Expert on Benefit of Dual HER-2 Directed Therapy, MA17R Trial

In an interview with <em>Targeted Oncology</em>, Frankie Holmes, MD, discusses HER2-directed therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

Frankie Holmes, MD

Dual HER2-directed therapy has proven efficacious in patients with breast cancer, but there is still a need for treatments for HER2-positive patients who don’t meet the present criteria for the regimen.

In an interview withTargeted Oncology, Frankie Holmes, MD, breast medical oncologist, Texas Oncology, discusses HER2-directed therapy with trastuzumab (Herceptin) and pertuzumab (Perjeta).

She also discuses recent MA17R trial, which explored an extension of adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. Patients were randomized to receive continued use of letrozole or placebo after receiving 5 years of letrozole from the earlier MA17 trial. Additional patients outside of the original trial who received the standard 5-year treatment of letrozole were also recruited to MA17R.

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


One of the key points is that with neoadjuvant dual HER2-directed therapy, we're seeing extremely high total pathologic complete response rates. For patients whose tumors are greater than 2 cm or who are node positive, dual anti-HER2 directed therapy with trastuzumab and pertuzumab—either with a taxane carboplatin backbone, or with a anthracycline cytoxin and then a taxane carboplatin backbone— has shown to be very effective and is the optimal choices of therapy for those patients.

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.

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


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.

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.

TARGETED ONCOLOGY:How do you interpret the MA17R trial?


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.

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.

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


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.