Top 5 Studies in Breast Cancer From ASCO 2021
PracticeUpdate: What were the main themes of the breast cancer studies presented at ASCO 2021?
Dr. Schwartzberg: There were several themes at ASCO 2021 that I'm going to talk about, and I think a big theme for breast cancer is de-escalation of therapy. As we've moved to more effective therapies, we're now able to experiment with reducing some of the intensity of the therapy and, therefore, reducing toxicity. Overall survival remains the most important end point for cancer clinical trials, and we have some updated data that was exciting at ASCO. Genomic profiling has been part of our experience and our practice for many years, and we have some updates on that. Targeted therapies continue to rise in breast cancer and an exciting practice-changing presentation in the plenary session on that. And of course, immunotherapies, while not as advanced in breast cancer as they are in some of the other cancers that we talk about and that we treat, continued to make some progress. And we'll speak about all of these in the top five stories from ASCO this past year.
Study #5: MINDACT Trial
We're going to start with what I would consider number five, which is looking at genomic profiling in the MINDACT trial using the 70-gene assay. The 70-gene assay is a excellent prognostic tool for determining high risk versus low risk by genomic features of recurrence in early breast cancer. The low-risk group can actually be divided into two groups, an ultra-low-risk group and the low-risk group. And they went back in the MINDACT trial, a prospective randomized trial that showed that patients with clinically high and genomic low scores do not generally need chemotherapy, but when they looked at the subgroup of patients that were ultra low, that represents about 15% of the MINDACT patients in the HR-positive, HER2 subgroup. And what they found was excellent distant metastasis-free interval rates for genomic low and ultra low patients.
In fact, in the ultra low patients, the 8-year distant metastasis-free interval was 97% and was still good in the low risk at 94.5% and not as good in the high risk. So these patients have an extremely good prognosis. There was some small difference by clinical risk. Those that had clinical high risk had a 95% 8-year DMFI [distant metastasis-free interval] while the clinical low and the ultra low genomic were 97.6%, so these patients are doing wonderfully well, which is very gratifying. A very interesting aspect of the MINDACT trial was that some patients did not take any endocrine therapy of their own volition. That was a small group, but when they looked at those that had no endocrine therapy in the ultra low subset, their 8-year DMFI was 97.8%. And those that got endocrine therapy was 97.4%, suggesting that we don't have to, in the ultra low group, especially those with clinically low-risk characteristics, if they have trouble with endocrine therapy, perhaps we can limit the amount of endocrine therapy and feel comfortable that their outcome is so good. And you could also translate these into the very clearly luminal A-type patients.
Study #4: ADAPT Trial
The next study I wanted to talk about, number four on my list, was a study from the West German Study Group, the ADAPT trial, that looked at HER2-positive hormone receptor-negative patients and de-escalating them to get either just anti-HER2 therapy with trastuzumab and pertuzumab or the well-known combination of single-agent weekly paclitaxel with pertuzumab and trastuzumab. And all of these patients were ER- and PR-negative and HER2-positive. The end point was pathologic complete response rate [pCR] and that's been previously reported, but what they presented at ASCO this year was the long-term outcome for these patients. As previously reported, the pCR rates were really pretty good even for the patients who got trastuzumab and pertuzumab only - no chemotherapy - with about 30% pCR rate, and it was very high for those patients who got the chemotherapy with paclitaxel, trastuzumab, and pertuzumab.
Now, further chemotherapy could be given after the initial surgery, and most patients who got only the anti-HER2 therapy got chemotherapy, but most patients who got just paclitaxel, trastuzumab, and pertuzumab did not get additional chemotherapy after a pCR. The long-term follow-up showed the 5-year invasive disease-free survival was excellent for the THP, that's with the paclitaxel arm, at 98% invasive disease-free survival. And the distant disease-free survival was good in both arms: 98% at 5 years for the chemotherapy arm and even 92% for the arm that did not get chemotherapy upfront, although most of them did afterwards. As expected, the pCR patients did very well, 98% 5-year IDFS regardless of what therapy they got, and that was true whether they got a pCR with invasive disease or without invasive disease.
So these data, I think, suggest to us in particular that we can de-escalate therapy, particularly those for smaller HER2-positive, ER-negative patients, and we perhaps don't have to give as intensive chemotherapy as we often do with TCHP, which does cause a lot of diarrhea and other toxicities. So for patients that are getting neoadjuvant chemotherapy, and particularly if they're low-risk patients, paclitaxel, trastuzumab, and pertuzumab would seem to be a good initial therapy for them.
Study #3 and #2: MONALEESA-3 and PALOMA-3 Trials
The next study I want to point out is actually a long-term survival from two studies, the MONALEESA-3 and the PALOMA-3 trials. These were studies, seminal trials, looking at CDK4/6 inhibitors in combination with fulvestrant in either the first- or the second-line setting for patients with HR-positive, HER2-negative breast cancer. MONALEESA-3 now reported long-term follow-up. In the overall population, there was a 10% improvement in overall survival, despite the fact that patients get multiple other lines of therapy after this early-line therapy, and at 5 years with less events, 15% improvement in overall survival. If you broke it up to the first-line patients, the median survival has not even been reached for fulvestrant and ribociclib compared to placebo and fulvestrant in the patients who received it in the first line. And in the second line, there was still a benefit of about 6 months in these patients, in terms of overall survival, who received ribociclib in combination with fulvestrant as their second-line therapy.
We saw similar results with PALOMA-3, which has now very long follow-up at 73 months, and there was a 20% improvement in overall survival with about a 6-month improvement in overall survival at the median from 28 to 35 months in these patients that had been previously treated with endocrine therapy and, in many cases, chemotherapy as well.
So I think this is very gratifying data, which emphasizes the use of CDK4/6 inhibitors. We have these reports from palbociclib and ribociclib, and that this class of agents, in general, should be used in the first-line setting because of the survival benefit we're starting to see. And if it is used in the second-line setting, it definitely has survival benefit as well.
Study #1: OlympiA Trial
Finally, the last study, the number one trial that I want to talk about from ASCO 2021, was a plenary session and it was the OlympiA trial. This was a targeted therapy trial looking at patients with early breast cancer who had a BRCA1 or 2 germline pathogenic mutation. They had to be either triple-negative or hormone receptor-positive stage II to III breast cancer. They could have received neoadjuvant chemotherapy but could not have had a pCR to that. And if they were hormone receptor-positive, they had to both have a non-pCR and have significant residual disease. They also were allowed to have adjuvant therapy, in which case they had to be node positive in the triple-negative group or at least 4 nodes positive in the hormone receptor-positive group.
All patients received their adjuvant or neoadjuvant chemotherapy, surgery, radiation, and then were randomized after that to olaparib, a PARP inhibitor, which is already approved in the metastatic setting at the standard dose 300 milligrams twice a day versus placebo twice a day. And the primary end point was invasive disease-free survival. With median follow-up of 3.5 years, there is a highly statistically, and I would argue, clinically significant improvement for this group of patients, with about a 9% improvement in invasive disease-free survival at 3 years from 77.5% to 86.1% in the patients that received olaparib; that's a 39% improvement in IDFS. In terms of distant disease-free survival, there was a 7% improvement at 3 years, and the curves continued to widen; that's a 43% improvement in distant disease-free survival.
The adverse events were generally well tolerated and no new signals were noted. Olaparib's major toxicity is some low-grade nausea, fatigue, and anemia. And those can be managed well by people experienced with using the drug. So I think this OlympiA is a practice-changing regimen for patients who have a germline BRCA mutation. This would make sense as the adjuvant therapy after standard neoadjuvant therapy if they have residual disease or at high risk. So this will hopefully be approved by the FDA and will become available to us in the future. Also, importantly is the fact that since we now have a therapy for germline BRCA-mutated patients, these patients ... we should really switch our thinking from who should get tested for germline BRCA to who shouldn't. In other words, the default should be we will test most people with early-stage breast cancer, particularly anyone who might be a candidate for a PARP inhibitor. And in my mind, that would include all triple-negative breast cancer patients and the majority of HR-positive, HER2-negative patients as well, even those with no family history, if they could potentially be candidates.
Moving down the line towards more and more testing for germline alterations in hereditary breast cancer genes. But this really will push us because we now have a therapy in the early breast cancer setting.
So, a very exciting ASCO, and we look forward to further analyses of these trials that will continue to improve our practice of breast cancer.
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