Video
Impact of Molecular Testing on Treatment Options in Breast Cancer
Shared insight on specific treatment options in breast cancer made available when patients are found to have actionable targets via molecular testing.
Transcript:
Joyce A. O'Shaughnessy, MD: Sarah, do you think that it'll be helpful for the pathologists to know about the trastuzumab deruxtecan [T-DXd] once we see the data in HER2 [human epidermal growth factor receptor 2]-low? There's been a press release from the DESTINY-Breast04 trial, which is a phase 3 trial in HER2, not amplified patients with HER2 [1+] and 2+ expression where they were randomized. They were either triple-negative or hormone receptor-positive and randomized to single-agent chemotherapy of physician's choice versus the trastuzumab deruxtecan. We heard that was a positive trial that'll be presented at the ASCO [American Society of Clinical Oncology] Annual Meeting 2022 in June this year. We'll have to see the data and wait for FDA approval. I worry that some of those that are very low-level expressions could potentially be called HER2-0. What's enough staining to be HER2-1? I worry less about the distinction between 1+ and 2+ unless we see a difference between that population. We'll just have to wait and see. I worry about zero and about 1+ and wanting to see benefit of the doubt for the patients. Talking to the pathologist, these are good tumor board discussions, aren't there? But what do you think about it in terms of the educational needs? Let's assume this becomes available to us for the HER2-low.
Sara A. Hurvitz, MD: You bring up a good point, because prior to these data that we're eagerly anticipating, it didn't matter to distinguish 0 from 1+ and 2+ as long as the tumor was not FISH-amplified or overexpressing; that was the important factor we needed. These very subtle differences from 1 pathologist saying it's 1+ and another saying it's 0 may become clinically relevant. This stain has been fraught with interpretive variability as well as reliance on the technique by which the stain is done, the fixation time, and the antibodies used. I wonder if this will have to undergo an overhaul if this therapy is available for patients, so that we can make sure that we are not missing patients who have some low level of expression in the tumor. There's a group of scientists who are beginning to ask whether there is truly any HER2-0 breast cancer because breast cancers have a higher level of HER2 expression than normal cells. It's possible that there are responses in patients who have HER2-0 by IHC [immunohistochemistry]. That threshold for expression level on the breast cancer cell must be defined in future studies. We're eagerly waiting to not only see this data, but the biomarkers, because they did central testing. That's going to be important.
Joyce A. O'Shaughnessy, MD: Yeah, that's great, it'll be interesting. It'll be another nice option for patients because we've all been very impressed with the T-DXd [trastuzumab deruxtecan] in the metastatic setting and the HER2 amplified patients. A few words on the metastatic molecular testing: we’re understanding who's not amplified, but who is HER2 one or two plus, erring on the side of calling 1+ rather than 0. If somebody is on that borderline, it’s important in patients with triple-negative breast cancer. The first thing we need to know about in the metastatic setting is PD-L1 expression using the 22C3 antibody and the combined positive score because of the availability of pembrolizumab for patients. We need to know the germline BRCA1 and BRCA2 status, and maybe even one could submit the germline PALB2 status because of data on olaparib that small numbers might be beneficial to patients with germline PALB2 somatic mutations. There's a growing number of mutations that could be of clinical utility. Somatic BRCA1 and -2 would be two of those. And again, small numbers, but 50% response rates in small numbers with olaparib in the somatic BRCA1 and -2. We would like to know about ESR1 mutations, particularly as we hopefully get United States Food and Drug Administration [FDA] approval of the first oral SERD [selected estrogen receptor degrader], an oral fulvestrant called elacestrant, that is more effective than fulvestrant in the ongoing EMERALD trial, and particularly effective in patients with ESR1 mutations, which is very interesting. I think that it will be of interest in patients whose breast cancer is progressing on a CDK4/6 inhibitor since we have alpelisib. It's interesting to note HER2 mutations. I just saw a patient with a HER2 mutation. She had been on palbociclib and an AI for a long time, she went onto capecitabine, she's progressing in her liver, a recent liver biopsy shows a HER2 mutation, she has a number of standard options available to her, but I didn't prioritize a HER2 mutation. In your own practice, Sarah, what are you doing when you see that? Because that's 1 of the mechanisms of resistance that can come up and can be acquired in the setting of the CDK4/6 inhibitors and the aromatase inhibitors.
Sara A. Hurvitz, MD: Until recently, we had the summit study open. There aren't cohorts enrolling at this time, at least in our institution, but I enrolled several patients who had HER2 mutations on the trial evaluating neratinib in combination with trastuzumab, and fulvestrant for those who had hormone receptor-positive HER2-mutated cancer. On my end, of 3 patients, I've seen 2 patients have great responses, which has made me a believer. You've been talking about this for some time and this data just continually emerges; there have been several poster presentations. Most recently, at San Antonio Breast Cancer Symposium, an oral presentation went over some of these data from the summit. The idea is that an oral tyrosine kinase inhibitor gets inside and targets the intracellular portion that is constitutively active, allowing HER2 to fire off in spite of it not being overexpressed or amplified at the genetic level. It's proof of principle data. I'm hoping that we see more trials, larger studies providing proof of principle, and maybe even an approval. As you said, there are patients who develop HER2 mutations, and it's interesting. I've seen lobular cancers, which are so tough to treat in the metastatic setting, and I've seen a few patients with HER2 mutations who have lobular cancers that have gone through all their endocrine therapy options. It'd be great if we had another option.
Joyce A. O'Shaughnessy, MD: I'll bet you. We'll just have to wait and see. If we have the trastuzumab deruxtecan available for the HER2-low, to what extent is there going to be an overlap with those who have HER2-mutant [breast cancer]? I suspect there'll be good overlap there that those patients may have another option in the T-DXd. We'll see. I suspect that there will be some degree of overexpression in those patients who are HER2-mutant. But I agree with you, I like the neratinib and fulvestrant, and more recently, the addition of the trastuzumab as a triple. I think that's very useful for patients, and it tends to work.
Transcript edited for clarity.
