This article is more than 5 years old. Information may no longer be current.
Guest Commentary: Debu Tripathy, MD, reviews highlights in breast cancer from ASCO 2017
Click Here to Manage Email Alerts
In this guest commentary, Debu Tripathy, MD, professor and chair of the department of breast medical oncology at The University of Texas MD Anderson Cancer Center and a HemOnc Today Editorial Board member, reviews highlights from the ASCO Annual Meeting in several subtypes of breast cancer, including HER-2–positive, hormone receptor–positive and triple-negative disease.
This year at ASCO, there were several developments in all subtypes of breast cancer that are immediately, or in the near future, going to have an impact on treatment. Many of these are extensions of findings that were published in the last several years.
In HER-2–positive breast cancer, we are continuing to make improvements in outcome. This is a type of disease with a clear target that is important even in multiple lines of therapy. The use of pertuzumab (Perjeta, Genentech), a second antibody against the HER-2 receptor, was initially shown to have an impact in metastatic disease, improving survival over and above that of trastuzumab. It is now routinely used in neoadjuvant therapy, where it increases the pathologic response rate. The big question is whether it can improve long-term, reoccurrence-free OS in early-stage breast cancer when used not only with chemotherapy, but when given for a full year in combination with trastuzumab. The data from the APHINITY trial was positive, so this is going to have a significant impact on how we practice medicine for a subset of cases that present at an early stage.
The key issue here is going to be what the absolute benefits are and how they trade off against side effects. Are there going to be sub-classes of patients that benefit more from the addition of pertuzumab, such as those with hormone receptor–positive disease? So far, it appears that the safety signals are minor and that this can be given without major toxicities, although there is slightly more diarrhea. Longer follow-up, looking at which subset benefits the most, is going to be important since the overall absolute benefit for recurrence-free survival at 3 years was only 1% overall and about 2% in the node+ subset. The approval that is likely to ensue will probably cover essentially all cases, potentially focusing on the higher-risk groups such as patients with disease that is node-positive or greater than or equal to stage 2. However, it remains unclear if adding pertuzumab just during the chemotherapy phase may confer similar benefits.
Emerging role of CDK4/6, PARP inhibitors
The other advances have been in hormone receptor–positive breast cancer. The use of newer biological drugs – initially with everolimus and then more recently with two cyclin-dependent kinase 4/6 inhibitors, palbociclib (Ibrance, Pfizer) and ribociclib (Kisqali, Novartis) – have really changed the management of all patients in the first and second lines of therapy. Just about everybody is a candidate now to receive drugs like palbociclib and ribociclib for first-line therapy in combination with aromatase inhibitors or for second-line therapy with fulvestrant (Faslodex, AstraZeneca).
One of the questions that has come up is whether we’re going to see a survival benefit, given the cost and the additional inconveniences of the testing that is required for these drugs. Data from the PALOMA-1 trial, a smaller, randomized phase 2 study, initially showed a dramatic benefit in PFS, which doubled. However, none of the studies so far have shown a survival benefit.
It’s important to recognize that these studies were not designed and powered to show a survival benefit, because the number of death events is still rather small; patients are living for quite a long time. Also, patients undergo many treatments after first-line hormonal therapy. We don’t record these treatments or their benefits and the PFS associated with second, third and fourth lines of therapy, so it’s very difficult to determine the impact of these other treatments. As a result, we may not actually know from these trials whether we are impacting survival.
We’re going to have to develop other metrics, such as the time to first treatment with chemotherapy, the cost of treatment and quality of life. We expect to see some of these details come later, but I must say that, at the moment, the vast majority of patients receive these biologic drugs.
Another issue is that we have very little information about how to treat a woman who progresses following treatment with a CDK4/6 inhibitor. Everything we know about second, third and fourth line therapy is in the pre-CDK4/6 inhibitor era. We’re going to have to learn how to use newer biological drugs and standard hormonal therapies in the population of patients who have progressed. Secondarily, the holy grail in the field right now is identifying a biomarker that predicts which patients will benefit specifically from CDK4/6 inhibition. These biomarkers have, to date, remained elusive, and more correlative studies from tissue collection trials are needed.
There have also been several developments in triple-negative breast cancer. This is a difficult cancer to treat, especially in the advanced setting where we have very few options apart from chemotherapy. The options we do have tend to result in transient responses, and it’s unclear whether they affect OS to a major degree, but some new strategies have emerged.
The first of these is the use of PARP inhibitors, which we know are primarily active in cancers that have germline BRCA1 or BRCA2 mutations. Given the fact that the BRCA1 mutation increases the likelihood of developing triple-negative breast cancer, there has been focused interest on these drugs.
We’ve known for some time that PARP inhibitors are active in BRCA-deficient cancers, particularly in ovarian cancers. PARP inhibitors have been approved in ovarian cancer and we now have the first glimpse of some of the newer PARP inhibitors in breast cancer. Talazoparib (BMN 673, Pfizer), for example, is one of the more potent PARP inhibitors; it has what’s called “high PARP-trapping” activity. The early phase 1 data, which was published earlier this year, did show benefits in several types of cancers; in breast cancer with BRCA mutations, the response rate was 50%. A larger phase 2 study was reported by Nicholas C. Turner, MD, PhD, a consultant medical oncologist at the Royal Marsden and a team leader at the Institute of Cancer Research in London, and his group at ASCO that showed a response rate in the 30% range among patients with BRCA mutations. The responses are not that long-lived.
The concern is that resistance may develop more rapidly. There was also a sense that patients previously exposed to platinum agents may not respond as well; there may be some overlapping activity between DNA-damaging agents like platinum-based chemotherapy and PARP inhibitors. We have to learn more about that interaction. I think the field is going to be looking for an expanded group of patients who have a wild-type germline BRCA mutation as well as other defects in DNA repair, and, secondarily, determining how to use combination drugs, such as signal transduction inhibitors and other drugs, that may synergize with PARP inhibitors.
Ongoing research examines use of immunotherapy
The other big area in triple-negative breast cancer is immunotherapy. It’s hypothesized that triple-negative breast cancers, because they have more genomic aberrations, subsequently more altered proteins more and therefore be more immunogenic. The focus has been in that area, where initial phase 1 trials have showed a response rate in the 20% range. A much larger study with pembrolizumab was presented at this meeting that showed more sobering response rates in the 5% to 6% range. PD-L1 positivity or negativity, did not seem to affect response rates. As a result, at least in breast cancer, there may be other markers that could select for patients who are going to have the best responses. We need to identify what these markers are, whether they’re simply tumor-infiltrating lymphocytes, whether there’s a particular phenotype or whether there may be other pathways or signatures that will elucidate the best group of patients to treat with these therapies.
Many believe that breast cancer is going to be one of the diseases where we need combination therapies for immunotherapy to work most effectively – for example, drugs that make a so-called “cold tumor hot,” or activate other facets of the immune system so that the checkpoint inhibitors can be more effective. Many of these trials are underway, even in some of the subtypes that are conventionally thought to be unresponsive to these therapies, such as hormone receptor–positive disease. There are many ongoing studies; the field is very active. This is the good news. The sobering news is that the response rates, at least with single-agent therapy, are low, but I still find a lot of room for optimism as we look forward.
References:
Emens LA, et al. Abstract 2859. Presented at: AACR Annual Meeting; April 18-22, 2015; Philadelphia.
Nanda R, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.64.8931.
Disclosures: Tripathy reports that he is an investigator for Novartis and that he receives consulting fees from Novartis and Puma Biotechnology and research funding from Pfizer and Novartis.