Evolving Role of HER2-Targeted Therapy in Breast Cancer

Erika P. Hamilton, MD: Let’s move on and discuss the evolving role of HER2-targeted therapy. You can talk a little about the history of trastuzumab and pertuzumab, and the combination.

Stephanie Graff, MD, FACP: Yes. Like you alluded to earlier, we’ve had trastuzumab since the 1990s. We all know, honestly, it’s one of those career-altering, life-altering discoveries—the work of Dennis Slamon, MD, PhD, —and it was definitely a flashbulb moment in the field of oncology when trastuzumab entered the field. But we started to see it used in combination with pertuzumab through the work of the CLEOPATRA investigators. In those studies, they combined it with pertuzumab, understanding that because pertuzumab works by inhibiting receptor dimerization that it would be complementary to trastuzumab for patients with HER2-positive metastatic breast cancer.

We ultimately saw an overall survival advantage for patients who got the dual HER2-targeted therapy of trastuzumab and pertuzumab that was dramatic and exciting. We saw that the median overall survival improved from 40 months to 56 months, with a hazard ratio of 0.68. That paper was practice-changing, and we now consider a taxane-based dual HER2-targeted therapy to be the standard of care in the upfront management of metastatic HER2-positive breast cancer. That really has set the pace for HER2 drug development. And since the CLEOPATRA study and pertuzumab has entered the stage, we’ve had all of these new drugs start to emerge, and that is really exciting.

Do you want to tell us a little bit about the T-DM1 [trastuzumab emtansine] story, because that was big at the same time and on the heels of the pertuzumab story?

Erika P. Hamilton, MD: Yes, absolutely. T-DM1 is an antibody-drug conjugate. I go through this silly spiel with my patients to explain exactly what an antibody-drug conjugate is. Is it chemotherapy? Is it not chemotherapy? Exactly what is it? An antibody-drug conjugate is where you have the chemotherapy attached to the antibody. I explain it as when we infuse that compound into the body, it just floats around, not really doing much. It’s not like a naked chemotherapy. It’s not going to attack all of the cells it’s seeing. Instead, when the antibody binds to the target cell—in this case if it’s trastuzumab, it’s the HER2 receptor—then that’s where the chemotherapy is released directly on the cell. It got coined in the media as being a smart bomb, right? It’s a targeted way to deliver chemotherapy directly to the cell that you’re trying to get at. T-DM1 is a beautiful example of this. It’s chemotherapy that is linked to the trastuzumab molecule and gets that molecule exactly where it needs to go to combat cancer.

T-DM1, as is the case with many drugs in breast cancer and oncology, was really first thoroughly explored in the metastatic setting. It’s kind of settled in as our second-line treatment of choice. After taxane, trastuzumab/pertuzumab, we often use T-DM1. T-DM1 has some advantages. I find that my patients feel pretty good on T-DM1 therapy. They don’t get as much neuropathy, hair loss. We do have to watch for low platelets and elevated liver function tests [LFTs] in patients. But again, for the large part, those are laboratory abnormalities that we can monitor and adjust dosing as needed.

There is some cumulative fatigue that I think a lot of patients experience with T-DM1 therapy as well, but I’ve certainly had patients do very well on T-DM1 therapy. It can be tolerated for a number of years. Stephanie, what’s been your experience with T-DM1?

Stephanie Graff, MD, FACP: I think that compared to trastuzumab/pertuzumab in combination, I see more diarrhea that can be limiting for some patients; although, again, the patients with dual HER2-blockade do great and have a great adverse effect profile/toxicity profile. With T-DM1, I agree. Mild platelets, LFT abnormalities that, for the most part, are lab changes that don’t necessarily have a clinical implication for the patient. However, I have had a few patients whose peripheral neuropathy continues to progress or amplify on T-DM1 therapy, so that’s definitely something I continue to monitor.

Transcript edited for clarity.