Continued Event-Free Survival Benefit of Neoadjuvant/Adjuvant Trastuzumab in HER2-Positive Locally Advanced Breast Cancer
As reported by Gianni et al in The Lancet Oncology, long-term follow-up of women with HER2-positive locally advanced breast cancer receiving neoadjuvant chemotherapy alone vs with neoadjuvant and adjuvant trastuzumab (Herceptin) in the phase III NOAH trial has shown continued event-free survival benefit of trastuzumab treatment and a strong association of event-free survival with pathologic complete response rate in trastuzumab recipients.
Study Details
In this open-label trial, 235 women with HER2-positive locally advanced or inflammatory breast cancer were randomly assigned to receive neoadjuvant chemotherapy alone (n = 118) or with 1 year of trastuzumab given concurrently with neoadjuvant chemotherapy and continued after surgery. (A parallel group with HER2-negative disease received neoadjuvant chemotherapy alone; outcomes in this group are not reported here.)
Neoadjuvant chemotherapy consisted of paclitaxel at 150 mg/m² plus doxorubicin at 60 mg/m² every 3 weeks for three cycles followed by paclitaxel at 175 mg/m² every 3 weeks for four cycles and then cyclophosphamide at 600 mg/m², methotrexate at 40 mg/m², and fluorouracil at 600 mg/m² on days 1 and 8 every 4 weeks for the final three cycles.
Neoadjuvant trastuzumab was given concurrently with chemotherapy as a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks for seven cycles and then every 4 weeks for an additional three cycles; adjuvant trastuzumab was given at 6 mg/kg every 3 weeks for up to 1 year. In the primary study analysis, neoadjuvant/adjuvant trastuzumab significantly improved pathologic complete response rates and event-free survival.
Survival Results
Updated results, after median follow-up of 5.4 years, show that the event-free survival benefit of trastuzumab has been maintained, with 5-year event-free survival rates of 58% vs 43% (unadjusted hazard ratio [HR] = 0.64, P = .016; HR adjusted for disease stage and hormone receptor status = 0.65, P = .024). In unadjusted analysis, trastuzumab was also associated with significantly better 5-year relapse-free survival (65% vs 47%, HR = 0.58, P = .012) and breast cancer–specific survival (77% vs 64%, HR = 0.59, P = .021) and a trend toward improved overall survival (74% vs 63%, HR = 0.66, P = .055).
Association of Pathologic Complete Response and Event-Free Survival
Event-free survival subgroup analyses consistently favored trastuzumab, with differences being significant for age > 50 years, N1/N2 nodal status, inflammatory disease, hormone receptor–negative status, and pathologic complete response. Among patients achieving pathologic complete response (45 in trastuzumab group, 23 in chemotherapy-alone group), trastuzumab was associated with an event-free survival hazard ratio of 0.29 (P = .0135), with 5-year event-free survival rates not differing between groups in patients without pathologic complete response (P = .70). Additional exploratory analysis showed that pathologic complete response was a significant predictor for event-free survival in the trastuzumab group (HR = 0.17, P < .0001), but not in the chemotherapy-alone group (P = .11).
The investigators concluded, “These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.”
Luca Gianni, MD, of San Raffaele Hospital, Milan, is the corresponding author for The Lancet Oncology article.
The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com.
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