Piscuoglio S, Ng CK, Murray MP, Guerini-Rocco E, Martelotto LG, Geyer FC, Bidard FC, Berman S, Fusco N, Sakr RA, Eberle C, De Mattos-Arruda L, Macedo GS, Akram M, Baslan T, Hicks J, King TA, Brogi E, Norton L, Weigelt B, Hudis CA, Reis-Filho JS
Clin Cancer Res. 2016 Aug 15;22(16):4045-56. doi: 10.1158/1078-0432.CCR-15-2840. Epub 2016 Mar 9.
The question of whether male breast cancer is the same as female breast cancer has not yet been completely answered. In the era of so called precision medicine – where therapies are increasingly selected based on detailed knowledge of specific mutations in cancer – this is an important question. Therefore, while it may already be known that the majority of male breast cancer is invasive ductal carcinoma, ER (estrogen receptor) /PR (progesterone receptor) positive, Her2 negative and luminal, this does not guarantee that the underlying abnormalities are the same as this group of female breast cancers. Arguably such knowledge would be most important for patients who have failed standard care and are seeking experimental therapies and trials.
Currently the focus of precision medicine is largely on genetic mutations in the cancer most of which arise spontaneously during the process of forming the cancer (i.e. are not inherited in predisposition syndromes). These mutations lead to the formation of abnormal proteins, or the abnormal level of proteins, and these can then be targeted with specific drugs designed specifically for the purpose by teams of researchers. Thanks to the rapid development of better and cheaper DNA sequencing techniques it is now possible to look at quite a few genes in a decent group of tumors at reasonable cost. This is what the authors have done, and their findings are interesting.
Piscuoglio and colleagues took 59 cases of male breast cancer – all were ER positive and only 2 were Her2 positive – and sequenced 241 genes that are know from many other tissue and lab studies to have mutations that are important in cancer, using two complementary approaches.
Overall they found that the rate and pattern of mutations were similar to female breast cancers of the same type. Many of the genes known to be mutated in women were also found to be mutated in men.
However, there were also some interesting differences:
- The mutation rate of some of the common genes was different. For example, PIK3CA, which encodes a major signaling molecule and against which drugs have been developed, is mutated at about half the frequency in men than in women (~20% vs ~40%). Conversely, the frequency of mutation of HERC2 was higher in men than women (~7% vs ~1%).
- Several genes known to be mutated in women were not found to be mutated in men, including RUNX1, AKT1 and NCOR1.
- Genes associated with the DNA repair pathway were more often mutated in men than in women (~30% vs ~15%).
- Overall 27 genes not seen to be mutated in women were found to be mutated in men and 10 of these may be ‘actionable’ meaning that drugs designed to target these mutant proteins already exist.
The authors conclude that the “mutational landscape” of male and female breast cancers of the same type, differ, and that these differences may be meaningful. They consider the fact that male and female breast tissue, although at first quite similar in the young, experience a very different hormonal milieu during maturation and life, and so that the cells that turn malignant might have quite a different biology. The mutational differences could reflect that these different cell types require or favor different alterations as they transform. The authors also suggest that this new molecular information be integrated into clinical research. They concede that 59 tumors is still a small series, especially compared to the many more female breast cancers that have been analyzed by this approach, and that rarer mutations may still turn up in future studies,
The finding that there are distinct mutations in male and female breast cancers (of the same type) is critical for the proper integration of men with breast cancer into the clinical trials of today. The findings that there are 10 actionable mutations in male breast cancer which are not found in female breast cancer should encourage clinicians writing trials for these drugs to include men with breast cancer in their eligibility group. The same thing goes for clinical studies of drugs targeting mutations in the DNA repair pathway. The converse is true for men and studies for mutations they don’t have. For PIK3CA I think men should still be considered for targeted trials if sequencing for mutations is part of the trial.
On the more basic biology side this paper is another indication that there are in fact important biological differences between male and female breast cancers that otherwise look the same. More study is needed. Particularly we need model of the disease. Perhaps a mouse model using mutations of key proteins in the DNA repair pathway that are targeted to the male breast could be tried?