Ruth O’Regan, MD, provides insight on the evolving landscapes of ER-positive and HER2-positive breast cancers, and what regimens remain solid approaches for effective patient outcomes.
Ruth O’Regan, MD
Researchers are merely cracking the surface of therapeutic regimens fit for patients with estrogen receptor (ER)-positive or HER2-positive breast cancers, as great work lies ahead in immunotherapy, biomarker identification, and the optimal use of CDK 4/6 inhibition.
“We have seen a huge, rapid approval of agents in the past few years, so it is kind of interesting,” said Ruth O’Regan, MD, a professor of medicine at University of Wisconsin School of Medicine and Carbone Cancer Center. “Up until about 3 years ago, we just had endocrine therapy, which of course is still very important, but now over the past few years, we have a number of targeted agents that all appear to enhance the efficacy of endocrine therapy.”
While CDK 4/6 inhibitors have taken the arena of ER-positive breast cancers by storm, immunotherapy is under investigation in HER2-positive disease, O’Regan adds, explaining that a subset of these patients may elicit responses to that treatment. However, the tried-and-true regimens with HER2-directed therapy remain solid standards, at least in the first- and second-line settings.
In an interview during the 2017 OncLive® State of the Science Summit on Metastatic Breast Cancer, O’Regan, who also chaired the event, provided insight on the evolving landscapes of ER-positive and HER2-positive breast cancers, and what regimens remain solid approaches for effective patient outcomes.O'Regan: Regarding endocrine therapy, 1 of the things that has come out in the last year or so is the data with fulvestrant versus anastrozole in the first-line setting. The data from the phase III randomized FALCON trial did show an improved outcome for patients who got fulvestrant at the 500-mg dosing schedule compared with anastrozole. However, the data results were not as profound as seen in the first randomized phase II study, so we will wait for more data from that study. There were data basically showing that, in patients who did not have visceral metastases, they did have quite a considerable improved outcome [with fulvestrant] versus anastrozole. I am not sure that every patient needs this in the first-line setting but, in the absence of a biomarker telling us whether a patient needs 1 or not, most of us lean toward giving those drugs to patients.
Then, we have the CDK 4/6 inhibitors, which are exciting. We had palbociclib (Ibrance) for several years approved in the frontline setting for hormone-refractory patients. Then, most recently, we got approval of ribociclib (Kisqali) in the first-line setting, as well. As far as those 2 agents go, they appear somewhat similar. There are some slightly different toxicities, but as we start using ribociclib, we will be able to work out how to use it in the real world for patients.
The third CDK 4/6 inhibitor, abemaciclib, has data as a single agent in patients who have heavily pretreated ER-positive metastatic breast cancer. It looks like a very interesting drug with a different toxicity profile, and it can be given continuously. It is clearly different from the other 2 CDK 4/6 inhibitors.
The other area of discussion is inhibiting the PI3K/mTOR pathway in patients with hormone-refractory metastatic breast cancer. Obviously, we have had everolimus (Afinitor) for a number of years. There are recent data of combining everolimus with fulvestrant that looks feasible and encouraging, so we now have an option of giving it with fulvestrant as well with exemestane and tamoxifen. There are some data looking at targeting the PI3K pathway with a pan-PI3K inhibitor in hormone-refractory metastatic breast cancer that showed some signal of activity but, unfortunately, the drug that was used—buparlisib—is quite toxic, so the future development of that drug in this area is probably going to be abandoned.
We are always talking about resistance mechanisms. One that has emerged recently that is very important is ESR1 mutations. They can be detected either in primary tissue or in cell-free DNA. They do appear to be very important because they appear to predict for resistance to aromatase inhibitors, specifically.
When you can look for mutations like this in circulating DNA or circulating tumor cells, it is very interesting. You can kind of see what the cancer is doing in real time versus just doing a biopsy once and correlating that essentially with the outcome of a given drug. It is a very exciting time for ER-positive metastatic breast cancer, and this is obviously going to benefit patients. Abemaciclib does appear to be a little bit different from the other 2 because it can be given continuously. Also, its toxicity is significant diarrhea, which can be managed with antidiarrheal medication. It is the only agent that we have data for showing single-agent activity, but in preclinical studies, it showed apoptosis—which the other 2 agents don’t associate with. This maybe explains the reasonable response rate seen in the MONARCH-1 study with single-agent abemaciclib. Really, it’s quite an interesting drug.
For immunotherapy in breast cancer, we are way behind the eight-ball compared with some of the other tumors. Obviously, there are some data in triple-negative breast cancer (TNBC). The checkpoint inhibitors don’t appear to be as effective in ER-positive breast cancers. The study that was looked at was very small, though, so we don’t really know.
The question with something like abemaciclib is, if you use that either before or with an immunotherapy agent, would you be able to make the cancer more immunogenic, and in turn, make the immunotherapy more effective? We honestly don’t know the answer to that, but there is interest in looking at that combination in the pre-operative setting.The CDK 4/6 inhibitors have been a huge advance for us. You’re looking at doubling progression-free survival (PFS) in the first-line setting with very impressive data. The questions are, first of all, does everybody need a CDK 4/6 inhibitor in the first-line setting? They are expensive, they have some toxicities, and patients do have to come in for blood work—so it’s a little more onerous than having these patients on endocrine therapy. It behooves us to find a biomarker for these drugs, so we can make sure that we are tailoring treatments specifically for patients.
The second big question, of course, is, what do you do when someone has had disease progression on a CDK 4/6 inhibitor? Right now, we have no data whatsoever. There are some preclinical data suggesting there may be some resistance or co-resistance between the different agents, but that has not been shown clinically. We are involved in a trial being run out of Columbia University Medical Center, where we are looking at ribociclib in patients with prior treatment with a CDK 4/6 inhibitor—which could be palbociclib or ribociclib in the first-line setting. That is a clinical study we need to look at.
Then, other combinations are gaining quite a bit of interest—particularly with palbociclib—and looking at them in the HER2-positive arena. I don’t think they are going to have a lot of activity in TNBC, based on what we know so far. However, maybe there is a subset of TNBCs that might benefit. We have just opened a study through the Big Ten Cancer Research Consortium where we are looking at the combination of bicalutamide and ribociclib in TNBCs that express the androgen receptor. Endocrine therapy clearly has been a big success story, but the main issue with it is the fact that cancer—always in the metastatic setting—eventually develops resistance. Looking at some of the targeted agents we have, we’re looking at other mechanisms of resistance to try and make the endocrine therapy last longer for patients. The ideal situation is to just use sequential lines of endocrine therapy with nontoxic targeted agents and prevent patients having to get chemotherapy—that is the key.
In the early-stage setting, toxicity is still an issue. There are patients who can’t tolerate endocrine therapy and that is very problematic, particularly when they have molecular profiling indicating that they do really need to take the drugs. That and compliance is an issue in the early-stage setting. HER2-positive breast cancer has been a big win for us overall. Going back to when the HER2 receptor was discovered, they were found to be very aggressive cancers. However, after that, we discovered trastuzumab (Herceptin) which has totally changed the outcome for patients with HER2-positive breast cancers.
Focusing on the metastatic setting, a pivotal trial showed a significant improvement in survival for patients who got trastuzumab added to chemotherapy if they had HER2-positive disease. That significantly improved overall survival. We have now come even further than that and the very interesting thing is that, based on the CLEOPATRA study, a patient diagnosed with HER2-positive metastatic breast cancer could expect to live for a median of 5 years, which is really quite remarkable—and from drugs that are not that toxic overall.
As far as how we manage patients with HER2-positive breast cancer, we are all very comfortable with the first-line setting using the CLEOPATRA regimen of paclitaxel with trastuzumab and pertuzumab (Perjeta). I don’t think that’s going to change anytime soon. Likewise, in the second-line setting, trastuzumab emtansine (T-DM1; Kadcyla) is the treatment of choice and we are all very comfortable using that agent. It has a very nice toxicity profile.
Obviously, 1 of the key questions is, could you move T-DM1 into the first-line setting with pertuzumab? The MARIANNE study did look at that comparing T-DM1 alone or with pertuzumab with a taxane and trastuzumab-based regimen. It didn’t show any significant difference between the arms; however, you have to keep in mind that using T-DM1 versus a taxane/trastuzumab/pertuzumab regimen might be an option for some patients because it has a better toxicity profile and it doesn’t cause alopecia. Some of us would do that in the first-line setting.
After the second-line setting, after you have used T-DM1, it is a little bit more unclear. That is an area that is right for clinical trials, although, thankfully, there aren’t as many of these patients to put on clinical trials as there used to be. Lapatinib (Tykerb), capecitabine, lapatinib/trastuzumab, or trastuzumab with a different chemotherapy agent would all be very reasonable in that setting.
The other thing that was presented at the 2016 San Antonio Breast Cancer Symposium is a new way of managing patients with cancers that are both HER2-positive and hormone receptor (HR)-positive. The results of the PERTAIN study were presented, which looked at adding in pertuzumab with trastuzumab and an aromatase inhibitor in patients with HR-positive/HER2-positive breast cancer.
Interestingly, they did allow some kind of induction chemotherapy on the study. What they found was whether the patients got induction chemotherapy or not, there was quite a marked improvement in PFS in the patients who got pertuzumab with trastuzumab and letrozole compared with trastuzumab and letrozole. One of the interesting things about that study was the control arm with letrozole and trastuzumab did quite well and much better than we saw in the prior TAnDEM study. I have not been able to find a good answer for why that happened.
For metastatic HER2-positive breast cancer, we are in a good space. There are some other nice agents coming down the pipeline that we will hear about as well. Again, it’s an area where immunotherapy is being investigated.
Moving into the early-stage setting, in general, most of us do use a preoperative approach for treating patients for HER2-positive breast cancer. The general cutoff is if the cancer is over 2 centimeters, we will do a pre-operative treatment. You have a choice of the NEOSPHERE regimen or the TRYPHAENA regimen, I personally prefer TRYPHAENA because it doesn’t contain an anthracycline, the pathologic complete response (pCR) is pretty equivalent between those regimens, and the pCR—particularly for ER-negative/ HER2-positive breast cancers—seems to be so important that, even if we had an adjuvant regimen that looked really great, most of us would still think about giving pre-operative regimens to these patients.
The APHINITY study, which is the adjuvant assessment of pertuzumab, will be presented at the 2017 ASCO Annual Meeting. We know it met its primary endpoint, but nobody knows how significantly positive the data is. However, I’m not sure how that is going to change our approach—most of us are going to lean toward doing a pre-operative approach for these patients.
Moving into the other end of the spectrum, which is patients with small HER2-positive cancers, [we wonder] how do we manage those patients? We are exploring a less-is-more type of approach, so the data from the ABT trial—where they gave 12 weeks of paclitaxel with trastuzumab and saw a very favorable 3-year disease-free survival—is being compared with T-DM1 for these low-risk cancers. This will be very interesting because, again, that offers you a regimen that doesn’t cause alopecia—which is a problem for patients—so that is certainly something that we are eagerly waiting to see.
The last topic I focused on was extending HER2-directed therapy. There are a lot of data about extending endocrine therapy. Is it the same for HER2-positive breast cancers? There is the ExteNET study that looked at randomizing patients with neratinib or placebo after they have received their 1 year of trastuzumab. That was a very interesting study; the patients did better with extended neratinib but it was restricted to ER-positive breast cancers, which is a very interesting finding. However, it’s not approved at this point in time. The ODAC meeting on neratinib is quickly approaching. What are your thoughts on this drug? One of the things about some of these HER2-directed therapies, particularly when you use a dual approach, you do get diarrhea. Diarrhea has been a huge problem with neratinib as it was to some extent with lapatinib. But if you look at the data, and if you are aggressive with antidiarrheal medication in the first and second cycle, it does appear to be pretty manageable for patients.
The bigger question is, would they approve neratinib just for ER-positive breast cancer—where the signal is? They have never done that before. But, if you have somebody with ER-negative breast cancer who has a pCR to your pre-operative treatment, that person does not need extended HER2-directed therapy because their likelihood of recurrence is very low. Therefore, you could make a case where maybe you consider it for a higher, riskier ER-positive cancer. I’m not sure exactly what they will do, but I wouldn’t be too concerned with the toxicity. The data clearly show that the diarrhea is much worse in the first cycle and, once you get past that, it appears to be fairly manageable. For HER2-positive breast cancer, we are going to see some interest in using checkpoint inhibitors. Particularly for the ER-negative/HER2-positive cancers, there appears to be an immune phenotype.
Going back to the less-is-more issue, these ER-positive/HER2-positive cancers are pretty different from ER-negative/HER2-positive cancers. Within the group of ER-positive/HER2-positive cancers, they are very heterogeneous; some of them have a luminal A phenotype. One of the things that will be interesting will be to focus specifically on those luminal A HER2-positive cancers and see if you can get away with a HER2-directed therapy—perhaps dual therapy with blocking HER2 and some endocrine therapy. That will be a great way to get around the issue of having to give everybody chemotherapy. That is really something that we would like to move away from. They are usually the ones that are very sensitive to endocrine therapy. They don’t benefit from chemotherapy; we know that because you hardly ever get a pCR with those cancers in the pre-operative setting. The surprise was the thought that, if the cancer is HER2-positive, then HER2 is driving that cancer—even if it’s ER-positive. Now, it looks like there is a subset of the ER-positive/HER2-positive cancers that may be driven by ER to some extent. However, there is a lot of crosstalk between the 2 pathways, so the idea of blocking both the ER and HER2 pathways aggressively makes some sense in those cancers, but it is just an area that hasn’t been explored. It is an important area because it would be great to avoid chemotherapy in some of these patients. I have actually been recommending cold caps for my patients for years. When I moved up to Wisconsin, nobody was using them. So, we have started using them at the University of Wisconsin. My experience with them is that if they are used properly, they work very well for the non—anthracycline-based regimens. I have some patients for whom I take photographs of; they say they are losing their hair but, in actuality, you wouldn’t even notice [that they are].
We still have some issues with them. They are a little onerous for the patient and they’re expensive. We do not have the Dignicap machine yet, so patients have to bring in dry ice and rent the caps themselves. We always talk to patients about them, but a lot of them choose not to do it because it can be cumbersome in terms of what it entails to do it properly. However, in the patients who have persevered, I have seen very good results.This State of the Science Summit is a great opportunity for us. We are delighted to be able to talk about an overview of breast cancer, what we are doing here at the University of Wisconsin, and let the community doctors know what research opportunities are available and what clinical trials we have. Really, it is a way of reaching out to them and having them come by and meet with us. Hopefully, it was quite social as well as informative.