Modernizing the Diagnosis of Male Breast Cancer

“I have a woman’s cancer.”

Unfortunately, this is a silent statement often internalized by men with breast cancer. Although the majority of the patient population is made up of women, males represent 1 in 100 cases diagnosed in the United States each year.¹ 

“Men have described the diagnosis as ‘feminizing.’ Men have decided, ‘I don't want to tell my boss about this.’ It's a shame,” said Patrick I. Borgen, MD, chair and surgery director of the Breast Cancer Program at Maimonides Medical Center. “When you come to our breast center, the gowns are a pinkish, peach color, and [are] very cozy and comfortable. Some men have sort of objected to the fact that it is really an environment that's designed for females, which is all true and unfortunate, but there have been some very, very alpha males who have gotten breast cancer and they've done very well. We have to continue the dialogue [of male breast cancer].”

Male breast cancer, Borgen said, is not a fundamentally more aggressive disease than what is seen in women; however, “it's a different disease in some ways. There are no lobules in the breast, but when you look at [factors] like amplification of the HER2 gene, it really is as frequently [observed] in men as it is in women.”

Sara A. Hurvitz, MD, director of the Breast Cancer Clinical Research Program and co-director of the Santa Monica University of California, Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, as well as an assistant professor of medicine in the Division of Hematology/Oncology of the David Geffen School of Medicine at UCLA, explained that a male breast cancer diagnosis tends to be presented at a later stage and higher grade compared with that in females. 

“This may be owing, in part, to the fact that we don't typically screen men with mammograms and men aren't attuned to look for problems in their chest and breast area,” Hurvitz said. 

Studies have looked at how prognosis varies between men and women with breast cancer. In a German retrospective analysis, investigators evaluated 108 patients with metastatic breast cancer with matched pairs of male and female for survival analyses. Results showed that the disease-free survival (DFS) at 5 years was 53.4% in the male cohort (95% CI, 54.1-66.3) and 62.6% (95% CI, 63.5-75.3) in the female cohort (P >.05).² The 5-year overall survival (OS) rates for men and women were 71.4% (95% CI, 62.1%-72.7%) in men and 70.3% (95% CI, 32.6%-49.6%) in women (P >.05).

The sole prognostic relevant factor was reported as progesterone receptor (PR) expression (P = .006). Correlative factors for poor outcomes in a multivariate analysis for OS was advanced tumor size (P = .01) and lack of PR expression (P = .01).

Similarly, in a matched analysis of which Borgen was the lead author, investigators compared 58 men with breast cancer treated between 1973 and 1989 vs 174 women who received treatment between 1976 and 1978 and were matched by disease stage and age at diagnosis. All patients underwent mastectomy and axillary dissection. Tumor histology differed significantly by gender (P <.05), and more men had estrogen receptor (ER)–positive disease (87%) vs women (55%; P <.001). At 10 years, the survival outcomes were similar among both genders through the multivariate analysis.³ 

“However, there's a caveat, and the caveat is that there's often a delay in diagnosis with male breast cancer. Again, sometimes the patient or their doctor just doesn't consider male breast cancer in the differential,” said Borgen. “There is also a relatively smaller envelope of tissue when we compare the male breast to the female breast. The incidence of nipple involvement or the incidence of muscle involvement is actually higher in men than in women. If we control for those factors, it's really very similar to female breast cancer.”

Symptoms, however, do vary.

“There are 2 things that are a warning sign for male breast cancer. The number one is: bloody nipple discharge in the absence of trauma; spontaneously having blood emanating from the male nipple is actually breast cancer about 90% of the time,” said Borgen. 

The second signal is a painless mass directly below the nipple, Borgen added.

Treatment Approaches: How Do They Differ Between Men and Women?

Localized treatments vary between men and women. Because the tumor is usually formed below the nipple, breast conservation is not a necessary approach for males. Local treatment often consists of mastectomy followed by either a sentinel node dissection or axillary dissection. Neoadjuvant treatment—comprising chemotherapy, immunotherapy, or hormonal treatment—however, is just as important in both genders. 

Aromatase inhibitors (AIs) have been utilized in this patient population, but their role is a little less clear, experts explained. Javier Cortes, MD, PhD, head of breast cancer program at IOB Institute of Oncology, Madrid and Barcelona, Spain, said that if AIs are given in a man with breast cancer, then gonadal suppression should be added.

“There are going to be some subtleties of male breast cancer,” commented Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief in the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer, and associate director of clinical investigation at University of Pittsburgh. “However, the rule of thumb, right now, is that we treat a [man with breast cancer], at least I do, as if it's a postmenopausal woman [with breast cancer].”

The subtypes of breast cancer in men are similar to that of women, such as invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ.

“Male breast cancers are overwhelmingly positive for the ER, and often for the PR, Borgen explained. “That gives us many weapons to use in fighting male breast cancer.”

One elephant in the room, however, is the lack of prospective clinical trials solely on men with breast cancer. 

“It’s too rare; it’s too uncommon,” said Borgen. “Therefore, we have to extrapolate [what we’ve learned] from trials in female breast cancer to [our male patients]. The good news is, is that it works. Tamoxifen, our ‘workhorse’ selective ER downregulator works just as well in men as it does in women.” 

Pooling information from the smaller male data sets of larger studies can help the breast cancer community learn lessons regarding this population, Borgen added.

Small Steps for Mankind

The explosion of awareness that have been seen in females with breast cancer has led to a deeper understanding of male breast cancer; that includes the BRCA2 mutation, which Borgen said occurs in about 6% of all cases of male breast cancer. 

“The most fascinating discovery in male breast cancer is the role of the BRCA2 gene,” Borgen said. “When we look at a family in whom you’re doing BRCA1/2 testing, the male side of the family—the paternal as well as the maternal side—obviously makes a difference. These are autosomal genes that have nothing to do with sex chromosomes. However, the BRCA2 phenotype is unique because it does increase the risk of male breast cancer.”

The PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna) can be utilized in men with BRCA1/2-positive breast cancer, Hurvitz added. 

Additionally, the androgen receptor has also become a wide area of interest in the management of male breast cancer, according to Brufsky.

Select therapeutics have garnered expanded indications to include men with breast cancer as well. For example, in April 2019, the FDA expanded the approval of palbociclib (Ibrance) capsules in combination with endocrine therapy for male patients with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer.

The approval was based on real-world data from electronic health records, which demonstrated encouraging response rates with the CDK4/6 inhibitor in combination with an AI or fulvestrant (Faslodex) in this patient population. In the study, the safety profile for men who received palbociclib was consistent with the tolerability observed in female patients who were treated with the agent.⁴

“As drugs have been approved, including anthracyclines, alkylating, agents, receptor downregulators, and of course, CDK4/6 inhibitors, these apply to men,” Borgen said.

These advances don’t end with systemic agents. Genomic profiling has also advanced to become inclusive of men, Borgen added.

A retrospective review of 358,497 patients which had 3068 males (0.8%) and 355,429 females (99.1%) with T1/T2, node-negative, HR–positive, HER2-negative breast cancer between 2010 and 2014 from the National Cancer Database. A smaller proportion of male patients (32%) underwent recurrence score testing vs that of females (35%; P <.001). Those male patients with a recurrence score were younger, had T2 tumors, lymphovascular invasion, and private insurance. 

Results showed that 4% of male patients with breast cancer with a low recurrence score underwent adjuvant chemotherapy vs 4.9% of female patients.⁵ Overall, chemotherapy recommendations varied based on recurrence score in male patients and how recurrence score utility impacts clinical outcomes in males with breast cancer remains unknown. 

A case report and literature review published in the American Journal of Men’s Health provided some insight on this unanswered question. Here, investigators utilized the 21-gene assay Oncotype DX on a 53-year-old male with left breast cancer who underwent modified radical mastectomy. Based on the results of the assay, endocrine treatment was chosen. Data showed that the patient remained in good health without evidence of recurrence at 18 months of follow-up.⁶

Borgen provided further insight, regarding a study of men with ER-positive, HER2-negative, node-negative breast cancer who were tested with Oncotype DX.

“When we did a frequency distribution by recurrent score, it matched female breast cancer exactly,” said Borgen. “Therefore, men derive the same benefit from genomic profiling in terms of really precisely getting the treatment right as female patients do.”

Boosting Awareness

Public awareness, which often unfortunately comes from celebrity spotlights on male breast cancer, is one factor that will help create a better dialogue of the patient subtype. 

“Men talking about it openly, as so many brave women have done, is really important,” Borgen said.

This cascades to a deeper understanding of the environmental factors tied to male breast cancer, as well.

“One of the tragic things we've seen here in New York, since [September 11, 2001,] is with the the men who worked on the area where the towers came down,” Borgen said. “We [have since] seen a very much higher rate of male breast cancer in men exposed to the toxins from 9/11. That continues to be true today, many years later.”

Family history of breast cancer is something that men should play particular attention to, Brufsky added.

“Someone estimated that a general surgeon in this country would see 1 case of male breast cancer in his or her career,” Borgen concluded. “Clearly, whatever we can do to continue to talk about this important condition is valuable.”

References

1. Breast cancer in men. Centers for Disease Control and Prevention. Updated August 11, 2020. Accessed March 11, 2021. https://www.cdc.gov/cancer/breast/men/index.htm.
2. Foerster R, Foerster FG, Wulff V, et al. Matched-pair analysis of patients with female and male breast cancer: a comparative analysis. BMC Cancer. 2011;11(335). doi:10.1186/1471-2407-11-335
3. Borgen PI, Senie RT, McKinnon WM, Rosen PP. Carcinoma of the male breast: analysis of prognosis compared with matched female patients. Ann Surg Oncol. 1997;4(5):385-388. doi:10.1007/BF02305550.
4. FDA Expands Approved Use of Metastatic Breast Cancer Treatment to Include Male Patients. FDA. Published April 4, 2019. https://bit.ly/2Ie3UTx. Accessed April 4, 2019.
5. Williams AD, McGreevy CM, Tchou JC, et al. Utility of Oncotype DX in male breast cancer patients and impact on chemotherapy administration: a comparative study with female patients. Ann Surg Oncol. 2020;27(10):3605-3611. doi:10.1245/s10434-020-08473-y
6. Zheng A, Zhang L, Ziyao J, Fan L. Oncotype DX for comprehensive treatment in male breast cancer: a case report and literature review. Amer J Mens Health. 2019;13(3):155798831984785. doi:10.1177/1557988319847856