Using neoadjuvant therapy response to guide adjuvant therapy in HER2+ breast cancer

With the use of HER2 directed therapies, outcomes for patients (pts) with early stage HER2+ breast cancer (BC) are now favorable for all but the highest risk pts. These favorable outcomes increase the importance of 1) risk stratification to minimize over and under treatment, and 2) de-escalation strategies to potentially further reduce the toxicities of therapy. Tumor size, lymph node status and hormone receptor (HR) status have well-established prognostic value in HER2+ early BC, and these can be utilized to risk stratify pts. However, one of the strongest prognostic markers in HER2+ BC is the degree of response to neoadjuvant therapy. Pts with a complete pathological response (pCR) to neoadjuvant therapy have a far more favorable disease-free and overall survival than pts with residual disease. This difference is seen in both HR-positive and HR-negative cancers, although the effect is stronger in HR-negative cancers. Thus, treating pts in the neoadjuvant setting provides prognostic data that otherwise would not be available. The KATHERINE study, which randomized 1486 pts with residual disease after neoadjuvant HER-2 directed therapy to 14 cycles of either adjuvant T-DM1 or trastuzumab, demonstrated a large benefit with the use of T-DM1 (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < 0.001). KATHERINE provides proof of concept that the results of neoadjuvant therapy can identify pts who can benefit from a change in therapy. The KATHERINE results therefore suggest that it is advantageous to treat most pts with moderate or high risk (Stage ≥2) HER2+ BC with neoadjuvant therapy (preferably pertuzumab based) in order to identify those pts with residual disease who may benefit from adjuvant T-DM1. It is worth noting that there are currently no data comparing T-DM1 to trastuzumab/pertuzumab (HP) in the adjuvant setting. However, given the large benefit seen in KATHERINE compared to the relatively small benefit of the addition of pertuzumab in APHINITY, it would seem unlikely that adjuvant T-DM1 would be inferior to HP. The ExteNET study demonstrated a benefit to a year of neratinib in ER+HER2+ pts completing a year of (neo)adjuvant HER2 directed therapy. Is there a role for neratinib in pts who received T-DM1 after neoadjuvant therapy? As there are no data on adjuvant neratinib after T-DM1 or pertuzumab, it is difficult to recommend neratinib in pts after T-DM1. However, in the absence of such data, neratinib can be considered in rare cases with extremely high risk ER+ pts (e.g. progression on neoadjuvant therapy, IBC, many nodes) after a year of T-DM1. In pts with low clinical risk HER2+ BC (e.g. stage 1), data from the APT trial of 12 weekly doses of paclitaxel with a year of trastuzumab (TH), demonstrate exceedingly good outcomes with this relatively well-tolerated regimen. Updated results show a 7-year recurrence free interval of 97.5% (95% CI, 95.9% to 99.1%). Given these very favorable results, there is no strong rationale for neoadjuvant therapy in this subgroup of pts, as a lack of pCR is unlikely to be meaningful, particularly in HR-positive BC. Summary: Response to neoadjuvant HER-2 directed therapy provides a clinically useful risk-stratification tool. Pts with Stage ≥2 BC should be considered for a standard neoadjuvant chemotherapy/HP regimen. For those pts with significant residual disease,14 cycles of T-DM1 is associated with improved outcomes. Studies are now needed to determine if favorable response to neoadjuvant therapy can be utilized to decrease need for systemic therapy (particularly chemotherapy). For pts with low risk (stage 1) BC, the TH regimen remains a standard of care.