Breast Cancer

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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

In the largest investigation into the issue to date, metformin did not improve survival of patients with high-risk, operable breast cancer when added to standard adjuvant treatments.

Metformin, a common option for patients with type 2 diabetes, had previously been shown in observational studies to be associated with improved survival of cancer patients. Those studies mostly involved older patients with cancer who also had diabetes.

These findings have led to trials of the use of metformin for patients with cancer who do not have diabetes, but two lung cancer trials found no effect on survival.

Now this latest trial in breast cancer, which included 3,649 patients with hormone receptor–positive or –negative disease – who did not have diabetes – also found that metformin had no effect on survival.

These results “tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped,” lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, said in a press release.

The negative results “underscore the need for well-conducted randomized trials” before observational studies are put into practice, Dr. Goodwin and her team said.

However, the investigators cautioned against extrapolating their results to patients with diabetes, noting that “because metformin is effective in type 2 diabetes, the results ... should not affect the use of metformin” in breast cancer patients who have diabetes.

The study was published online in JAMA.

Patients were enrolled from 2010 to 2013 while undergoing adjuvant treatment – chemotherapy, radiotherapy, hormone therapy, and/or others – following complete resection of T1-3, N0-3 tumors. They were almost exclusively women (mean age, 52.4 years), and almost 90% were non-Hispanic White. They were primarily from the United States and Canada, with some patients from the United Kingdom and Switzerland.

Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Median follow-up was about 8 years.

Among 2,533 patients with estrogen receptor– and/or progesterone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years in the metformin group, vs. 2.74 per 100 patient-years in the placebo arm (hazard ratio [HR], 1.01, P = .93). There were 1.46 deaths per 100 patient-years with metformin, vs. 1.32 with placebo (HR, 1.10, P = .47).

Metformin was stopped early at about 3 years for the 1,116 hormone receptor–negative patients after futility was declared on interim analysis. The incidence of invasive disease–free survival events was 3.58 with metformin, vs. 3.60 with placebo per 100 patient-years (HR, 1.01, P = .92). There were 1.91 deaths per 100 patient-years in the metformin arm, vs. 2.15 in the group that received placebo (HR, 0.89, P = .46).

However, the findings were different and suggested a signal among the small subset of patients (17% of the total) who had HER2-positive disease. There were 1.93 disease-free survival events with metformin per 100 patient-years, vs. 3.05 events with placebo (HR, 0.64, P = .03), and 0.78 deaths in the metformin arm, vs. 1.43 deaths per 100 patient-years in the placebo arm (HR, 0.54, P = .04).

The benefit seen in this HER2-postive subgroup was limited to patients with any C allele of the rs11212617 single-nucleotide variant.

This was an exploratory analysis, so the results need to be confirmed in a randomized trial, but it’s possible that metformin “could provide an additional treatment option for HER2-positive breast cancer,” Dr. Goodwin said.

Grade 3 or higher adverse events were more common with metformin (21.5% vs. 17.5%). The most common such events were hypertension (2.4% vs. 1.9%), irregular menses (1.5% vs. 1.4%), and diarrhea (1.9% vs. 0.8%).

The study was conducted by the Canadian Cancer Trials Group and was funded by the Canadian Cancer Society, the National Cancer Institute, and others. Dr. Goodwin has disclosed no relevant financial relationships. Several coauthors reported ties to Pfizer, Eli Lilly, Roche, and a number of other companies. One coauthor is an AstraZeneca employee.

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

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.

Male breast cancer is linked to infertility, according to a new case-control study from the Institute of Cancer Research in London. The report follows other studies that generally failed to identify a statistically significant association, but the resources of Great Britain’s National Health Service made it possible to achieve greater power than previous efforts.

“It’s a very difficult disease to study because it’s about 100 times rarer than female breast cancer. To do the equivalent study, you either have to make your study 100 times bigger, or think laterally and approach it a different way. (That’s) why we did a case control study where you identify the cases and find controls, rather than wait for men to develop breast cancer,” said Michael Edwin Jones, PhD, the lead author of the study, which was published online in Breast Cancer Research.

The new study found that men who self-reported infertility had a doubled risk of breast cancer, while there was no difference if the fertility was linked to their female partner. Sex hormones are known to play a key role in female breast cancer, and they have a suspected role in male breast cancer as well, though it’s hard to pin down because there is no concentrated source of exposure like hormone therapy or activity from the ovary to cause spiked levels. “It’s more subtle in men, but there’s a reason to think it’s important,” Dr. Jones said.

Although the results hint at a possible role of sex hormones, the research can’t confirm that. Blood draws were taken from participants, but many were conducted after treatment had begun, leading to inconsistent results. Dr. Jones called for more research into biological mechanisms that might explain the increased risk, and suggested that such efforts could lead to a better understanding of breast cancer overall, since the disease in men is not effected by factors like pregnancy and menopause.

Historically, few clinical trials for breast cancer drugs included men, and this has resulted in few approved treatments. However, the impact of breast cancer on men is increasingly being recognized, and most such trials now accept male patients. The Food and Drug Administration has even produced a guidance document for inclusion of men in development of breast cancer drugs, which states that men should be excluded only if there is a clear scientific rationale. When there are too few male participants to draw direct conclusions, it may be possible to extrapolate findings in women to men for FDA approval, provided the mechanism of action suggests that there should be no difference in efficacy.

The Breast Cancer Now study included 1,998 cases and 1,597 controls, who were asked about infertility and whether they had children. Men with male-origin infertility had a higher risk of breast cancer (odds ratio, 2.03; 95% confidence interval [CI], 1.18-3.49), but not men who reported female-origin infertility (OR, 0.86; 95% CI, 0.51-1.45). There was also a heightened risk among men who had not fathered children versus those who had (OR, 1.50; 95% CI, 1.21-1.86).

The association was statistically significant for invasive tumors (OR, 1.96; P = .02), but only a trend was observed for in situ breast cancer (OR, 1.72; P = .39). A possible explanation is that diagnosis of in situ breast cancer is less common than invasive cancer in men, which could have led to the study being underpowered. “Unfortunately, there were too few in-situ breast cancers to allow us to say anything definitive,” said Dr. Jones.

Dr. Jones has no relevant financial disclosures. The study was funded by Breast Cancer Now.

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

Key clinical point: Patients with left-sided breast cancer (BC) who received radiation doses to the left anterior descending artery (LAD) experienced an elevated risk for adverse cardiac outcomes.

Major finding: Mean dose to LAD was associated with an increased risk for any cardiac event (hazard ratio [HR] 1.09; P = .006) and major cardiac events (HR 1.08; P = .022). Receiver operating characteristics analysis identified 2.8 Gy (area under the curve 0.69) as the mean LAD dose threshold, above which the risk for any cardiac event was higher (P = .001).

Study details: Findings are from a retrospective study of 375 consecutively treated female patients with nonmetastatic, left-sided BC who received breast-conserving surgery/mastectomy and adjuvant radiation therapy.

Disclosures: This study did not receive any funding. The authors declared no conflict of interests.

Source: Zureick AH et al. Dose to the left anterior descending artery correlates with cardiac events following irradiation for breast cancer. Int J Radiat Oncol Biol Phys. 2022 (Apr 24). Doi: 10.1016/j.ijrobp.2022.04.019

Key clinical point: Patients with left-sided breast cancer (BC) who received radiation doses to the left anterior descending artery (LAD) experienced an elevated risk for adverse cardiac outcomes.

Major finding: Mean dose to LAD was associated with an increased risk for any cardiac event (hazard ratio [HR] 1.09; P = .006) and major cardiac events (HR 1.08; P = .022). Receiver operating characteristics analysis identified 2.8 Gy (area under the curve 0.69) as the mean LAD dose threshold, above which the risk for any cardiac event was higher (P = .001).

Study details: Findings are from a retrospective study of 375 consecutively treated female patients with nonmetastatic, left-sided BC who received breast-conserving surgery/mastectomy and adjuvant radiation therapy.

Disclosures: This study did not receive any funding. The authors declared no conflict of interests.

Source: Zureick AH et al. Dose to the left anterior descending artery correlates with cardiac events following irradiation for breast cancer. Int J Radiat Oncol Biol Phys. 2022 (Apr 24). Doi: 10.1016/j.ijrobp.2022.04.019

Key clinical point: Patients with left-sided breast cancer (BC) who received radiation doses to the left anterior descending artery (LAD) experienced an elevated risk for adverse cardiac outcomes.

Major finding: Mean dose to LAD was associated with an increased risk for any cardiac event (hazard ratio [HR] 1.09; P = .006) and major cardiac events (HR 1.08; P = .022). Receiver operating characteristics analysis identified 2.8 Gy (area under the curve 0.69) as the mean LAD dose threshold, above which the risk for any cardiac event was higher (P = .001).

Study details: Findings are from a retrospective study of 375 consecutively treated female patients with nonmetastatic, left-sided BC who received breast-conserving surgery/mastectomy and adjuvant radiation therapy.

Disclosures: This study did not receive any funding. The authors declared no conflict of interests.

Source: Zureick AH et al. Dose to the left anterior descending artery correlates with cardiac events following irradiation for breast cancer. Int J Radiat Oncol Biol Phys. 2022 (Apr 24). Doi: 10.1016/j.ijrobp.2022.04.019

Key clinical point: Young age at diagnosis of human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC) was not associated with any detrimental prognostic value and had no effect on the efficacy of adjuvant dual anti-HER2 targeted therapy.

Major finding: Young age had no effect on invasive disease-free survival (adjusted hazard ratio [aHR] 1.07; 95% CI 0.84-1.35), regardless of hormone receptor status (positive: aHR 1.10; 95% CI 0.82-1.44 or negative: aHR 0.99; 95% CI 0.62-1.51) and anti-HER2 treatment administered (chemotherapy+trastuzumab+pertuzumab: aHR 1.20; 95% CI 0.83-1.68 or chemotherapy+trastuzumab+placebo: aHR, 0.99; 95% CI, 0.71-1.35).

Study details: Findings are from the phase 3 APHINITY trial including 768 patients aged ≤40 years with HER2+ early BC who were randomly assigned to receive chemotherapy+trastuzumab+placebo or chemotherapy+trastuzumab+pertuzumab.

Disclosures: The APHINITY trial was supported by F Hoffmann-La Roche Ltd/Genentech. Some authors declared receiving research funding, honoraria, grants, or nonfinancial support or serving as advisors, speakers, or consultants for several sources, including Roche/Genentech.

Source: Lambertini M et al. Impact of age on clinical outcomes and efficacy of adjuvant dual anti-HER2 targeted therapy. J Natl Cancer Inst. 2022 (May 5). Doi: 10.1093/jnci/djac096 

Key clinical point: Young age at diagnosis of human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC) was not associated with any detrimental prognostic value and had no effect on the efficacy of adjuvant dual anti-HER2 targeted therapy.

Major finding: Young age had no effect on invasive disease-free survival (adjusted hazard ratio [aHR] 1.07; 95% CI 0.84-1.35), regardless of hormone receptor status (positive: aHR 1.10; 95% CI 0.82-1.44 or negative: aHR 0.99; 95% CI 0.62-1.51) and anti-HER2 treatment administered (chemotherapy+trastuzumab+pertuzumab: aHR 1.20; 95% CI 0.83-1.68 or chemotherapy+trastuzumab+placebo: aHR, 0.99; 95% CI, 0.71-1.35).

Study details: Findings are from the phase 3 APHINITY trial including 768 patients aged ≤40 years with HER2+ early BC who were randomly assigned to receive chemotherapy+trastuzumab+placebo or chemotherapy+trastuzumab+pertuzumab.

Disclosures: The APHINITY trial was supported by F Hoffmann-La Roche Ltd/Genentech. Some authors declared receiving research funding, honoraria, grants, or nonfinancial support or serving as advisors, speakers, or consultants for several sources, including Roche/Genentech.

Source: Lambertini M et al. Impact of age on clinical outcomes and efficacy of adjuvant dual anti-HER2 targeted therapy. J Natl Cancer Inst. 2022 (May 5). Doi: 10.1093/jnci/djac096 

Key clinical point: Young age at diagnosis of human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC) was not associated with any detrimental prognostic value and had no effect on the efficacy of adjuvant dual anti-HER2 targeted therapy.

Major finding: Young age had no effect on invasive disease-free survival (adjusted hazard ratio [aHR] 1.07; 95% CI 0.84-1.35), regardless of hormone receptor status (positive: aHR 1.10; 95% CI 0.82-1.44 or negative: aHR 0.99; 95% CI 0.62-1.51) and anti-HER2 treatment administered (chemotherapy+trastuzumab+pertuzumab: aHR 1.20; 95% CI 0.83-1.68 or chemotherapy+trastuzumab+placebo: aHR, 0.99; 95% CI, 0.71-1.35).

Study details: Findings are from the phase 3 APHINITY trial including 768 patients aged ≤40 years with HER2+ early BC who were randomly assigned to receive chemotherapy+trastuzumab+placebo or chemotherapy+trastuzumab+pertuzumab.

Disclosures: The APHINITY trial was supported by F Hoffmann-La Roche Ltd/Genentech. Some authors declared receiving research funding, honoraria, grants, or nonfinancial support or serving as advisors, speakers, or consultants for several sources, including Roche/Genentech.

Source: Lambertini M et al. Impact of age on clinical outcomes and efficacy of adjuvant dual anti-HER2 targeted therapy. J Natl Cancer Inst. 2022 (May 5). Doi: 10.1093/jnci/djac096 

Key clinical point: Age, tumor subtype, surgery, and brain metastasis are independent risk factors for survival in male patients with breast cancer (BC) and bone metastases and should be considered when devising a treatment strategy.

Major finding: Overall survival (OS) and cancer-specific survival (CSS) were significantly lower in patients aged >60 years (hazard ratio [HR] 1.671; P = .014 and HR 1.806; P = .009, respectively), with triple-negative BC (HR 3.029; P = .003 and HR 3.025; P = .004, respectively), and without surgery (HR 1.764; P = .012 and HR 1.734; P = .023, respectively), and with brain metastasis worsening OS (HR 2.045; P = .028) but not CSS (P = .056).

Study details: Findings are from a retrospective study including 207 male patients with BC and bone metastases.

Disclosures: This study did not report any source of funding. The authors declared no conflict of interests.

Source: Zhou X et al. Survival analysis in male breast cancer with bone metastasis based on the SEER database. Front Oncol. 2022;12:659812 (Apr 13). Doi: 10.3389/fonc.2022.659812 

Key clinical point: Age, tumor subtype, surgery, and brain metastasis are independent risk factors for survival in male patients with breast cancer (BC) and bone metastases and should be considered when devising a treatment strategy.

Major finding: Overall survival (OS) and cancer-specific survival (CSS) were significantly lower in patients aged >60 years (hazard ratio [HR] 1.671; P = .014 and HR 1.806; P = .009, respectively), with triple-negative BC (HR 3.029; P = .003 and HR 3.025; P = .004, respectively), and without surgery (HR 1.764; P = .012 and HR 1.734; P = .023, respectively), and with brain metastasis worsening OS (HR 2.045; P = .028) but not CSS (P = .056).

Study details: Findings are from a retrospective study including 207 male patients with BC and bone metastases.

Disclosures: This study did not report any source of funding. The authors declared no conflict of interests.

Source: Zhou X et al. Survival analysis in male breast cancer with bone metastasis based on the SEER database. Front Oncol. 2022;12:659812 (Apr 13). Doi: 10.3389/fonc.2022.659812 

Key clinical point: Age, tumor subtype, surgery, and brain metastasis are independent risk factors for survival in male patients with breast cancer (BC) and bone metastases and should be considered when devising a treatment strategy.

Major finding: Overall survival (OS) and cancer-specific survival (CSS) were significantly lower in patients aged >60 years (hazard ratio [HR] 1.671; P = .014 and HR 1.806; P = .009, respectively), with triple-negative BC (HR 3.029; P = .003 and HR 3.025; P = .004, respectively), and without surgery (HR 1.764; P = .012 and HR 1.734; P = .023, respectively), and with brain metastasis worsening OS (HR 2.045; P = .028) but not CSS (P = .056).

Study details: Findings are from a retrospective study including 207 male patients with BC and bone metastases.

Disclosures: This study did not report any source of funding. The authors declared no conflict of interests.

Source: Zhou X et al. Survival analysis in male breast cancer with bone metastasis based on the SEER database. Front Oncol. 2022;12:659812 (Apr 13). Doi: 10.3389/fonc.2022.659812 

Key clinical point: A breast cancer (BC) diagnosis within 5 years of childbirth (postpartum BC [PPBC]) was associated with worse prognosis than no childbirth prior to diagnosis (nulliparous BC), with the association being strongest in young women diagnosed at the age of <35 years and in those with stage I disease.

Major finding: Women diagnosed with nulliparous BC vs. PPBC at age of <45 years had better overall survival (hazard ratio [HR] 0.61; 95% CI 0.42-0.87), with the difference being more pronounced in women with stage I tumors (HR 0.30; 95% CI 0.11-0.79) and in women diagnosed at the age of ≤35 years (HR 0.44; 95% CI 0.23-0.84).

Study details: The study evaluated a pooled dataset of 2519 women diagnosed with BC at the age of ≥18 years.

Disclosures: This study was funded by grants from the University of Colorado Cancer Center, National Institutes of Health, and other sources. The authors declared no conflict of interests.

Source: Shagisultanova E et al. Overall survival is the lowest among young women with postpartum breast cancer. Eur J Cancer. 2022;168:119-127 (May 4). Doi: 10.1016/j.ejca.2022.03.014

Key clinical point: A breast cancer (BC) diagnosis within 5 years of childbirth (postpartum BC [PPBC]) was associated with worse prognosis than no childbirth prior to diagnosis (nulliparous BC), with the association being strongest in young women diagnosed at the age of <35 years and in those with stage I disease.

Major finding: Women diagnosed with nulliparous BC vs. PPBC at age of <45 years had better overall survival (hazard ratio [HR] 0.61; 95% CI 0.42-0.87), with the difference being more pronounced in women with stage I tumors (HR 0.30; 95% CI 0.11-0.79) and in women diagnosed at the age of ≤35 years (HR 0.44; 95% CI 0.23-0.84).

Study details: The study evaluated a pooled dataset of 2519 women diagnosed with BC at the age of ≥18 years.

Disclosures: This study was funded by grants from the University of Colorado Cancer Center, National Institutes of Health, and other sources. The authors declared no conflict of interests.

Source: Shagisultanova E et al. Overall survival is the lowest among young women with postpartum breast cancer. Eur J Cancer. 2022;168:119-127 (May 4). Doi: 10.1016/j.ejca.2022.03.014

Key clinical point: A breast cancer (BC) diagnosis within 5 years of childbirth (postpartum BC [PPBC]) was associated with worse prognosis than no childbirth prior to diagnosis (nulliparous BC), with the association being strongest in young women diagnosed at the age of <35 years and in those with stage I disease.

Major finding: Women diagnosed with nulliparous BC vs. PPBC at age of <45 years had better overall survival (hazard ratio [HR] 0.61; 95% CI 0.42-0.87), with the difference being more pronounced in women with stage I tumors (HR 0.30; 95% CI 0.11-0.79) and in women diagnosed at the age of ≤35 years (HR 0.44; 95% CI 0.23-0.84).

Study details: The study evaluated a pooled dataset of 2519 women diagnosed with BC at the age of ≥18 years.

Disclosures: This study was funded by grants from the University of Colorado Cancer Center, National Institutes of Health, and other sources. The authors declared no conflict of interests.

Source: Shagisultanova E et al. Overall survival is the lowest among young women with postpartum breast cancer. Eur J Cancer. 2022;168:119-127 (May 4). Doi: 10.1016/j.ejca.2022.03.014

Key clinical point: The overall incidence of synchronous bilateral breast cancer (BBC) and metachronous BBC (MBBC) in patients with a history of lobular carcinoma in situ (LCIS) was 2%, with the risk for MBBC being even lower in women with hormone receptor-positive BC and those receiving endocrine therapy (ET).

Major finding: The estimated 5-year risk of developing MBBC was 6.4% (95% CI 1.9%-10.7%) among women with a remaining contralateral breast at risk, with the risk being lower among those with estrogen (hazard ratio [HR] 0.13; P = .015) or progesterone (HR 0.24; P = .047) receptor-positive BC and those who received ET (HR 0.17; P = .005).

Study details: This study included 1651 women with a history of LCIS, of which 249 women developed unilateral or bilateral BC during a median follow-up of 7 years.

Disclosures: This study was partly supported by the US National Institutes of Health/National Cancer Institute Cancer Center. TA King declared receiving speakers' honoraria and serving on advisory boards for several sources. The other authors declared no conflicts of interest.

Source: Mallory MA et al. Synchronous and metachronous bilateral breast cancer among women with a history of lobular carcinoma in situ. Breast Cancer Res Treat. 2022 (Apr 29). Doi: 10.1007/s10549-022-06532-4 

Key clinical point: The overall incidence of synchronous bilateral breast cancer (BBC) and metachronous BBC (MBBC) in patients with a history of lobular carcinoma in situ (LCIS) was 2%, with the risk for MBBC being even lower in women with hormone receptor-positive BC and those receiving endocrine therapy (ET).

Major finding: The estimated 5-year risk of developing MBBC was 6.4% (95% CI 1.9%-10.7%) among women with a remaining contralateral breast at risk, with the risk being lower among those with estrogen (hazard ratio [HR] 0.13; P = .015) or progesterone (HR 0.24; P = .047) receptor-positive BC and those who received ET (HR 0.17; P = .005).

Study details: This study included 1651 women with a history of LCIS, of which 249 women developed unilateral or bilateral BC during a median follow-up of 7 years.

Disclosures: This study was partly supported by the US National Institutes of Health/National Cancer Institute Cancer Center. TA King declared receiving speakers' honoraria and serving on advisory boards for several sources. The other authors declared no conflicts of interest.

Source: Mallory MA et al. Synchronous and metachronous bilateral breast cancer among women with a history of lobular carcinoma in situ. Breast Cancer Res Treat. 2022 (Apr 29). Doi: 10.1007/s10549-022-06532-4 

Key clinical point: The overall incidence of synchronous bilateral breast cancer (BBC) and metachronous BBC (MBBC) in patients with a history of lobular carcinoma in situ (LCIS) was 2%, with the risk for MBBC being even lower in women with hormone receptor-positive BC and those receiving endocrine therapy (ET).

Major finding: The estimated 5-year risk of developing MBBC was 6.4% (95% CI 1.9%-10.7%) among women with a remaining contralateral breast at risk, with the risk being lower among those with estrogen (hazard ratio [HR] 0.13; P = .015) or progesterone (HR 0.24; P = .047) receptor-positive BC and those who received ET (HR 0.17; P = .005).

Study details: This study included 1651 women with a history of LCIS, of which 249 women developed unilateral or bilateral BC during a median follow-up of 7 years.

Disclosures: This study was partly supported by the US National Institutes of Health/National Cancer Institute Cancer Center. TA King declared receiving speakers' honoraria and serving on advisory boards for several sources. The other authors declared no conflicts of interest.

Source: Mallory MA et al. Synchronous and metachronous bilateral breast cancer among women with a history of lobular carcinoma in situ. Breast Cancer Res Treat. 2022 (Apr 29). Doi: 10.1007/s10549-022-06532-4 

Key clinical point: The combination of ibandronate and endocrine therapy (ET) failed to improve disease-free survival (DFS) compared with ET alone in postmenopausal women with estrogen receptor-positive (ER+) early breast cancer (BC).

Major finding: During a median follow-up of 8.5 years, DFS was not significantly different between the ibandronate+ET and ET treatment arms (hazard ratio [HR] 0.97; log-rank P = .811). Overall, the incidence of adverse events, particularly osteonecrosis (P = .002) and dyspepsia (P < .001), was higher in the ibandronate+ET vs. ET treatment arm.

Study details: This phase 3, TEAM-IIB trial included 1116 postmenopausal women with invasive stage I-III ER+ BC who were randomly assigned to receive ET for 5 years with or without 50 mg adjuvant oral ibandronate once daily for 3 years.

Disclosures: This study was supported by grants from Roche Nederland B.V. and Pfizer Nederland B.V. Some authors declared serving as consultants, advisors, or receiving research funding, honoraria, travel support, or accommodation expenses from several sources, including Roche and Pfizer.

Source: Vliek SB, Noordhoek I, et al. Daily oral ibandronate with adjuvant endocrine therapy in postmenopausal women with estrogen receptor–positive breast cancer (BOOG 2006-04): Randomized phase III TEAM-IIB trial. J Clin Oncol. 2022 Apr 20. doi: 10.1200/JCO.21.00311.

Key clinical point: The combination of ibandronate and endocrine therapy (ET) failed to improve disease-free survival (DFS) compared with ET alone in postmenopausal women with estrogen receptor-positive (ER+) early breast cancer (BC).

Major finding: During a median follow-up of 8.5 years, DFS was not significantly different between the ibandronate+ET and ET treatment arms (hazard ratio [HR] 0.97; log-rank P = .811). Overall, the incidence of adverse events, particularly osteonecrosis (P = .002) and dyspepsia (P < .001), was higher in the ibandronate+ET vs. ET treatment arm.

Study details: This phase 3, TEAM-IIB trial included 1116 postmenopausal women with invasive stage I-III ER+ BC who were randomly assigned to receive ET for 5 years with or without 50 mg adjuvant oral ibandronate once daily for 3 years.

Disclosures: This study was supported by grants from Roche Nederland B.V. and Pfizer Nederland B.V. Some authors declared serving as consultants, advisors, or receiving research funding, honoraria, travel support, or accommodation expenses from several sources, including Roche and Pfizer.

Source: Vliek SB, Noordhoek I, et al. Daily oral ibandronate with adjuvant endocrine therapy in postmenopausal women with estrogen receptor–positive breast cancer (BOOG 2006-04): Randomized phase III TEAM-IIB trial. J Clin Oncol. 2022 Apr 20. doi: 10.1200/JCO.21.00311.

Key clinical point: The combination of ibandronate and endocrine therapy (ET) failed to improve disease-free survival (DFS) compared with ET alone in postmenopausal women with estrogen receptor-positive (ER+) early breast cancer (BC).

Major finding: During a median follow-up of 8.5 years, DFS was not significantly different between the ibandronate+ET and ET treatment arms (hazard ratio [HR] 0.97; log-rank P = .811). Overall, the incidence of adverse events, particularly osteonecrosis (P = .002) and dyspepsia (P < .001), was higher in the ibandronate+ET vs. ET treatment arm.

Study details: This phase 3, TEAM-IIB trial included 1116 postmenopausal women with invasive stage I-III ER+ BC who were randomly assigned to receive ET for 5 years with or without 50 mg adjuvant oral ibandronate once daily for 3 years.

Disclosures: This study was supported by grants from Roche Nederland B.V. and Pfizer Nederland B.V. Some authors declared serving as consultants, advisors, or receiving research funding, honoraria, travel support, or accommodation expenses from several sources, including Roche and Pfizer.

Source: Vliek SB, Noordhoek I, et al. Daily oral ibandronate with adjuvant endocrine therapy in postmenopausal women with estrogen receptor–positive breast cancer (BOOG 2006-04): Randomized phase III TEAM-IIB trial. J Clin Oncol. 2022 Apr 20. doi: 10.1200/JCO.21.00311.