De-Escalation of Trastuzumab Remains Controversial in HER2+ Breast Cancer

After more than 7 years of follow-up, the phase III PHARE trial failed to show that 6 months of adjuvant trastuzumab therapy was noninferior to 12 months in patients with HER2-positive early breast cancer. The question of de-escalation in this setting remains controversial.

Several large trials previously showed a significant reduction in the risk of relapse and death with 1 year of trastuzumab therapy. “This 1-year treatment duration has been challenged by several published and ongoing trials,” wrote study authors led by Xavier Pivot, MD, PhD, of the Centre Paul Strauss in Strasbourg, France. An interim analysis of the PHARE trial in 2013 did not show noninferiority of the shorter duration; the new report included a final analysis of the trial based on a prespecified number of events.

The study included 3,384 patients with HER2-positive early breast cancer treated at 156 centers in France, randomized to receive either 12 months (1,691 patients) or 6 months (1,693 patients) of trastuzumab. Patients had a median age of 54 to 55 years, and just over half of both groups had node-negative disease. Results of the analysis were published in Lancet Oncology.

A total of 704 disease-free survival (DFS) events were reported; of those, 345 were in the 12-month group (20.4%) and 359 were in the 6-month group (21.2%). The adjusted hazard ratio for DFS was 1.08 (95% CI, 0.93–1.25; P = .39); because the confidence interval included the prespecified noninferiority margin of 1.15, the results are considered inconclusive.

At 3 years, the DFS rate with 12 months of trastuzumab therapy was 92.2%, compared with 89.3% with 6 months of therapy. At 5 years, these rates were 86.2% and 84.2%, respectively, and at 7 years they were 82.3% and 80.6%, respectively.

A total of 170 patients in the 12-month group (10.1%) and 186 patients in the 6-month group (11.0%) died during the study period. The hazard ratio for overall survival was 1.13 (95% CI, 0.92–1.30). The authors noted that after the completion of trastuzumab therapy, “few safety events occurred over time.”

In an accompanying editorial, Sara A. Hurvitz, MD, of the David Geffen School of Medicine at UCLA, wrote that “the selection of optimal systemic therapy for early HER2-positive breast cancer has become exceedingly complex.” Several new medications introduced since the advent of trastuzumab can offer incremental benefit in some patients, and trials still differ on the concept of de-escalation of trastuzumab therapy.

The PERSEPHONE trial, with shorter follow-up than PHARE, has shown noninferiority of 6 months of therapy, but Hurvitz points out the difference rests largely on where the noninferiority margin was set. “The subject of what constitutes an acceptable margin for equivalence, especially in a setting where the goal is to achieve remission from an aggressive form of cancer, is quite subjective and hence, debatable,” she wrote.

Hurvitz also noted that these studies may not even be asking a clinically relevant question, given their safety when given without anthracyclines. “Are studies evaluating shorter duration trastuzumab with anthracycline-free regimens really worthwhile, when the risks of adjuvant trastuzumab in this setting are so low?”