Can Anthracyclines be Excluded From Neoadjuvant HER2+ Breast Cancer Tx?

A comparison of chemotherapy regimens given in combination with anti-HER2 therapy in the neoadjuvant setting showed that the addition of anthracyclines to a paclitaxel-carboplatin regimen is not necessary for patients with HER2-positive breast cancer. There was a high rate of response in both groups, and the anthracyclines added to the toxicity profile of the treatments.

“Neoadjuvant polychemotherapy plus trastuzumab and pertuzumab results in high numbers of treated patients achieving pathological complete responses in HER2-positive breast cancer, but this treatment is not without toxicity,” wrote study authors led by Mette S. van Ramshorst, MD, of the Netherlands Cancer Institute in Amsterdam. “The optimal chemotherapy backbone with respect to both efficacy and safety has not been identified.”

The TRAIN-2 study was an open-label, randomized, phase III trial including a total of 438 patients (418 evaluable for primary endpoint) with stage II to III HER2-positive breast cancer. All patients received trastuzumab and pertuzumab, and were randomized to also receive either fluorouracil, epirubicin, and cyclophosphamide followed by paclitaxel and carboplatin, or just the carboplatin and paclitaxel regimen. The results were published in Lancet Oncology.

The median age in the anthracycline group was 49 years, and 48 years in the non-anthracycline group. Just over half of both groups were premenopausal, and just under 60% of both groups were estrogen receptor positive and/or progesterone receptor positive. The patients were followed for a median of 19 months.

In the anthracycline group, 141 of 212 patients (67%) achieved a pathologic complete response. In the non-anthracycline group, 140 out of 206 patients (68%) achieved such a response, for a difference of −1.5% (P = .95). A post-hoc analysis found that more patients with hormone receptor (HR)-negative tumors achieved a pathologic complete response than those with HR-positive tumors.

In the anthracycline group, 15% of patients discontinued treatment early due to adverse events; in the non-anthracycline group, this rate was 12%. A total of 61 patients receiving anthracyclines had a serious adverse event (28%), compared with 49 in the non-anthracycline group (22%). Similar proportions in each group had a left ventricular ejection fraction (LVEF) decrease of 10% or more and LVEF below 50% (5% and 3%; P = .32).

The most common grade 3 or worse adverse event in both groups was neutropenia, though grade 4 neutropenia was more common in the anthracycline group (18% vs 6%; P = .0004). Grade 3 or 4 febrile neutropenia was also more common with anthracyclines, at 10% compared with 1% (P < .0001).

“Consequently, omitting anthracyclines might be an attractive approach for the treatment of HER2-positive breast cancer in the presence of dual HER2 blockade,” the authors concluded, adding that further follow-up and overall survival data are still needed to confirm the similar efficacies seen in this analysis.

In an accompanying editorial, Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne, agreed that “the evidence continues to support the notion that anthracyclines could be reasonably excluded in the presence of pertuzumab with trastuzumab.” She also noted that this trial should “give clinicians the confidence” to use paclitaxel in place of docetaxel, though other research has raised the question of whether the carboplatin is actually adding any benefit to the regimen. In the future, she wrote, studies will need to further elucidate which patients will fare well with these treatment options and which might need a different approach. In particular, surveillance with circulating tumor DNA shows promise in guiding treatment, she wrote. “This information might eventually spare us the cost and time required for large randomized adjuvant studies, as we will be able to precisely define the patients for whom survival outcomes need to be improved.”