【原】缘分天注定，肿瘤化疗毒性或也天注定

　　卡培他滨对于乳腺癌等恶性肿瘤的化疗至关重要，但是可能引起腹泻和手足综合征，影响坚持用药和生活质量。众所周知，肿瘤的发生发展既有外因、也有内因，既有后天决定因素、也有先天遗传因素。同样，肿瘤化疗毒性既可能有后天决定因素，或许也有先天遗传因素。明确化疗毒性的先天遗传因素，有助于采取预防措施、减少化疗毒性、提高患者依从性和生活质量，或可实现“逆天改命”。

　　2020年5月6日，施普林格自然旗下《乳腺癌研究与治疗》在线发表美国芝加哥大学、梅奥医学中心、范德堡大学、德克萨斯大学MD安德森癌症中心、印第安那大学、阿拉巴马大学伯明翰分校、密歇根大学、乔治城大学、贝勒医学院、芝加哥大学北岸医疗中心、杜克大学、旧金山加利福尼亚大学、北卡罗来纳大学、霍普金斯大学的乳腺癌转化研究联盟TBCRC-015研究报告，探讨了乳腺癌卡培他滨化疗毒性相关遗传基因多态性的药物基因组学临床预测因素。

TBCRC-015: Investigation of Genetic Determinants of Capecitabine Toxicity (NCT00977119)

　　该多中心临床研究于2009年12月～2013年5月从美国14家医院入组晚期乳腺癌卡培他滨化疗患者259例。卡培他滨每天每平方米体表面积2000毫克，每21天连续口服14天、暂停7天。每21天的第1天与患者当面完成毒性调查问卷，第8、15天通过自动电话呼入进行毒性评定。主要终点为基因型与早期和总体毒性的相关性。

　　结果，腹泻和手足综合征发生于52%和69%的患者，其中三级分别占17%和9%。仅29%的患者完成4个周期化疗且未减量或停药。39%的最严重毒性来自电话报告。

　　腹泻发生比例显著较高的基因点突变包括：

• 二氢嘧啶脱氢酶DPYD*5基因突变（比值比：4.9，P=0.0005）

• 亚甲基四氢叶酸还原酶MTHFR错义突变（比值比：3.3，P=0.02）

• 甲硫氨酸合成酶还原酶MTRR上游突变（比值比：3.0，P=0.03）

　　手足综合征发生比例显著较高的基因点突变包括：

• 肿瘤坏死因子配体TNFSF4（OX40L）基因附近突变（比值比：3.0，P=0.0007）该基因与自身免疫相关，包括自身免疫性皮肤病，此前从未被发现与手足综合征相关

• 皮肤组织成纤维细胞生长因子转录激活控制基因CHURC1的rs11158568突变（β=-0.74，P=1.46×10-23）代表此前未知的手足综合征机制

　　因此，该研究首次通过电话自行报告和当面调查问卷，进行癌症药物毒性相关基因组学特征分析，证实了三种化疗腹泻相关可遗传基因突变，并且新发现了两种化疗手足综合征相关可遗传基因突变。故有必要开展进一步研究对这些基因标志进行验证，有助于卡培他滨的个体化用药，或可实现“逆天改命”。

Breast Cancer Res Treat. 2020 May 6. [Epub ahead of print]

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

Peter H. O'Donnell, Vassily Trubetskoy, Ashley Nurhussein-Patterson, Julianne P. Hall, Aritro Nath, Dezheng Huo, Gini F. Fleming, James N. Ingle, Vandana G. Abramson, P. K. Morrow, Anna Maria Storniolo, Andres Forero, Catherine Van Poznak, Minetta C. Liu, Jenny C. Chang, Douglas E. Merkel, Jeffrey M. Peppercorn, Hope S. Rugo, E. Claire Dees, Olwen M. Hahn, Philip C. Hoffman, Gary L. Rosner, R. Stephanie Huang, Mark J. Ratain, Nancy Cox, Olufunmilayo I. Olopade, Antonio C. Wolff, M. Eileen Dolan, Rita Nanda; Translational Breast Cancer Research Consortium (TBCRC).

The University of Chicago, Chicago, IL, USA; Mayo Clinic, Rochester, USA; Vanderbilt University, Nashville, USA; MD Anderson Cancer Center, Houston, USA; Indiana University, Bloomington, USA; University of Alabama-Birmingham, Birmingham, USA; University of Michigan, Ann Arbor, USA; Georgetown University, Washington, USA; Baylor College of Medicine, Houston, USA; NorthShore University Health System, Evanston, USA; Duke University, Durham, USA; University of California, San Francisco, USA; University of North Carolina, Chapel Hill, USA; Johns Hopkins University, Baltimore, USA.

PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool.

METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint.

RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea—DPYD*5 (odds ratio [OR] 4.9; P=0.0005), a MTHFR missense SNP (OR 3.3; P=0.02), and a SNP upstream of MTRR (OR 3.0; P=0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P=0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta=-0.74; P=1.46×10-23), representing a previously unidentified mechanism for HFS.

CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

KEYWORDS: Capecitabine, Fluorouracil, Toxicity, Pharmacogenetics, Pharmacogenomics

DOI: 10.1007/s10549-020-05603-8