toxicity profile. At least one serious adverse event occurred in 26.5% of patients in the 2-year group and in 40.2% in the 5-year group. Investigator-assessed serious adverse events that were judged to be related to anastrozole occurred in 2.3% and 4.0% of patients, respectively.
Osteoarthritis, the most frequently reported adverse event, was documented in 1.7% of patients in the 2-year group and in 4.3% in the 5-year group.
AI duration still unclear
“We did not investigate the value of extending adjuvant endocrine therapy per se, since the benefit of extending aromatase inhibitors after 5 years of adjuvant tamoxifen has been well established. In contrast, the most effective duration of adjuvant aromatase inhibitor therapy remains unclear in randomized trials,” Dr. Gnant and colleagues commented.
In her editorial, Dr. Goodwin summarized potential approaches for improving late outcomes for patients with hormone receptor–positive breast cancers, including the use of biomarkers to detect minimal residual disease and therapies to treat it.
She noted that the detection of circulating tumor cells in patients with HR-positive breast cancer 5 years after diagnosis is associated with a 13-fold increase in risk for recurrence and a median time to clinical recurrence of 2.8 years.
“This interval may be sufficiently long that therapeutic intervention can prevent the development of incurable clinical metastases. Continued improvement in these assays and the development of new therapies that target the unique biologic features of dormant cells will no doubt be required for a major reduction in late recurrence risk,” she wrote.
The study was supported by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group. Dr. Gnant has received lecture fees from AstraZeneca and others. Dr. Goodwin has received institutional research funding from the Breast Cancer Research Foundation and EPIC Sciences.
A version of this article first appeared on Medscape.com.
That’s a question that has been vexing oncologists for more than a decade, but final results from a large study now suggest that, after an initial 5 years of adjuvant endocrine therapy with tamoxifen and/or an AI, an additional 5 years of AI therapy offer no clinical benefits, compared with an additional 2 years of therapy.
What’s more, 5 years of additional treatment were associated with a significantly increased risk for fractures, compared with 2 years of therapy, Michael Gnant, MD, from the Medical University of Vienna, and colleagues reported in the phase 3 Austrian Breast and Colorectal Cancer Study Group Trial 16 (ABCSG-16).
“Thus, in postmenopausal women with hormone receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, the extension of aromatase inhibitor therapy for 2 years rather than 5 years was sufficient to maximize the benefits of such therapy in most patients without extending the exposure to toxic effects,” they concluded.
The study was published online on July 28, 2021, in the New England Journal of Medicine.
The new results “in patients with hormone-receptor–positive breast cancer who are at low or average risk underscore the importance of avoiding iatrogenic complications when making these decisions,” Pamela J. Goodwin, MD, from the Lunenfeld–Tanenbaum Research Institute at the University of Toronto, wrote in an accompanying editorial.
She noted that these latest results echo those of two earlier studies: the DATA trial and the optimistically named IDEAL trial, both of which showed no benefit of short-term versus longer-term adjuvant endocrine therapy with regard to either disease-free survival (DFS) or overall survival (OS).
“These results provide strong evidence against the routine use of more than 2 years of extended aromatase inhibitor therapy in women who are at low or average risk, similar to those who were included in this trial,” Dr. Goodwin commented.
ABCSG-16 details
Dr. Gnant and colleagues enrolled 3,484 women aged 80 years or younger with HR-positive stage I, II, or III breast cancer for whom there was no evidence of recurrence at baseline. The patients had all received adjuvant tamoxifen or an AI for 5 years; for some patients, the two drugs were administered in sequence until 12 months before randomization.
The patients were randomly assigned to receive oral anastrozole 1 mg daily for either 2 or 5 additional years.
Among all patients, 3,208 had experienced no recurrence 2 years after randomization. These patients were included in the primary DFS analysis. Of this group, 1,635 (51%) had received tamoxifen alone for 5 years, 235 (7.3%) had received an AI alone, and 41.7% had received sequential AIs and tamoxifen.
At a median follow-up of 118 months after randomization, disease progression or death occurred in 670 women – 335 in each trial arm.
The rate of DFS 10 years after randomization was 73.6% in the 2-year additional-therapy group and 73.9% in the 5-year group. The hazard ratio for disease recurrence or death was 0.99 and was not significant. After adjustment for potential confounding factors, the HR remained essentially unchanged (HR, 1.0).
Overall survival at 8 years, a secondary endpoint, was virtually identical between the groups, at 87.5% in the 2-year group and 87.3% in the 5-year group. The HR for death from any cause was 1.02 and was not significant.
The HR for contralateral breast cancer was 1.15, and the HR for a second primary cancer was 1.06; neither was statistically significant.
Although the use of bone-targeted medication was similar between the groups, among patients in the 2-year group, the incidence of clinical bone fractures 5 years after randomization was lower, at 4.7% versus 6.3%, which translates to an HR for fracture with 5 additional years of AI therapy of 1.35 (95% confidence interval, 1.00-1.84).
Adverse events with anastrozole were consistent with its known toxicity profile. At least one serious adverse event occurred in 26.5% of patients in the 2-year group and in 40.2% in the 5-year group. Investigator-assessed serious adverse events that were judged to be related to anastrozole occurred in 2.3% and 4.0% of patients, respectively.
Osteoarthritis, the most frequently reported adverse event, was documented in 1.7% of patients in the 2-year group and in 4.3% in the 5-year group.
AI duration still unclear
“We did not investigate the value of extending adjuvant endocrine therapy per se, since the benefit of extending aromatase inhibitors after 5 years of adjuvant tamoxifen has been well established. In contrast, the most effective duration of adjuvant aromatase inhibitor therapy remains unclear in randomized trials,” Dr. Gnant and colleagues commented.
In her editorial, Dr. Goodwin summarized potential approaches for improving late outcomes for patients with hormone receptor–positive breast cancers, including the use of biomarkers to detect minimal residual disease and therapies to treat it.
She noted that the detection of circulating tumor cells in patients with HR-positive breast cancer 5 years after diagnosis is associated with a 13-fold increase in risk for recurrence and a median time to clinical recurrence of 2.8 years.
“This interval may be sufficiently long that therapeutic intervention can prevent the development of incurable clinical metastases. Continued improvement in these assays and the development of new therapies that target the unique biologic features of dormant cells will no doubt be required for a major reduction in late recurrence risk,” she wrote.
The study was supported by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group. Dr. Gnant has received lecture fees from AstraZeneca and others. Dr. Goodwin has received institutional research funding from the Breast Cancer Research Foundation and EPIC Sciences.
A version of this article first appeared on Medscape.com.
That’s a question that has been vexing oncologists for more than a decade, but final results from a large study now suggest that, after an initial 5 years of adjuvant endocrine therapy with tamoxifen and/or an AI, an additional 5 years of AI therapy offer no clinical benefits, compared with an additional 2 years of therapy.
What’s more, 5 years of additional treatment were associated with a significantly increased risk for fractures, compared with 2 years of therapy, Michael Gnant, MD, from the Medical University of Vienna, and colleagues reported in the phase 3 Austrian Breast and Colorectal Cancer Study Group Trial 16 (ABCSG-16).
“Thus, in postmenopausal women with hormone receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, the extension of aromatase inhibitor therapy for 2 years rather than 5 years was sufficient to maximize the benefits of such therapy in most patients without extending the exposure to toxic effects,” they concluded.
The study was published online on July 28, 2021, in the New England Journal of Medicine.
The new results “in patients with hormone-receptor–positive breast cancer who are at low or average risk underscore the importance of avoiding iatrogenic complications when making these decisions,” Pamela J. Goodwin, MD, from the Lunenfeld–Tanenbaum Research Institute at the University of Toronto, wrote in an accompanying editorial.
She noted that these latest results echo those of two earlier studies: the DATA trial and the optimistically named IDEAL trial, both of which showed no benefit of short-term versus longer-term adjuvant endocrine therapy with regard to either disease-free survival (DFS) or overall survival (OS).
“These results provide strong evidence against the routine use of more than 2 years of extended aromatase inhibitor therapy in women who are at low or average risk, similar to those who were included in this trial,” Dr. Goodwin commented.
ABCSG-16 details
Dr. Gnant and colleagues enrolled 3,484 women aged 80 years or younger with HR-positive stage I, II, or III breast cancer for whom there was no evidence of recurrence at baseline. The patients had all received adjuvant tamoxifen or an AI for 5 years; for some patients, the two drugs were administered in sequence until 12 months before randomization.
The patients were randomly assigned to receive oral anastrozole 1 mg daily for either 2 or 5 additional years.
Among all patients, 3,208 had experienced no recurrence 2 years after randomization. These patients were included in the primary DFS analysis. Of this group, 1,635 (51%) had received tamoxifen alone for 5 years, 235 (7.3%) had received an AI alone, and 41.7% had received sequential AIs and tamoxifen.
At a median follow-up of 118 months after randomization, disease progression or death occurred in 670 women – 335 in each trial arm.
The rate of DFS 10 years after randomization was 73.6% in the 2-year additional-therapy group and 73.9% in the 5-year group. The hazard ratio for disease recurrence or death was 0.99 and was not significant. After adjustment for potential confounding factors, the HR remained essentially unchanged (HR, 1.0).
Overall survival at 8 years, a secondary endpoint, was virtually identical between the groups, at 87.5% in the 2-year group and 87.3% in the 5-year group. The HR for death from any cause was 1.02 and was not significant.
The HR for contralateral breast cancer was 1.15, and the HR for a second primary cancer was 1.06; neither was statistically significant.
Although the use of bone-targeted medication was similar between the groups, among patients in the 2-year group, the incidence of clinical bone fractures 5 years after randomization was lower, at 4.7% versus 6.3%, which translates to an HR for fracture with 5 additional years of AI therapy of 1.35 (95% confidence interval, 1.00-1.84).
Adverse events with anastrozole were consistent with its known toxicity profile. At least one serious adverse event occurred in 26.5% of patients in the 2-year group and in 40.2% in the 5-year group. Investigator-assessed serious adverse events that were judged to be related to anastrozole occurred in 2.3% and 4.0% of patients, respectively.
Osteoarthritis, the most frequently reported adverse event, was documented in 1.7% of patients in the 2-year group and in 4.3% in the 5-year group.
AI duration still unclear
“We did not investigate the value of extending adjuvant endocrine therapy per se, since the benefit of extending aromatase inhibitors after 5 years of adjuvant tamoxifen has been well established. In contrast, the most effective duration of adjuvant aromatase inhibitor therapy remains unclear in randomized trials,” Dr. Gnant and colleagues commented.
In her editorial, Dr. Goodwin summarized potential approaches for improving late outcomes for patients with hormone receptor–positive breast cancers, including the use of biomarkers to detect minimal residual disease and therapies to treat it.
She noted that the detection of circulating tumor cells in patients with HR-positive breast cancer 5 years after diagnosis is associated with a 13-fold increase in risk for recurrence and a median time to clinical recurrence of 2.8 years.
“This interval may be sufficiently long that therapeutic intervention can prevent the development of incurable clinical metastases. Continued improvement in these assays and the development of new therapies that target the unique biologic features of dormant cells will no doubt be required for a major reduction in late recurrence risk,” she wrote.
The study was supported by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group. Dr. Gnant has received lecture fees from AstraZeneca and others. Dr. Goodwin has received institutional research funding from the Breast Cancer Research Foundation and EPIC Sciences.
A version of this article first appeared on Medscape.com.