title: Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: A systematic review and meta-analysis of population-based studies including 522,739 patients.
abstract: Radiotherapy plays an essential role in early breast cancer treatment, but is also associated with an increased risk of second malignancies decades after the exposure.
  
  
  
  We systematically searched the data-bases Medline/Pubmed, Cochrane, Embase, and Cinahl, for cohort studies estimating the risk of second non-breast cancer after primary breast cancer. Every included study was to report the standardized incidence ratio [SIR] of second cancers, comparing the risk among either irradiated or unirradiated female breast cancer patients to the risk of the general female population. From each study the SIRs were extracted and then pooled using random-effects meta-analysis. SIRs were pooled as an overall estimate and according to time since breast cancer diagnosis.
  
  
  
  22 studies were eligible for inclusion, comprising 245,575 irradiated and 277,164 non-irradiated women. Irradiated patients had an overall increased risk of second non-breast cancer, with a SIR of 1.23 (95% confidence interval [CI] 1.12-1.36). For non-irradiated patients the SIR was 1.08 (95% CI, 1.03-1.13). For irradiated patients the incidence of second cancers including the lung, esophagus, thyroid and connective tissues progressively increased over time, peaking at 10-15years following breast cancer diagnosis. Summary estimates at ⩾15years after breast cancer irradiation were 1.91 for lung, 2.71 for esophagus, 3.15 for thyroid and 6.54 at ⩾10years for second sarcomas. Non-irradiated patients had no increased risk of second lung or esophagus cancer, neither overall nor over time. For non-irradiated patients' risk of second thyroid cancer (SIR 1.21) and sarcomas (SIR 1.42) were increased overall, but with no remaining risk ⩾10 after breast cancer.
  
  
  
  Radiotherapy for breast cancer is associated with an excess risk of second non-breast cancer, overall and in organs adjacent to the previous treatment fields. The growing number of long-term survivors after breast cancer highlights the need for an improved individualized approach toward identifying patients with an expected benefit from radiation and patients with no added radiation-benefit.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. Electronic address: grantzau@oncology.au.dk.
authors.forename: Trine
authors.initials: T
authors.lastname: Grantzau
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000532:radiotherapy* / Q000601:surgery; D015331:Cohort Studies; D005260:Female; D006801:Humans; D015994:Incidence; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000209:etiology*; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000209:etiology*; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D012107:Research Design; D012307:Risk Factors
keywords: Breast cancer; Radiotherapy; Second cancer