Panelists: Mark Pegram, MD, Stanford Cancer Institute; Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center
Mark Pegram, MD: There have been considerable advances in our understanding of the use of chemotherapy in different subclasses of breast cancer. In particular, there are some recent data looking at the activity of platinums in the setting of triple-negative advanced breast cancer. There was a trial, called the TNT trial, where carboplatin was compared head-to-head against docetaxel. And for patients who had germline BRCA1 or BRCA2 mutations, the patients responded particularly well to the carboplatin. Moreover, even in the patients who didn’t have those mutations, carboplatin faired as well as docetaxel and, arguably, is probably better tolerated. So, there’s growing enthusiasm now for the use of platinum salts early on, usually in first-line and triple-negative metastatic breast cancer. However, since the enthusiasm for platinums is gaining also in early stage disease, now we’re often confronted with patients who have already had platinums, either as part of their neoadjuvant or adjuvant therapy. Then, that makes the difficult decision as to whether to try a platinum again in the first-line.
After a platinum-based regimen, we’re typically using the classical sequence of the most active agents used in sequences, probably starting with taxanes and moving through the lines to the vinca alkaloids to eribulin, etc. And in triple-negative disease, that is the mainstay of the management of metastatic breast cancer outside of the clinical trial. For steroid receptor-positive disease, the principles are nearly the same as for triple-negative, except for the use of platinum salts, which is probably less advised. But the principle of using sequential single agents still applies. In the ER-positive arena, we’re usually starting with the least toxic, most convenient, and easy chemotherapeutics. For example, capecitabine is often the first foray into the chemotherapeutics class of treatment from targeting estrogen receptor approaches.
After capecitabine, then we typically are looking at probably using taxanes. The alkaloids are also very active. Vinorelbine, for example, is very well-tolerated and can be given for quite some time until first neuropathy or cytopenias intervene. Eribulin is another active agent. We’ve moved through these lines at the stage of disease progression with each agent, and in many cases, we try to maybe alternate mechanism of action, too, to try to avoid the same drug classes. For example, if you used a taxane, you may not use another taxane in the series. You might want to switch to a different drug class after progression on the taxane. But the principles are largely the same: sequential single-agent chemotherapy after progression on endocrine therapy.
Finally, for the HER2-positive states, unfortunately, even with the advent of HER2-targeting agents, we’re still using chemotherapy combinations because of the synergism between chemotherapeutics and anti-HER2 agents. And this is true both with antibody-based therapeutics as well as small molecules. And typically for HER2-positive first-line metastatic disease, we’re looking at the CLEOPATRA trial-like regimens, which were docetaxel, pertuzumab, and trastuzumab. They have a major survival advantage. And the only nuance on that update is that you can probably substitute in weekly paclitaxel for docetaxel in that regimen because it is much better tolerated than docetaxel. And in a nonrandomized but still sizable clinical trial of weekly paclitaxel/pertuzumab/trastuzumab, the point estimate on a median progression-free survival in that study matched the experimental arm of the CLEOPATRA trial. So, I feel comfortable using weekly paclitaxel in that sense.
After progression on a CLEOPATRA-like regimen with HER2-positive disease, we’re typically looking at treating with TDM1 next. TDM1 is very well tolerated. You just have to monitor the liver function tests and monitor for thrombocytopenia, and make dose modifications as needed. But it’s, overall, particularly well tolerated and doesn’t have so many chemotherapy-like side effects compared to giving free chemotherapeutic agents. However, the principle of TDM1 is that it does have a chemotherapeutic species. It’s just covalently linked to the trastuzumab antibody backbone. So, there are some chemotherapy effects—a little bit of nausea, sometimes some alopecia, etc. After that, then we’re looking at lapatinib-based regimens typically, either lapatinib/capecitabine—which is FDA-approved—or sometimes lapatinib in combination with trastuzumab. And then, following progression on a lapatinib-based regimen, you’re basically looking at a chemotherapy backbone with continued trastuzumab, typically in the salvage setting. So, sometimes for the breast cancer in the advanced disease setting, we’re still using chemotherapy as the mainstay and the backbone of treatment of this disease.
Many times, it’s necessary to discuss various chemotherapeutic options with patients because they might have a concern about a particular side effect with one class of chemotherapy versus another. Since we have many options to treat patients with, it’s often the case that we present a balanced discussion of a range of 2, or even 3, different potential chemotherapeutic options. And then, based on the description of expectations, in terms of effectiveness but also side effect profile, patients may weigh in on the decision about which treatment they want to use next based on the toxicity profile. This is a typical approach, and it’s often the case that you’re not looking at just one type of chemotherapy in a treatment decision for advanced breast cancer.