Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models. Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14–14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size. Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

中文翻译：

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良性乳腺疾病女性肿瘤特征影响乳腺癌发展的危险因素

在被诊断患有浸润性乳腺癌的女性中，30% 的女性事先被诊断为良性乳腺疾病 (BBD)。因此，确定 BBD 患者中增加浸润性癌症风险的因素很重要。在一般人群中，危险因素的关联因临床病理特征而异；然而，患有 BBD 的女性是否在她们发展的乳腺癌类型中表现出病因异质性仍然未知。使用在社区医疗保健计划 (Kaiser Permanente Northwest) 中进行的 BBD 和乳腺癌风险的嵌套病例对照研究，我们评估了 BBD 活检中的组织学特征和患者特征与随后的乳腺癌风险之间的关系，并测试了雌激素关联的异质性受体 (ER) 状态、肿瘤等级和大小。该研究包括 1971 年至 2006 年间诊断为增殖性或非增殖性 BBD 的 514 例浸润性乳腺癌病例（BBD 诊断后中位随访 9 年）和 514 名匹配对照，随访至 2015 年年中。优势比 (OR) 和 95% 置信区间 (CI) 是使用多变量多分逻辑回归模型获得的。乳腺癌主要为 ER 阳性 (86%)、高分化或中分化 (73%)、小 (74% < 20 mm) 和 I/II 期 (91%)。与非增殖性 BBD 患者相比，具有非典型性的增殖性 BBD 增加了 ER 阳性癌症的风险（OR = 5.48，95% CI = 2.14–14.01），只有一个 ER 阴性病例，P 异质性 = 0.45。BBD 诊断时柱状细胞病变 (CCL) 的存在与 1. ER 阳性和 ER 阴性肿瘤的风险增加 5 倍，在绝经后妇女 (56%) 中观察到增加 2 倍 (95% CI = 1.21–3.58)，与有或没有 BBD 的增殖状态无关异型。我们没有发现肿瘤分级或大小在危险因素关联方面的统计学显着差异。该队列中大多数在 BBD 诊断后发展的肿瘤是高度可治疗的低阶段 ER 阳性肿瘤。BBD 活检中的 CCL 可能与中等风险增加有关，与 BBD 组织学无关，与 ER 状态无关。该队列中大多数在 BBD 诊断后发展的肿瘤是高度可治疗的低阶段 ER 阳性肿瘤。BBD 活检中的 CCL 可能与中等风险增加有关，与 BBD 组织学无关，与 ER 状态无关。该队列中大多数在 BBD 诊断后发展的肿瘤是高度可治疗的低阶段 ER 阳性肿瘤。BBD 活检中的 CCL 可能与中等风险增加有关，与 BBD 组织学无关，与 ER 状态无关。