高负荷和低负荷转移性激素敏感性前列腺癌中BRCA1/2及同源重组修复改变：患病率及其对预后的影响

BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes.

作者信息

Olmos D, Lorente D, Jambrina A, Tello-Velasco D, Ovejero-Sánchez M, Gonzalez-Ginel I, Romero-Laorden N, Nunes-Carneiro D, Balongo M, Gutierrez-Pecharromán A M, Llácer C, Prieto J D, Pérez-Argüelles D, Alberca Del Arco F, Miguel-Masiá J, Ruiz-Vico M, Santos R, Esteban-Villarrubia J, Gonzalez-Billalabeitia E, Jürgens A, Capone C, Trevisan M, Van Sanden S, Stulnig G, Hernández D, López-Casas P P, Rodriguez-Antolin A, Castellano D E, Herrera-Imbroda B, Castro E

机构信息

Genomics and Therapeutics in Prostate Cancer Group, I+12 Biomedical Research Institute, Madrid, Spain; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.

Medical Oncology Department, Instituto Valenciano de Oncología, Valencia, Spain. Electronic address: https://twitter.com/Dav_Lorente.

出版信息

Ann Oncol. 2025 Jun 2. doi: 10.1016/j.annonc.2025.05.534.

DOI:10.1016/j.annonc.2025.05.534

PMID:40467032

Abstract

BACKGROUND

Alterations in BRCA1/2 (BRCA) and other homologous recombination repair (HRR) genes have a negative impact on outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Poly(adenosine diphosphate-ribose) polymerase inhibitors, the only treatment demonstrated to improve the prognosis of patients with mCRPC, are also being developed for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC). To fully assess their potential benefit in this setting, it is essential to understand how BRCA and HRR defects may influence the prognosis of conventionally treated patients with low and high disease volume.

PATIENTS AND METHODS

Eligible mHSPC patients diagnosed between January 2018 and December 2023 underwent paired somatic/germline DNA sequencing. Cases with alterations in one or more HRR genes were classified as BRCA, HRR non-BRCA, non-BRCA or non-HRR. Radiographic progression-free survival, time to castration resistance and overall survival were reported for all subgroups; associations between mutations and outcomes were assessed after controlling for treatment modality and baseline characteristics using inverse probability of treatment weighting models.

RESULTS

Of 556 patients, 159 (28.6%) had HRR gene alterations: 69 (12.4%) with BRCA and 90 (16.2%) with HRR non-BRCA mutations. mHSPC was synchronous in 451 patients (81.1%) and was classified as high-volume (CHAARTED criteria) in 306 (55%) patients. Within the HRR subgroup, patients with BRCA mutations had significantly worse outcomes across all endpoints (P < 0.005 for all comparisons). Differences in prognosis by BRCA and HRR status were observed in both low- and high-volume subgroups and were independent of treatment with androgen receptor pathway inhibitors or taxanes.

CONCLUSION

Presence of HRR mutations, particularly BRCA alterations, significantly worsened prognosis, regardless of disease volume or treatment regimen. These findings underscore the importance of integrating tumour biology for accurate risk stratification in mHSPC and the design of new treatment strategies and follow-up.

摘要

背景

BRCA1/2（BRCA）及其他同源重组修复（HRR）基因的改变对转移性去势抵抗性前列腺癌（mCRPC）患者的预后有负面影响。聚（二磷酸腺苷 - 核糖）聚合酶抑制剂是唯一被证明可改善mCRPC患者预后的治疗方法，目前也正在开发用于治疗转移性激素敏感性前列腺癌（mHSPC）患者。为了全面评估其在这种情况下的潜在益处，了解BRCA和HRR缺陷如何影响传统治疗的低疾病负荷和高疾病负荷患者的预后至关重要。

患者与方法

2018年1月至2023年12月期间确诊的符合条件的mHSPC患者接受了配对的体细胞/种系DNA测序。一个或多个HRR基因发生改变的病例被分类为BRCA、HRR非BRCA、非BRCA或非HRR。报告了所有亚组的影像学无进展生存期、去势抵抗时间和总生存期；使用治疗权重逆概率模型在控制治疗方式和基线特征后评估突变与预后之间的关联。

结果

556例患者中，159例（28.6%）存在HRR基因改变：69例（12.4%）有BRCA突变，90例（16.2%）有HRR非BRCA突变。451例患者（81.1%）的mHSPC为同步性，306例（55%）患者根据CHAARTED标准被分类为高疾病负荷。在HRR亚组中，BRCA突变患者在所有终点的预后均明显较差（所有比较P < 0.005）。在低疾病负荷和高疾病负荷亚组中均观察到BRCA和HRR状态对预后的差异，且与雄激素受体途径抑制剂或紫杉烷治疗无关。