Better understanding of disease biology triggers ‘revolution’ in male breast cancer

Breast cancer is the most common malignancy in the United States.

It also is the most highly funded, accounting for nearly one-sixth of NCI’s annual research budget.

The financial investment has yielded tremendous insights into breast cancer biology, the importance of tailoring treatment based on patients’ genetic make-up, and the potential value of screening.

However, experts contend one key aspect — the nature of the disease in men — remains woefully understudied.

“Male breast cancer is poorly understood, primarily because of the rarity of the disease,” Xiaoxian (Bill) Li, MD, PhD, assistant professor in the department of pathology and laboratory medicine at Emory University School of Medicine, told HemOnc Today. “We are unable to conduct large prospective clinical trials in men because of the small number of patients.”

Photo by Donna M. Martin, director, pathology resources & development, department of pathology and laboratory medicine, Emory University

As with many other orphan diseases, research funding for male breast cancer is minimal. The lack of knowledge is compounded by the fact that an estimated two-thirds of breast cancer clinical trials exclude men.

“Most information on breast cancer in men has been collected from retrospective studies spanning several decades, and treatment recommendations have been extrapolated from results of trials in female patients,” Sharon H. Giordano, MD, MPH, chair of the department of health services research at The University of Texas MD Anderson Cancer Center, wrote in a review article published in The Oncologist. “[Although] breast cancer in men is similar to female breast cancer, there are distinct features that should be appreciated.”

HemOnc Today spoke with oncologists and investigators about the challenges associated with studying and treating male breast cancer, the insights recent studies have provided into disease biology, the need for expanded trial access and the potential that additional research could lead to tailored treatments for men.

Incidence, risk factors

Nearly 250,000 Americans will be diagnosed with invasive breast cancer this year, according to NCI estimates. Only 2,600 of them — approximately 1% — will be men.

Median age at diagnosis for men is 68 years, compared with 61 years for women.

“The most common age group is between 60 and 70 years,” Richard L. White, MD, FACS, chief of the division of surgical oncology and co-director of the breast and melanoma programs at Levine Cancer Institute at Carolinas HealthCare System, told HemOnc Today. “I am not sure that we know the answer as to why this appears to be a disease that occurs in older males.”

A population-based study by Giordano and colleagues showed male breast cancer cases in the United States increased by 25% between 1973 and 1998. During that time, incidence rose from 0.86 cases to 1.08 cases per 100,000 people (P < .001).

Researchers determined men had an older median age at diagnosis than women. Men also were more likely to have lymph node involvement and advanced disease stage at diagnosis (P < .001 for all). Multivariate analysis showed lymph node involvement and larger tumor size were associated with shortened survival.

Research into potential causes of breast cancer in men has been limited.

Risk factors include obesity, older age, prior radiation to the chest and presence of a BRCA2 mutation. The risk for breast cancer in a man with a BRCA2 mutation is about 7% to 8%, whereas woman have roughly a 50% risk, White said. The average man has a 0.1% risk, or one in 1,000.

“Many of the risk factors are similar in men and women,” Andrew D. Seidman, MD, medical oncologist at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, said in an interview. “One common thread is high estrogen levels or high estrogen exposure during one’s lifetime. For men, obesity is one condition that affects estrogen levels.”

Matthew P. Humphries, PhD, postdoctoral research fellow at Leeds Institute for Cancer and Pathology at University of Leeds and St. James University Hospital in England, and colleagues examined the potential association between the global increase in obesity and increased incidence of breast cancer in men.

The investigators searched PubMed for studies and abstracts from 2014 about male breast cancer. They identified 68 relevant publications.

Their evidence review revealed increases in male breast cancer and obesity “are inextricably linked.” They suggested men at elevated risk for breast cancer, such as those with BRCA2 mutations or Klinefelter syndrome — a chromosomal condition that causes men to have lower levels of androgens and higher levels of estrogen — should be made aware of the association so they can take pre-emptive risk-reducing measures.

Brinton and colleagues conducted one of the largest studies to date on male breast cancer, reviewing data from 21 studies that included 2,400 men with the disease and 52,000 men without it.

The results, published in 2014 in Journal of the National Cancer Institute, showed significant associations between breast cancer risk and weight (OR for highest vs. lowest tertile = 1.36; 95% CI, 1.18-1.57), BMI (OR = 1.3; 95% CI, 1.12-1.51) and height (OR = 1.18; 95% CI, 1.01-1.38).

Klinefelter syndrome (OR = 24.7; 95% CI, 8.94-68.4) and gynecomastia (OR = 9.78; 95% CI, 7.52-12.7) — swelling of the breast tissue caused by an imbalance of testosterone and estrogen — were significantly associated with breast cancer risk independent of BMI.

“Significant obesity causes the fat cells in the body to create estrogen in men, and morbidly obese men develop breast tissue or gynecomastia,” White said. “It will be interesting to see what happens with male breast cancer rates as obesity rates increase in the United States.”

O’Malley and colleagues — who analyzed data from 1,759 men in California diagnosed with breast cancer between 1988 and 2000 — determined race may contribute to risk.

Researchers calculated higher age-adjusted incidence among black men (1.65 per 100,000 men) and white men (1.31) than Hispanics (0.68) and Asians/Pacific Islanders (0.66). Blacks also appeared more likely to be diagnosed at a younger age (P = .001) and a more advanced disease stage (P = .001) than whites or Asians/Pacific Islanders.

Lack of awareness

Historical data suggest nearly one-third of men with breast cancer present with stage III or stage IV disease, whereas only 10% to 15% of women present with late-stage disease.

Limited awareness among men that they are at risk for breast cancer is the primary theory for this disparity, as it may lead to delayed diagnosis.

“A lot of my male patients tell me they did not know they could get breast cancer,” Giordano said. “It honestly did not even cross their conscience that they could be susceptible. Because there is no indication for mammography in men, any tumor detected is clinically apparent. This automatically shifts men to more advanced disease.”

Eileen Thomas, PhD, RN, assistant professor at University of Colorado Denver, assessed awareness of male breast cancer among 28 English-speaking men. The men had no personal breast cancer history, but they all had at least one maternal blood relative with the disease.

Approximately 80% of study participants said they were unaware men could develop breast cancer. Also, even though the men were at higher risk because of their family histories, all of them indicated their health care providers had never talked with them about the disease.

“This study provides much-needed insight into men’s awareness and knowledge of male breast cancer,” Thomas wrote. “While further research with larger samples is needed, these findings offer a starting point for the development of evidence-based, gender-specific health promotion and disease prevention interventions for men.”

Absence of screening guidelines for men — even those with family history or other risk factors — and little public education about the potential benefits of self-exams or clinician exams in asymptomatic men also may contribute to differences in presenting characteristics among men.

Even when symptoms arise, most men may not consider breast cancer as a possible cause, Seidman said. Most men who feel a lump or notice nipple inversion — two common symptoms of breast cancer — speculate they banged into something or simply developed a fatty nodule, he said.

‘Equal opportunity’

Only about one-twentieth of breast cancer funding goes toward research in men, according to an analysis of clinicaltrials.gov performed by Oliver Bogler, PhD, senior vice president of academic affairs and professor in the department of neurosurgery at The University of Texas MD Anderson Cancer Center.

The lack of knowledge is compounded by the fact that only about one-third of breast cancer clinical trials are open to men, Bogler — diagnosed with stage III breast cancer in 2012 — determined via an analysis of clinicaltrials.gov.

“I ask colleagues in the medical community to carefully consider whether men should be included and, if not, perhaps they should justify this from an ethical point of view just as they would justify including or excluding any other group,” Bogler told HemOnc Today. “Sometimes men are excluded for good reasons. In other cases, the exclusion criteria do not make sense. Sometimes it seems researchers are simply following the template used in a previous trial. It really is a question of equal opportunity.”

The FDA acknowledged men historically have been excluded from breast cancer trials and has urged pharmaceutical companies to expand eligibility criteria.

“We are actively encouraging drug companies to include men in all breast cancer trials unless there is a valid scientific reason not to,” Tatiana M. Prowell, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and breast cancer scientific lead at the FDA’s Office of Hematology & Oncology Products, said in a post on the FDA’s website. “The number of men in breast cancer trials will still be small because male breast cancer is a rare condition, but any information to help men facing this disease is better than none.”

The awareness campaign could yield benefits given that the traditional exclusion of men from trials “is not necessarily intentional,” said Giordano, the oncologist who treated Bogler.

“Sometimes researchers begin writing eligibility criteria and just simply do not think of men,” Giordano said. “There is no reason why trials should not be open to both men and women other than for trials that are examining hormonal therapy approaches. These are more complicated, because there are different hormonal environments between men and women, and some drugs may work differently between genders.”

Biological differences

Despite the lack of research into male breast cancer, men often experience favorable disease outcomes.

Nearly all individuals diagnosed with stage 0 or stage I breast cancer — regardless of sex — survive at least 5 years. Although men are more likely to present with advanced-stage disease, 5-year survival rates between men and women are comparable among those diagnosed with stage II (91% vs. 93%), stage III (72% vs. 72%) or stage IV (20% vs. 22%) disease.

A decade ago, researchers established that men were more likely than women to have ER– or PR–positive breast cancers.

Other key biological differences in the disease exist based on sex, according to study results presented in March at the European Breast Cancer Conference.

Carolien van Deurzen, MD, a pathologist at Erasmus Medical Centre in the Netherlands, and colleagues evaluated 1,203 breast cancer tumor samples from men.

Median follow-up for OS was 7 years. Researchers classified 85% of carcinomas as ductal carcinomas, half of which were grade 2.

Results showed histologic grade — significantly associated with outcomes in women — did not affect OS among men (HR for grade 2 vs. grade 1 = 1.27; 95% CI, 0.95-1.7; HR for grade 3 vs. grade 1 = 1.39; 95% CI, 1-1.93). This finding persisted in a subgroup analysis stratified by disease stage, as well as chemotherapy and endocrine therapy administration.

However, van Deurzen and colleagues observed a significant association among men between mitotic activity index and OS (HR for one-unit increase = 1.02; 95% CI, 1.01-1.03). Also, men with a fibrotic focus (HR = 1.39; 95% CI, 1.11-1.74) and lower density of tumor-infiltrating lymphocytes (HR for moderate vs. minimal = 0.71; 95% CI, 0.49-1.03; HR for mild vs. minimal = 0.68; 95% CI, 0.53-0.87) had increased mortality risk.

Researchers also determined a high percentage of male breast cancers were luminal — or ER–positive — whereas triple-negative and HER-2–positive subtypes occurred less frequently among men than women.

“This subtyping of breast tumors does not seem to result in an optimal risk classification for [men],” van Deurzen said. “Additional tests that are well established in women, including gene-expression profiling, may result in identification of more accurate prognostic and predictive markers.

“These could enable us to make better treatment choices, individualized for each patient, particularly in regard to the use of chemotherapy and new targeted agents,” she added. “In the meantime, we believe that our findings will help focus research in the field, since they indicate that we should be focusing on improving the management of luminal cancers as opposed to other subtypes in these patients.”

International collaboration

The study van Deurzen and colleagues conducted was part of the International Male Breast Cancer Program, a collaborative effort between the Translational Breast Cancer Research Consortium and the EORTC.

The initiative — which includes sites in North America, South America and Europe, as well as Egypt — consists of three components intended to better characterize male breast cancer and ultimately improve the quality of treatments.

Investigators began by collecting tissue specimens and clinical data from 1,500 men diagnosed with breast cancer within the past 20 years. Ongoing analyses will help investigators better determine how breast cancer differs between men and women.

The second part of the program included creation of a worldwide prospective registry of men with newly diagnosed breast cancer. More than 300 men are included so far, and researchers will follow them to assess clinical outcomes and quality of life.

“Beyond data collection, a main point of this project was to see how many patients are coming through this network and to determine if it would be feasible to run a therapeutic clinical trial,” said Giordano, who is leading the U.S. effort. “If we opened a study, would we really be able to recruit patients to it and answer our questions?”

Researchers hope to launch the third component of the program — a clinical trial — within the next year.

“This effort has really pulled together a lot of different cooperative groups across the world,” Giordano said. “In the past, we all published our own experiences at our own institutions, but only 50 or so patients would come through our respective institutions during a 50-year span. Therefore, it has been difficult to generalize the information. To have the power of [data] from many different countries — and to get enough patients that we can actually answer these questions — is really exciting. It will be meaningful.”

‘A new revolution’

Some subtle differences exist between breast cancer treatments administered to men and women.

Men are more likely to undergo mastectomy rather than lumpectomy because men do not have as much breast tissue and their tumors are more centrally located.

The type of hormonal blockade also varies. Tamoxifen is a standard for men, but controversy exists about whether men derive benefit from aromatase inhibitors.

Otherwise, men and women tend to be treated the same.

The experts calling for expanded trial access for men, as well as proponents of initiatives like the International Male Breast Cancer Program, hope these efforts help pave the way for something that, so far, has proved unattainable: tailored treatments for men with breast cancer.

“Unfortunately, due to the lack of specific data in men with breast cancer, most treatment options are extrapolated from data on the management of female breast cancer,” Jose P. Leone, MD, clinical assistant professor of internal medicine at University of Iowa Carver College of Medicine, told HemOnc Today. “Traditional treatments like surgery, hormonal therapies, and radiation and chemotherapy are mainly used in men as they have been in women. Hopefully this will change in the near future.”

Leone and colleagues conducted a population-based study to analyze patient characteristics and prognostic factors in 2,992 male breast cancers diagnosed between 2003 and 2012.

Results, published earlier this year in Breast Cancer Research and Treatment, showed the majority of men had ER–positive (95.1%), PR–positive (86%) and ductal (85%) breast cancer. Only 12.4% had grade 1 tumors, but 73% of men presented with stage I or stage II disease.

“We were surprised by the finding that overall, most male breast cancers were diagnosed early. This is different from what previous data suggest,” Leone said. “We were also very surprised that grade 1 disease was uncommon. Many physicians believe male breast cancer is similar to postmenopausal female breast cancer, but most female patients have a higher rate of grade 1 disease, which leads us to believe that the disease may be more different between men and women than we think.”

In another study — presented this year at the ASCO Annual Meeting — Leone and colleagues used the SEER database to evaluate locoregional treatments for 1,263 men with lower-risk (T1a,b,cN0M0) breast cancer. They found breast-conserving surgery and mastectomy yielded comparable survival, as did having one to five lymph nodes examined compared with more than five.

“These results represent a strong argument in favor of decreasing the high rates of mastectomy and extensive lymph nodes resection that are commonly used in men, in light of the similar survival observed with the more conservative techniques,” Leone said.

Piscuoglio and colleagues conducted a multicenter study to assess whether male breast cancers harbored somatic genetic alterations in genes frequently altered in female breast cancers.

The analysis included 59 men; all had ER–positive disease, and all but two had HER-2–negative tumors.

The researchers performed massively parallel sequencing that targeted all exons of 241 genes. They compared somatic mutations and copy number alterations identified in samples from men with those of subtype-matched female breast cancers.

Piscuoglio and colleagues determined ER–positive, HER-2–negative breast cancers in men were less likely than the same subtype in women to harbor 16q losses, PIK3CA mutations and TP53 mutations. Male breast cancers also were significantly enriched for mutations in genes such as PALB2 and FANCM, both of which are involved with DNA damage repair.

Li and colleagues used the SEER database to identify 172,847 breast cancer cases among women and 1,442 cases among men from 2010 to 2012 to assess prognosis and clinic-pathological features. They identified a higher percentage of hormone receptor-positive, HER-2–negative cancers among men (78.3% vs. 67.4%), and a higher percentage of hormone receptor-negative, HER-2–negative cancers among women (10.9% vs. 2.1%).

Men were more likely than women to be diagnosed with stage III or IV disease (24.9% vs 17.2%). After adjustments for age, ethnicity and tumor grade, men with stage I (P = .0011) or stage II (P = .00229) disease had significantly shorter OS than women with stage-matched breast cancer.

“We were very surprised and excited by our findings,” Li told HemOnc Today. “We thought male breast cancer behaved the same way as female breast cancer. In fact, the NCI website states, ‘survival for men with breast cancer is similar to survival for women with breast cancer.’ As per our study, it appears male breast cancer is more aggressive than female disease, especially in men with hormone receptor-positive disease. Male patients with even T1aN0 hormone receptor-positive/HER-2–negative breast cancer may have worse prognosis than females.”

Although additional studies are needed to better establish the biological differences between breast cancer in men and women, the investigations already completed may lay the groundwork for dramatic changes in the treatment landscape, Seidman said.

“These findings could lead us in the direction of more tailored, rational therapies for men,” Seidman said. “This represents a new revolution in how we are now thinking about male breast cancer.” – by Jennifer Southall

To read more on this issue, click here.

References:

Brinton LA, et al. J Natl Cancer Inst. 2014;doi:10.1093/jnci/djt465.

FDA. Breast cancer — Men get it, too. Available at www.fda.gov/ForConsumers/ConsumerUpdates/ucm402937.htm. Accessed on May 24, 2016.

Fentiman IS. Crit Rev Oncol Hematol. 2016;doi:10.1016/j.critrevonc.2016.02.017.

Giordano SH, et al. Cancer. 2004;101:51-57.

Giordano SH, et al. Oncologist. 2005;10:471-479.

Humphries MP, et al. BMC Med. 2015;doi:10.1186/s12916-015-0380-x.

Leone JP, et al. Abstract 1056. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Leone JP, et al. Breast Cancer Res Treat. 2016;doi:10.1007/s10549-016-3768-1.

Li X, et al. Abstract 209. Presented at: United States and Canadian Academy of Pathology Annual Meeting; March 12-18, 2016; Seattle.

Lubischer A. Funding the cancer war. 2014. Available at: chicagohealthonline.com/funding-the-cancer-war. Accessed on May 23, 2016.

NCI. Common cancer types. Available at: www.cancer.gov/types/common-cancers. Accessed on May 23, 2016.

O’Malley C, et al. Breast Cancer Res Treat. 2005;93:145-150.

Piscuoglio S, et al. Clin Cancer Res. 2016;10.1158/1078-0432.CCR-15-2840.

Thomas E. Am J Nurs. 2010;doi:10.1097/01.NAJ.0000389672.93605.2f.

For more information:

Sharon H. Giordano, MD, MPH, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030; email: sgiordan@mdanderson.org.

Jose P. Leone, MD, can be reached at The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242; email: jose-leone@uiowa.edu.

Xiaoxian (Bill) Li, MD, PhD, can be reached at Emory University Hospital, 1364 Clifton Road, Atlanta, GA 30322; email: bill.li@emory.edu.

Andrew D. Seidman, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: seidmana@mskcc.org.

Richard L. White, MD, FACS, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: richard.white@carolinashealthcare.org.

Disclosure: Giordano, Leone, Li, Seidman and White report no relevant financial disclosures.

 

 

Should breast-conserving surgery be offered to men with breast cancer?

Yes, breast-conserving therapy can be offered to appropriately selected patients.

Approximately 2,000 men are diagnosed with breast cancer every year. This accounts for 1% of all breast cancer, with a peak incidence at age 71 years.

Men with breast cancer tend to present with a more advanced stage due to poor awareness of the disease and, therefore, a delay in diagnosis.

Additionally, men tend to have small breast size, and the majority of male breast cancer is located directly behind the nipple areolar complex where the ductal tissue is located. This makes the ability for breast conservation challenging and, conventionally, a contraindication to lumpectomy.

Therefore, traditionally, men with breast cancer would undergo mastectomy.

However, in recent years, research has shown that — just like women — survivorship issues and body self-image are important to men. Studies designed to evaluate men with breast cancer have suggested that they should be offered the same surgical treatment options as women (mastectomy vs. lumpectomy and radiation).

In some cases, such as with a small-sized cancer in a favorable anatomical location — where the nipple is not involved — a man may be able to save his breast, and breast conservation should be offered.

A SEER analysis evaluated the surgical treatment of men with breast cancer and showed that the majority of men did undergo mastectomy. Yet, 15% of men had lumpectomy, and researchers reported no statistically significant difference in OS between the surgical groups.

Just as in women with breast cancer, breast conservation with lumpectomy and radiation can be offered safely to an appropriately selected male patient with early-stage breast cancer.

 

References:

Cloyd JM, et al. Ann Surg Oncol. 2013;doi:10.1245/s10434-013-2918-5.

Giordano SH. Ann Surg Oncol. 2013;doi:10.1245/s10434-013-3003-9.

Golshan M, et al. Breast. 2007;16:653-656.

Kamila C, et al. Breast. 2008;17:319.

Stephanie A. Valente, DO, FACS, is a breast surgeon in the department of breast services at Cleveland Clinic. She can be reached at valents3@ccf.org. Disclosure: Valente reports no relevant financial disclosures.

Breast-conserving surgery should not be recommended to men with early-stage breast cancer simply because we can perform these operations.

Breast-conserving surgery (BCS) — also known as lumpectomy, partial mastectomy or segmental mastectomy — removes only part of the breast with cancer. Total mastectomy removes the entire breast.

BCS is the standard operation for small, early-stage breast cancer for women. Given the advances in systemic therapies, there is now a large body of evidence that indicates wide margins are not necessary when removing invasive breast cancer.

Indeed, it has been well proven that survival outcomes are no different between BCS and total mastectomy. In other words, BCS does not have significant survival benefit over total mastectomy. Preservation of the breast tissue and shape are the major advantage of BCS.

Because breast cancer is far less common in men than women, there is no solid evidence on the benefit of BCS in males. On the other hand, the number of BCS procedures for male breast cancer appears to be on the rise, based on a comparison of the percentages of BCS cases in a large case series that spanned different time frames.

A review of 489 male breast cancers operated between 1990 and 2005 in France revealed that only 42 (8.6%) patients underwent BCS.

On the other hand, 17% of 1,777 men with early-stage breast cancer registered in the SEER database underwent breast-conserving therapy from 1998 to 2011. In the North American Association of Central Cancer Registries, 1,254 of 6,332 (19.8%) men with early-stage breast cancer underwent BCS from 2004 to 2011.

Equivocally, these studies report that BCS offers comparable survival compared with total mastectomy. In other words, BCS is feasible for male breast cancer. With that said, what benefit does BCS provide to male patients? Male breast cancers are commonly located centrally, so total mastectomy is indicated. With breast tissue remaining after BCS, the patient needs to undergo adjuvant radiation, which takes time and resources. Adjuvant therapies are not free from complications. With the minimal volume of the breast, follow-up mammograms will be more painful for men than women with larger breasts.

Again, the benefit of BCS for women is to preserve breast tissue and shape, and there is no survival benefit compared with total mastectomy.

How many of our male patients with breast cancer prefer to preserve their breasts? I agree that breast-conserving therapy is feasible; however, is not recommended for male breast cancer unless the patient has the specific desire for it. We have reviewed the male breast cancer cases in our own institution from 1990 to 2015, and we found that only two (2.5%) of the 78 patients for whom records were available underwent BCS.

 

References:

Bouganim N, et al. Breast Cancer Res Treat. 2013;doi:10.1007/s10549-013-2561-7.

Cutuli B, et al. Crit Rev Oncol Hematol. 2010;doi:10.1016/j.critrevonc.2009.04.002.

Jemal A, et al. JAMA Surg. 2015;doi:10.1001/jamasurg.2015.2657.

Sousa B, et al. Eur J Pharmacol. 2013;doi:10.1016/j.ejphar.2013.03.037.

Zaenger D, et al. Clin Breast Cancer. 2016;doi:10.1016/j.clbc.2015.11.005.

Kazuaki Takabe, MD, PhD, FACS, is Alfiero Foundation chair and professor of breast oncology and surgery at Roswell Park Cancer Institute. He can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263. Disclosure: Takabe reports no relevant financial disclosures.