Dual HER2-targeting without chemotherapy and estrogen deprivation in the neoadjuvant setting.

Trastuzumab has had a major impact on outcomes in HER2-positive breast cancer, but innate or acquired resistance to it is recognized as a problem that can limit its effectiveness. Given its locus of action, the oral tyrosine kinase inhibitor lapatinib would be expected to counteract many of the proposed mechanisms of trastuzumab resistance. It has demonstrated activity in trastuzumab-resistant patients, and neoadjuvant studies in HER2+ patients have demonstrated higher pathologic complete response (pCR) rates with the addition of lapatinib to trastuzumab and chemotherapy. TBCRC006 was a phase II neoadjuvant trial that studied the efficacy of the lapatinib and trastuzumab combination without concurrent chemotherapy, but with estrogen deprivation therapy in ER+ patients. In 65 patients with T2-3 HER2+ cancers, the overall pCR rate was 27%, including 36% in ER-tumors. A total 54% of ER+/HER2+ patients had either a pCR or were downstaged to T <1 cm. Correlative studies on tissue obtained prior to and during neoadjuvant therapy are underway. These results suggest that a significant fraction of HER2+ patients will respond to dual HER2-targeted therapy without cytotoxic chemotherapy, and that antihormonal therapy to block ER/HER2 'crosstalk' may be necessary to achieve optimal responses in ER+/HER2+ patients.