Commenting on the PHARE trial and HERA update presented at ESMO, ASCO President Sandra M. Swain, MD, of Washington Hospital Center’s Washington Cancer Institute, said “Today we have seen that 12 months of trastuzumab is better than 6 months, and 12 months is the same as 2 years of treatment, so overall, 1 year of trastuzumab remains the standard of care.”

Dr. Swain said that having been involved in designing National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, she could say that “the 1-year choice for trastuzumab was absolutely arbitrary.” This arbitrariness led to the implementation of PHARE, HERA, and other studies to further evaluate duration in nearly 14,000 patients to date.

12 Months Better than 6 Months

Commenting on PHARE, Dr. Swain noted the disease-free survival hazard ratio of 1.28, and the lower boundary of the confidence interval of 1.05 (exceeding 1.00). “Visually [on the Forest plot], it looks more like 6 months is inferior, and not noninferior,” she said. Her conclusion would be that 12 months “is better than” 6 months, she said.

She further noted that the hazard ratio for sequential treatment (which 42% of patients received, mostly early in the trial) was higher than for concurrent treatment (1.39 vs 1.17). This suggests there may be less treatment benefit with sequential delivery, and thus, 6 months may not have been as effective. It is also likely that other mechanisms of action for trastuzumab are in play, such as antibody-dependent cellular cytotoxicity that could be even more important with a lower burden of disease.

Finer Points

Longer follow-up and more detailed analysis are needed to sift out these finer points, she said. “The other explanation is that we really do need 12 months of treatment in all patients,” she acknowledged.

“It is also possible that we do need concurrent therapy,” she said. The fact that all patients in HERA received sequential treatment may help explain the higher hazard ratio (0.76) for disease-free survival, compared with other adjuvant trials that used trastuzumab concurrently with a taxane. In the joint analysis of B-31 and North Central Cancer Treatment Group (NCCTG) 9831, for example, the hazard ratio was 0.52, and in the Finalnd Herceptin (FinHER) study it was 0.42. The greater proportion of patients with negative lymph nodes in HERA, and thus the lower risk of recurrence coupled with crossover, may also be responsible for the differences in the hazard ratios, she added.

An overview of data from all the adjuvant trastuzumab trials is underway. This will be very helping in answering questions regarding sequential vs concurrent delivery, and in exploring the possibility that hormone receptor–negative patients benefit from 2 years of treatment. ■

Disclosure: Dr. Swain receives research support from and is on advisory boards (uncompensated) for Genentech/Roche.