Other Targets in HR+ Breast Cancer: PARP Inhibition and Immune Checkpoint Inhibitors


Expert panelists consider the appropriate use of PARP and immune checkpoint inhibitors, respectively, in the setting of HR+ metastatic breast cancer.


Jules Cohen, MD: Dr Mortimer, is there anything about ER-positive HER2-negative metastatic breast cancer that we haven’t discussed that you would like to bring up?

Joanne Mortimer, MD, FACP, FASCO: My research actually involves functional imaging. Functional imaging of the estrogen receptor is an FDA-approved imaging agent. This is F18- labeled estradiol. I think the trade name or the people who make it is Cerianna. The use of FES [fluoroestradiol F18] PET as a predictor of endocrine sensitivity has certainly been shown in studies. I think 1 of the important data from the study isn’t just identifying who is responsive to endocrine therapy. Most of the data was derived pre-CDK4/6 [cyclin-dependent kinase 4/6] inhibitors. We have a trial in Akron, Ohio, that has just completed accrual. We’ll find out if it predicts responsiveness to endocrine therapy with CDK4/6 inhibitors. What this PET study does, importantly, is tell you who does not respond to endocrine therapy, which may be more important because you don’t waste the time of endocrine therapy on patients, and you can go right to nonendocrine interventions. I guess that would be my comment. We haven’t talked about the impact it has on HR-positive HER2-negative breast cancer yet.

Jules Cohen, MD:Very nice. Dr Iyengar?

Neil M. Iyengar, MD: Well, I think we’ve certainly hit all the high points, but I think that 1 of the really encouraging things is that with all of the agents that we are seeing come through—in terms of new molecular therapies, new endocrine therapies, as well as the ADCs [antibody drug conjugates]—we’re moving the needle in terms of time to chemotherapy. I think that’s particularly important for our younger patients with metastatic disease. We talked a little bit about our premenopausal patients and the approach in premenopausal patients, but I think that the field is really moving towards sparing folks of chemotherapy, at least in earlier lines. Those number of lines are increasing before we have to resort to chemotherapy. I find that to be very encouraging for our patients.

Jules Cohen, MD:Absolutely. Dr Slamon, is there anything else you’d like to add that we haven’t covered?

Dennis J. Slamon, MD, PhD: No, I think we’ve covered things fairly well. I think the excitement coming out of this year’s symposium is really the spectrum of therapeutic options that are becoming available to us, that are effective, and that aren’t just statistically significantly different, but are clinically meaningful. You don’t need to be sitting in the first row to see the difference in the 2 Kaplan-Meier curve lines. The differences are getting to be pretty impressive when we know what therapeutics to use for what specific subpopulation when it’s indicated. It's very exciting and it’s great news for breast cancer patients.

Jules Cohen, MD:This is particularly important in this subgroup of ER+ HER2-negative patients, especially if they have bone-only disease or lower better prognostic features. It’s really become more of a chronic disease than a lethal disease or terminal disease. I think we can share that with our patients and give them a lot of hope, in addition to getting them through treatment and keeping them on treatment for years at a time. I think we might finish. Is that too early?

Joanne Mortimer, MD, FACP, FASCO: We missed the PARPs [poly (ADP-ribose) polymerases].

Jules Cohen, MD:I missed the PARPs. Do you want to talk about the PARPs?

Joanne Mortimer, MD, FACP, FASCO: We probably should talk about PARPs.

Jules Cohen, MD:We can talk about the PARPs. Dr Mortimer, what about patients with germline BRCA mutations, BRCA1 and BRCA2 mutations? Do we have any additional options for them?

Joanne Mortimer, MD, FACP, FASCO: When we were discussing these patients, the guidelines currently support doing germline testing in all women with metastatic disease. I think the compliance with that is not quite as high as it should be. The value of knowing that is if you identify a patient who has a BRCA mutation, is that somewhere down the road—we’ve discussed so many different options for patients — that the PARP inhibitors can be potentially helpful in their therapies and other oral agents that don’t cause hair loss. I don’t know how to sequence them because we’ve only talked about all these incredibly wonderful HR+ endocrine therapies in combinations with other agents. Certainly, since this is a chronic disease, having an option of a PARP inhibitor needs to be considered, so doing germline testing in all patients as metastatic disease is supported.

Jules Cohen, MD:Just to be clear, the PARPs can be used independent of ER status. It’s not just the ER-negative patients who benefit from the PARPs.

Joanne Mortimer, MD, FACP, FASCO: That’s really important. I think the reason that we focus on ER-negative is because BRCA1 is predominantly triple-negative breast cancer, and nobody seems to forget to do germline testing in a triple-negative patient. Actually, most breast cancer is ER+ and HER2-negative, and we can’t neglect to do germline testing in those women.

Jules Cohen, MD:Do you think that the PARPs will be effective in patients who have a somatic mutation in BRCA1 or BRCA2?

Joanne Mortimer, MD, FACP, FASCO: There certainly is data that the PARP inhibitors can be effective in some of those patients. I’m not sure which patients. For all of those, there was a recent series that looked at other DNA repair defects and found that using PARP inhibitors was not very effective. I think we’re just beginning to look at how PARP inhibitors are not effective in those other germline mutations.

Jules Cohen, MD:Dr Iyengar, is there any role for immune therapy in ER+ disease?

Neil M. Iyengar, MD: I think that the development of immunotherapy in ER+ breast cancer is nuanced by where, in the natural history, the cancer is. Earlier on, when the cancers are more endocrine sensitive, I would say that the drivers are hormone- and molecular-based. We haven’t seen great activity of immunotherapeutic approaches in that setting. That being said, as the tumors become endocrine resistant, I think that there is potentially a role for immunotherapy, though we still need to see clinical data in this setting. There are also specific scenarios where immunotherapy may be helpful. For example, an MSI- [microsatellite instability] high tumor is not very common in ER+.

Jules Cohen, MD:I was going to say, have you ever seen that?

Neil M. Iyengar, MD: Certainly, I think we can all probably come up with very specific scenarios where immunotherapy may be useful in the HR+ setting. For now, we need to await more clinical trial data before this becomes incorporated into practice.

Jules Cohen, MD:I guess tumor mutation burden is a little more common than MSI in unstable tumors in breast cancer. That’s a so-called tissue agnostic indication. It doesn’t apply to breast cancer exclusively. It could be any tumor, independent of tissue origin. As long as they have a tumor mutation burden of 10 or above, they could be candidates for treatment with pembrolizumab.

Transcript edited for clarity.

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