Available data suggest that younger age is an independent risk factor for disease recurrence and death in women with breast cancer. However, there has not been adequate study of the interaction of age with human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. In an analysis of outcomes in the HERA trial in women with early-stage invasive HER2-positive breast cancer, Ann H. Partridge, MD, MPH, Associate Professor of Medicine at Harvard Medical School and Director of the Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute, Boston, and colleagues found that age was not strongly associated with risk of early recurrence or benefit from trastuzumab (Herceptin) therapy.¹

The analysis included 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 randomly assigned to observation after completion of chemotherapy in the HERA trial. Analyses of outcomes used 2-year median data and dichotomized age at ≤ 40 years vs > 40 years.

Younger vs Older Subgroups

Overall, younger women were more likely to have had no assessment of nodal status (15% vs 10%, due to receipt of neoadjuvant therapy), less likely to have node-negative disease (28% vs 34%), and more likely to have estrogen receptor (ER)-positive (51% vs 44%) and progesterone receptor (PR)-positive disease (41% vs 32%). In addition, younger women were treated more often with taxanes (32% vs 25%), anthracyclines (97% vs 93%), and hormonal therapy (56% vs 49%).

No Difference in Survival by Age

Uncontrolled Cox proportional hazards models showed no significant differences in disease-free survival for patients aged ≤ 40 vs > 40 years in the observation group (hazard ratio [HR] = 1.16, P = .27) or in the trastuzumab group (HR = 1.18, P = .30). No effect of age on disease-free survival was observed when age was analyzed as a continuous variable in either the observation group (HR = 0.99, P = .07) or trastuzumab group (HR = 1.004, P = .60).

Similarly, there were no significant differences in overall survival for patients aged ≤ 40 vs > 40 years in the observation group (HR = 1.05, P = .85) or trastuzumab group (HR = 1.44, P = .20). Analysis of age as a continuous variable also showed no significant effect of age on overall survival in the observation group (HR = 1.00, P = .89) or trastuzumab group (HR = 1.02, P = .16).

On multivariate analysis controlling for prognostic and predictive factors, there was no significant difference in disease-free survival for age ≤ 40 vs > 40 years in the observation group (HR = 1.18, P = .22) or trastuzumab group (HR = 1.11, P = .53). Similarly, there was no significant difference in overall survival by dichotomized age in the observation group (HR = 1.01, P = .97) or trastuzumab group (HR = 1.18, P = .58).

When an interaction term for dichotomized age and trastuzumab treatment was added to multivariate models including all patients in both treatment groups, the P values for the interaction terms were 0.89 for disease-free survival and 0.55 for overall survival, indicating that age was not a predictive factor for trastuzumab benefit. A subpopulation treatment effect pattern plot analysis of 3-year disease-free survival according to age and treatment group confirmed that differences in 3-year disease-free survival percentages between the observation and trastuzumab groups did not differ significantly across age subgroups (P = .6 for interaction).

Factors Associated with Survival

On multivariate analysis, factors significantly associated with improved disease-free survival were ER-positive tumors in the observation group and tumor size ≤ 2 cm in both the observation and trastuzumab groups. Factors associated with worse disease-free survival were nodal status not assessed and positive nodal status in the observation and trastuzumab groups and grade 3 tumors in the trastuzumab group.

Factors significantly associated with overall survival in the two groups were similar except that the effect of tumor size ≤ 2 cm was borderline significant in the observation group. In addition, receipt of taxane therapy was associated with significantly poorer overall survival (HR = 2.65, P < .001) and receipt of anthracyclines with significantly better overall survival (HR = 0.29, P = .007) in the trastuzumab group.

The investigators noted that the analysis is limited by the relatively short follow-up and that results for patients with ER-positive disease, in particular, might change with longer-term follow-up. Longer-term follow-up will need to adjust for the crossover to trastuzumab among observation group patents after the demonstration of efficacy of trastuzumab in HERA. They also emphasize that the unanticipated associations of taxane treatment with reduced overall survival and anthracycline treatment with prolonged overall survival in trastuzumab patients are hypothesis-generating and warrant further investigation.

They concluded, “In [this] retrospective analysis of a large randomized controlled trial of women with early-stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes.” ■

Disclosure: Dr. Partridge has had an unpaid consultant or advisory role with Genentech. For full disclosures of all study authors, visit jco.ascopubs.org.

Reference

1. Partridge AH, Gelber S, Piccart-Gebhart MJ, et al: Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: results from a Herceptin adjuvant trial. J Clin Oncol. June 10, 2013 (early release ­online).