A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer

Smita Bhatia, Melanie R. Palomares, Lindsey Hageman, Yanjun Chen, Wendy Landier, Kandice Smith, Heidi Umphrey, Caroline A. Reich, Kathryn W. Zamora, Saro H. Armenian, Therese B. Bevers, Anne Blaes, Tara Henderson, David Hodgson, Melissa M. Hudson, Larissa A. Korde, Susan A. Melin, Sofia D. Merajver, Linda Overholser, Sandhya PruthiF. Lennie Wong, Judy E. Garber

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Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n ¼ 34, placebo: n ¼ 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P ¼ 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P ¼ 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Original languageEnglish (US)
Pages (from-to)967-975
Number of pages9
JournalClinical Cancer Research
Issue number4
StatePublished - Feb 15 2021

Bibliographical note

Funding Information:
This work was supported by the NCI at the NIH (R01CA140245, to S. Bhatia; P30CA046592, to Benjamin Allen); and the Breast Cancer Research Foundation; and Tempting Tables. The funding sponsors had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or preparation of the article and the decision to submit for publication.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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