Division of Oncological Sciences, Oregon Health & Science University, Portland.
Knight Cancer Institute, Oregon Health & Science University, Portland.
JAMA Netw Open. 2024 Apr 1;7(4):e247421. doi: 10.1001/jamanetworkopen.2024.7421.
IMPORTANCE: In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. OBJECTIVE: To determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023. EXPOSURE: Time between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status. RESULTS: Among 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]). CONCLUSIONS AND RELEVANCE: These findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.
重要性:在年轻型乳腺癌(YOBC)中,产后 5 至 10 年内诊断出乳腺癌与死亡率增加有关。携带种系 BRCA1/2 致病性变异(PVs)的女性更有可能在较年轻的年龄被诊断出乳腺癌,但产后对死亡率的影响尚不清楚。 目的:确定最近一次分娩与 YOBC 和种系 BRCA1/2 PV 患者的乳腺癌诊断之间的时间间隔是否与死亡率相关。 设计、地点和参与者:本前瞻性队列研究纳入了 1950 年至 2021 年间在英国被诊断为 45 岁或以下的 I 期至 III 期乳腺癌且携带种系 BRCA1/2 PV 的女性,随访至 2021 年 11 月。数据分析于 2021 年 12 月 3 日至 2023 年 11 月 29 日进行。 暴露因素:最近一次分娩与随后的乳腺癌诊断之间的时间间隔,最近分娩定义为 0 至不到 10 年,进一步细分为 0 至不到 5 年和 5 至不到 10 年。 主要结局和测量:主要结局是全因死亡率,以 YOBC 诊断后 20 年为截点。与最近产后组和 10 年以上产后组相比,比较了未生育妇女的死亡率。使用 Cox 比例风险回归分析进行调整,包括年龄、肿瘤分期,并按肿瘤雌激素受体(ER)和 BRCA 基因状态进一步分层。 结果:在 903 名携带 BRCA PV 的女性中(诊断时的平均[标准差]年龄为 34.7[6.1]岁;平均[标准差]随访时间为 10.8[9.8]年),419 名女性在产后 0 至不到 10 年内被诊断为乳腺癌,包括 228 名产后不到 5 年内被诊断的女性和 191 名产后 5 至不到 10 年内被诊断的女性。与未生育的女性和产后 10 年以上被诊断的女性相比,产后 5 年至不到 10 年内被诊断的女性全因死亡率增加(风险比[HR],1.56[95%CI,1.05-2.30]),提示产后风险存在短暂的持续时间。在产后不到 5 年内被诊断为 ER 阳性乳腺癌的女性(HR,2.35[95%CI,1.02-5.42])和产后 5 至不到 10 年内被诊断为 ER 阴性乳腺癌的女性(HR,3.12[95%CI,1.22-7.97])中,死亡率的风险更高与未生育的女性相比。按 BRCA1 或 BRCA2 分层,产后 5 至不到 10 年内的死亡率显著增加,但仅在 BRCA1 携带者中(HR,2.03[95%CI,1.15-3.58])。 结论和相关性:这些发现表明,携带种系 BRCA PV 的 YOBC 如果在最近一次分娩后 10 年内被诊断出,与全因死亡率增加相关,风险最高的是产后不到 5 年内被诊断为 ER 阳性乳腺癌的患者,而产后 5 至不到 10 年内被诊断为 ER 阴性乳腺癌的患者则风险更高。BRCA1 携带者在产后 5 至不到 10 年内被诊断时预后最差。BRCA2 携带者则没有观察到这种关联。这些结果应该为携带 BRCA PV 的女性提供遗传咨询、预防和治疗策略。
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