CFAH RAD51 as a biomarker of homologous recombination deficiency & predictor of clinical outcomes in patients with triple-negative breast cancer – VHIO – Vall d'Hebron Institute of Oncology

RAD51 as a biomarker of homologous recombination deficiency & predictor of clinical outcomes in patients with triple-negative breast cancer

  • Developed in-house by VHIO’s Experimental Therapeutics Group, the RAD51 diagnostic test now steps up as a viable identifier of patients with homologous recombination deficient primary triple-negative breast cancer.
  • Directed by Violeta Serra, multicenter biomarker analysis from the GeparSixto randomized clinical trial demonstrates the utility of RAD51 as a clinically relevant biomarker of homologous recombination deficiency and a predictor of response to platinum-based neoadjuvant chemotherapy in patients with triple-negative breast cancer.
  • Having previously been validated in the context of other tumor types, results from this VHIO-led study published in Annals of Oncology (1) support further development to incorporate RAD51 testing in clinical decision making.

Barcelona, October 13, 2021. Over the past few years, research pioneered by VHIO’s Experimental Therapeutics Group, led by Violeta Serra, has focused on the development and application of its RAD51 immunohistology-based diagnostic test to predict those patients who would be most likely to benefit from agents including chemotherapy and PARP inhibitors (PARPi). Regarding PARPi, this assay has already been shown to facilitate the more precise identification of patients with breast and ovarian cancer who could respond to this class of targeted treatments.

Thanks to the support received through the Spanish Association against Cancer (AECC) as well as the   ”la Caixa” Foundation (CaixaResearch) funding programs, Violeta Serra’s team has continued to develop their RAD51 test to better guide the stratification of patients to clinical trials to evaluate the efficacy of PARPi across additional tumor types including ovarian cancers. Based on DNA repair functionality, the RAD51 assay has been proven to complement genomic testing in clinical practice, and most recently, in the context of prostate cancer (2).

Now, results from a multicenter study recently published in the flagship journal of the European Society for Medical Oncology (ESMO), Annals of Oncology (1), support RAD51 as a valid identifier of patients with untreated triple-negative breast cancer (TNBC), with homologous recombination-mediated DNA repair deficiency (HRD), and a predictive tool to select those patients who would most likely respond to treatment with platinum-based neoadjuvant chemotherapy.

“Results of our biomarker substudy of the GeparSixto randomized clinical trial, represent a significant next step towards the clinical validation of our RAD51 assay, and now, in the breast cancer setting,” said Violeta Serra, Principal Investigator of VHIO’s Experimental Therapeutics Group and Corresponding Author of this present study.  She continued, “Building on the positive results of our previous studies across other tumor types, we are confident that our latest findings support the further development of our assay for its future incorporation in clinical decision making.”

Predicting patients’ sensitivity to platinum-based neoadjuvant chemotherapy

TNBC tumors have an increased sensitivity to DNA damaging agents such as platinum salts. However, the toxicity associated with these therapies, coupled with the lack of a conclusive correlation with survival outcomes, raise concern about their use in treating early-stage disease.

The observed high sensitivity of TNBC to platinum-based chemotherapy can be explained by the high proportion of these tumors that harbor genetic or epigenetic alterations that lead to double strand DNA break repair deficiency in the homologous recombination repair (HRR) pathway. These alterations include inherited mutations in the BRCA1 and BRCA2 genes, as well as less frequent alterations such as PALB2, RAD51C and RAD51D mutations,” added Violeta Serra, who also highlighted that identifying tumors harboring these genetic alterations represents a clinical challenge.

Genomic scars and signatures have shown a high correlation with HRR gene alterations. However, neither BRCA1/BRCA2 mutations nor genomic scars signatures have facilitated the identification of those patients who would be most likely to benefit from treatment with platinum-based chemotherapy.

Importantly, some HRR deficient tumors can evolve towards restoring HRR and thus acquire resistance to DNA damaging agents. These tumors would consequently be misclassified based on their underlying genomic scar or signatures,” highlighted Alba Llop-Guevara, a Post-Doctoral Fellow of Violeta Serra’s Group. For this reason, a functional, reliable and dynamic measurement of HRR is required to establish the actual status of HRD.

“By demonstrating the validity of quantifying RAD51 nuclear foci in this patient population, establishing its concordance with genomic-based assays, and showing it association with clinical outcomes, our results could respond to this unmet need,” added Alba Llop-Guevara, a co-first author of this study.

Biomarker analysis from the GeparSixto trial

To test the utility of the RAD51 foci analysis, the investigators conducted retrospective, blinded biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received treatment with neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel with or without carboplatin. Data showed that the patients who most benefited from carboplatin were those with tumors with HRD by the biomarker RAD51.

“This study supports the clinical validity of the RAD51 assay as a functional HRD test and an independent predictive biomarker of response to carboplatin in untreated TNBC” concluded Violeta Serra.

Carried out in collaboration with colleagues at other leading cancer research centers in Germany, this study also counted on the expertise of other VHIO investigators including co-authors, Judith Balmaña, PI of our Hereditary Cancer Genetics Group, Rodrigo Dienstmann, PI of VHIO’s Oncology Data Science (ODysSey) Group, Guillermo Villacampa, a Biostatistician of Rodrigo Dienstmann’s team, and Andrea Herencia-Ropero, Graduate Student of Violeta Serra’s Experimental Therapeutics Group.

References:

  1. Llop-Guevara A, Loibl S, Villacampa G, Vladimirova V, Schneeweiss A, Karn T, Zahm DM, Herencia-Ropero A, Jank P, van Mackelenbergh M, Fasching PA, Marmé F, Stickeler E, Schem C, Dienstmann R, Florian S, Nekljudova V, Balmaña J, Hahnen E, Denkert C, Serra V. Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann Oncol. 2021 Sep 11:S0923-7534(21)04478-1. doi: 10.1016/j.annonc.2021.09.003. Epub ahead of print. PMID: 34520831.
  2. Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov. 2021 May 27:candisc.0007.2021. doi: 10.1158/2159-8290.CD-21-0007. Epub ahead of print. PMID: 34045297.

 

13/10/2021|