Advances on the Horizon for ER+/HER2+ Breast Cancer, But Questions Remain

Sunil Verma, MD

Breast cancer that is both ER-positive and HER2-positive presents a host of unique treatment challenges. Treatment is often based only on HER2 status, but ER status should also be considered, says Sunil Verma, MD, department head, Clinical Department of Oncology, Calgary Zone, medical director, Tom Baker Cancer Centre.

“In some ways, there has been a bit of a lag in progress with the treatment of ER-positive/HER2-positive breast cancer because we’ve incorporated our treatment protocols, regardless of ER status,” says Verma. “I think we need to further identify that these are a different subset of patients, both in the early-stage and the metastatic settings.”

Options for the treatment of ER+/HER2+ disease include combination treatments with both antiestrogen and anti-HER2 drugs and extended adjuvant therapy. ER+/HER2+ patients may also benefit from CDK 4/6 inhibitors, says Verma.

OncLive: What is on the horizon for the treatment of ER+/HER2+ breast cancer?

In an interview with OncLive, Verma discusses advancing treatment in ER+/HER2+ breast cancer, specific therapies that should be considered for this subgroup, upcoming clinical trials, and the biggest challenges and questions that remain in this setting.Verma: In the metastatic setting, we have data from the TAnDEM study to suggest that we can combine antiestrogen drugs, such as anastrozole or letrozole, along with the anti-HER2 drugs lapatinib (Tykerb) or trastuzumab (Herceptin).

There is also a study looking at letrozole and lapatinib together. They have all shown an improvement in progression-free survival, but no improvement in overall survival. There is a lot of interest in the metastatic setting to see if we can combine new targeted agents with endocrine therapy.

An ongoing European study is looking at antiestrogen drugs with trastuzumab and pertuzumab (Perjeta) compared with chemotherapy, trastuzumab, and pertuzumab, to see if chemotherapy can potentially be delayed for some of our hormone receptor (HR)—positive patients. I think that kind of approach is what is being investigated in the metastatic setting.

In the adjuvant setting, I think there is a lot of interest to see if HR-positive disease behaves differently. We do know that the pattern of recurrence is different and, because of that, these patients may require extended antiestrogen treatment.

There was initially some suggestion that these patients may respond more favorably to aromatase inhibitors, but recent data in this area suggest that benefit is seen both with tamoxifen and aromatase inhibitors. One is not better than the other. It may be that we just need to extend the duration of therapy, regardless of which type of therapy we use.

There is also interest in this space because of the ExteNET trial, which looked at neratinib. This suggested that there is potentially a benefit, specifically seen with patients who are HR+/HER2+ in the adjuvant setting. There are some toxicity concerns with neratinib, so that will need to be an area of further evaluation.

What are the biggest challenges in treating ER+/HER2+ patients?

Is there a potential benefit to extending endocrine therapy beyond 5 years for ER+/HER2+ patients?

In the neoadjuvant setting, given that pathological complete response rates tend to be lower, the question is, “Can we use a different approach?” That is where the ADAPT trial comes in. I think we need to see if we can move away from chemotherapy.This is a heterogeneous space, and that can be challenging. At times, these HR+ patients may still derive a benefit from a number of our standard progesterone receptor—positive approaches. CDK 4/6 inhibitors will also be investigated in this space, as well, because ER+/HER2+ patients may also derive a benefit from CDK 4/6 inhibitors. Those trials will be planned and open for accrual shortly.We don’t have any data yet on extended adjuvant therapy, but it will be coming later this year. One of the trials we do have data from is MA.17, which looked at 5 years and beyond on aromatase inhibitors, and 10 years and beyond in those patients who received tamoxifen followed by an aromatase inhibitor.

We don’t have any data to suggest what we should be doing at the present time; however, clinical practice is varied, and a lot of clinicians, including myself, do consider extended therapy to be beneficial for some of our patients.

Will there always be a role for chemotherapy with this patient population?

For now, clinicians have to individualize the treatment decisions for these patients, including HER2+ patients, but understand that these patients do remain at a high risk for recurrence beyond 5 years, and they should have a discussion with them regarding extended therapy until we get the data.We are not ready to give up on chemotherapy in ER+/HER2+ patients yet, but I think that is where the science needs to go.