Researchers at Massachusetts General Hospital (MGH) have identified a biomarker that appears to predict which women with estrogen-receptor positive (ER+) breast cancer are at risk for late recurrence and will therefore benefit from extended letrozole (Femara®) therapy.1

“Most patients with early-stage, ER+ breast cancer remain cancer-free after 5 years of tamoxifen treatment, but they remain at risk of recurrence for 15 years or longer after their initial treatment,” said Dennis Sgroi, MD, lead author of the study. “Our biomarker identifies the subgroup of patients who continue to be at risk of recurrence after tamoxifen treatment and who will benefit from extended therapy with letrozole, which should allow many women to avoid unnecessary extended treatment.”

In tamoxifen-treated patients, more than half of recurrences and about two-thirds of breast cancer–related deaths occur more than 5 years after diagnosis. No currently available tests are able to predict benefit from extended adjuvant hormonal therapy.

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The research team had previously demonstrated that the ratio of expression of two genes—HOXB13/IL17BR (H/I)—is a useful prognostic marker in tamoxifen-treated and untreated women with early-stage ER+ breast cancer. In this study, the investigators examined data from the National Cancer Institute of Canada Clinical Trials Group MA.17, a phase 3 trial that enrolled postmenopausal patients with breast cancer who remained disease-free after 5 years of standard tamoxifen treatment and randomly assigned them to letrozole or placebo for 5 years.

Using a nested case-control design, Dr. Sgroi and his team examined tumor samples from 83 patients (31 in the letrozole group and 52 in the placebo group) with local, regional, or distant recurrence and matched them with tumors from 166 patients (91 letrozole, 75 placebo) without recurrence. High and low H/I groups were defined using a cut-off point of 0.06, which had been validated in previous studies.

In the placebo group, women with high H/I had more than twice the risk of recurrence than those with low H/I (odds ratio [OR], 2.15; 95% CI: 1.00-4.64; P=0.05). By contrast, in the letrozole group, H/I did not predict late recurrence.

Patients with high H/I who took letrozole had a 67% reduction in the risk of recurrence compared with high H/I patients treated with placebo (OR, 0.33; 95% CI: 0.15-0.73; P=0.006).

Among women with low H/I, letrozole therapy improved 4-year recurrence-free survival by 4%, whereas in women with high H/I, letrozole therapy improved recurrence-free survival by 16.5%.

Paul E. Goss, MD, PhD, director of the Breast Cancer Research Program at the MGH Cancer Center and a co-author of the report, said, “This discovery means that about 60% of women with the most common kind of breast cancer can be spared unnecessary treatment with the concomitant side effects and costs. But more importantly, the 40% of patients who are at risk of recurrence can now be identified as needing continued therapy with letrozole, and many will be spared death from breast cancer.”  He and Dr. Sgroi note that their findings need to be validated by additional studies before they can be put into clinical practice.


1. Sgroi DC, Carney E, Zarrella E, et al. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst. 2013; June 28 [Epub ahead of print].