A systematic review of #malebreastcancer biomarkers from @ProfValS and her group shows that they are different

A new systematic review of the different ‘omic’ biomarkers of male breast cancer by the team led by Prof. Valerie Speirs at the University of Aberdeen does a fantastic job of summarizing many years of studies, and makes a clear determination: male breast cancer is significantly different in its molecular landscape. In the age of personalized, molecular medicine this means that it is time to study the male disease in its own right, so that men with breast cancer can also benefit from personalized therapy down the road.

Defining genomic, transcriptomic, proteomic, epigenetic, and phenotypic biomarkers with prognostic capability in male breast cancer: a systematic review.
Subarnarekha Chatterji, Emma Krzoska, Christopher W Thoroughgood, John Saganty*, Peng Liu, Beatrix Elsberger, Rasha Abu-Eid, Valerie Speirs
Lancet Oncol 2023; 24: e74–85
https://doi.org/10.1016/S1470-2045(22)00633-7

The authors set out to summarize what is known from existing studies, rather than do a new primary study. Gathering data from 197 articles spanning a 29-year period (1992-2021) and sorting through it all, they find 304 biomarkers and then focus in on those most commonly studied. Some of these are very familiar, and their significance is well established. We know that ERalpha and PR are commonly expressed in the male disease, and are positive predictors of overall survival, particularly when they occur together. HER2 is the opposite. AR, which is more commonly positive in male breast cancer than female, is also positively associated with survival. In contrast High Ki-67 and MIB-1, indicators of the rate of cancer cell division, are predictors of reduced overall survival.

However, this systematic review makes it very clear that there are several other markers that have associations with disease characteristics like metastasis, outcomes like progression or disease free survival and the classic markers mentioned above and so have important information. These more recently recognized markers are currently observed in the context of the limited studies that Chatterji and colleagues assemble for us here, and are not routinely assessed in clinical practice. For that reason, these markers do not yet form the basis of clinical decision making for most patients. This paper suggests that it might be time to more routinely incorporate their measurement in care delivery.

The review also describes a variety of clusters of the male disease, based on these molecular markers. Clustering is a computational process that groups cases with similar characteristics together on the assumption that they share biology and in an attempt to find groups that might be treated similarly, for example with targeted therapies aimed at their specific characteristics. At a very basic level we cluster ER/PR+ and Her+ positive tumors into those two groups, and treat the first with hormone therapy and the second with herceptin. But the molecular data in the studies discussed in this paper suggest that there may be further levels of clustering that could be helpful in deploying targeted therapies, and that is something that should be investigated further.

“Beyond the established breast cancer markers, we highlighted that STC2, DDX3, and DACH1 could have grounds for further investigation. We also identified ATM, CCND1, FGFR2, GATA3, HIF1A, MDM2, and MYC as well studied predictors of poor prognosis.“

Looking at the markers with a biological eye, rather than a clinical one, the summarized findings also suggest that there are meaningful differences in the biology of the female and male disease. Even the differences that don’t immediately suggest specific clinical approaches show that the diseases each merit study in their own right, just like inflammatory breast cancer and triple negative breast cancer are studied as separate entities. We should move on from the status quo where men are treated in the clinic like women, based on clinical trials that don’t include men and in the absence of systematic biological investigation of the male disease. As Chatterjee and colleagues say, straight from my heart:

“Considering the differences between male and female breast cancers, the roles of ERα, PR, and AR need to be re-established in a male-specific setting. Developing suitable male breast cancer laboratory models are necessary to achieve this target. “

I want to thank Prof. Speirs and her co-workers for writing this review and making the case so clearly. Now we know, and it is time to act.