Breast Cancer ICYMI

The new standard of care for women with persistent, recurrent, or perhaps primary metastatic cervical cancer should be pembrolizumab added to chemotherapy with bevacizumab in [the] biomarker-positive population.

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.

The new standard of care for women with persistent, recurrent, or perhaps primary metastatic cervical cancer should be pembrolizumab added to chemotherapy with bevacizumab in [the] biomarker-positive population.

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.

The new standard of care for women with persistent, recurrent, or perhaps primary metastatic cervical cancer should be pembrolizumab added to chemotherapy with bevacizumab in [the] biomarker-positive population.

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.

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

[email protected]

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

[email protected]

Breast density in women aged 65 years and older may confer an increased risk of invasive breast cancer, much as it does in women aged 40-65 years, a large prospective cohort study suggests.

The findings, based on an analysis of Breast Cancer Surveillance Consortium data from Jan. 1, 1996, to Dec. 31, 2012, have potential implications for screening mammography decisions in older women – particularly those aged 75 years and older, for whom screening guidance is limited by a paucity of data, Dejana Braithwaite, PhD, of the University of Florida Health Cancer Center, Gainesville, and colleagues reported in JAMA Network Open.

The investigators analyzed 221,714 screening mammograms from 193,787 women aged 65 and older in the United States. About 65% of the mammograms were from women aged 65-74 years and about 35% were from women aged 75 years and older, who comprised 38% of the study population.

During a mean follow-up of 6.3 years, 5,069 invasive breast cancers were diagnosed, the authors noted.

The 5-year cumulative incidence of invasive breast cancer increased in tandem with increasing breast density among those aged 65-74 years and among those aged 75 and older: The cumulative incidence per 1,000 women aged 65-74 years was 11.3 for those with almost entirely fatty breasts, 17.2 for those with scattered fibroglandular densities, and 23.7 for those with extremely or heterogeneously dense breasts. The cumulative incidence rates for those aged 75 years and older were 13.5, 18.4, and 22.5 per 1,000 women, respectively, they found.

Extreme or heterogeneous breast density was associated with increased risk of breast cancer, compared with scattered fibroglandular breast density, in both age categories (hazard ratios, 1.39 and 1.23 for those aged 65-74 years and 75 years and older, respectively), whereas the risk of invasive breast cancer was about 30% lower among women with almost entirely fatty breasts, compared with women with scattered fibroglandular breast density (HRs, 0.66 and 0.73 for the 65-74 and 75-plus age groups, respectively).

The associations between breast density and breast cancer were statistically significant after adjustment for body mass index (BMI) and other risk factors.

However, no significant differences were seen between breast density and breast cancer risk based on BMI, noted the authors, who investigated this potential association as part of their effort to identify subpopulations of older women who might benefit from screening, “especially because the U.S. Preventive Service Task Force guidelines state that the current evidence is considered insufficient to recommend routine breast cancer screening for women aged 75 years or older,” they wrote.

Further, although breast density is important in risk assessment and could be evaluated in older women, some risk prediction models exclude women aged 75 or older in risk assessments, they noted, adding that this is concerning given “the aging of the population in the U.S. and worldwide.”

“The positive associations found in this study between breast density and breast cancer among women aged 75 years or older suggest that breast density and life expectancy should be considered together when discussing the potential benefits and harms of continued screening mammography in this population,” they concluded.

The new findings supplement those from prior studies and highlight “the intersection of ... two subjects that have garnered considerable lay public, healthy policy, and academic interest” in recent years: screening mammography in older women and the risk of breast cancer caused by breast density in older women, Catherine M. Tuite, MD, of ChristianaCare Helen F. Graham Cancer Center and Research Institute, Newark, Del., wrote in a commentary published with the study.

“Although there is a linear association between age and mammographic density, age is not a perfect surrogate for the latter, and there are meaningful numbers of older women with mammographically dense breast tissue,” she said, noting that a 75-year-old woman in the United States has a life expectancy of 12-14 additional years, and that “continuation of screening mammography in healthy women aged 75 years or older may offer a substantial opportunity to avoid morbidity and mortality from breast cancer in this age group.”

However, overdiagnosis also remains a concern, she said.

“Breast density and age are only a few of the many factors currently under investigation in the drive toward risk-based or personalized breast cancer screening,” she wrote. “We must remain cautious in the application of restrictive screening for women of any age with supposedly lower than average risk ... ultimately, the decision of when to stop screening is personal, and each woman deserves the agency to weigh her own wishes, values, and life experiences with an accurate and unbiased discussion of risks and benefits of screening mammography in making that decision.”

This study was supported by grants from the National Cancer Institute and the Breast Cancer Surveillance Consortium. Cancer and vital status data collection was supported in part by several state public health departments and cancer registries. Dr. Advani and Dr. Tuite each reported having no disclosures.

[email protected]

A headache severity score compiled by assessing various migraine symptoms can help predict the likelihood of doctor visits and missed work or school, according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.

“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.

To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.

After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
 

Tracking multiple variables

“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.

“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”

He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.

“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”

The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”

The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.

A headache severity score compiled by assessing various migraine symptoms can help predict the likelihood of doctor visits and missed work or school, according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.

“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.

To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.

After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
 

Tracking multiple variables

“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.

“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”

He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.

“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”

The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”

The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.

A headache severity score compiled by assessing various migraine symptoms can help predict the likelihood of doctor visits and missed work or school, according to an analysis of data from thousands of headache sufferers who recorded variables like pain and duration in a daily digital diary.

“Our hope is that this work serves as foundational basis for better understanding the complexity of headache as a symptom-based condition,” James S. McGinley, PhD, of Vector Psychometric Group in Chapel Hill, N.C., and coauthors wrote. The study was published in Cephalalgia.

To evaluate whether keeping track of daily headache features can produce a useful, predictive score, the researchers reviewed data from migraine patients that were collected via N1‑Headache, a commercial digital health platform. Ultimately, information from 4,380 adults with a self-reported migraine diagnosis was analyzed; the sample was 90% female and their mean age was 37 years. Study participants reported an average of 33 headaches per month over the last 3 months. Nine patient-reported variables were initially considered in calculating the Headache Day Severity (HDS) score: pain intensity, headache duration, aura, pulsating/throbbing pain, unilateral pain, pain aggravation by activity, nausea/vomiting, photophobia, and phonophobia.

After determining that unilateral pain was not a meaningful variable, the researchers’ model found that, for every 1 standard deviation increase in HDS, the patient’s odds of physician visit increased by 71% (odds ratio, 1.71; 95% confidence interval, 1.32-2.21) and the odds of an ED visit increased by 342% (OR, 4.42; 95% CI, 2.23-7.60). They also found that the likelihood of missed work or school increased by 190% (OR, 2.90; 95% CI, 2.56-3.29), the chances of missing household work increased by 237% (OR, 3.37; 95% CI, 3.06-3.72) and the odds of missing other leisure or social activity increased by 228% (OR, 3.28; 95% CI, 2.97-3.64).
 

Tracking multiple variables

“We encourage all of our patients to monitor their headaches; there are just too many variables to try to keep it in your head,” Robert Cowan, MD, professor of neurology and chief of the division of headache medicine at Stanford (Calif.) University, said in an interview. He referenced a previous study from the University of Washington where patients were asked to track their headaches; that data was then compared against their self-reported headaches at a quarterly physician visit.

“What they found was there was absolutely no correlation with reported frequency of headache at the visit and what was seen in the tracker,” he said. “If patients had a headache in the previous 3 days before their visit, they felt that their headaches were poorly controlled. If they hadn’t, they thought their headaches were under good control. So the value of tracking is pretty clear.”

He added that, while not every headache sufferer needs to track their daily routines and symptoms, once those symptoms interfere with your life on a day-to-day basis, it’s probably time to consider keeping tabs on yourself with a tool of some sort. And while this study’s calculated HDS score supports the idea of migraine’s complexity, it also leaves unanswered the question of how to treat patients with severe symptoms.

“Frequently,” he said, “we’ll see patients who say: ‘I can deal with the pain, but the nausea makes it impossible to work, or the light sensitivity makes it impossible to go outside.’ The big question within the headache community is, can you treat migraine and have it address the whole spectrum, from dizziness to light sensitivity to sound sensitivity to vertigo, or should you be going after individual symptoms? That’s a controversy that rages on; I think most of us go for a combination. We’re in a polypharmacy phase: ‘If nausea is a big problem, take this, but we also try to prevent the whole migraine complex, so take this as well.’ ”

The authors acknowledged their study’s limitations, including the inability to determine how many participants’ migraines were formally diagnosed by a trained medical professional and the lack of generalizability of data from a convenience sample, though they added that patients who independently track their own headaches “may be representative of those who would participate in a clinical trial.” In addition, as seven of the nine features were collected in N1‑Headache on a yes/no scale, they recognized that “increasing the number of response options for each item may improve our ability to measure HDS.”

The study was funded by Amgen through the Competitive Grant Program in Migraine Research. The authors declared several potential conflicts of interest, including receiving funding, research support, salary, and honoraria from various pharmaceutical companies.

There is a link between ADHD and risk for Alzheimer’s disease (AD) and other dementia types, results from a large, multigenerational study show.

“The findings suggest there are common genetic and/or environmental contributions to the association between ADHD and dementia,” study investigator Zheng Chang, PhD, from the department of medical epidemiology and biostatistics at Karolinska Institute, Stockholm, said in a statement.

“There have been few studies previously on the link between ADHD and dementia, all with limited sample size,” Dr. Chang said in an interview.

“This is the first study to look at ADHD and dementia within extended families. It’s a large population-based study including over 2 million individuals and their over 5 million biological relatives,” he noted.

The study was published online Sept. 9, 2021, in the journal Alzheimer’s & Dementia.
 

Shared familial risk

The researchers identified roughly 2.1 million people born in Sweden between 1980 and 2001. Overall, 3.2% of the cohort had a diagnosis of ADHD. 

Using national registries, they linked these individuals to more than 5 million of their biological relatives including parents, grandparents, uncles, and aunts and determined which of these relatives developed dementia over time.

In adjusted analyses, parents of individuals with ADHD had 34% higher risk for any dementia than parents of those without ADHD (hazard ratio, 1.34; 95% CI, 1.11-1.63).

The risk for AD, the most common type of dementia, was 55% higher in parents of individuals with ADHD (HR, 1.55; 95% CI, 1.26-1.89).

Individuals with ADHD were more likely to have parents with early-onset dementia rather than late-onset dementia. However, the absolute risk for dementia was low for the parent cohort: Only 0.17% of the parents were diagnosed with dementia during follow-up.

The association between ADHD and dementia was not as strong for second-degree relatives of individuals with ADHD. For example, grandparents of individuals with ADHD had a 10% increased risk for dementia, compared with grandparents of individuals without ADHD.

The finding of attenuated associations with decreasing genetic relatedness (parents > grandparents and uncles/aunts), points to shared familial risk between ADHD and AD, the researchers said. 

There could be “undiscovered genetic variants that contribute to either traits or family-wide environmental risk factors, such as socioeconomic status, that may have an impact on the association,” Dr. Chang said in the news release.

“There are no direct clinical implications from this study, but research like this could lead to further research with goals for improved detection, prevention, and treatment,” he said in an interview.
 

More questions than answers

Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association that the way different brain diseases are linked “is a question the Alzheimer’s Association is often asked, and it is a part of our funding portfolio to get that question answered.”

This study looking at ADHD and dementia is “intriguing,” Dr. Snyder said, “because, right now, there is limited information available. That said, this is an association study; it shows that two things are somehow connected. Because of how the study was conducted, it does not – and cannot – prove causation,” Dr. Snyder said. “But it is interesting all the same. More research is needed to uncover specifically why and how these two diseases are related. That might eventually give us insight into how to manage risk or even improve treatment.”

The study was supported by grants from the Swedish Council for Health, Working Life and Welfare, the Swedish Research Council, the Swedish Brain Foundation, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie, the Fredrik & Ingrid Thurings Stiftelse, and the Karolinska Institutet Research Foundation. Dr. Chang and Dr. Snyder disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There is a link between ADHD and risk for Alzheimer’s disease (AD) and other dementia types, results from a large, multigenerational study show.

“The findings suggest there are common genetic and/or environmental contributions to the association between ADHD and dementia,” study investigator Zheng Chang, PhD, from the department of medical epidemiology and biostatistics at Karolinska Institute, Stockholm, said in a statement.

“There have been few studies previously on the link between ADHD and dementia, all with limited sample size,” Dr. Chang said in an interview.

“This is the first study to look at ADHD and dementia within extended families. It’s a large population-based study including over 2 million individuals and their over 5 million biological relatives,” he noted.

The study was published online Sept. 9, 2021, in the journal Alzheimer’s & Dementia.
 

Shared familial risk

The researchers identified roughly 2.1 million people born in Sweden between 1980 and 2001. Overall, 3.2% of the cohort had a diagnosis of ADHD. 

Using national registries, they linked these individuals to more than 5 million of their biological relatives including parents, grandparents, uncles, and aunts and determined which of these relatives developed dementia over time.

In adjusted analyses, parents of individuals with ADHD had 34% higher risk for any dementia than parents of those without ADHD (hazard ratio, 1.34; 95% CI, 1.11-1.63).

The risk for AD, the most common type of dementia, was 55% higher in parents of individuals with ADHD (HR, 1.55; 95% CI, 1.26-1.89).

Individuals with ADHD were more likely to have parents with early-onset dementia rather than late-onset dementia. However, the absolute risk for dementia was low for the parent cohort: Only 0.17% of the parents were diagnosed with dementia during follow-up.

The association between ADHD and dementia was not as strong for second-degree relatives of individuals with ADHD. For example, grandparents of individuals with ADHD had a 10% increased risk for dementia, compared with grandparents of individuals without ADHD.

The finding of attenuated associations with decreasing genetic relatedness (parents > grandparents and uncles/aunts), points to shared familial risk between ADHD and AD, the researchers said. 

There could be “undiscovered genetic variants that contribute to either traits or family-wide environmental risk factors, such as socioeconomic status, that may have an impact on the association,” Dr. Chang said in the news release.

“There are no direct clinical implications from this study, but research like this could lead to further research with goals for improved detection, prevention, and treatment,” he said in an interview.
 

More questions than answers

Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association that the way different brain diseases are linked “is a question the Alzheimer’s Association is often asked, and it is a part of our funding portfolio to get that question answered.”

This study looking at ADHD and dementia is “intriguing,” Dr. Snyder said, “because, right now, there is limited information available. That said, this is an association study; it shows that two things are somehow connected. Because of how the study was conducted, it does not – and cannot – prove causation,” Dr. Snyder said. “But it is interesting all the same. More research is needed to uncover specifically why and how these two diseases are related. That might eventually give us insight into how to manage risk or even improve treatment.”

The study was supported by grants from the Swedish Council for Health, Working Life and Welfare, the Swedish Research Council, the Swedish Brain Foundation, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie, the Fredrik & Ingrid Thurings Stiftelse, and the Karolinska Institutet Research Foundation. Dr. Chang and Dr. Snyder disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There is a link between ADHD and risk for Alzheimer’s disease (AD) and other dementia types, results from a large, multigenerational study show.

“The findings suggest there are common genetic and/or environmental contributions to the association between ADHD and dementia,” study investigator Zheng Chang, PhD, from the department of medical epidemiology and biostatistics at Karolinska Institute, Stockholm, said in a statement.

“There have been few studies previously on the link between ADHD and dementia, all with limited sample size,” Dr. Chang said in an interview.

“This is the first study to look at ADHD and dementia within extended families. It’s a large population-based study including over 2 million individuals and their over 5 million biological relatives,” he noted.

The study was published online Sept. 9, 2021, in the journal Alzheimer’s & Dementia.
 

Shared familial risk

The researchers identified roughly 2.1 million people born in Sweden between 1980 and 2001. Overall, 3.2% of the cohort had a diagnosis of ADHD. 

Using national registries, they linked these individuals to more than 5 million of their biological relatives including parents, grandparents, uncles, and aunts and determined which of these relatives developed dementia over time.

In adjusted analyses, parents of individuals with ADHD had 34% higher risk for any dementia than parents of those without ADHD (hazard ratio, 1.34; 95% CI, 1.11-1.63).

The risk for AD, the most common type of dementia, was 55% higher in parents of individuals with ADHD (HR, 1.55; 95% CI, 1.26-1.89).

Individuals with ADHD were more likely to have parents with early-onset dementia rather than late-onset dementia. However, the absolute risk for dementia was low for the parent cohort: Only 0.17% of the parents were diagnosed with dementia during follow-up.

The association between ADHD and dementia was not as strong for second-degree relatives of individuals with ADHD. For example, grandparents of individuals with ADHD had a 10% increased risk for dementia, compared with grandparents of individuals without ADHD.

The finding of attenuated associations with decreasing genetic relatedness (parents > grandparents and uncles/aunts), points to shared familial risk between ADHD and AD, the researchers said. 

There could be “undiscovered genetic variants that contribute to either traits or family-wide environmental risk factors, such as socioeconomic status, that may have an impact on the association,” Dr. Chang said in the news release.

“There are no direct clinical implications from this study, but research like this could lead to further research with goals for improved detection, prevention, and treatment,” he said in an interview.
 

More questions than answers

Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association that the way different brain diseases are linked “is a question the Alzheimer’s Association is often asked, and it is a part of our funding portfolio to get that question answered.”

This study looking at ADHD and dementia is “intriguing,” Dr. Snyder said, “because, right now, there is limited information available. That said, this is an association study; it shows that two things are somehow connected. Because of how the study was conducted, it does not – and cannot – prove causation,” Dr. Snyder said. “But it is interesting all the same. More research is needed to uncover specifically why and how these two diseases are related. That might eventually give us insight into how to manage risk or even improve treatment.”

The study was supported by grants from the Swedish Council for Health, Working Life and Welfare, the Swedish Research Council, the Swedish Brain Foundation, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie, the Fredrik & Ingrid Thurings Stiftelse, and the Karolinska Institutet Research Foundation. Dr. Chang and Dr. Snyder disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated levels of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1) are associated with a reduced risk for amyotrophic lateral sclerosis (ALS), new research shows.

The study also linked a higher ratio of total cholesterol to HDL with an increased risk for ALS. These findings, investigators noted, point to potential future biomarkers in screening for ALS and perhaps an approach to reduce risk or delay onset of ALS in the longer term.

“They may help build a biochemical picture of what’s going on and who might be at risk of developing ALS in the near future, particularly in people with a genetic predisposition to ALS,” study investigator Alexander G. Thompson, DPhil, Medical Research Council clinician scientist, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom, said in an interview.

He emphasized that although the current observational study cannot show cause and effect, such a relationship may exist.

The study was published online September 13 in the Journal of Neurology, Neurosurgery and Psychiatry.
 

Registry data

ALS is a disorder of progressive degeneration of upper and lower motor neurons. Genetic variants account for fewer than 15% of cases. The factors that are associated with the greatest risk are unclear.

To investigate, the researchers used data from the UK Biobank, a prospective cohort study of persons aged 39-72 years. Participants underwent an initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years.

In addition to providing demographic and health information, participants provided blood samples for biochemical analysis. This included measurements of total cholesterol, HDL, low-density lipoprotein (LDL) cholesterol, triglycerides, apoA1, apolipoprotein B (apoB), A1c, and creatinine.

Researchers used diagnostic codes in inpatient health records and death certificate information to verify ALS diagnoses.

The analysis included data from 502,409 participants. The mean age of the participants was 58 years, and 54.4% were women. During follow-up, 343 participants were diagnosed with ALS, yielding a crude incidence of 5.85 per 100,000 per year (95% confidence interval, 5.25-6.51).

After controlling for sex and age, results showed that higher HDL (hazard ratio, 0.84; 95% CI, 0.73-0.96; P = .010) and higher apoA1 (HR, 0.83; 95% CI, 0.72-0.94, P = .005) were associated with a reduced risk for subsequent ALS.

A higher ratio of total cholesterol to HDL was associated with increased ALS risk.

A rise in neurofilaments and other markers of neuronal loss typically occur within about a year of ALS symptom onset. To ensure that they were capturing participants whose blood samples were taken before the onset of neurodegeneration, the researchers performed a secondary analysis that excluded ALS diagnoses within 5 years of the baseline study visit.

Results of the analysis were largely consistent with models incorporating all participants with regard to magnitude and direction of associations. In addition, the findings persisted in models that controlled for statin use, smoking, and vascular disease.
 

Mechanism unclear

To more closely examine lipid status prior to ALS diagnosis, the researchers performed a nested case-control analysis that involved matching each participant who developed ALS with 20 participants of similar age, sex, and time of enrollment who did not develop the disease.

Linear models showed that levels of LDL and apoB, which are closely correlated, decrease over time in those who developed ALS. This was not the case for HDL and apoA1. “This suggests LDL levels are going down, and we think it’s happening quite some time before symptoms start, even before neurodegeneration starts,” said Dr. Thompson.

How blood lipid levels correlate with ALS risk is unclear. Dr. Thompson noted that LDL is an oxidative stressor and can provoke inflammation, whereas HDL is an antioxidant that is involved in healing. However, given that LDL and HDL don’t cross into the brain in great amounts, “the lipid changes may be a reflection of something else going on that contributes to the risk of ALS,” he said.

More evidence of a causal relationship is needed before any clinical implications can be drawn, including the potential manipulation of lipid levels to prevent ALS, said Dr. Thompson. In addition, even were such a relationship to be established, altering lipid levels in a healthy individual who has no family history of ALS would be unlikely to alter risk.

Dr. Thompson added that among those with a genetic predisposition, lipid changes “may be a marker or clue that something’s going wrong in the nervous system and that ALS might be about to start. That would be the ideal time to treat people at risk of ALS with gene therapy.”
 

Metabolism gone awry

Commenting on the findings, Stephen Goutman, MD, director, Pranger ALS Clinic, associate professor of neurology, Neuromuscular Program, University of Michigan, Ann Arbor, called the study “very interesting.” Of particular note was a trend of decreasing LDL and apoB levels prior to an ALS diagnosis, said Dr. Goutman.

The results are in agreement with several studies that show an alteration in metabolism in individuals with ALS, he said. “These altered metabolic pathways may provide some signal that something has gone awry,” he commented.

He agreed that an “ultimate goal” is to identify factors or biomarkers that can be used to predict whether individuals will develop ALS and to enable intervention to decrease the risk.

This new research highlights the value of population-based registries and large prospective cohorts, said Dr. Goutman. “These help to better define the genetic, environmental, and metabolic factors that increase and predict ALS risk,” he said.

But more work is needed, said Dr. Goutman. He noted that in the study, only 192 participants were diagnosed with ALS more than 5 years after enrollment. “This means additional large cohort studies are needed, especially those that reflect the diversity of the population, for us to solve the mystery of ALS and to prevent it,” he said.

Dr. Thompson and Dr. Goutman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated levels of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1) are associated with a reduced risk for amyotrophic lateral sclerosis (ALS), new research shows.

The study also linked a higher ratio of total cholesterol to HDL with an increased risk for ALS. These findings, investigators noted, point to potential future biomarkers in screening for ALS and perhaps an approach to reduce risk or delay onset of ALS in the longer term.

“They may help build a biochemical picture of what’s going on and who might be at risk of developing ALS in the near future, particularly in people with a genetic predisposition to ALS,” study investigator Alexander G. Thompson, DPhil, Medical Research Council clinician scientist, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom, said in an interview.

He emphasized that although the current observational study cannot show cause and effect, such a relationship may exist.

The study was published online September 13 in the Journal of Neurology, Neurosurgery and Psychiatry.
 

Registry data

ALS is a disorder of progressive degeneration of upper and lower motor neurons. Genetic variants account for fewer than 15% of cases. The factors that are associated with the greatest risk are unclear.

To investigate, the researchers used data from the UK Biobank, a prospective cohort study of persons aged 39-72 years. Participants underwent an initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years.

In addition to providing demographic and health information, participants provided blood samples for biochemical analysis. This included measurements of total cholesterol, HDL, low-density lipoprotein (LDL) cholesterol, triglycerides, apoA1, apolipoprotein B (apoB), A1c, and creatinine.

Researchers used diagnostic codes in inpatient health records and death certificate information to verify ALS diagnoses.

The analysis included data from 502,409 participants. The mean age of the participants was 58 years, and 54.4% were women. During follow-up, 343 participants were diagnosed with ALS, yielding a crude incidence of 5.85 per 100,000 per year (95% confidence interval, 5.25-6.51).

After controlling for sex and age, results showed that higher HDL (hazard ratio, 0.84; 95% CI, 0.73-0.96; P = .010) and higher apoA1 (HR, 0.83; 95% CI, 0.72-0.94, P = .005) were associated with a reduced risk for subsequent ALS.

A higher ratio of total cholesterol to HDL was associated with increased ALS risk.

A rise in neurofilaments and other markers of neuronal loss typically occur within about a year of ALS symptom onset. To ensure that they were capturing participants whose blood samples were taken before the onset of neurodegeneration, the researchers performed a secondary analysis that excluded ALS diagnoses within 5 years of the baseline study visit.

Results of the analysis were largely consistent with models incorporating all participants with regard to magnitude and direction of associations. In addition, the findings persisted in models that controlled for statin use, smoking, and vascular disease.
 

Mechanism unclear

To more closely examine lipid status prior to ALS diagnosis, the researchers performed a nested case-control analysis that involved matching each participant who developed ALS with 20 participants of similar age, sex, and time of enrollment who did not develop the disease.

Linear models showed that levels of LDL and apoB, which are closely correlated, decrease over time in those who developed ALS. This was not the case for HDL and apoA1. “This suggests LDL levels are going down, and we think it’s happening quite some time before symptoms start, even before neurodegeneration starts,” said Dr. Thompson.

How blood lipid levels correlate with ALS risk is unclear. Dr. Thompson noted that LDL is an oxidative stressor and can provoke inflammation, whereas HDL is an antioxidant that is involved in healing. However, given that LDL and HDL don’t cross into the brain in great amounts, “the lipid changes may be a reflection of something else going on that contributes to the risk of ALS,” he said.

More evidence of a causal relationship is needed before any clinical implications can be drawn, including the potential manipulation of lipid levels to prevent ALS, said Dr. Thompson. In addition, even were such a relationship to be established, altering lipid levels in a healthy individual who has no family history of ALS would be unlikely to alter risk.

Dr. Thompson added that among those with a genetic predisposition, lipid changes “may be a marker or clue that something’s going wrong in the nervous system and that ALS might be about to start. That would be the ideal time to treat people at risk of ALS with gene therapy.”
 

Metabolism gone awry

Commenting on the findings, Stephen Goutman, MD, director, Pranger ALS Clinic, associate professor of neurology, Neuromuscular Program, University of Michigan, Ann Arbor, called the study “very interesting.” Of particular note was a trend of decreasing LDL and apoB levels prior to an ALS diagnosis, said Dr. Goutman.

The results are in agreement with several studies that show an alteration in metabolism in individuals with ALS, he said. “These altered metabolic pathways may provide some signal that something has gone awry,” he commented.

He agreed that an “ultimate goal” is to identify factors or biomarkers that can be used to predict whether individuals will develop ALS and to enable intervention to decrease the risk.

This new research highlights the value of population-based registries and large prospective cohorts, said Dr. Goutman. “These help to better define the genetic, environmental, and metabolic factors that increase and predict ALS risk,” he said.

But more work is needed, said Dr. Goutman. He noted that in the study, only 192 participants were diagnosed with ALS more than 5 years after enrollment. “This means additional large cohort studies are needed, especially those that reflect the diversity of the population, for us to solve the mystery of ALS and to prevent it,” he said.

Dr. Thompson and Dr. Goutman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Elevated levels of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1) are associated with a reduced risk for amyotrophic lateral sclerosis (ALS), new research shows.

The study also linked a higher ratio of total cholesterol to HDL with an increased risk for ALS. These findings, investigators noted, point to potential future biomarkers in screening for ALS and perhaps an approach to reduce risk or delay onset of ALS in the longer term.

“They may help build a biochemical picture of what’s going on and who might be at risk of developing ALS in the near future, particularly in people with a genetic predisposition to ALS,” study investigator Alexander G. Thompson, DPhil, Medical Research Council clinician scientist, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom, said in an interview.

He emphasized that although the current observational study cannot show cause and effect, such a relationship may exist.

The study was published online September 13 in the Journal of Neurology, Neurosurgery and Psychiatry.
 

Registry data

ALS is a disorder of progressive degeneration of upper and lower motor neurons. Genetic variants account for fewer than 15% of cases. The factors that are associated with the greatest risk are unclear.

To investigate, the researchers used data from the UK Biobank, a prospective cohort study of persons aged 39-72 years. Participants underwent an initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years.

In addition to providing demographic and health information, participants provided blood samples for biochemical analysis. This included measurements of total cholesterol, HDL, low-density lipoprotein (LDL) cholesterol, triglycerides, apoA1, apolipoprotein B (apoB), A1c, and creatinine.

Researchers used diagnostic codes in inpatient health records and death certificate information to verify ALS diagnoses.

The analysis included data from 502,409 participants. The mean age of the participants was 58 years, and 54.4% were women. During follow-up, 343 participants were diagnosed with ALS, yielding a crude incidence of 5.85 per 100,000 per year (95% confidence interval, 5.25-6.51).

After controlling for sex and age, results showed that higher HDL (hazard ratio, 0.84; 95% CI, 0.73-0.96; P = .010) and higher apoA1 (HR, 0.83; 95% CI, 0.72-0.94, P = .005) were associated with a reduced risk for subsequent ALS.

A higher ratio of total cholesterol to HDL was associated with increased ALS risk.

A rise in neurofilaments and other markers of neuronal loss typically occur within about a year of ALS symptom onset. To ensure that they were capturing participants whose blood samples were taken before the onset of neurodegeneration, the researchers performed a secondary analysis that excluded ALS diagnoses within 5 years of the baseline study visit.

Results of the analysis were largely consistent with models incorporating all participants with regard to magnitude and direction of associations. In addition, the findings persisted in models that controlled for statin use, smoking, and vascular disease.
 

Mechanism unclear

To more closely examine lipid status prior to ALS diagnosis, the researchers performed a nested case-control analysis that involved matching each participant who developed ALS with 20 participants of similar age, sex, and time of enrollment who did not develop the disease.

Linear models showed that levels of LDL and apoB, which are closely correlated, decrease over time in those who developed ALS. This was not the case for HDL and apoA1. “This suggests LDL levels are going down, and we think it’s happening quite some time before symptoms start, even before neurodegeneration starts,” said Dr. Thompson.

How blood lipid levels correlate with ALS risk is unclear. Dr. Thompson noted that LDL is an oxidative stressor and can provoke inflammation, whereas HDL is an antioxidant that is involved in healing. However, given that LDL and HDL don’t cross into the brain in great amounts, “the lipid changes may be a reflection of something else going on that contributes to the risk of ALS,” he said.

More evidence of a causal relationship is needed before any clinical implications can be drawn, including the potential manipulation of lipid levels to prevent ALS, said Dr. Thompson. In addition, even were such a relationship to be established, altering lipid levels in a healthy individual who has no family history of ALS would be unlikely to alter risk.

Dr. Thompson added that among those with a genetic predisposition, lipid changes “may be a marker or clue that something’s going wrong in the nervous system and that ALS might be about to start. That would be the ideal time to treat people at risk of ALS with gene therapy.”
 

Metabolism gone awry

Commenting on the findings, Stephen Goutman, MD, director, Pranger ALS Clinic, associate professor of neurology, Neuromuscular Program, University of Michigan, Ann Arbor, called the study “very interesting.” Of particular note was a trend of decreasing LDL and apoB levels prior to an ALS diagnosis, said Dr. Goutman.

The results are in agreement with several studies that show an alteration in metabolism in individuals with ALS, he said. “These altered metabolic pathways may provide some signal that something has gone awry,” he commented.

He agreed that an “ultimate goal” is to identify factors or biomarkers that can be used to predict whether individuals will develop ALS and to enable intervention to decrease the risk.

This new research highlights the value of population-based registries and large prospective cohorts, said Dr. Goutman. “These help to better define the genetic, environmental, and metabolic factors that increase and predict ALS risk,” he said.

But more work is needed, said Dr. Goutman. He noted that in the study, only 192 participants were diagnosed with ALS more than 5 years after enrollment. “This means additional large cohort studies are needed, especially those that reflect the diversity of the population, for us to solve the mystery of ALS and to prevent it,” he said.

Dr. Thompson and Dr. Goutman have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.

Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.

“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.

“Monitoring prolactinemia and addressing hyperprolactinemia are important in women with schizophrenia who are treated with prolactin-increasing antipsychotics,” he said.

The study was published online Aug. 30, 2021, in The Lancet.
 

A ‘relevant contribution’

Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.

In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.

Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”

They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”

The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.

Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.

Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.

In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
 

‘Clinically meaningful’ risk

Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.

A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.

On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.

Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).

“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.

“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”

Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
 

Clinical implications premature?

Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”

Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”

Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.

Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”

Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”

The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.

“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.

Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.

A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.

“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”

This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.

The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).

“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.

The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.

For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
 

Certain cancer types persist after 1 year

Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.

“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.

“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.

The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.

Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.

Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.

“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
 

Link to mortality data

The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.

A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.

An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.

However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.

Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.

Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.

Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.

“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.

Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.

A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.

“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”

This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.

The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).

“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.

The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.

For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
 

Certain cancer types persist after 1 year

Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.

“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.

“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.

The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.

Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.

Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.

“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
 

Link to mortality data

The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.

A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.

An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.

However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.

Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.

Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.

Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.

“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.

Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.

A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.

“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”

This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.

The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).

“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.

The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.

For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
 

Certain cancer types persist after 1 year

Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.

“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.

“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.

The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.

Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.

Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.

“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
 

Link to mortality data

The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.

A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.

An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.

However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.

Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.

Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.