Expert Perspectives On Advanced Hormone Receptor-Positive Breast Cancer - Episode 9

Risk of Recurrence in Early-Stage HR+ Breast Cancer

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Sara Hurvitz, MD: Let’s turn our focus now to the latter half of our program—an active and exciting, if not confusing, area—early stage hormone receptor-positive breast cancer. Let’s first take a high-level view.

Sara, can you talk to us about the rates of recurrence that we should be quoting to our patients with early stage hormone receptor-positive breast cancer who receive endocrine therapy? There are a lot of data, but a lot of it emanates from patients who were treated 10, 15 years ago, not necessarily with modern chemotherapy or modern regimens. What do we know about the risk of recurrence in a patient who comes in with early stage disease? What sort of features are associated with an increased risk of recurrence?

Sara M. Tolaney, MD, MPH: Traditionally we’ve thought of very simple prognostic indicators based on clinical and pathologic features. First and foremost, we’ve always thought of tumor size, tumor grade, and nodal involvement as probably the most classic prognostic indicators that we have. But I think we’ve gotten a little more sophisticated as time has gone on, now understanding that we can potentially utilize molecular and genomic prognostic indicators to help better understand someone’s risk. We know, for example, that the 21-gene recurrence score could provide us with prognostic information in addition to predictive information. So the prognostic information that we get really helps us understand what someone’s risk of recurrence is. We also know Ki-67 is an assay that has been found to be prognostic, which, although a little more controversial, given some challenges with reproducibility of this assay.

From a very basic level, integrating clinical pathologic features and genomic/molecular prognostic indicators are probably our best understanding of how to put together someone’s potential risk of recurrence. I think the challenge in ER-positive disease is that biologically, these tumors can be very different. And so while we don’t classically utilize intrinsic subtype in the clinic, we do know that there are luminal B cancers that typically are higher grade, less endocrine-sensitive tumors, and then we sort of have the luminal B pathology, where there tends to be lower grade, more endocrine-sensitive tumors. How those cancers behave are just so different.

Not all ER-positive breast cancers behave the same, and so we see timing of recurrence is also different based on these different biologies, where we can have patients who have more aggressive luminal B cancers that are tending to be, again, these high-grade cancers that tend to recur earlier, and then tend to also see the reverse in patients who have more luminal B pathology where we can see very late recurrences.

I think we’re all trying to best understand how to figure out who’s going to recur and who’s going to recur early versus late, and there’s a lot of work being done in this field to tease this out further. But I think at a basic level, some of our prognostic factors really haven’t changed in terms of size, grade, and lymph node involvement. But now we’re getting a little trickier adding in these molecular and genomic features.

Sara Hurvitz, MD: Excellent overview. Massimo, tell me which biomarkers and gene expression assays are available for our patients with early-stage disease. Can you sort out for us which are predictive versus which are prognostic markers?

Massimo Cristofanilli, MD: Sure. The most important question we have been asking in the last few years is which patients we can de-escalate? When you think a patient is at high risk, you usually need to use your best therapy and your best chemotherapy possible. The Oncotype DX test has been used in node negative as well as node positive. Clearly, with a high Oncotype recurrence score, these patients need to receive chemotherapy. That may not even be enough, and I think this is the next level of care. For patients with an intermediate score, a lot depends on the clinical factors—the lymph node and the menopausal status. It seems like independently of what the recurrence score may be in this group, or independent of what the tumor size may be, there is a benefit from chemotherapy. This is something that probably needs to be discussed in more detail—what we should do with these patients when you have a molecular test that may not be so predictive.

Of course the alternative test, or the test has been used in the clinic, is the MammaPrint, 70 genes, which provides a score for high risk to low risk. It’s most of the time reported together with subtype, so you can have a luminal high risk, or a luminal low risk. Or you may find out if the disease is totally different, particularly in the group of patients who have very low expression. I think it is very useful to identify this as a luminal. But irrespective, I think as has been shown, when you have a patient who is genomic high risk, obviously there is benefit with chemotherapy. If you have clinically high risk in genomic 12, maybe this patient may be spared chemotherapy, and de-escalation is possible. There’s not a complete overlap between the two, but clearly most of the time they tend to indicate similar tumor characteristics.

Then the other question is the late recurrence. I think the EndoPredict test tries to define which patient needs standard endocrine therapy. I think this is less used and less known, but it’s a research question and a clinical question that probably we need to address now that we have all these molecular tests. I know there will be more and more effort to try to incorporate clinical issues, especially because women want to know. This is not a therapy that’s without adverse effects. They’re going to take 5 years of tamoxifen, and then 5 years an AI [aromatase inhibitor], with all the things that comes with it: hot flashes, weight gain, joint pain, and so forth. They’re going to take 10 years of tamoxifen, doubling essentially the exposure time to the drug. What if this patient develops a recurrence, how does this look molecularly in more aggressive and less aggressive subtypes? I think there will be a lot of use of this molecular test, again to de-escalate in this case the length of endocrine therapy when it’s possible, and maybe to add more combined therapy with the high risk.

Transcript Edited for Clarity