The Spectrum of HR+ Breast Cancer: Approaching Treatment


Joyce A. O’Shaughnessy, MD: ER-positive, HER2-negative breast cancer is a very heterogenous disease. Luminal A disease is more ER-driven with coexpression of the progesterone receptor and, generally speaking, more indolent in biology with simpler genomes such as a PI3-kinase mutation. Then we have luminal B biology, which is ER-positive but maybe a little bit less strongly so sometimes, PR-negative or weakly PR-positive, and generally higher grade; with higher Ki-67, is more highly proliferative, and with genomes that are much more complex. There may be p53 mutations, which lend to a lot of cumulative mutations in the cancer: unstable genomes with amplicons in cyclin D1, FGFR1, MIC, or loss of PTEN. Those are much more complex cancers not driven just by the estrogen receptor but codriven by a wide variety of other pathways that are less endocrine-therapy sensitive. So, this is a big spectrum of disease but in those 2 broad categories.

Stephen Johnston, MA, PhD, FRCP: We now understand that ER-positive breast cancer is a group of different diseases with different prognoses and outcomes. In advanced-stage disease, we can have some patients who will have a prognosis, measured in many years, and live with their secondary breast cancer well controlled by different treatments; meanwhile, others who ostensibly have the same ER-positive breast cancer can have a more aggressive subtype where their prognosis might be measured in 6 to 12 to 18 months. We’re understanding more about the different biological features that help us determine which subgroups those patients are in.

Joyce A. O’Shaughnessy, MD: Hormone receptor—positive, HER2-negative metastatic breast cancer has a very wide spectrum of biology and natural history. The median survival from the time of diagnosis of metastatic, ER-positive disease is in the 30-month range: on average, 2 or 2 and a half years. Of course, 50% will live shorter than that and 50% will live longer. So, how do we as clinicians look at a newly diagnosed hormone receptor–positive metastatic breast cancer patient? What kinds of things do we look at to understand the prognosis of those patients and thereby fashion the best treatments for them?

Number one is the disease-free interval: How long did it take from the time of diagnosis to the development of metastatic disease? The shorter, the worse; that’s very aggressive biology. Time from end of treatment to the development of metastatic disease is another factor. How long did that cancer take off of treatment to recur? There are sites of metastasis, visceral versus nonvisceral. Particularly, liver metastasis or brain metastasis are grave areas where patients’ survival is shortened. The original grade of disease plays a role, grade 3 disease versus grade 1 or 2 disease. There’s tempo of disease and the propensity for metastasis, genicities. Is it just 1 or 2 organs of metastasis or multiple sites of metastasis?

What about the strength of the estrogen receptor and the progesterone receptor? Are they both still intact? Do you still have evidence of strong signaling to the estrogen receptor, or is the progesterone receptor now gone? We’re suggesting that this cancer’s not all about the estrogen receptor. Those are the main prognostic factors we look at, the grave clinical features that tell us this is a much more serious metastatic breast cancer and the patient’s survival is likely to be shortened.

Transcript Edited for Clarity

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