Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer-associated genes is unknown. In a population-based case-control study, we examined the association between RT, variants in ATM, BRCA1/2, or CHEK2*1100delC, and CBC risk. We analyzed 708 cases of women with CBC, and 1,399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985-2000, <55 years of age at diagnosis, and screened for variants in breast cancer-associated genes. Rate ratios and 95% confidence intervals were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (e.g., BRCA1/2 pathogenic variant carriers without RT, RR: 3.52, 95% CI: 1.76-7.01; BRCA1/2 pathogenic variant carriers with RT, RR: 4.46, 95% CI: 2.96-6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT, RR: 0.38, 95% CI: 0.09-1.55; carriers of ATM rare missense variants of uncertain significance with RT, RR: 2.98, 95% CI: 1.31-6.80). Further mechanistic studies will aid clinical decision-making related to RT.

中文翻译：

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放射治疗，ATM，BRCA1 / 2和CHEK2 * 1100delC致病变体以及对侧乳腺癌的风险。

尚不知道放射治疗（RT）是否会影响具有中度至高穿透性乳腺癌相关基因的病原种系变异的女性的对侧乳腺癌（CBC）风险。在一项基于人群的病例对照研究中，我们检查了RT，ATM变异，BRCA1 / 2或CHEK2 * 1100delC与CBC风险之间的关联。我们分析了708例CBC妇女和1399例单侧乳腺癌对照，这些对照均在1985-2000年之间被诊断为首次浸润性乳腺癌，诊断时年龄小于55岁，并筛选了与乳腺癌相关的基因变异。率比和95％置信区间使用多变量条件逻辑回归进行估算。RT没有改变已知病原体变异与CBC风险之间的关联（例如，没有RT的BRCA1 / 2病原体携带者，RR：3.52，95％CI：1.76-7。01; 具有RT的BRCA1 / 2致病变异载体，RR：4.46，95％CI：2.96-6.71），这表明修改乳腺癌年轻女性的RT计划是不必要的。罕见的ATM错义变体（目前尚未确定为致病性）与RT相关的CBC风险增加相关（ATM罕见的错义变体的携带者，没有RT的意义不明，RR：0.38，95％CI：0.09-1.55; ATM的罕见具有RT，RR：2.98、95％CI：1.31-6.80的不确定性的错义变体。进一步的机理研究将有助于与RT相关的临床决策。与RT相关的CBC风险增加相关（无显着性的ATM罕见错义变体携带者，无RT，RR：0.38，95％CI：0.09-1.55;具有显着性的ATM罕见错义变体携带者，RT，RR：2.98 ，95％CI：1.31-6.80）。进一步的机理研究将有助于与RT相关的临床决策。与RT相关的CBC风险增加相关（无显着性的ATM罕见错义变体携带者，无RT，RR：0.38，95％CI：0.09-1.55;具有显着性的ATM罕见错义变体携带者，RT，RR：2.98 ，95％CI：1.31-6.80）。进一步的机理研究将有助于与RT相关的临床决策。