Panel members agreed that based on current epidemiologic and histopathologic data, male breast cancer seems to resemble postmenopausal hormone receptor–positive disease in women. However, in view of the paucity of data, the rarity of the disease, and different hormonal milieu, male breast cancer should be considered and managed as a distinct entity. Although there seem to be racial and ethnic differences in both incidence and survival of male breast cancer, additional data are needed to confirm these observations. Discussants agreed that given the rarity of male breast cancer, large collaborative efforts are crucial to moving research forward. Two major consortial efforts were discussed, one led from the United States and one from the BIG and the European Organisation for Research and Treatment of Cancer. The National Cancer Institute and NIH Office of Rare Diseases are planning an epidemiologically focused male breast cancer meeting. It will bring together investigators from large cohort studies with banked blood and biomarker data to further examine risk factors for male breast cancer and to look at specific associations between biomarkers such as endogenous hormone levels and breast cancer risk in men.
The second planned research collaboration is an International Male Breast Cancer Program, coordinated by the European Organisation for Research and Treatment of Cancer under the BIG and NABCG networks. This program has three planned parts. The main objective of part 1, or the retrospective part, is to perform a meta-analysis of clinical data and a central pathology review of tumor specimens from patients with male breast cancer diagnosed at participating institutions over the last 20 years. This effort has the potential to overcome many of the difficulties seen in individual studies where biomarker data suffered from lack of harmonization in both definitions and techniques used. Proposed analyses using paraffin-embedded tumor material include quantitative ER and PgR protein levels, HER2 status, Ki67, androgen receptors, cyclin D1, p21, p27, intertumoral aromatase, and survivin. Gene expression profiling studies using frozen tumor material are planned to evaluate the presence and relative incidence of the breast cancer biologic subtypes (basal, luminal, and HER2), the prognostic value of the 70-gene profile, the wound signature, and the stromal signature, among others.
Part 2, or the prospective part, of the program consists of a prospective international registry of all patients with male breast cancer diagnosed at participating institutions for a period of 2 years. The registry would initially use a virtual tumor bank until funding is secured for central analysis of the biologic material collected (paraffin-embedded and frozen tumor samples and blood/serum). Additionally, data on demographics, risk factors, treatment, and outcome will be collected through a remote data capture system.
Data collected from the first two parts of the International Male Breast Cancer Program will enable us to determine the feasibility of a randomized clinical trial that could be launched as part 3 of the program. In view of the failure of previous attempted male breast cancer clinical trials to accrue patients, it is crucial to establish a fully committed global effort to successfully run such a trial.
To date, far more than 19 research groups have expressed interest in participating in the retrospective component of this effort, which would provide approximately 1,700 patients. It is estimated that paraffin blocks can be obtained in 75% to 80% of patients, with frozen material available for 25% to 30%. For the prospective part, more than 16 research groups have confirmed their interest, which should lead to accrual of approximately 100 patients per year.
Funding for such a non–drug-related, purely academic effort is an important hurdle. Thus far, grants have been obtained from the Breast Cancer Research Foundation for the retrospective part and from the European Breast Cancer Conference for the prospective registry. Efforts continue to be made to find the remaining funds needed for this major cooperative academic endeavor for male breast cancer research.
Panel members noted that efforts to understand the biology of male breast cancer, such as those described earlier, are essential to guiding therapy. Most data regarding treatment of male breast cancer is retrospective in nature and comes from small single-institution series; thus, the choice of treatment modalities is generally guided by extrapolation of data from female breast cancer. The established standard of care for male breast cancer is modified radical mastectomy followed by tamoxifen for endocrine-responsive positive disease, although other options are being explored. SLN biopsy seems to be feasible and accurate in men with small tumors and clinically negative axillae. Chemotherapy seems to benefit patients with endocrine-nonresponsive disease, large tumors, and/or node-positive disease.
Patterns of care studies suggest that aromatase inhibitors are being used in the community for treatment of hormone receptor–positive disease despite a lack of solid data supporting their use. Indeed, this is in contradiction to biologic hypotheses that aromatase inhibitors might increase circulating testosterone in men, leading to an increase in androgen available for conversion to estrogen.64
Aside from case reports, there are no clinical studies addressing the efficacy of aromatase inhibitors for male breast cancer. Biologic data suggest that if used in men, aromatase inhibitors should be combined with surgical or medical orchidectomy.64,65
The consensus among panel members was that although it would be reasonable to study aromatase inhibitors in male breast cancer, tamoxifen should remain the standard of care for adjuvant treatment of endocrine-responsive male breast cancer and that use of aromatase inhibitors for male breast cancer should be limited to the clinical trial setting until additional data on aromatase inhibitors in male breast cancer are available. To this end, a small study analyzing the pharmacokinetics and pharmacodynamics of aromatase inhibitors in men is being run as a joint effort between some members of the panel. For the treatment of metastatic tamoxifen-resistant male breast cancer, aromatase inhibitors may be considered but should only be administered in combination with surgical or medical orchidectomy (LHRH agonist).
Members felt that the development of treatment guidelines for male breast cancer would be beneficial. To our knowledge, the Arbeitsgemeinschaft Gynäkologische Onkologie is currently the only organization with published guidelines for male breast cancer, and the majority of data used to form these recommendations come from small case series and expert opinion. The panel stressed that male breast cancer should be considered a rare and unique disease, rather than being considered as analogous to postmenopausal female breast cancer. Treatment of male breast cancer should be driven by data collected from studies that include male participants. Furthermore, it was felt that an educational session at one of the large breast cancer meetings would be helpful in educating physicians on the current data regarding treatment options for male breast cancer.
Several discussion points regarding the prospect of clinical trials in male breast cancer were raised. First, it was felt that more etiologic data are necessary before embarking on clinical trials. Second, given the past experience with poor accrual, a large-scale international effort with a pre-existing infrastructure is strongly advised if a trial of this nature is to succeed; to this end, the International Male Breast Cancer Program is being developed through the BIG and NABCG networks. In addition, awareness at the community oncology level of such an effort is crucial. This could be facilitated through educational sessions at national meetings and potentially through raising awareness of clinical trial availability at the advocacy level.
Several trial design issues were also discussed. Because the majority of male breast tumors are endocrine responsive, the most logical first step would be to develop a trial on endocrine therapy options for these patients. One possibility would be to create a trial looking at tamoxifen versus an aromatase inhibitor with a safety, rather than an efficacy, end point. This would facilitate performing a smaller study and would provide important toxicity data on tamoxifen in men (for which there is scant information currently), as well as preliminary data on aromatase inhibitors. A second suggestion was the creation of a blanket orphan disease protocol that could be opened at multiple institutions and could facilitate gathering information on many of the rarer subsets of patients with breast cancer, including male breast cancer, inflammatory breast cancer, breast cancer in pregnant women, and breast cancer after treatment for Hodgkin's lymphoma. A third option would be to have a separate stratum for male breast cancer in large clinical trials in female breast cancer; this would allow for the collection of data on male breast cancer across studies that could be looked at in meta-analyses.