Joyce O’Shaughnessy, MD: Metastatic hormone receptor-positive breast cancer that’s HER2 [human epidermal growth factor receptor 2]-negative, first of all, is very, very common. It’s probably about 60% to two-thirds of the metastatic disease that we see, and the biology is very heterogeneous. There are basically 2 main categories. There are those who tend to be endocrine therapy sensitive, the luminal A group, who are more slowly proliferative and have quite stable genomes, with some mutations but not a lot of genomic instability. The other group is less sensitive to endocrine therapy. They’re more rapidly proliferative, have a faster natural history, and genomically tend to have p53 mutations, amplifications, deletions. They’re much more genomically unstable and much more difficult to treat with endocrine therapy alone. There are basically 2 major buckets, but certainly a spectrum in between.

Metastatic breast cancer that is less aggressive, first of all, tends to either be de novo metastatic from the beginning and very endocrine therapy sensitive—or, it recurs some years after the primary diagnosis—and it is generally indolent. The Ki-67 staining is low. Initially, it might be grade 1 or grade 2 at the primary diagnosis, or even de novo metastatic. From a genomic standpoint, PI3 kinase mutations are quite common, maybe around 40%, as well as E-cadherin mutations and invasive lobular breast cancer. But they’ll lack p53 mutations, for example. They won’t have an amplification of FGFR1 [fibroblast growth factor receptor 1] or cyclin D1, some of the much more aggressive amplifications, or a loss of PTEN.

They’re genomically stable. They’re slow growing, so it takes them a while to accumulate more and more mutations over time. These are the patients who we do very well with clinically, and when we treat them with endocrine therapy plus other targeted agents, they benefit. You go on and on and on with a number of different endocrine therapies. They retain endocrine sensitivity for a great period of time before requiring chemotherapy. They tend to metastasize to the bones, lung, lymph nodes, and—less commonly—the liver. It can metastasize to the liver, but less commonly the liver. The more endocrine therapy sensitive sites of metastasis are bone, lung, and lymph nodes.

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