Less May Be More: Refining HER2-Positive Breast Cancer Care

Mothaffar Rimawi, MD

The failure of dual HER2-blockade with lapatinib (Tykerb) and trastuzumab (Herceptin) to improve outcomes versus trastuzumab alone in early breast cancer reverberated throughout the field when the phase III ALTTO data were reported.

“It really showed us that we cannot keep accumulating 1 treatment on top of the other, and that we need to consider a measured approach of replacing or de-escalating treatments to maintain outcomes without increasing toxicity,” Mothaffar Rimawi, MD, associate professor, Breast Center Clinic, Baylor College of Medicine, said in an interview with OncLive.

“As we start to accumulate treatments on top of each other, does everyone need everything?” Rimawi added.

OncLive: How has the understanding and treatment of HER2-positive beast cancer evolved in recent years?

In an interview with OncLive, Rimawi discusses key recent data with HER2-targeted agents and the need to identify patients for whom optimal care may mean de-escalating therapy.Rimawi: HER2-positive breast cancer represents approximately 20% of all breast cancers. It is unique in the overexpression of the molecule HER2 that drives tumor growth and progression, and so it became a very attractive target. Multiple treatments have been developed for it, including the monoclonal antibodies trastuzumab, pertuzumab (Perjeta), and TDM-1 (ado-trastuzumab emtansine; Kadcyla), as well as TKIs such as lapatinib, afatinib (Gilotrif), and neratinib.

With the proliferation of all these drugs the question became, “How do we treat individual patients?” The preclinical and clinical evidence seems to suggest that inhibiting the HER2-pathway would be clinically advantageous. The way that we look at HER2-positive breast cancer changed around 2005 when data from the adjuvant trastuzumab trial were presented. These showed a remarkable improvement in outcomes with the addition of 1 year of trastuzumab.

However, clues from the lab told us that, if you inhibit the pathway incompletely, say with trastuzumab alone, then the pathway could still be partially on and the cancer cell could still survive. There are some animal models that show that if you actually combine multiple agents, you can improve the outcomes of these tumors and the mice would respond nicely to treatment. Another thing that we saw in the animal models is that, if the tumors were also expressing the estrogen receptor, they should also be inhibited to avoid tumor progression.

What trials have been pivotal to better understanding trastuzumab combinations?

In the clinic, the same concept was developed. Several clinical trials looked at the addition of a second HER2 agent to trastuzumab and chemotherapy. This was shown to significantly improve outcomes in terms of response to treatment. The challenge is: does that really save more lives? The ALTTO trial, which added lapatinib either alone, in sequence, or in combination with trastuzumab to standard chemotherapy, taught us a lot. That trial did not really demonstrate any benefit to the addition of lapatinib, which came as a letdown. However, it really showed us that we cannot keep accumulating 1 treatment on top of the other, and that we need to consider a measured approach of replacing or de-escalating treatments to maintain outcomes without increasing toxicity.

What did we learn from the ExteNET trial?

Another thing we learned from those trials is that patients are doing well, which indicates that, yes, we have to do better for the patients who are not doing well. However, we also need to care about the toxicity of the patients who are doing well, which are the consequences they are getting from treatment. The ExteNET trial looked at neratinib given after the completion of adjuvant trastuzumab versus placebo. We recently received some updated data on that trial. We learned that the addition of neratinib does result in a small but statistically significant improvement in survival.

With the goal of de-escalating treatment, what approaches are being considered for patients who don’t need as much therapy?

There are 2 issues with this trial. First, the trial was amended several times and there were several changes made to the trial during its course. Secondly, and importantly, neratinib results in a significant amount of toxicity with diarrhea. In a drug that needs to be given for 1 year, we need to be mindful of the toxicity it provides. Despite these issues, the trial still presented some intriguing data that we need to consider. We went over several trials that looked at a targeted therapy only approach—some with targeted HER2 or ER when either is expressed. These showed that there is a minority, but a good portion, of patients who achieve pathological complete response in a clinical trial without the need for chemotherapy.

The question then becomes, “How can we spare those patients who won’t benefit from chemotherapy?” Clearly, we need to do more studies on molecular predictors and perhaps imaging predictors to try and identify these patients upfront. There are other trials that examined de-escalating chemotherapy in small tumors and that approach has been successful, as well.

The main message is that we really need to have a wide, large-scale, collaborative, deliberate effort on de-escalating treatment to patients without compromising outcomes. It is a service to science to understand the drivers of the tumor and treat it more intelligently. It’s a service to our patients to spare them unnecessary cost and toxicity.