Triple-negative breast cancer has a reputation for being a particularly challenging malignancy, but breast cancer specialist Nancy Davidson, MD, Senior Vice President of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, Seattle, put this in perspective in a recent article in the Journal of Oncology Practice,1 which she authored with V.K. Gadi, MD, PhD. Dr. Davidson described the promising avenues of research and shared her thoughts on management strategies, in her article and in this interview with The ASCO Post.
Misconceptions and Opportunities
What are the main misconceptions about triple-negative breast cancer?
This is a cancer for which we could say there are unmet needs but also many opportunities. There is sometimes the misconception that triple-negative breast cancer is a horrible kind of breast cancer without good treatment options; nothing could be further from the truth. Triple-negative breast cancer is often very chemosensitive. And as we are increasing our understanding about the biology of this cancer, we are raising possibilities for new investigational approaches that may optimize treatment in the future. Clinicians need to be attuned to the state-of-the-art treatments and apply them in their patients, encouraging them to enroll in clinical trials.
There is the belief that triple-negative breast cancer is associated with worse outcomes than most other breast cancer subtypes? Is this true?
The difference between triple-negative and other breast cancer subtypes is that we don’t have obvious targeted therapies for it, as we do for HER2-positive and hormone receptor–positive disease. The challenge is to understand whether there are subsets of triple-negative tumors with biologic pathways that we can take advantage of. For example, some of these tumors are dependent on androgen receptor signaling, and this brings for us the opportunity of possibly using a drug that targets the androgen receptor.
Current and Future Diagnostic Methods
A more refined classification system using gene-expression classifiers (ie, luminal vs basal) is becoming available, which may be an improvement over immunohistochemistry profiling. When can physicians expect to be using it?
This is a work in progress. The first critical thing in any breast cancer diagnosis is accurate ascertainment of the receptor status. If tumors express any receptors, we use appropriately targeted treatment. If they don’t, it’s not totally clear what kind of profiling we should do next. We often think about germline testing for BRCA mutations, and this testing has implications not only for the patient’s treatment but for testing family members. At this time, the standard in practice is to rely on good immunohistochemistry and then perform germline BRCA sequencing as appropriate. We are evaluating more sophisticated molecular diagnostic methods to define the various subsets of this type of cancer and perhaps do a better job in trial allocation, but this remains an area to watch and is not yet applied in the clinic.
Jury Still Out on Platinums
Why has it been difficult to design better chemotherapy regimens for triple-negative breast cancer, and how is this changing?
We have had an expanding repertoire of drugs in breast cancer, although not all have had completely new mechanisms of action. We are beginning to get some information about biomarkers that we can use to select among our chemotherapy options. One of the questions in triple-negative breast cancer is when we should or should not take advantage of the platinums. Work is emerging on this topic, but it still remains an area of active clinical investigation. In some patients, especially those with BRCA mutations, we may think about incorporating platinums into more conventional regimens. The jury is still out as to their benefit in patients with triple-negative breast cancer without BRCA mutations.
Can you offer a few clinical pearls for managing triple-negative breast cancer?
It is important to realize that triple-negative disease affects a significant fraction of patients with breast cancer, and reasonable treatment options are currently available with chemotherapy, surgery, and radiotherapy. Oncologists and patients should use these options in an optimal fashion.
The first pearl is triple-negative breast cancers are frequently very chemosensitive, so chemotherapy can also be viewed as a targeted therapy in these patients. With this type of breast cancer, multiagent regimens are important in early-stage disease—anthracyclines, taxanes, and alkylators. These agents are often used as neoadjuvant chemotherapy, not only to make surgical resection easier but to give us a sense of the chemotherapy responsiveness of the tumor, which has prognostic significance. Of course, the best option would be a trial evaluating a novel agent on a chemotherapy backbone.
How do you address residual disease after neoadjuvant chemotherapy?
A study from Asia, reported a few years ago in San Antonio and recently published in The New England Journal of Medicine,2 showed benefit with postsurgical capecitabine in patients with residual disease after neoadjuvant chemotherapy. So, capecitabine is an option I discuss with my patients who are not eligible for a clinical trial or do not choose to enroll in a clinical trial should one be available to them. Even though capecitabine is an oral agent that is pretty well tolerated, some patients have had enough of chemotherapy. We discuss the pros and cons.
For whom would you consider PARP inhibitors (if any) at this point?
The study of poly ADP-ribose polymerase (PARP) inhibitors in triple-negative breast cancer is an exciting area. They are approved in certain ovarian cancer settings, and work is underway to see whether there will be a U.S. Food and Drug Administration (FDA) indication for these agents in breast cancer. The most interest is in patients with germline BRCA mutations, where PARP inhibitors are being tested in both early-stage and advanced disease.
There is sometimes the misconception that triple-negative breast cancer is a horrible kind of breast cancer without good treatment options; nothing could be further from the truth.— Nancy Davidson, MD
We have now learned that the results are positive for the phase III OlympiAD trial, which compared olaparib (Lynparza) to physician’s choice of chemotherapy in HER2-negative metastatic breast cancer patients with BRCA mutations. At the 2017 ASCO Annual Meeting, the investigators reported a statistically significant improvement in progression-free survival associated with olaparib in women with HER2-negative metastatic breast cancer that was either hormone receptor–positive or triple-negative in patients who had a germline BRCA mutation.3
PARP inhibitors have also gained some traction in the neoadjuvant setting, where they have shown a signal of activity in the I-SPY 2 trial.4 I-SPY 2 is evaluating a variety of biologics given in addition to paclitaxel, with the endpoint of pathologic complete response. The data from many of our trials are promising for PARP inhibitors, but they are not part of routine practice at this time. We are still trying to sort out their value.
Which experimental approaches do you believe hold the most promise in triple-negative breast cancer?
There is great interest in determining whether a subset of patients with triple-negative breast cancer will be especially susceptible to immunotherapy and which conventional agents will likely be paired with immunotherapy agents, since we are unlikely to use immunotherapy alone. There is also great interest in antiandrogens for patients who express the androgen receptor. We have some encouraging early data for this. We are also trying to determine whether there are superior chemotherapy options and targeted agents that we can add in selected patients. And finally, we are working to further subtype triple-negative breast cancer. We know there are at least six different subsets, and we can no longer think of this type of breast cancer as a single disease. ■
DISCLOSURE: Dr. Davidson reported no conflicts of interest.
1. Gadi VK, Davidson, NE: Practice approach to triple-negative breast cancer. J Oncol Pract 13:293-300, 2017.
2. Masuda N, Lee SJ, Ohtani S, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.
3. Robson ME, Im S-A, Senkus E, et al: OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and germline BRCA mutation. 2017 ASCO Annual Meeting. Abstract LBA4. Presented June 4, 2017.
4. Rugo HS, Olopade OI, DeMichele A, et al: Adaptive randomization of veliparib–carboplatin treatment in breast cancer. N Engl J Med 375:23-34, 2016.