乳腺癌放療誘發纖維化的基因預測

最新 07-26

對於早期乳腺癌女性，保乳手術＋全乳放療可以提高保乳成功率和乳腺癌相關生存率。不過，全乳放療也可誘髮乳腺纖維化。既往研究發現遺傳因素可以影響放療敏感性，例如轉化生長因子β1基因（TGFB1）啟動子區等位基因變異C-509T，但是尚不明確能否通過遺傳因素髮現存在放療纖維化風險的患者。

2018年7月19日，《美國醫學會雜誌》腫瘤學分冊在線發表德克薩斯大學MD安德森癌症中心、俄勒岡醫科大學的隨機臨床研究二次分析報告，探討了C-509T與早期乳腺癌患者放療3年後放療所致正常乳腺組織纖維化毒性反應的相關性。

該預設前瞻隊列研究嵌套於一項非盲隨機臨床研究（NCT01266642），2011年2月～2014年2月在社區和學術癌症中心進行，入組287例年齡≥40歲且經病理證實為0～IIA期乳腺癌並接受保乳手術治療的女性患者，隨機分配接受保乳手術後大分割全乳放療（42.56Gy分割為16次，138例）或常規分割全乳放療（50Gy分割為25次，149例）。隨訪至少3年。通過單側費希爾精確檢驗和多因素邏輯回歸，對結局進行比較。檢測TGFB1基因相對於第一個主要轉錄起始位點的第509位C→T單核苷酸多態性（C-509T）。主要結局指標為放療3年後≥2級乳腺纖維化，根據LENT/SOMA量表（範圍：0～3）進行評定。

最後，174例患者可獲得TGFB1基因型和3年放療誘發毒性反應數據，其中89例患者（51%）存在C-509T變異，她們的平均年齡為60±8歲。

乳腺纖維化≥2級發生率：

C-509T患者：13.8%

無變異患者：3.8%

相差絕對值：10.0%（95%置信區間：1.7%～18.4%，P=0.02）

多因素分析結果表明，乳腺纖維化風險顯著相關因素：

有C-509T變異（比值比：4.47，95%置信區間：1.25～15.99，P=0.02）

術後美觀結局（比值比：7.09，95%置信區間：2.41～20.90，P

目前，該研究為首項前瞻驗證放射性纖維化基因組遺傳標誌的研究，結果表明TGFB1等位基因C-509T為乳腺纖維化風險的關鍵決定因素。

因此，評定TGFB1基因型有助於乳腺癌局部區域治療決策更個體化。

JAMA Oncol. 2018 Jul 19. [Epub ahead of print]

Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Grossberg AJ, Lei X, Xu T, Shaitelman SF, Hoffman KE, Bloom ES, Stauder MC, Tereffe W, Schlembach PJ, Woodward WA, Buchholz TA, Smith BD.

The University of Texas MD Anderson Cancer Center, Houston; Oregon Health and Science University, Portland.

This cohort study of female participants with stage 0 to IIA breast cancer treated with breast-conserving surgery and whole-breast irradiation assesses whether radiation-induced toxicities of normal breast tissue 3 years after radiotherapy are associated with the transforming growth factor β gene variant C-509T.

QUESTION: Does an association exist between C-509T polymorphism of the TGFB1 gene and radiotherapy-induced toxicity of normal breast tissue among women with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery and whole-breast irradiation?

FINDINGS: This prospective cohort study evaluating 174 participants in a randomized clinial trial found grade 2 or higher breast fibrosis 3 years after radiotherapy in 13.8% of patients with the C-509T variant allele vs 3.8% of patients without the variant allele, a significant difference.

MEANING: The C-509T variant allele may be used prospectively as a genetic marker to identify patients at elevated risk for fibrosis following radiotherapy.

IMPORTANCE: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed.

OBJECTIVE: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy.

DESIGN, SETTING, AND PARTICIPANTS: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression.

EXPOSURES: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene.

MAIN OUTCOMES AND MEASURES: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy.

RESULTS: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P=.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P=.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P

CONCLUSIONS AND RELEVANCE: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.

DOI: 10.1001/jamaoncol.2018.2583