Advertisement

Advertisement

Newly Diagnosed HER2-Negative Metastatic Breast Cancer

This is Part 1 of Updates in Breast Cancer, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Drs. Sara A. Hurvitz, William J. Gradishar, and Sara M. Tolaney discuss current treatment options for newly diagnosed HER2-negative metastatic breast cancer. Dr. Hurvitz presents the case of a 49-year-old perimenopausal Latina woman with intermediate-grade T2N1 left breast cancer that is estrogen receptor/progesterone receptor–positive and HER2-negative, with bone and liver metastases. The faculty walk through how they would choose between chemotherapy and endocrine-based options for this patient and discuss recent data on CDK4/6 inhibitors showing improved outcomes in the first-line setting.


More From This Roundtable

Advertisement
Advertisement

Transcript

Dr. Hurvitz: Welcome to The ASCO Post Roundtable Series on Updates in Breast Cancer. I'm Dr. Sara Hurvitz, medical oncologist, professor of medicine at the University of California, Los Angeles Jonsson Comprehensive Cancer Center. Joining me today are two of my colleagues, Bill Gradishar and Sara Tolaney. Bill, can you introduce yourself? Dr. Gradishar: Sure. I'm a breast medical oncologist at Northwestern University and chief of the Division of Hematology/Oncology. Dr. Hurvitz: Thanks, Bill. I'm glad you're here. Sara, can you introduce yourself? Dr. Tolaney: I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston. Dr. Hurvitz: Welcome, Sara. So today we'll be discussing recent updates in breast cancer, including data presented at the 2021 ASCO Annual Meeting and integrating these new developments into four patient case studies. Our first installment will focus on treatment options for newly diagnosed HER2-negative metastatic breast cancer, including CDK4/6 inhibitors. Let's turn to our first case. We have a 49-year-old perimenopausal Latina, single mom who's been diagnosed with a T2N1 left breast cancer, ER and PR strongly positive. HER2-negative intermediate grade. She detected this after missing her screening mammography for 2 years with issues due to the COVID pandemic. Her work schedule and home responsibilities prevented her from seeing a doctor regularly, and then the COVID pandemic hit. She is found to have a biopsy-proven liver metastasis. Actually, there are multiple liver metastases comprising 50% of the volume of her liver and painful pelvic bone metastases. She does have an elevation in the ALT and AST up to three times upper limit of normal, but her bilirubin is normal. So Bill, I want to turn to you and ask you how you approach a certain situation like this. When I was in training, I know a lot of us would knee-jerk to chemotherapy with this sort of visceral involvement, but how are you approaching this type of case in present day? Dr. Gradishar: Yeah, well, I share those sentiments because what we try to tell the fellows, our trainees, is that simply the presence of visceral disease does not demand chemotherapy, but that said, the description of this patient is a little bit worrisome and it really highlights the need to individually make an assessment and determine how symptomatic she is and really get an appreciation of the bulk of the disease and the rapidity of the disease. So the fact that she has visceral disease does not automatically mean she must get chemotherapy. Although I'll be honest, even though I'm inclined, as I know you are, to consider endocrine therapy in such a patient. I would have a low threshold for considering chemotherapy in this patient. And the reason I say that is because if the disease is rapidly progressing and the patient is really symptomatic, you may have only one opportunity to really bring things under a little bit of control or slow the tempo of the disease. But if that wasn't your major concern as you meet the patient, I would certainly consider endocrine therapy and I would partner her with a CDK4/6 inhibitor. Dr. Hurvitz: Yeah, I agree. It's definitely an important discussion point and understanding the pace of disease is something that is important. Sara, what do you think about making the decision between chemotherapy and use of the CDK4/6 inhibitor? What does the data tell us about the comparison in terms of outcomes that we don't have a lot of direct comparisons, although some data are emerging comparing CDK4/6 inhibitors to chemotherapy in this type of setting? Dr. Tolaney: I know it's a challenging case. You know, as Bill noted, when you start to see someone who's got symptomatic disease with transaminitis, it always makes you a little anxious. And so just as Bill noted here, we're really trying to decide between endocrine therapy and CDK4/6 inhibition versus chemo. I think traditionally we've thought of endocrine therapy as taking time to lead to response, but that really has been changed pretty dramatically with the addition of CDK4/6 inhibition. And so in fact, the response rate that we see with the combination of endocrine therapy and CDK4/6 are actually really high, and I think that surprises many people cause we don't usually think of endocrine-based therapy as actually having high response rates. But in fact, if you look at response rates in the first-line setting, they're usually around the 50 to 60% range; that's actually very high and in truth higher than we often see with chemotherapy. There is some randomized data, as you alluded to, that's really compared the combination of endocrine treatment and CDK4/6 inhibition to chemo. We have a couple of studies. One was a randomized phase II, the young-PEARL study that was specifically in premenopausal patients and had compared endocrine therapy with CDK4/6 inhibition with ovarian suppression to keep sight of it. It found that there was improvement in outcomes using endocrine treatment with CDK4/6 although again, randomized phase II trial. And then we have the PEARL data, which looked at postmenopausal women comparing endocrine treatment with CDK4/6 to capecitabine. And in fact the outcomes were really the same. There's a numerical benefit for capecitabine over the endocrine CDK4/6 but in essence, no statistical difference. So I think those data give me comfort to say that we really do see pretty similar outcomes to chemotherapy. And so if you feel like the patient is an appropriate candidate, I tend to err towards endocrine treatment and CDK4/6, but these cases, it can be tricky because it's when someone is sort of hitting that visceral crisis phase that I tend to turn to chemo. And this person sounds a little bit on edge of that. Dr. Hurvitz: Yes, thank you very much. And those data are really important and I think it's quite impressive, the objective response rates we are seeing with a non-chemo regimen. Now this particular patient actually wants to avoid the infusion room at all costs. She wants to limit the amount of time she's in the clinic. She's very busy at work. She's taking care of kids and she's very interested in pursuing an endocrine therapy–based option. We do, as you mentioned, have a number of studies that have been done looking at CDK4/6 inhibitors. So let me start with Sara here. Can you take us through a little bit of the data in the frontline setting with CDK4/6 inhibitors and how you might approach choosing among the agents in this woman who is perimenopausal at the age of 49? Dr. Tolaney: I think we're very fortunate that we have a lot of randomized data here. And so, really with every single CDK4/6 inhibitor with endocrine therapy, we have a randomized pivotal study and what's really pretty remarkable is that in the first-line setting, you really see the same hazard ratios across the different trials that looked at endocrine treatment, specifically AI therapy with or without a CDK4/6 inhibitor where the hazard ratios are generally around 0.5 to 0.55 in the first-line setting. So in essence, we're doubling progression-free survival by adding a CDK4/6 inhibitor to an endocrine backbone. And we're seeing PFS that can hit around a median of 30 months. And so that's really a dramatic change compared to what we used to see. We also are now starting to see emergence of survival benefits with adding CDK4/6 inhibition to endocrine treatment. Although that being said, most of the survival data has really predominantly come from the second-line setting. Although we do have some first-line data, actually there's a subgroup of patients in MONALEESA-3 that were first-line where we did see survival benefit as well. And then specifically for this patient being technically premenopausal, we do have one randomized trial that was specific to premenopausal patients, and that was the MONALEESA-7 study. That study took premenopausal patients. All of them had to have ovarian suppression and then the physician could choose which endocrine backbone they wanted to use, whether it be tamoxifen or an AI. And then they got randomized to receive that with ribociclib or placebo. And what we saw was, again, a doubling of progression-free survival. And in fact, we also saw overall survival benefit in this study. And so, this is really our only randomized study that is specific to premenopausal patients and is showing benefit both in terms of PFS and OS. Dr. Hurvitz: Thank you. That was a great overview. Bill, the MONALEESA-3 study was updated at ASCO just a few weeks ago now. Looking at the longer-term overall survival data, do you want to just briefly touch on what that study showed since it did have a subset of patients albeit in the postmenopausal setting who were treated in the frontline setting? Dr. Gradishar: Yeah. So as Sara mentioned, that was updated by your colleague Dr. Slamon and showed a sustained survival benefit. And now we can see that you look at 4 years, you look at 5 years, the lines are still separate. You look at the subset of patients who were getting therapy as first-line therapy, you've got an advantage and even the patients who were receiving chemotherapy as second line. And another way of interpreting the rather impressive data that Sara outlined, the PFS is actually in a way a surrogate of delaying the time until you get chemotherapy. Now, granted, if you respond very well to endocrine therapy, you may go onto another endocrine therapy, but many patients go on to chemotherapy. So pushing out the time where you pull the trigger on chemotherapy to almost two years is a very significant thing when it comes to quality of life and just the whole mindset of a patient with metastatic disease. Dr. Hurvitz: Absolutely. And especially for a patient like this, who's really quite desperate to stay out of the infusion room as well. So let's turn back to our patient. She does choose to receive an aromatase inhibitor with goserelin and ribociclib. She has a terrific response, does really well, normalization in liver markers and shrinkage of the liver tumors. She does have this response for about 30 months, but then again, progresses in the liver. ctDNA is sent and it does show a PIK3CA mutation. So back to you, Bill, how would you approach second-line therapy for this particular patient? Again, assuming that she is not in visceral crisis, her LFTs are reasonable for treatment of your choice. What would you do in this case post-CDK? Dr. Gradishar: Right. So I think this is a patient where considering alpelisib would be a reasonable thought. The patient does have a mutation. I think it's worth mentioning that when the SOLAR-1 trial was done, which was a comparison of fulvestrant with alpelisib versus fulvestrant, there was an advantage for those patients who had a mutation with respect to PFS. So this would be a perfect option for this patient. And I think the other thing worth mentioning, and it was elaborated upon in a couple of trials, one in SOLAR-1, the number of patients who had previously received a CDK4/6 inhibitor was quite modest, but there was clearly a hint that it would respond as well, whether you got a CDK4/6 inhibitor or not in the past, and then the subsequent BYLieve trial confirmed that. So I think that there's now this notion that if you've gotten a CDK4/6 inhibitor, you're somehow not going to respond to alpelisib. The second thing I just wanted to mention is in SOLAR-1, there were a finite number of mutations that made you eligible for the trial. And of course in the real world, which was another presentation at ASCO this year, there are more mutations that have been identified for which people act upon, whether all of those are activating mutation or driver mutations, who knows, but some of those patients that had mutations outside the context, what made you eligible for SOLAR-1 did respond. So bottom line is I would consider alpelisib. Dr. Hurvitz: Thank you very much. So I think we'll summarize our take-homes from this section: CDK4/6 inhibitors significantly improve objective response rate and PFS, and now we're seeing data that at least two of them improve overall survival—ribociclib and abemaciclib—in the metastatic setting for hormone receptor–positive breast cancer. In the frontline setting, ribociclib demonstrated survival benefit in both the postmenopausal setting in combination with fulvestrant and in pre- and perimenopausal patients in the first-line setting in combination with an aromatase inhibitor and ovarian suppression. We're all eagerly awaiting overall survival data to mature and be reported from PALOMA-2 and MONARCH-3 with abemaciclib in the first-line setting, and also MONALEESA-2. The use of alpelisib in patients with PIK3CA mutations does significantly improve progression-free survival, and the BYLieve Study does indicate that benefits should be seen in patients who have been pretreated with a CDK4/6 inhibitor. So this brings us to the end of this case. Please see the other segments for further discussion about the latest data in breast cancer or visit ASCOPost.com. Thank you so much.
Advertisement