Originally published as JCO Early Release 10.1200/JCO.2007.16.0192 on October 14 2008

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Roles of Radiotherapy and Chemotherapy in the Development of Contralateral Breast Cancer

Maartje J. Hooning, Berthe M.P. Aleman, Michael Hauptmann, Margreet H.A. Baaijens, Jan G.M. Klijn, Ruth Noyon, Marilyn Stovall, Flora E. van Leeuwen

From the Departments of Epidemiology, Radiation Oncology, and Bioinformatics and Statistics, the Netherlands Cancer Institute, Amsterdam; Departments of Radiation Oncology and Medical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; and the Department of Radiation Physics, The University of Texas, M. D. Anderson Cancer Center, Houston, TX

Corresponding author: Flora E. van Leeuwen, PhD, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands; e-mail: f.v.leeuwen{at}nki.nl

Purpose Few studies have examined whether modern radiotherapy and chemotherapy affect the risk of contralateral breast cancer (CBC), and results are inconclusive.

Patients and Methods We assessed long-term risk of CBC in a predominantly young breast cancer (BC) population (n = 7,221), focusing on the effects of radiation dose, chemotherapy, and family history of BC. Risk of CBC was evaluated using Cox proportional hazards regression models.

Results Radiotherapy-associated risk of CBC increased with decreasing age at first treatment (age < 35 years, hazard ratio [HR] = 1.78; 95% CI, 0.85 to 3.72; age > 45 years, HR = 1.09; 95% CI, 0.82 to 1.45). Postmastectomy radiotherapy using direct electron fields led to a significantly lower radiation exposure to the contralateral breast than postlumpectomy radiotherapy using tangential fields. Women treated before age 45 years with postlumpectomy radiotherapy experienced 1.5-fold increased risk of CBC compared with those who had postmastectomy radiotherapy. The joint effects of postlumpectomy radiotherapy and strong family history for BC on risk of CBC were greater than expected when individual risks were summed (HR = 3.52; 95% CI, 2.07 to 6.02; P_{departure from additivity} = .043). Treatment with adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) was associated with a nonsignificantly decreased risk of CBC in the first 5 years of follow-up but did not reduce CBC risk in subsequent years.

Conclusion Young patients with BC irradiated with breast tangentials experience increased risk of CBC, especially in those with a positive family history of BC. This finding should be taken into account when advising breast radiation with tangential fields to young patients with BC. Adjuvant chemotherapy seemed to reduce the risk of CBC during the first 5 years after treatment only.

published online ahead of print at www.jco.org on October 13, 2008

Supported by Dutch Cancer Society Grant No. NKI 98-1833.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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