同源重组缺陷检测在乳腺癌个体化治疗中的应用价值

The application value of homologous recombination deficiency detection in personalized treatment of breast cancer

摘要

目的 通过分析西安交通大学第一附属医院经同源重组缺陷(homologous recombination deficiency, HRD)检测乳腺癌患者的临床病理特征及诊疗过程,深入探讨HRD检测对乳腺癌临床治疗决策的指导价值。方法 采用回顾性队列研究设计,收集2021年10月至2024年5月期间在西安交通大学第一附属医院接受HRD检测的乳腺癌患者127例。根据AmoyDx(AmoyDx,中国厦门)提供的HRD检测试剂盒的标准判读体系,将研究对象分为HRD阴性组与HRD阳性组。通过对比分析两组间的临床病理特征及接受HRD检测前后临床决策改变情况,评估HRD检测在乳腺癌个体化治疗决策制定中的临床应用价值。结果 本研究共纳入127例乳腺癌患者,HRD阳性患者占比54.3%(69/127)。其中,HRD阳性组内雌激素受体(estrogen receptor, ER)阴性、孕激素受体(progesterone receptor, PR)阴性、人表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)阴性患者的比例显著高于HRD阴性组(P＜0.05)。同时,HRD阳性组分子亚型为三阴性型(triple-negative breast cancer, TNBC)(72.5% vs. 43.1%)和组织学分级3级(50.7% vs. 20.7%)的比例较HRD阴性组显著升高(P＜0.05)。临床决策分析显示,HRD状态显著影响术前新辅助治疗方案选择(McNemar检验,P=0.015)及术后铂类药物和聚腺苷二磷酸核糖聚合酶抑制剂(poly ADP-ribose polymerase inhibitors, PARPi)的应用(McNemar检验,P＜0.001)。多因素Logistic回归分析表明,组织学分级3级与HRD阳性独立相关(OR=3.97,95% CI:1.70～9.26,P=0.001),而PR阳性(OR=0.35,95% CI:0.15～0.79,P=0.012)和HER2低表达(OR=0.40,95% CI:0.18～0.91,P=0.028)为保护因素。结论 HRD阳性患者多为TNBC,同时伴有Ki-67高表达及高组织学分级。HRD检测可为乳腺癌患者临床决策的制定尤其是铂类化疗药物和PARPi的选择和应用方面提供重要的指导价值。

Abstract

Objective To assess the application of homologous recombination deficiency (HRD) detection in breast cancer diagnosis and treatment at The First Affiliated Hospital of Xi'an Jiaotong University, and to analyze the clinicopathological features of HRD-positive breast cancer patients and explore the role of HRD testing in guiding treatment decisions. Methods For this retrospective cohort study, we collected complete clinicopathological data and genetic testing reports of breast cancer patients who underwent HRD detection at The First Affiliated Hospital of Xi'an Jiaotong University from October 2021 to May 2024. Patients were classified into HRD-positive and HRD-negative groups based on their test results. Differences in clinicopathological characteristics and changes in clinical decision-making before and after HRD testing were analyzed to assess the clinical utility of HRD testing in guiding individualized treatment strategies. Results This study included a total of 127 breast cancer patients, of whom the HRD positive detection rate was 54.3%(69/127). The proportion of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2)-negative and triple-negative breast cancer (72.5% vs. 43.1%) with histological grade 3 (50.7% vs. 20.7%) was significantly higher in HRD-positive patients than in HRD-negative patients (P＜0.05). Clinical decision analysis revealed that HRD testing results significantly affected preoperative neoadjuvant therapy selection (McNemar test, P=0.015) and the postoperative use of platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitor (PARPi) (McNemar test, P＜0.001). Multivariate Logistic regression identified histological grade 3 as an independent risk factor for HRD positivity (OR=3.97, 95% CI: 1.70-9.26, P=0.001), while PR positivity (OR=0.35, 95% CI: 0.15-0.79, P=0.012) and low HER2 expression (OR =0.40, 95% CI: 0.18-0.91, P=0.028) were protective factors. Conclusion HRD-positive patients mainly present with negative expressions of ER, PR, and HER2, accompanied by high expression of Ki-67 and high histological grade. HRD detection can provide important reference for clinical decision-making in breast cancer patients, especially in selection and application of platinum chemotherapy drugs and PARPi. Histological grade, PR status and HER2 status are independent predictors of HRD positivity.

关键词

同源重组修复缺陷 / 乳腺癌 / 临床决策 / 临床病理特征 / 个体化治疗

Key words

homologous recombination deficiency / breast cancer / clinical decision-making / clinicopathological characteristic / personalized treatment

参考文献

[1] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.

[2] NIK—ZAINAL S, MORGANELLA S. Mutational signatures in breast cancer:the problem at the DNA level[J]. Clin Cancer Res, 2017, 23(11): 2617-2629.

[3] QU Y, QIN S, YANG Z, et al. Targeting the DNA repair pathway for breast cancer therapy:beyond the molecular subtypes[J]. Biomed Pharmacother, 2023, 169: 115877.

[4] TUFAIL M. DNA repair pathways in breast cancer:from mechanisms to clinical applications[J]. Breast Cancer Res Treat, 2023, 200(3): 305-321.

[5] ZHU L, LIU J, CHEN J, et al. The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers[J]. J Hematol Oncol, 2021, 14(1): 206.

[6] CRAGUN D, WEIDNER A, LEWIS C, et al. Racial disparities in BRCA testing and cancer risk management across a population—based sample of young breast cancer survivors[J]. Cancer, 2017, 123(13): 2497-2505.

[7] DALY M B, PILARSKI R, BERRY M, et al. NCCN guidelines insights:genetic/familial high—risk assessment:breast and ovarian,version 2.2017[J]. J Natl Compr Canc Netw, 2017, 15(1): 9-20.

[8] HUANG Y, QIU Y, DING L, et al. Somatic mutations in four novel genes contribute to homologous recombination deficiency in breast cancer:a real—world clinical tumor sequencing study[J]. J Pathol Clin Res, 2024, 10(2): e12367.

[9] LOIBL S, WEBER K E, TIMMS K M, et al. Survival analysis of carboplatin added to an anthracycline/taxane—based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto[J]. Ann Oncol, 2018, 29(12): 2341-2347.

[10] ROBSON M E, IM S A, SENKUS E, et al. OlympiAD:phase Ⅲ trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2—negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm)[J]. J Clin Oncol, 2017, 35(18_suppl): LBA4.

[11] INCORVAIA L, PEREZ A, MARCHETTI C, et al. Theranostic biomarkers and PARP—inhibitors effectiveness in patients with non—BRCA associated homologous recombination deficient tumors:still looking through a dirty glass window?[J]. Cancer Treat Rev, 2023, 121: 102650.

[12] MORICE P M, COQUAN E, WEISWALD L B, et al. Identifying patients eligible for PARP inhibitor treatment:from NGS—based tests to 3D functional assays[J]. Br J Cancer, 2021, 125(1): 7-14.

[13] GOU R, DONG H, LIN B. Application and reflection of genomic scar assays in evaluating the efficacy of platinum salts and PARP inhibitors in cancer therapy[J]. Life Sci, 2020, 261: 118434.

[14] KORSHOLM L M, BROECKER V, MIRZA M R, et al. Implementing MyChoice© CDx HRD testing for the nordics:lessons from 2021 to 2023[J]. Acta Oncol, 2024, 63: 34139.

[15] MILBURY C A, CREEDEN J, YIP W K, et al. Clinical and analytical validation of Foundation One© CDx,a comprehensive genomic profiling assay for solid tumors[J]. PLoS One, 2022, 17(3): e0264138.

[16] GRADISHAR W J, MORAN M S, ABRAHAM J, et al. NCCN guidelines© insights:breast cancer,version 4.2023[J]. J Natl Compr Canc Netw, 2023, 21(6): 594-608.

[17] 中国抗癌协会乳腺癌专业委员会, 中华医学会肿瘤学分会乳腺肿瘤学组. 中国抗癌协会乳腺癌诊治指南与规范(2024年版)[J]. 中国癌症杂志, 2023, 33(12): 1092-1186.

[18] The Society of Breast Cancer China Anti—Cancer Association,Breast Oncology Group of the Oncology Branch of the Chinese Medical Association. Guidelines for breast cancer diagnosis and treatment by China Anti—cancer Association(2024 edition)[J]. China Oncology, 2023, 33(12): 1092-1186.

[19] GIULIANO A E, EDGE S B, HORTOBAGYI G N. Eighth edition of the AJCC cancer staging manual:breast cancer[J]. Ann Surg Oncol, 2018, 25(7): 1783-1785.

[20] YUAN W, NI J, WEN H, et al. Genomic Scar Score:a robust model predicting homologous recombination deficiency based on genomic instability[J]. BJOG, 2022, 129(Suppl 2): 14-22.

[21] KANG K, WU Y, HAN C, et al. Homologous recombination deficiency in triple—negative breast cancer:multi—scale transcriptomics reveals distinct tumor microenvironments and limitations in predicting immunotherapy response[J]. Comput Biol Med, 2023, 158: 106836.

[22] POGODA K, NIWIŃSKA A, SARNOWSKA E, et al. Effects of BRCA germline mutations on triple—negative breast cancer prognosis[J]. J Oncol, 2020, 2020: 8545643.

[23] STAAF J, GLODZIK D, BOSCH A, et al. Whole—genome sequencing of triple—negative breast cancers in a population—based clinical study[J]. Nat Med, 2019, 25(10): 1526-1533.

[24] TUNG N, ARUN B, HACKER M R, et al. TBCRC 031:randomized phase II study of neoadjuvant cisplatin versus doxorubicin—cyclophosphamide in germline BRCA carriers with HER2—negative breast cancer (the INFORM trial)[J]. J Clin Oncol, 2020, 38(14): 1539-1548.

[25] TUTT A N J, GARBER J E, KAUFMAN B, et al. Adjuvant olaparib for patients with BRCA1— or BRCA2—mutated breast cancer[J]. N Engl J Med, 2021, 384(25): 2394-2405.

[26] MA D, CHEN S Y, REN J X, et al. Molecular features and functional implications of germline variants in triple—negative breast cancer[J]. J Natl Cancer Inst, 2021, 113(7): 884-892.

[27] WENG L, ZHOU J, GUO S, et al. The molecular subtyping and precision medicine in triple—negative breast cancer—based on Fudan TNBC classification[J]. Cancer Cell Int, 2024, 24(1): 120.

[28] WANG Z, LU Y, HAN M, et al. Association between homologous recombination deficiency status and carboplatin treatment response in early triple—negative breast cancer[J]. Breast Cancer Res Treat, 2024, 208(2): 429-440.

[29] TELLI M L, TIMMS K M, REID J, et al. Homologous recombination deficiency (HRD) score predicts response to platinum—containing neoadjuvant chemotherapy in patients with triple—negative breast cancer[J]. Clin Cancer Res, 2016, 22(15): 3764-3773.

[30] DALY G R, NAIDOO S, ALABDULRAHMAN M, et al. Screening and testing for homologous recombination repair deficiency (HRD) in breast cancer:an overview of the current global landscape[J]. Curr Oncol Rep, 2024, 26(8): 890-903.

[31] BALLOT E, GALLAND L, MANANET H, et al. Molecular intrinsic subtypes,genomic,and immune landscapes of BRCA—proficient but HRD—high ER—positive/HER2—negative early breast cancers[J]. Breast Cancer Res, 2022, 24(1): 80.

基金资助

国家自然科学基金青年科学基金项目(82504145)

西安交通大学第一附属医院国自然培育青年项目(2024-QN-30)

西安交通大学第一附属医院横向课题(HX202428)