In this expert roundtable series, Seth Wander, MD, PhD, Massachusetts General Hospital, Boston, Massachusetts, leads a 3-part panel discussion on the management of patients with PIK3CA-mutant metastatic breast cancer with Megan Kruse, MD, Cleveland Clinic, Cleveland, Ohio; Janice Lu, MD, PhD, Northwestern University, Chicago, Illinois; and Kelly McCann, MD, PhD, University of California-Los Angeles.

In the first part of this discussion, our experts give an overview of the PI3 kinase pathway and its role in cancer, as well as when and how to approach genomic testing for PI3 kinase alterations.

Click here to view Part 2 of this discussion.

Transcript:

Seth Wander, MD, PhD: Welcome to Oncology Learning Network. My name is Seth Wander. I'm an assistant professor of medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital. It's my pleasure to moderate today's discussion on PIK3CA-mutant hormone receptor-positive metastatic breast cancer. I'm joined by a distinguished panel of experts in this field. Would each of you like to introduce yourselves and tell us a little bit about your roles? We'll start with Dr McCann.

Kelly McCann, MD, PhD: I'm Kelly McCann. I'm an assistant professor and breast medical oncologist at University of California, Los Angeles.

Janice Lu, MD, PhD: I'm Janice Lu. I'm a professor of medicine and director of breast medical oncology at Northwestern University Feinberg School of Medicine.

Megan Kruse, MD: And I'm Megan Kruse, assistant professor and medical oncologist at Cleveland Clinic.

Dr Wander: Welcome, everyone. Thank you for joining us today. We've made tremendous progress in the development of novel therapeutic options for hormone receptor-positive metastatic breast cancer. These new therapies, many of which have recently entered clinical practice, include novel anti-estrogen agents, targeted therapies, and antibody-drug conjugates. Over the last several years, we've also seen the first 4 FDA approvals based upon specific molecular genomic alterations for patients with hormone receptor-positive metastatic breast cancer. And this represents critically important progress as we strive to deliver upon the promise of precision oncology. Three of these agents, alpelisib, capivasertib, and inavolisib, are designed to target alterations in the PI3 kinase oncogenic signaling pathway, and we will focus our discussion on this important topic today.

We're going to start today's discussion with an overview of the PI3 kinase pathway itself, the important biologic roles it plays within the cancer cell, and the best approach to genomic testing for these alterations.

Let's start, Dr McCann, if you can help us describe the biologic roles the PI3 kinase pathway plays within the cancer cell itself.

Dr McCann: Sure. So, PI3 kinase pathway is downstream of tyrosine kinase receptors. It is upregulated in about 70% of breast cancers, but it also has a high predominance of activating mutations: up to 40% of patients who have hormone receptor-positive, HER2-negative breast cancers.

Dr Wander: Great. And Dr Lu, when you think about your clinical practice, how often do you think you see alterations in the PI3 kinase pathway, and what are the most common types of alterations or mutations you might find?

Dr Lu: Yeah, it's up to about 30% to 40%. It’s a truncal mutation, it's given. It’s not like ESR mutation which is more like acquired. It’s very important to my patients. I check this now as a second-line therapy, after CDK4/6 inhibitor with endocrine therapy. It’s about a 30% to 40% chance there's a PIK3CA mutation. And AKT and P10 alteration is less, about 5% to 10%. This is something great for the patients for the precision oncology era.

Dr Wander: I think this is a really important point, this concept of when we test, which we'll get back to in a minute. But can you tell us a little bit more about the idea of truncal versus acquired, and for folks who are now getting used to using more testing like this in the breast cancer population?

Dr Lu: Yeah, my understanding is truncal is there. Acquired is when the patients get treatment endocrine therapy with and without CDK, like ESR1 mutation, the rate is very low to start with, maybe less than 5%, but gradually, it's acquired and then you have up to probably 30% of chance you'll have ESR1 mutation. The longer treatment, perhaps give patients more chance to get acquired mutation.

Dr Wander: Right, so the truncal alteration of PIK3CA, in theory, is there early on. You can test via solid or liquid biopsy at any time and sort of hope to pick it up, particularly in the metastatic setting, but the acquired alterations, for example, as you said, ESR1, would be missed potentially if you only test at the time of metastatic diagnosis and maybe become more frequent over time later on. I think this is a really important point and it underscores the complexity of when and how we should be testing.

Dr Kruse, that was going to be my next question: Broadly speaking, how should we approach testing for these molecular alterations? And there's a few components to this part of the discussion. So maybe we can start with, which patients should be tested?

Dr Kruse: I think it's highly variable when we test, but who we test is probably a little bit more uniform. We know that these mutations alterations are targetable for our patients with hormone receptor-positive, HER2-negative, metastatic breast cancer. For me, I'm thinking about the patient who has progressed on endocrine therapy and a CDK4/6 inhibitor, or more recently, and we'll get into this in other discussions, for those patients who have very quick relapse on their adjuvant endocrine therapy. You may be thinking about looking for an alteration in this pathway early on and targeting it early on. I think for most patients, I would get this after their first-line metastatic therapy, but there'll be a select few that I want to know the information earlier on in their disease course.

Dr Wander: And before we move on to other aspects of testing for the others, how do you feel about that in terms of when you're testing and who you're testing. I think we all agree, obviously here we're talking about hormone receptor-positive metastatic disease, and I think your point's well taken about when to test in terms of acquisition and when is it clinically actionable. Traditionally, up until just recently, we would argue it would be in the second-line setting or beyond, but we're going to talk today about how that's changed with the inavolisib.

How about you, Kelly, in terms of when would you test within the hormone receptor-positive population?

Dr McCann: The PI3 kinase mutations are present from the start of the cancer, and so you're going to pick those up whenever you test for them, usually. ESR1 being an acquired mutation, we used to test after an AI [aromatase inhibitor] exposure to pick up a lot of different mutations and figure out what our next plan of therapy is going to be. With the inavolisib data now, we're probably going to start testing much earlier than we might have.

I think another very important consideration is, what do we test? Do we test with a liquid biopsy? Do we test with tissue? Because sometimes patients don't have enough of a tumor burden in order to see it in the blood, so you might pick up different mutations as the tumor burden increases, and might consider a biopsy if your next treatment plan is going to change based on that biopsy.

Dr Wander: Let me try something a little bit different to help our colleagues who are watching us here. I'll ask each of you in turn, based on everything you just said, first, when would you test? Would you test at the time of metastatic diagnosis, at the time of progression, or both?

Dr McCann: For liquid biopsies or for tissue? If you have a patient who is newly metastatic, you should test tissue because you want to know, in the immunohistochemistry, do they still have estrogen receptor, progesterone receptor, HER2, may be even tests for KI67. Usually, I send for liquid biopsy at that point as well.

Dr Wander: At metastatic diagnosis?

Dr McCann: At the time of metastatic diagnosis. And then when do we send again? It would be after an aromatase inhibitor, and tried to pick up those ESR1 mutations, which are acquired.

Dr Wander: And how about you, Janice?

Dr Lu: Yeah, I agree. In the past, I only checked as the second line because I feel like the first line is not going to change my treatment plan. The standard is CDK with endocrine therapy. But now with the new data with inavolisib, INAVO120, patients who got primary or secondary resistance to endocrine therapy, those who got metastases while on adjuvant treatment, or those finished within like 12 months. This group of patients I would consider checking liquid biopsy right away at the first line because I would consider about using inavolisib, the combination with 3 drugs altogether in addition to, I mean besides just CDK with endocrine therapy.

Dr Wander: And we're going to review that data momentarily. How about you, Megan, in terms of when would you test and how would you test?

Dr Kruse: I think very similar to what we've already heard. If I have a patient in the first line metastatic setting, I usually have tissue and blood. There will be a rare patient where you might not be able to access a metastatic site with tissue, you're relying a little bit more on blood. Sometimes there I'll even go back to the original breast tissue because, to our point, this mutation, if it's in this pathway, typically happens early, right? So, you may even find it in the original breast tumor. But I think it's such a rare situation where that happens. Most of the time you have a metastatic tissue biopsy, and you also have blood. I think my inclination has been to move testing earlier and earlier as the testing has become more accessible, and become more reliable. And it's just kind of nice to know what I might be thinking about in second-line therapy, maybe even before we get there.

Dr Wander: I think we have consensus, right? Which is that all of us are feeling like there's value both in looking at solid tumors at the time of metastatic diagnosis as well as liquid biopsies. As a general rule, I think we're shifting toward earlier testing. And understanding that repeat testing particularly with a liquid biopsy can pay dividends in terms of identifying acquired molecular alterations. Great.

Thank you all for sharing your insights and thanks to the audience for watching. Please join us for the next session as we start to talk about some of the key agents that are available for targeting the PI3 kinase pathway.