Optimal Extent of Neoadjuvant Letrozole to Permit Breast Conservation

San Antonio, TX—The 4 to 6 months of neoadjuvant letrozole (Femara) traditionally given to permit breast-conserving surgery in patients with early breast cancer is far too short, according to an interim analysis of a multicenter prospective phase IV trial presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Instead, the optimal duration appears to be closer to 10 months.

The finding is “potentially practice changing for the use of neoadjuvant letrozole for ER-positive patients who want to keep their breasts, when on presentation they would have been destined for mastectomy,” said the study’s principal investigator Rob Carpenter, MD.

The standard 4- to 6-month duration for neoadjuvant letrozole in this setting was derived from data using traditional chemotherapy regimens rather than definitive data with endocrine agents. “Even though we know that endocrine agents don’t cause a response in the way that chemotherapy does, it just became conventional that 4 months was the time period that patients received it,” said Dr Carpenter, who was head of the breast service at St. Bartholomew’s Hospital, West Smithfield, London, at the time the analysis was done. He is now head of the breast service at University College Hospital in South Manchester.

Previous retrospective studies in the neoadjuvant setting in localized hormone receptor—positive breast cancer suggested a benefit for continued use of letrozole beyond 4 months, with significant tumor shrinkage observed with use of up to 12 months. However, no prospective studies investigated treatment beyond 6 months.

In the single-arm, open-label study that Dr Carpenter presented, postmenopausal women with primary invasive, estrogen receptor— and/or progesterone receptor–positive breast cancer with large tumors (≥stage T2) that were initially not eligible for breast conservation surgery were treated with 2.5 mg of letrozole daily. The primary endpoint was the time at which patients were reclassified as eligible for breast-conserving surgery.

Data from 103 women who had at least one post-baseline assessment of tumor response were available for analysis. (The final analysis will include 117 patients; currently 83 have been confirmed as completing the trial.) The optimal duration of therapy was indicated by tumor shrinkage sufficient for breast-conserving surgery, disease progression, or reaching a maximum of 12 months of treatment.

The median time to breast conservation was 8.2 months. The response during the first 4 months of treatment was rapid, after which the rate of response slowed and remained constant for an additional 6 months. The response rate at 4 months was 9.4%, improving to 32.2% at 6 months.

“At 4 months, a small proportion of patients, maybe 10%, will be ready for breast conservation,” said Dr Carpenter.“That goes up to 70% by 10 months.” The response at 6 months was 32.2%; and at 8 months, it was 49.3%. The reduction in tumor volume was 65% to 80% by the time of surgery.

“The last patient in the trial will be through [with therapy] by January. By looking at how strong the trend is in this study, I don’t think that the analysis of another 30 patients is going to change the final outcome.” Final data are expected to be ready in time for the 2010 conference of the American Society of Clinical Oncology in June. SABCS Abstract 1082.