Treatment After Progression on CDK 4/6i in mBC

Testing for ESR1 mutations after disease progression in metastatic breast cancer.


Hope S. Rugo, MD:Hello and welcome to thisAJMC Peer Exchange®, “Expanding Treatment Options for Metastatic Breast Cancer.”

I’m Dr Hope Rugo from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. Joining me to today in this virtual discussion are my excellent and expert colleagues: Dr Claudine J. Isaacs from the Lombardi Comprehensive Cancer Center at Georgetown University; Dr. Priyanka Sharma from the University of Kansas Cancer Center; Dr. Tiffany A. Traina from Memorial Sloan Kettering Cancer Center; and Dr John Fox, vice president of Clinical Transformation at Spectrum Health.

We have great experts on our panel today, and are excited to have John Fox, MD, MHA, as well to give us a different perspective on treatment choices for patients with metastatic breast cancer. Today we are going to highlight a number of topics pertaining to the systemic treatment for breast cancer and the impact of recent clinical trial data on clinical decision-making.

Let's get started on our first topic which is treatment after progression on a CDK4/6 [cyclin D/cyclin-dependent kinases 4 and 6] inhibitor plus endocrine therapy. One of the big questions that comes up, Tiffany, is whether or not we routinely re-biopsy or reorder molecular testing at disease progression in patients with hormone receptor-positive metastatic breast cancer, and whether you actually test and decide on treatment forESR1mutation status. Also, if it's positive or negative do you retest in the future since it might impact your treatments? Then of course attached to this is what we know now about mechanisms of resistance to CDK4/6 inhibitors. Can you tell us a little bit about those areas?

Tiffany A. Traina, MD:Sure. I think there is a lot in there to unpack, but to start with, I think having tissue material for biomarker assessment in the setting of metastatic breast cancer is important. We know in the first-line setting to never assume, to recheck your ER [estrogen receptor], PR [progesterone receptor], and HER2 status so that we’re not missing the opportunity to use appropriate targeted therapy. Together with that, I think in the first-line setting, although while often using a CDK4/6 inhibitor, it is a nice opportunity to start your molecular testing for PI3K [Phosphoinositide 3-kinase] status knowing then that you may have an opportunity in later lines of therapy to use a PI3 kinase inhibitor.

I do find that often in first-line metastatic breast cancer routinely we’re doing a biopsy, sending those hormone receptors again, and beginning the molecular profiling. To your question aboutESR1mutations, many of our women have had an adjutant aromatase inhibitor which drives the development of anESR1mutation. There’s a great rationale for thinking that fulvestrant and SERDS [selective estrogen receptor degraders] may be better in the setting of anESR1mutation. Often, I will use the clinical circumstances to help guide me in what that first-line choice may be for an endocrine therapy backbone, and theESR1mutation can sometimes guide that.

Hope S. Rugo, MD:That's really interesting. That that is a question that I think is of interest to everyone’s patients, but would you serially test forESR1, for example, with ctDNA [circulating tumor DNA]?

Tiffany A. Traina, MD:It is an option. Over time, we have considered doing cell-free DNA testing more looking for an actionable mutation like the PI3 kinase alteration. In my experience forESR1, I haven't seen it crop up in later-line endocrine therapy, but it may just be that I haven't seen enough of that. I'd be curious to hear what other people think in that setting.

Hope S. Rugo, MD:Claudine, do you test serially forESR1mutations?

Claudine J. Isaacs, MD:We test more forPI3 kinasemutations. In doing so we often get theESR1mutation as well, but we're starting to do that. I think the other question is what the difference is in ctDNA versus tumor biopsy, and might you be seeing differences between those. We've tried. We've had a few patients who are trying to be on top of things and say “Okay, looking forward to the next thing. I'm on a CDK4/6 inhibitor. Do I have a PI3 kinase mutation?”

Some of what we've heard is that the optimal time to test is when a patient really has disease progression and not while they're having response to the treatment they're currently on. I’d also be interested in how people think about doing this because we like to be organized and thinking ahead, but at the same time testing while somebody is responding to their current treatment might not be the best time to do it.

Hope S. Rugo, MD:I think it is a good point, and we've seen thatESR1mutations come and go. We may not have even been getting a very accurate representation of what's going on. Personally, I don't serially test but I could see a situation where you might. Also, it does appear thatPIK3CAmutations are conserved so that you gain a few in the metastatic setting and with progression but not a lot so that you could probably safely test while you're doing treatment. I usually test when they're starting to look like they might be progressing sometime in the near future.

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