Gentler Regimen for HER2+ Breast Cancer Gets Good Grades in 5-Year Report

Abbreviated treatment with neoadjuvant paclitaxel, trastuzumab, and pertuzumab (Perjeta) was tied to “excellent” long-term outcomes in patients with HER2-positive breast cancer, a secondary analysis of the phase II DAPHNe trial showed.

Among 98 patients with stage II to III disease, the 5-year event-free survival rate was 99%, the recurrence-free interval was 98%, the distant recurrence-free interval was 100%, and the overall survival rate was 99% with the combination, reported Adrienne G. Waks, MD, of Dana-Farber Cancer Institute in Boston, and colleagues in JAMA Oncology.

In a circulating tumor (ct)DNA analysis among 57 patients, baseline ctDNA was detected in 89.5%. After neoadjuvant therapy, ctDNA clearance occurred in 96.1%, with just two patients remaining ctDNA-positive preoperatively. One patient experienced a local recurrence, with ctDNA detected at the time of recurrence and cleared following resection.

Nearly 90% of patients with stage II to III HER2-positive breast cancer remain disease-free at 8 years with the use of HER2-targeted agents. Over time, the “focus has gradually shifted to developing better-tolerated regimens through shortening the duration and reducing the intensity of traditional polychemotherapy regimens,” Waks and team explained.

In this study, patients received neoadjuvant therapy with paclitaxel, trastuzumab, and pertuzumab (THP) for 12 weeks — a shorter schedule than that currently recommended in National Comprehensive Cancer Network guidelines, which recommend 18 t0 24 weeks of neoadjuvant polychemotherapy with dual HER2 blockade.

Primary results from the DAPHNe trial showed that more than half of patients (56.7%) achieved a pathologic complete response (pCR) at surgery, and the adherence rate to de-escalated antibody-only adjuvant therapy was 98.2%, meeting the primary endpoint.

“The findings reported in this secondary analysis of the DAPHNe nonrandomized clinical trial raise the hypothesis that favorable outcomes may be achieved with an abbreviated, de-escalated regimen,” Waks and team wrote, adding that de-escalated THP produced “near-universal ultrasensitive ctDNA clearance after treatment, warranting further validation of ultrasensitive ctDNA as a prognostic tool in this setting.”

In a commentary accompanying the study, Naoto T. Ueno, MD, PhD, of the University of Hawaii Cancer Center in Honolulu, observed that the trial was not randomized and included fewer than 100 patients, which “should limit the extent to which the results are applied.”

Ueno and the study authors noted that the ongoing CompassHER2-pCR trial is evaluating whether patients with stage II to IIIA HER2-positive breast cancer who achieve pCR after neoadjuvant THP can omit postoperative chemotherapy, with recurrence-free survival as the key endpoint.

“If recurrence-free survival remains excellent, the trial could help establish abbreviated THP followed by response-adapted adjuvant therapy as a broader treatment option,” Ueno wrote. “Until then, the DAPHNe trial should be considered encouraging but not practice-defining outside the risk profile represented in the trial.”

“This study does not argue that abbreviated therapy is appropriate for everyone,” he added. “It provides long-term follow-up supporting the feasibility of abbreviated THP in a favorable risk population and offers biomarker data that help define the next set of clinical questions.”

Patients were enrolled in the DAPHNe trial from November 2018 to January 2020 at a multicenter academic cancer center and affiliated community practices. Patients received neoadjuvant THP for 4 cycles, followed by surgery and adjuvant systemic therapy per physician discretion, with ongoing trastuzumab and pertuzumab, but without chemotherapy in case of pCR.

Overall, the 98 included patients had a median age of 49.5 years, and most had stage II disease (92.9%) and hormone receptor-positive tumors (66.3%).

Similarly, the 57 patients in the ctDNA analysis had a median age of 50 years, and most had stage II tumors (93%) and hormone receptor-positive tumors (67%).

Waks and colleagues acknowledged that the study had several limitations, including its nonrandomized design, and the relatively small sample size of the ctDNA cohort.