Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.
Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.
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DOI：
10.1016/s1470-2045(17)30891-4
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发表时间：
2018-03
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影响因子：
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通讯作者：
Eccles DM
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作者：
Copson ER;Maishman TC;Tapper WJ;Cutress RI;Greville-Heygate S;Altman DG;Eccles B;Gerty S;Durcan LT;Jones L;Evans DG;Thompson AM;Pharoah P;Easton DF;Dunning AM;Hanby A;Lakhani S;Eeles R;Gilbert FJ;Hamed H;Hodgson S;Simmonds P;Stanton L;Eccles DM
回顾性研究对遗传因素对乳腺癌患者预后的影响提供了相互矛盾的解释。本研究的主要目的是确定种系BRCA1或BRCA2突变对年轻发病乳腺癌患者乳腺癌结局的影响。我们做了一项前瞻性队列研究，招募了来自英国127家医院、年龄在40岁或以下、首次诊断（经组织学证实）为浸润性乳腺癌的女性患者。既往有浸润性恶性肿瘤（非黑色素瘤性皮肤癌除外）的患者被排除在外。患者在初步诊断后12个月内被确定。使用招募时收集的血液DNA鉴定BRCA1和BRCA2突变。临床病理资料以及治疗和长期结果的资料，包括疾病复发的日期和部位，从6个月、12个月的常规医疗记录中收集，然后每年收集，直到死亡或失去随访。主要结局是所有BRCA1或BRCA2突变携带者（brca阳性）与所有非携带者（brca阴性）在诊断后2年、5年和10年的总生存率。对三阴性乳腺癌患者的总生存率进行了预先指定的亚组分析。招募于2008年完成，长期随访仍在继续。从2000年1月24日到2008年1月24日，我们招募了2733名女性。基因分型在338例（12%）患者中检测到致病性BRCA突变（201例为BRCA1, 137例为BRCA2）。在中位随访8.2年（IQR为6.0 ~ 9.9）后，678例死亡中有651例（96%）死于乳腺癌。在多变量分析中，brca阳性和brca阴性患者在任何时间点的总生存率均无显著差异（2年：97.0% [95% CI 94.5 - 98.4] vs 96.6%[95.8 - 97.3]； 5年：83.8% [73.3 - 85.5]vs 85.0%[83.5 - 84.4]； 10年：73.4% [64.4 - 78.5]vs 71%[67.7 - 72.3]；风险比[HR] 0.96 [95% CI 0.76 - 1.22]; p= 0.76）。在558例三阴性乳腺癌患者中，BRCA突变携带者在2年的总生存率优于非携带者（95% [95% CI 89-97]对91% [88-94]；HR 0.59 [95% CI 0.35 - 0.99]; p= 0.047），但在5年（81%[73-87]对74% [70-78]；HR 1.13 [0.70 - 1.84]; p= 0.62）或10年（72%[62 - 80]对69% [63-74]；HR 2.12 [0.82 - 2.49]; p= 0.12）的总生存率优于非携带者。携带BRCA突变的年轻乳腺癌患者与非携带者的生存率相似。然而，与非携带者相比，三阴性乳腺癌BRCA突变携带者在诊断后的头几年可能具有生存优势。为减少未来的第二原发癌风险而决定额外手术的时机时，应考虑与第一恶性肿瘤相关的患者预后和患者的偏好。英国癌症研究中心，英国国家癌症研究网络，威塞克斯癌症信托基金，乳腺癌现在，和PPP医疗保健信托基金。
Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5–98·4] vs 96·6% [95·8–97·3]; at 5 years: 83·8% [79·3–87·5] vs 85·0% [83·5–86·4]; at 10 years: 73·4% [67·4–78·5] vs 70·1% [67·7–72·3]; hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89–97] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047) but not 5 years (81% [73–87] vs 74% [70–78]; HR 1·13 [0·70–1·84]; p=0·62) or 10 years (72% [62–80] vs 69% [63–74]; HR 2·12 [0·82–5·49]; p= 0·12). Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.