Expert Sheds Light on Efficacy of Dual HER2-Directed Therapy

Frankie Holmes, MD

Dual HER2-directed therapy has demonstrated promising efficacy as a treatment approach for patients with breast cancer.

For example, the NOAH trial explored neoadjuvant chemotherapy with or without trastuzumab (Herceptin) in women with HER2-positive locally advanced or inflammatory breast cancer. The trail showed a clear difference in the trastuzumab arm, which demonstrated benefit of the combination regimen. The 5-year event-free survival rate was 58% (95% CI, 48-66) for the trastuzumab group and 43% (95% CI, 34-52) for the chemotherapy control group. Overall survival (OS) rates at 5 years were 74% (95% CI, 64-81) for the experimental group and 63% (95% CI, 53-71) for the control.

Despite these positive findings, there remains a need for further research pertaining to therapies for HER2-positive patients who do not meet the current criteria for this neoadjuvant regimen.

"There are still many questions that remain to help us decide who really needs the full-court press with its attendant complications," said Frankie Holmes, MD. "I think we need science to discover those biomarkers so that we can really give the patients who need maximum therapy what they need."

OncLive: How has neoadjuvant HER2-directed therapy management evolved and what challenges remain?

Are there questions within this space that you would like to see addressed?

In an interview with OncLive, Holmes, breast medical oncologist, Texas Oncology, discusses HER2-directed therapy with trastuzumab and pertuzumab (Perjeta). She also shares her interpretation of the recent MA17R trial, which evaluated an extension of adjuvant letrozole for 5 years following completion of an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.Holmes: In the neoadjuvant setting with HER2-positive disease, I don't see major challenges now. I see major opportunities because the response rates are so high with the dual-targeted agents.One of the questions in the neoadjuvant treatment space right now is the need for the dual anti-HER2 targeted therapy in patients who don't meet the present criteria. That is, patients whose tumors are less than 2cm and who do not have lymph nodes that are positive. Patients who are ER-negative, who have the HER2-enriched phenotype, have a much more aggressive phenotype. It may be that even these smaller tumors are the ones that will need the dual HER2-targeted therapy, whereas the more luminal HER2-based tumors may not need that dual-targeted therapy.

How do you interpret the MA17R trial?

There are still many questions that remain to help us decide who really needs the full-court press with its attendant complications. Pertuzumab causes severe diarrhea in some patients, and of course there are the cost issues. I think we need science to discover those biomarkers so that we can really give the patients who need maximum therapy what they need. Perhaps we need something like a 21 gene recurrence score for HER2 to find out who are the really bad HER2 patients and who are the good HER2 patients.The MA17R trial initially was a little bit overwhelming when they showed that the major effect was on contralateral and local recurrence— 3% versus only 1% with distant recurrence—but I think the trial was put into focus, at least for me, with the subsequent day presentation of the 20-year overview. That overview showed that there is a continued recurrence out to 20 years, and this trial was reported only at a median follow-up of a little over 10 years. Even though the trial seems that it has late reporting, it's really somewhat young in terms of the overall natural history of breast cancer. I think that we haven't seen all of the relapses to give us the full input.

What tools are out there to decide if an extension of aromatase inhibition is right for a particular patient?

Questions that were raised about the tolerance are again the ones that are troubling, because these were the patients that were self-selected to continue on this treatment. They didn't seem to have any problems, but all of us in practice have those patients who are just counting off the days to stop their aromatase inhibitors. Again, I think one of the themes that continues to emerge is that we have to do a risk analysis of who really is at risk for these types of problems of late recurrence.The BCI, or Breast Cancer Index, is one of those tools out there that many of us are using in practice. It's the same as in the very beginning when we only had Adjuvant Online. We would use that to figure out what a person's risk of recurrence was and if we should we give chemotherapy in addition to anti-hormone therapy. Then the 21 gene recurrence score came out and we said "Hey, the Adjuvant Online resource is a statistical evaluation looking at hundreds of patients, but the 21 gene score is you. It will tell us about you." I think the BCI, or other tools that come along like that, may help us individualize and personalize that discussion for each of our patients. For now, we are actually going over the data with patients, and I have copies of the graphs on my phone. So we pop them up, we look at the 20-year recurrence rates by particular tumor and node size, and then have that discussion with the patient and what their thoughts might be.