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Dr. Erika Hamilton:
Welcome to The ASCO Post Roundtable Series on Updates in Early-Stage Breast Cancer. I'm Dr. Erika Hamilton. I'm the Director of the Breast Cancer Research Program at Sarah Cannon Research Institute. And joining me today are two of my colleagues, Dr. Jhaveri and Dr. Danso. Dr. Jhaveri, would you like to introduce yourself?
Dr. Komal Jhaveri:
Thank you. Happy to be here today with both of you. So I'm Komal Jhaveri. I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center. I serve as Section Head for our Endocrine Therapy Research Program here, and I'm also the Clinical Director for our Early Drug Development Service.
Thank you so much for joining us. Dr. Danso?
Dr. Michael Danso:
Thank you very much for the invitation. Looking forward to discussing these cases with you. So I'm Michael Danso. I'm a Medical Director and Research Director at Virginia Oncology Associates, part of the Sarah Cannon Research Institute Network.
Thank you so much. So today, we're going to be discussing the treatment of early breast cancer and we're going to follow three patient cases. Our first installment will focus on the treatment of hormone receptor–positive, HER2-negative early breast cancer.
So to dive into the case, this is a 42-year-old female who presented with a right breast palpable lump that had been there for about 2 months. She ultimately had a mammogram that revealed about a 3-cm abnormality, and biopsies showed ER 100%, PR 90%, HER2 0. This was invasive ductal carcinoma and high grade. Breast MRI corresponded with a 3.2-cm abnormality with no abnormal appearing lymph nodes, and Oncotype recurrence score returned at 21.
Dr. Danso, maybe I'll throw this to you first. What would you be thinking about in this case? And are you thinking about this lady perhaps needing chemotherapy or not?
So yes, I think I would offer this young lady chemotherapy. She's a young premenopausal woman. She has a 3-cm mass that is high grade. From subset analysis of the 21-gene assay comparing endocrine therapy alone vs chemo endocrine therapy in intermediate-risk score premenopausal women, there appears to be about a 6% benefit for a score between 21 and 25. I think this is sufficient justification to offer her preoperative chemotherapy.
Yeah, absolutely. Dr. Jhaveri, any different thoughts on that?
No, I would completely agree for all the points that Dr. Danso pointed out about the risk.
And Dr. Jhaveri, how important is age when you think about a case like this? Would your recommendation for chemotherapy change if she was postmenopausal, in her 50s?
Yeah. I think the data that we have now from the TAILORx trial for node-negative women where we have Oncotype scores of less than 25, we did not necessarily see a benefit in postmenopausal women. And so there, I think we're more comfortable with endocrine therapy alone rather than endocrine therapy with chemotherapy. It changes a little bit with premenopausal women such as this woman, and certainly gets even more blurrier in premenopausal women when the scores are even on the lower side of the intermediate but not quite very low, with very low meaning less than 11. And so that's where we're thinking, how much of the contribution is from the chemotherapy? Could it be from ovarian suppression? That we would offer these women, but I think we're awaiting definitive data from ongoing efforts in our cooperative group studies to hopefully better answer those questions. But for now, I think for this node-negative woman, if she was a postmenopausal women with an Oncotype of 21, I'd feel comfortable skipping chemotherapy and offering endocrine therapy alone.
Yeah, I completely agree. So back to the original case and her being 42, she does end up undergoing four cycles of TC chemotherapy. She tolerates this relatively well. She does have a dose reduction at her last cycle for grade 1 neuropathy of her taxane. She ultimately goes on to have a lumpectomy. This reveals 1.5 cm of residual carcinoma, still high grade, and we do have one out of three positive lymph nodes, and this is involved with a 5-millimeter cancer deposit. She undergoes adjuvant breast radiation due to the lumpectomy, and then we're moving to endocrine therapy. Dr. Danso, what endocrine therapy would you be thinking about? Tamoxifen alone, tamoxifen with ovarian function suppression, AI, AI with ovarian function suppression, or as we like to say, the kitchen sink, ovarian function suppression AI and considering CDK4/6?
I think I would certainly offer ovarian suppression and an aromatase inhibitor based on updates from the combined analysis of the SOFT/TEXT trial that demonstrated a clear improvement in disease-free survival of about 6% in patients that were high-risk enough to require chemotherapy, and she clearly was. In addition, I would offer a CDK4/6 inhibitor based on the positive results of both the monarchE trial that showed abemaciclib plus endocrine therapy was superior to endocrine therapy alone in terms of invasive disease-free survival in high-risk disease. And the NATALEE trial that also showed benefit of ribociclib plus an endocrine therapy over endocrine therapy in high- and intermediate-risk patients.
So yes, I would offer ovarian suppression and a cyclin-dependent kinase inhibitor. One point I would go on to make about the chemotherapy choice that she had, having made a decision to offer chemotherapy, I generally would likely offer anthracycline taxane-based chemotherapy over a nonanthracycline regimen, particularly if treating preoperatively, as I believe it would offer a greater chance of a pathological complete response. And in this case, we did not see a pathological complete response with TC. It's certainly not wrong to offer a nonanthracycline regimen such as TC, but in the ABC trial comparing TC vs anthracycline-based chemotherapy published by Joanne Blum, anthracyclines improve invasive disease-free survival of a TC chemotherapy. But with ER-positive disease that is apparently node negative, it's certainly not wrong to offer TC chemotherapy, but anecdotally I've rarely seen a pathological complete response with TC chemotherapy.
Yeah, I agree. I think if we had known about the lymph node upfront, that may have influenced people. Dr. Jhaveri, do you feel strongly about TC over anthracycline-containing knowing what we knew initially in this case and are you, too, thinking that this woman has high enough risk to offer a CDK4/6?
So yeah, to answer your first questions first, so her presentation, it's not necessary that this woman had to be treated with neoadjuvant chemotherapy. This patient could have been treated with adjuvant chemotherapy and had upfront surgery as well. It wasn't that it was an inoperable tumor, she was node negative. So at that point in time, either upfront surgery would've been appropriate, but because we had already made a decision about chemotherapy, we know that the data for neoadjuvant chemotherapy and adjuvant chemotherapy when it pertains to survival is identical. And so I think giving her neoadjuvant or adjuvant is appropriate because we were going to offer her chemotherapy to begin with. Because she was node negative, I did not necessarily feel very strongly about giving her an anthracycline. I think for a node-positive patient, I would've definitely considered or certainly considered or favored an anthracycline-based regimen in a young woman.
But I'm not sure if I am consistently doing that for node-negative patients, especially given what we know about the absolute benefits that we can now obtain with ovarian suppression with addition of CDK4/6 inhibitors as well. To your second question about CDK4/6, I completely agree with Dr. Danso. I would offer her abemaciclib based on the monarchE approval that we have currently for the CDK4/6 inhibitor in the early-stage setting, given the absolute 6% benefit that we've seen with a median follow-up of 42 months. And we've seen that benefit not only with invasive disease–free survival, but we've also seen that now with resistant relapse-free survival from the updated data where also it was approximately 6%. So I think that would be something I would certainly discuss with this patient.
Yeah, absolutely. Obviously, this patient qualifies based on her positive lymph node and the fact that she was high grade, not based on tumor size, et cetera, or having four or more positive lymph nodes. What were your impressions of NATALEE, Dr. Jhaveri? Does this make you more willing to offer CDK4/6 to more intermediate risk patients? Obviously, this drug is not approved yet, but how are you going to be deciding between abemaciclib and ribociclib?
Yeah. I think it's a very interesting question and certainly something that we will have to pay close attention to. I think what is comforting from the NATALEE data is that now we have two positive signals. We already have mature dataset from the monarchE with longer and longer follow-up, even that it was the first study to report out and we have approval for. And so certainly we have that for our really high-risk patients and node-positive patients, and the criteria that you just described that in this particular case was not related to the four positive nodes, but given the fact that she is N1 or node positive with a high grade. I think that does qualify her for abemaciclib. For NATALEE, I think it was really nice. The attempt was to see can we broaden the utility of CDK4/6 to a broader group of patients even within intermediate risk, including, say, the T3N0s.
So larger tumors that might be node negative or even the stage II node negative, which were also included in the trial. And it was nice to see that at least with the follow-up that we had at 27 months, we did see a statistically significant delta benefit in the order of 3.3%. What I think I'm still waiting for is obviously the label and the approval for the ribociclib medication in this setting, but also maybe a little bit more follow-up. So as we know, NATALEE is looking at 3 years of ribociclib compared to abemaciclib, which is approved for 2 years of adjuvant abemaciclib in this setting. And the median follow-up that currently we had was 27 months with about 20% of the patient population in NATALEE that had completed the intended 3-year duration, and 57% that were still ongoing.
And so I think it would be nice to look at, with more mature follow-up, how those curves behave and how those data pan out with a deepening of benefit as we did see in the monarchE setting. But I'm looking forward to those data. I'm excited by the signal. I'm happy to have choices for our patients hopefully very soon, but I'm looking for more additional follow-up as well to be really comforted by the fact that I have to offer. Ultimately, I think it'll be a discussion given that it's a 2-year duration vs a 3-year duration. Toxicity profiles would be something that we will be discussing with our patients the way we do in the metastatic setting, and it would be a shared patient-physician decision making process.
Yeah, I absolutely agree. I've got a question for you, Dr. Danso, but let's go through just a little bit of the data. As we know in the monarchE trial, this really was for women or men that had high-risk hormone receptor–positive disease, automatic qualified for trial for four or more positive nodes, or if one to three positive lymph nodes had to have a grade 3 disease or tumor size of at least 5 cm. Patients were randomized to endocrine therapy or endocrine therapy with abemaciclib for a 2-year period and then went on to finish their standard endocrine therapy. What I think has been very reassuring about monarchE is when we first saw this data at 2-year follow-up, the benefit was 2.8% in disease-free survival. And I think we were all quite encouraged by this, but also had the question in the back of our mind is, well, did these patients have subclinical metastatic disease?
Are these curves going to close when people progress? And at 3-year followup, we saw this widen to 4.8%. At 4-year, it's now almost 6.5%, and almost all of these events are distant recurrence-free survival events as well. So we really are translating some patients to cure. In terms of safety, there's no doubt it is definitely tougher to tolerate endocrine therapy with abemaciclib than endocrine therapy alone, diarrhea really being the most prominent side effect. Also, we certainly can see neutropenia, although less so with abemaciclib compared to ribociclib and palbociclib, but it is reassuring that we see quality of life being preserved on adjuvant abemaciclib. It does not appear that this is really getting in the way of patients once they learn to tolerate. Also, NATALEE, this was a different study design. If we call monarchE high risk, NATALEE, I would say, is high to intermediate risk, very similar in the fact that patients received endocrine therapy and then also received ribociclib.
But this was for 3 years' duration and the ribociclib dose was at 400 mg a day, so not the same dose that we're used to seeing in the metastatic setting. So some important differences here. We can also note that some patients that were node negative were included in this, and so this gets into a little bit of a different risk profile. And what we saw in early results of disease-free survival, the follow-up was a little over 2-year and the absolute benefit was 3.3%. Again, we only have one look at this data. I completely agree with you, Dr. Jhaveri, that it will be more reassuring over time if we see this also widen like we saw with the monarchE data. And in terms of safety, neutropenia really was the most prominent side effect. A little bit less than we see in metastatic setting at the higher dose, but we did see really upwards of over 40% of patients still having grade 3 neutropenia. And for something in the adjuvant setting that patients are going to be on for years, this can be meaningful.
I'm going to go back to you, Dr. Danso. Does the side effect profile weigh in your mind if you ultimately have a choice between giving ribociclib or abemaciclib, or does the duration of data weigh in your mind with abemaciclib? How are you going to pick for the individual patient what you might be thinking about?
So clearly, we have more data presently for abemaciclib. So given the option of using either agent, I would likely use abemaciclib in high-risk patients and consider switching to ribociclib should patients have experienced significant GI toxicity, for example, diarrhea. So I would tend to use abemaciclib for high-risk patients. For intermediate risk patients, certainly when ribociclib was approved, I would use ribociclib in that situation. But I imagine that I would use both agents interchangeably based on toxicity profile. So if I have LFT abnormalities with ribociclib, I imagine I will change to abemaciclib. If I have diarrhea toxicity with abemaciclib, I imagine I will change to ribociclib. So yes, I imagine I will use both agents interchangeably based on toxicity profile.
Fantastic. So our key takeaways from this case is the recommendation for chemotherapy is not only dependent on the genomic risk score, but also menopausal status and age currently. Abemaciclib is our currently approved CDK4/6 inhibitor for high-risk early breast cancer in conjunction with an aromatase inhibitor, and again, is indicated in one to three positive nodes with a high grade or large tumor size, or for patients that have four or more positive nodes. And we also have recent positive data for adjuvant ribociclib in both high as well as intermediate risk patients, although not currently FDA approved.
This brings us to the end of case one. Please see the other segments for further discussion about the latest data in breast cancer or visit ascopost.com.