Recent advances in hormone receptor–positive, HER2-negative metastatic breast cancer have led to questions about the timing of genetic testing and the optimal treatment choices for patients. “I, like many others, have changed my personal practice,” says Azka Ali, MD, a medical oncologist at the Cleveland Clinic Taussig Cancer Institute in Ohio. She and Robert A. Figlin, MD, the Steven Spielberg Family Chair in Hematology-Oncology at the Cedars-Sinai Cancer Center in Los Angeles, discuss what newly approved medications for patients with PIK3CA mutations mean for oncologists. “I think the breast cancer landscape is changing faster than we can all keep up with it,” Dr. Ali explains. She breaks down current genetic testing concerns and how she approaches treatment decisions that sometimes take place in a “data-free zone.”
Dr. Ali reported no relevant financial disclosures.
Dr. Figlin reported various financial relationships.
Transcript
This transcript has been lightly edited for clarity.
Robert A. Figlin, MD: Good afternoon. This is Bob Figlin, the Steven Spielberg Family Chair in Hematology Oncology at Cedars-Sinai Cancer in Los Angeles. And I’m delighted today to speak with Azka Ali, MD, who is a breast medical oncologist from the Taussig Cancer Center at Cleveland Clinic. Azka, thanks so much for joining us today.
Azka Ali, MD: Thank you for having me. It’s a pleasure to be here.
Dr. Figlin: We really want to focus on the population of patients who are hormone receptor–positive, HER2-negative, PIK3CA mutation–positive. Who are those patients, and how do you identify them through either sequencing or other methodology?
Dr. Ali: That is a great question. When we talk about hormone receptor–positive, HER2-negative disease, it is really almost its own thing in terms of treating breast cancer. PIK3CA, it is important to know, is what is called a truncal mutation, which means that it is present at the time of breast cancer diagnosis.
A lot of these patients with mutations are going to have the mutation if we go back to the original biopsy. Of course, we don’t do that because we don’t need to; it’s not actionable in the early setting. Which means you could theoretically pick it up either at the level of tissue or at the level of blood.
Now, you ask a great question: What is the incidence of PIK3CA? Up to about 35% to 40% of patients are going to have a PIK3CA mutation. This is very important to know because that obviously dictates the therapy choices that we offer to patients.
Dr. Figlin: It’s interesting that you mentioned that it is not usual at breast cancer diagnosis to undergo next-generation sequencing (NGS) because you are really looking at things like HER2 positivity and hormone receptor positivity. Should we be doing more NGS early in the course of a breast cancer journey, as opposed to waiting until they progress and need additional therapy?
Dr. Ali: That’s a great question. I would say that I usually get asked that by patients. Because obviously, patients are looking to know what additional testing could be done, what biomarkers could be done, anything that we could do beyond standard of care that could dictate the risk of recurrence.
I don’t frequently recommend genetic or somatic testing primarily in early breast cancer. Now obviously, genetic testing is very complicated. I explain that to patients. There is the germline testing that some patients are going to get, based on their individual risk. Then there is somatic testing, and then there is liquid biopsy testing. Obviously, we’re talking about tumor testing here.
I don’t recommend that, primarily because it is not actionable. And it doesn’t really dictate the risk of recurrence independently. I’m not sure what to do with that information. And if we do have a mutation, then I would hate for patients to just live with that information, which may not impact them at all if they don’t have a recurrence, hopefully.
Dr. Figlin: And of the 30%–35% who have these mutations, are they demographically or by biology any different than those who do not?
Dr. Ali: That’s a great question. There is a good amount of variability in patients. We don’t identify any demographic trends or any trends that are based on the sex of patients that certain groups of people are more likely to have the mutation. I think there’s a little bit of heterogeneity in the mutation carriers, which tells us that we should be screening everybody.
Dr. Figlin: Yeah, I totally agree with that. So, the patient presents to you. You’ve done the testing. You know that the patient has a PIK3CA mutation. How do you then decide, through the spectrum of treatments available, what would be your first approach? Why don’t you have with me a conversation similar to what you would have with the patient, in terms of what the expectations of the outcomes may be?
Dr. Ali: For hormone receptor–positive, HER2-negative patients in the metastatic setting, historically we were using monotherapy endocrine therapy in the form of an aromatase inhibitor. Then we’ve used fulvestrant monotherapy for a while. With the advent of CDK4/6 inhibitors, which I describe to patients as biologics, they are cell cycle arrest drugs; they have really changed the landscape of how we treat hormone receptor–positive, HER2-negative metastatic breast cancer.
In the first line, I would advocate for CDK4/6 inhibitors with an endocrine therapy partner. Now, what partner? I think that is also a discussion in its own right, where I think there is a lot at play here. Especially in terms of the pattern of recurrence, timing of recurrence from adjuvant therapy, and patients who are in adjuvant therapy or patients who are de novo metastatic. We know about 5% or 10% of patients are going to be de novo metastatic.
Now to your point, which is a good one: How do you integrate PI3K testing and that information that is available in your treatment decisions? If you had asked me that question a few months ago, I would have said right now that the rule for that testing is probably in the second line. Once they have had that progression on the first line, hopefully with the CDK4/6, then it is the perfect opportunity to go test it if we don’t have that information available.
For many years, we had just one drug available called alpelisib that we could partner with fulvestrant. There was also some data on partnering with letrozole. As of last year, we had a second drug approval for capivasertib, also with fulvestrant. So that is a great alternative. What I and many people like me like about that drug is that there is less hyperglycemia with it, probably because of the more favorable dosing. It is four days on, three days off during the week. So, patients tolerate that a little better.
Now, as of a few months ago, because I think the breast cancer landscape is changing faster than we can all keep up with it, we have a new drug approval: a third PI3-kinase inhibitor called inavolisib in combination with palbociclib and endocrine therapy. And it’s approved for patients who have had a recurrence either on adjuvant endocrine therapy or those who have had a recurrence within 12 months of adjuvant endocrine therapy. So, patients who we truly feel are high-risk in terms of endocrine resistance. For those patients, there was about a five- to six-month delta improvement in progression-free survival, from 7–8 months to 14 months with the upfront triplet.
So, it brings us to the question now: When do you test? I, like many others, have changed my personal practice. I would now check to look for that information upfront. The last thing that I would add to that story is that the second drug that I mentioned, capivasertib, that does actually have action in not just PI3K but also the mutations of the AKT alteration and the PTEN alteration, which are more downstream.
So, in the metastatic recurrent patients, up to 40% can have a PI3K mutation, an additional 5% can have AKT, and an additional 5% can have PTEN. So, when you add those numbers up, now we’re saying about up to 50% of these patients can have PI3K pathway alterations. And for that, capivasertib is the only drug that’s approved for the additional mutations.
Dr. Figlin: Help me understand. If you start with the triplet because of the recent information, does that preclude the use of the other agents with progression?
Dr. Ali: You ask a great question. And to be honest, we don’t know how the other drugs are going to be active because we do not have those data. And those are some of the harder discussions that I’m having with patients in clinic because so much of that is a data-free zone.
Obviously, when we give a triplet upfront and patients have progression, I think the concern is that these patients are probably going to become endocrine-resistant much faster. But you could also make the argument, we have preselected for a high-risk population. They were either on adjuvant endocrine therapy or patients have had a quick progression to metastatic recurrence. So, it does make sense to target the mutation that might be implicated in endocrine resistance.
To your point, do we go back and use some of the other agents? We don’t have data, so we have no idea if it is going to work. I think in the right patient, it may be worth trying. I’m not sure if I would use that approach for somebody who is having a quick progression or somebody who is having a high-burden disease progression. Because that may tell us that it may be time for chemotherapy.
Dr. Figlin: And with respect to the targets of action, does it work just as well in visceral and nonvisceral disease and brain metastases, across the blood-brain barrier?
Dr. Ali: So in terms of our PI3-kinase targeted agents, I think one limitation that we have seen across the board, at least with the two agents that have been available for a longer duration, is for patients who get past the first line – that is, for hormone receptor–positive, HER2-negative metastatic patients. The first line is typically an endocrine partner with a CDK4/6 inhibitor, which by the way has a median progression-free survival of about two years – 24 months. And many patients, they do better. Of course, some unfortunately do worse.
The dilemma I think right now in breast cancer treatment is that the subsequent lines, they don’t give us enough durability of treatment. So, if you look at some of the data from the BELIEVE study or SOLAR-1, the progression-free survival is about six to eight months for those patients. There is not a great deal of central nervous system penetration, and not a great deal of activity with visceral crises.
Historically for visceral crisis, we have equated that with chemotherapy treatment. We often don’t do double agents. Single agent works just as well for these patients. Up until recently, we were doing primarily chemotherapy for visceral crisis. The phase 2 RIGHT Choice trial, which came out a couple of years ago, looked at upfront endocrine therapy in combination. It studied endocrine therapy plus CDK4/6 inhibitor versus chemotherapy in the upfront setting but in visceral crisis. And in the upfront setting, it actually looks like the endocrine therapy plus CDK4/6 might be better than chemotherapy in terms of time to response, and obviously toxicity.
In the second line, I don’t know if I would get overly excited or expect a lot of benefit. I would actually argue that if patients are quickly progressing through endocrine therapy, especially with a CDK4/6 and endocrine therapy backbone, I’d be worried that they are becoming endocrine-resistant. And again, it might be time for chemotherapy. Or as we know now, time for antibody drug conjugates, as we have learned from DESTINY-Breast06.
Dr. Figlin: Azka, thank you so much for taking the time and chatting with us today. That was just a great summary, and I wish you a happy holiday.
Dr. Ali: Thank you.
