Kekeeva Tatiana, Dudina Irina, Andreeva Yulia, Tanas Alexander, Kalinkin Alexey, Musatova Victoria, Chernorubashkina Natalia, Khokhlova Svetlana, Tikhomirova Tatiana, Volkonsky Mikhail, Kutsev Sergey, Zaletaev Dmitry, Strelnikov Vladimir
Laboratory of Epigenetics, Research Centre for Medical Genetics, Moskvorechie st., 1, 115522 Moscow, Russia.
Day Hospital No. 1, Moscow Municipal Oncological Hospital No. 62, 143515 Moscow, Russia.
Int J Mol Sci. 2024 Dec 18;25(24):13549. doi: 10.3390/ijms252413549.
Homologous recombination repair deficiency (HRD) is involved in the development of high-grade serous ovarian carcinoma (HGSOC) and its elevated sensitivity to platinum-based chemotherapy. To investigate the heterogeneity of the HRD-positive HGSOC we evaluated the HRD status, including BRCA mutations, genomic scar score, and methylation status of genes in 352 HGSOC specimens. We then divided the HRD-positive cohort into three molecular subgroups, the BRCA mutation cohort (BRCA+), BRCA1 methylation cohort (Meth+), and the rest of the HRD+ cohort (HRD+BRCA-Meth-), and evaluated their first-line chemotherapy response, benefit from olaparib, and progression-free survival (PFS). HRD-positive status was detected in 65% (228/352) of samples. The first group, BRCA+, accounted for 45% (102/228) of HRD positive cases and showed the best outcome in platinum therapy (ORR 96%), the highest olaparib benefit ( = 0.006) and the highest median PFS (46 months). The frequency of the second cohort, Meth+, among HRD-positive patients was 23% (52/228). Patients with Meth+ HGSOC showed a significantly poorer outcome, with a median PFS of 19 months, a significantly lower ORR to platinum therapy (84%) and a modest, but not significant, benefit from olaparib maintenance. The third HRD+BRCA-Meth- group accounted for 32% (74/228) of HRD-positive patients and showed an ORR to platinum therapy similar to that of the BRCA+ group (90%), a higher, but not statistically significant, benefit from olaparib and a median PFS of 23 months. In conclusion, Meth+ subgroup had poor outcomes in terms of chemotherapy response, olaparib benefit, and PFS compared to the other HRD+ subgroups, requiring a more thorough follow-up.
同源重组修复缺陷（HRD）与高级别浆液性卵巢癌（HGSOC）的发生发展及其对铂类化疗的高敏感性有关。为了研究HRD阳性HGSOC的异质性，我们评估了352例HGSOC标本中的HRD状态，包括BRCA突变、基因组瘢痕评分和基因的甲基化状态。然后，我们将HRD阳性队列分为三个分子亚组，即BRCA突变队列（BRCA+）、BRCA1甲基化队列（Meth+）和其余的HRD+队列（HRD+BRCA-Meth-），并评估了它们的一线化疗反应、奥拉帕利获益情况以及无进展生存期（PFS）。65%（228/352）的样本检测到HRD阳性状态。第一组BRCA+占HRD阳性病例的45%（102/228），在铂类治疗中显示出最佳结果（客观缓解率96%）、最高的奥拉帕利获益（P = 0.006）和最高的中位PFS（46个月）。HRD阳性患者中第二队列Meth+的频率为23%（52/228）。Meth+ HGSOC患者的结局明显较差，中位PFS为19个月，铂类治疗的客观缓解率显著较低（84%），奥拉帕利维持治疗有一定但不显著的获益。第三个HRD+BRCA-Meth-组占HRD阳性患者的32%（74/228），铂类治疗的客观缓解率与BRCA+组相似（90%），奥拉帕利获益更高但无统计学意义，中位PFS为23个月。总之，与其他HRD+亚组相比，Meth+亚组在化疗反应、奥拉帕利获益和PFS方面结局较差，需要更密切的随访。
