Villacampa Guillermo, Llop-Guevara Alba, Filmann Natalie, Herencia-Ropero Andrea, Fasching Peter A, Karn Thomas, Marmé Frederik, Klare Peter, Müller Volkmar, Stefek Andrea, Schem Christian, Uleer Christoph, Fehm Tanja, Doering Gabriele, Stickeler Elmar, van Mackelenbergh Marion, Felder Bärbel, Nekljudova Valentina, Balmaña Judith, Denkert Carsten, Loibl Sibylle, Serra Violeta
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany.
Clin Cancer Res. 2025 Mar 3;31(5):808-814. doi: 10.1158/1078-0432.CCR-24-3148.
The randomized GeparOLA trial reported comparable pathologic complete response (pCR) rates with neoadjuvant treatment containing olaparib versus carboplatin. In this study, we evaluate the association between functional homologous recombination deficiency (HRD) by RAD51 foci and pCR and the potential of improving patient selection by combining RAD51 and stromal tumor-infiltrating lymphocytes.
This is a post hoc blinded biomarker analysis from the randomized GeparOLA trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad MyChoice or BRCA1/BRCA2 mutations were randomized 1:1 to receive (i) paclitaxel plus olaparib or (ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
Overall, 90 of 97 (92.8%) samples were evaluable for RAD51 testing, and 72 of 90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), whereas it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathologic factors and treatment, the RAD51 score remained significantly associated with pCR (OR = 12.03; 95% confidence interval, 2.60-55.73; P = 0.002). Patients with RAD51-low and high stromal tumor-infiltrating lymphocytes in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory disease-free survival analysis, no differences were observed between RAD51 groups (high vs. low: HR = 0.85; 95% confidence interval, 0.25-2.97).
In a preselected population with HRD, according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARP inhibitor-based or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.
随机GeparOLA试验报告称，含奥拉帕利的新辅助治疗与含卡铂的新辅助治疗的病理完全缓解（pCR）率相当。在本研究中，我们评估了通过RAD51灶检测的功能性同源重组缺陷（HRD）与pCR之间的关联，以及联合使用RAD51和基质肿瘤浸润淋巴细胞改善患者选择的潜力。
这是一项来自随机GeparOLA试验的事后盲法生物标志物分析。对通过Myriad MyChoice或BRCA1/BRCA2突变评估为HRD的早期HER2阴性乳腺癌患者按1:1随机分组，分别接受（i）紫杉醇加奥拉帕利或（ii）紫杉醇加卡铂治疗，随后均接受表柔比星/环磷酰胺治疗。功能性HRD预先定义为RAD51评分≤10%（RAD51低）。
总体而言，97份样本中有90份（92.8%）可用于RAD51检测，90份中有72份（80.0%）为RAD51低。RAD51低肿瘤患者的pCR率为66.7%（48/72），而RAD51高的患者中该率降至22.2%（4/18）。在包含临床病理因素和治疗的多变量模型中，RAD51评分仍与pCR显著相关（OR = 12.03；95%置信区间，2.60 - 55.73；P = 0.002）。肿瘤中RAD51低且基质肿瘤浸润淋巴细胞高的患者pCR率为75.0%（27/36）。奥拉帕利或卡铂治疗组观察到类似结果。在探索性无病生存分析中，RAD51组之间未观察到差异（高 vs. 低：HR = 0.85；95%置信区间，0.25 - 2.97）。
在根据基因检测预先选择的HRD人群中，RAD51检测可识别出在基于PARP抑制剂或铂类的治疗下具有不同pCR率的患者。未来基于生物标志物的研究应考虑这些信息以优化分层因素并改善患者选择。
