pCR and Improved Survival in Breast Cancer?

Lapatinib With Trastuzumab for HER2-Positive Early Breast Cancer (NeoALTTO): Survival Outcomes of a Randomised, Open-Label, Multicentre, Phase 3 Trial and Their Association With Pathological Complete Response

de Azambuja E, Holmes AP, Piccart-Gebhart M, et al
Lancet Oncol. 2014;15:1137-1146

Study Summary

Prior studies have shown that achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy was associated with improvement in event-free survival and overall survival (OS). The NeoALTTO investigators previously reported that dual HER2 blockade using trastuzumab and lapatinib with paclitaxel chemotherapy led to higher rates of pCR than trastuzumab alone.^[1] Here, de Azambuja and colleagues describe results of prespecified secondary outcomes of OS and the association between pCR and OS.

In the study, women with HER2-positive (HER2+) early breast cancer were randomly assigned to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose, followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for six weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m²). Definitive surgery was done four weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m² plus epirubicin 100 mg/m² plus cyclophosphamide 500 mg/m²) given intravenously every three weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy.

The primary endpoint was pCR. Secondary endpoints included event-free survival and OS, and the association between pCR and event-free survival or OS.

A total of 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of almost four years, three-year event-free survival was 78% in the lapatinib group, 76% in the trastuzumab group, and 84% in the combination group. Event-free survival did not differ between the groups receiving lapatinib or trastuzumab, or between the groups receiving lapatinib plus trastuzumab or trastuzumab alone. Three-year OS was 93% for lapatinib, 90% for trastuzumab, and 95% for combination therapy. OS did not significantly differ between the groups receiving either lapatinib or trastuzumab, or between those receiving the combination therapy or trastuzumab alone.

Analyses showed that three-year event-free survival was significantly improved for women who achieved pCR compared with those who did not; three-year overall survival was also higher in those women who achieved pCR. Adverse events were as expected and in keeping with what is known about each of these two drugs.

The investigators concluded that their analysis confirms that achieving pCR after neoadjuvant chemotherapy is associated with longer event-free survival and OS. This benefit was more robust for patients with HER2+ and estrogen receptor-negative (ER-) cancers.

Viewpoint

This new analysis lends support to the notion that achieving pCR after neoadjuvant therapy for HER2+ cancer is associated with improved outcomes, including survival. Perhaps the take-home message for clinicians is the noteworthy differences in outcome between biological subsets: patients with HER2+/ER+ and HER2+/ER- disease. The greatest benefits were seen in women who were HER2+/ER-. For women with HER2+/ER+ disease, the correlation between pCR and outcome was less clear. This underscores the need for additional research and guidelines in managing patients with HER2+/ER+ breast cancer.

Abstract

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