Optimizing Chemotherapy for Metastatic Breast Cancer

Transcript:Joyce O’Shaughnessy, MD: How exactly to optimize the use of chemotherapy for the various metastatic subsets of patients truly is a practice-long, lifelong, multi-decade practice, if you will. Let’s start with the triple-negative patients. There is a small group of triple-negative patients that have very highly proliferative, so-called basal-like, triple-negative breast cancer. I always rebiopsy patients when they recur with metastatic disease. And there’s a group of the triple-negative patients that have a phenotype of highly proliferative disease, really ER-PR-HER2 zero. Particularly those—and it’s demonstrated in the Steven Isakoff JCO paper from 2015, I think it is—patients have metastases of their triple-negative to thoracic lymph node disease, parenchymal lung, or in the breast. There’s a very small percentage of triple-negative, about 10%, that will go into a multi-year complete response with cisplatin. A few patients with carboplatin—carboplatin AUC of 6, cisplatin 75 mg/m2—will go into a CR. At least by the time he finished publishing the paper, these patients were 4 or 5 years out and they had not recurred. I never want to miss that opportunity. It’s very rare in triple-negative breast cancer to get highly durable responses. So, I always utilize that Isakoff paper for that phenotypic group of patients.

But other patients have more luminal sites of metastasis. They have, for example, bone disease or bone liver disease. And I’m not as certain that they will at least initially get a strong benefit from a platinum-based regimen, either platinum alone or gemcitabine/carboplatin. There are exciting new data about nab-paclitaxel/carboplatin presented by Denise Yardley at San Antonio this past year. But a taxane is a very good place to start for a lot of these patients, if it’s been a number of years since they’ve had a neoadjuvant or adjuvant taxane, for example. And I find very good success with that if they have particularly liver-bone type metastasis.

Some patients that had a lot of tumor burden and are very, very symptomatic—visceral crisis in liver or shortness-of-breath difficulty, breathing with just lung volume metastasis—they need combination chemotherapy. And this combination of nab-paclitaxel and carboplatin has been shown, in this randomized phase II trial that Denise Yardley had at San Antonio last year, that the nab-paclitaxel/carboplatin was superior to nab-paclitaxel/gemcitabine and to gemcitabine/carboplatin with regard to progression-free survival and response rate. I think of it as a double evidence-based doublet therapy. That’s one of the few studies we have looking at the various doublets. So, I think that’s an excellent option for patients who really are in desperate need for an immediate deep cytoreduction.

Other agents in triple-negative breast cancer include eribulin because eribulin is a very non—cross-resistant agent. It’s one of the few agents—and this is really true for all of the 3 subtypes of breast cancer—that’s not so much subtype specific. It’s getting at this mesenchymal biology that’s highly invasive that, unfortunately, all of these cancers develop by the time they’re heavily pretreated. Because if the chemotherapy doesn’t kill the cell, it wounds it and then it goes from becoming proliferative to protecting itself. It gets more metastatic and more invasive-like to get out of there basically, and our chemotherapy agents don’t tend to work as well. They’re more proliferative, not as much mesenchymal. And eribulin is both. It’s both antiproliferative, and it is antimesenchymal. And so, it’s an agent that I utilize quite a lot for any site of triple-negative breast cancer in pretreated patients, particularly those who had had a prior taxane, for example, or a prior platinum. It’s quite non–cross-resistant because most patients have had a prior anthracycline in triple-negative breast cancer.

So, for estrogen receptor-positive breast cancer, that is now endocrine therapy-resistant. Generally, we try to have patients have multiple lines of endocrine therapy. Unfortunately, there comes a time where they really do need to go on to chemotherapy, and generally speaking, I utilize single-agent capecitabine. Because a lot of our anti-estrogen therapies—CDK4-6 inhibitors, mTOR inhibitors—are really aimed at the PI3 kinase pathway, you get outgrowth proliferative breast cancer. Capecitabine can really be an excellent therapy for those patients. It’s very well tolerated. It can give quite durable responses. Most of us will go on to a taxane next, including myself, for those patients after capecitabine. And generally, the third-line agent is eribulin. Again, we don’t have that many things that are non—cross-resistant, and eribulin has shown a survival advantage in later-line metastatic breast cancer because of this non–cross-resistance.

And then, lastly in HER2-positive disease, there is a series of treatments that are a little bit more algorithmic because of the way the agents have been serially developed. So, definitely the first-line treatment for HER2-positive metastatic breast cancer is a taxane, docetaxel or paclitaxel, with trastuzumab and pertuzumab, per the CLEOPATRA trial. That’s clearly the first-line treatment: give about 6 to 8 cycles of chemotherapy, stop the chemotherapy, and continue the anti-HER2 agents indefinitely until the time of progression.

The NCCN guidelines then call for a TDM1 for second-line treatment in HER2-positive disease, which is a very reasonable option. And also, the lapatinib-capecitabine combination is another one. Capecitabine with trastuzumab is also very well worked out. So, these are the main sequences we use of chemotherapy in HER2-positive disease.

Transcript Edited for Clarity