Using Genomic Profiling to Select the Right Therapy for Metastatic Breast Cancer

At the San Antonio Breast Cancer Symposium (SABCS), researchers presented the results of the phase II SAFIR02-BREAST trial, which aimed to determine if genomic profiling can help improve outcomes in patients with metastatic breast cancer.

In addition, an analysis of the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials demonstrated that patients with luminal A, luminal B, and HER2-enriched tumor subtypes had improved overall survival when treated with ribociclib (Kisqali) plus endocrine therapy versus endocrine therapy alone.

MedPage Today brought together three expert leaders in their field — moderator Virginia G. Kaklamani, MD, of UT Health San Antonio, Ruth M. O’Regan, MD, of the University of Rochester Medical Center in New York, and William J. Gradishar, MD, of Northwestern University Feinberg School of Medicine in Chicago — for a virtual roundtable discussion on these studies. This is the third of four exclusive episodes.

Following is a transcript of their remarks:

Kaklamani: Hello. My name is Virginia Kaklamani, professor of medicine at UT Health San Antonio, MD Anderson Cancer Center, and leader of the breast cancer program. Today I have with me two esteemed colleagues: Dr. Ruth O’Regan, who is chair of medicine at the University of Rochester, and Dr. William Gradishar, who is the chief of the division of medical oncology at Northwestern University. We’re going to be talking about the San Antonio Breast Cancer Symposium 2021 highlights and themes.

Now, moving on to some more ER-positive data in tumor genomic profiling, selecting the right treatment. There were a couple of presentations at SABCS — one was the SAFIR02 trial, and the other one were a couple trials on the MONALEESA trial results. Dr. O’Regan, would you like the comment on those?

O’Regan: Yeah, so the MONALEESA data, so that basically was a combination of MONALEESA-2, 3, and 7, that they have mainly primary tissue from. In the MONALEESA studies, patients were randomized to ribociclib with endocrine therapy versus endocrine therapy alone. And what they showed was that the benefit of ribociclib was seen across intrinsic subtypes. So, for luminal A, luminal B, and the HER2 phenotype, there was a clear benefit for the addition of ribociclib to endocrine therapy. Interestingly, in the basal-like subtype, which was a small number, they had a worse outcome overall, and it didn’t appear in that group that the addition of ribociclib actually improved outcome. But, again, the caution there is that the numbers are small.

I think it’s interesting data. My concern always with a study like this is that I’m not sure for hormone receptor-positive breast cancers that the primary cancer is necessarily representative of the metastatic cancer. Because we know these cancers change. In fact, you and I had a paper years ago showing that these, when they become metastatic, they can actually gain HER2. So, I do think they change. So that’s the one caveat with that study.

The SAFIR study basically took patients with HER2-negative metastatic breast cancer that had at least some clinical benefit at about 6 months, did genomic testing to see if there was any actionable mutations in the tumor, and then if there was, they randomized them to either chemotherapy or the relevant targeted therapy. If they didn’t have an actual mutation, they were randomized to the addition of durvalumab [Imfinzi] or not. We’ve seen data from that before.

In the group of the actionable mutations, what they showed was that if you actually treated the patient with the appropriate targeted agent for the mutation they had, those patients had a longer progression-free survival than those on chemotherapy and actually did better than the overall population. So, again, it’s kind of precision medicine. What was nice about the SAFIR study is that the genomics were done on the metastatic tissue, obviously. And some of that was PI3 kinase mutations, but there was also other mutations they looked at.

So, again, some proof that these molecular tumor boards that we do, where we try and find agents for patients, do kind of make sense and potentially can improve outcome.

Kaklamani: And so looking at MONALEESA, what I liked and we’ve seen this before, is that both luminal A’s and luminal B’s seem to have the exact same benefit from CDK4/6 inhibitors. And people have argued in the past that, well, in the metastatic setting if you have a patient who has what looks like a luminal A tumor, maybe we should be starting them with endocrine therapy instead of giving them a combination. Dr. Gradishar, how do you look at those patients? Do you always give them a CDK4/6 inhibitor in the first-line setting?

Gradishar: Pretty much, yes. So, I think the collective data with all the registration trials, with the CDK4/6 inhibitors show a clear improvement in outcome. That’s not something you need a magnifying glass to identify. And, as such, I think for most patients, unless they have some reason on an individual basis why they couldn’t tolerate it or get it, we generally would recommend it. And I think to the point of, are we delaying the time until we have to do something that’s more toxic? When you have progression-free survival that can be measured in many, many, many, many months, then I think that becomes a very attractive reason to be choosing a CDK4/6 inhibitor for the vast majority of patients.

O’Regan: And I would think I would rephrase that — endocrine sensitive versus endocrine resistant in some ways. And we know that the CDK inhibitors are very effective in the first-line setting potentially of endocrine-sensitive cancers, but also in the endocrine-resistant setting, like, for example, PALOMA-3.

I think we’ll get more data because I am concerned about the fact that they were primary cancers, but I think the adjuvant setting, we’re probably going to get a better answer to that. And, as we know, the FDA really kind of approved abemaciclib [Verzenio] adjuvantly for more of luminal B-type phenotype, but the data really does suggest it does work in these low KI-67 tumors that are probably luminal A as well. So, we’ll wait and see further data on that as well.

Kaklamani: And the other thing that struck me with SAFIR02, and I guess every positive has a negative, that the majority of patients did not have any actionable mutations. And, what do you do with those patients, right?

O’Regan: Yeah. I mean that’s a big problem, and we know that in our molecular tumor boards that we see that all the time and I think there’s just more work to be done. And it doesn’t sound like immunotherapy is particularly effective, which makes sense because obviously immunotherapies work better when there’s kind of higher tumor mutations. So, that kind of makes sense. I agree with that’s a big problem.

Gradishar: Yeah, and to that point as well, if you look at the duration that study was operational, I think starting back in whatever, 2012 or 2014, and 1,200 some patients, and then when you actually look at the number that we’re actually on, it’s a very labor-intensive approach. So, they should be commended for doing it. But, nonetheless, it also didn’t bear fruit for most patients.

O’Regan: And I think we have to be very upfront with our patients when we send off genomic testing, that the likelihood that you find something is actually pretty low.

Watch episode 1: Latest on Immunotherapy in Triple-Negative Breast Cancer

Watch episode 2: Study Shows Promise for Oral SERD in Breast Cancer