The analysis of homologous recombination DNA repair in primary breast and ovarian tumours in patients with pathogenic germline variants in the RAD51C or RAD51D genes could be useful for steering decisions on therapy and improving survival rates in these patients. This is the conclusion reached by a study led by the Hereditary Cancer Genetics Group and the Experimental Therapeutics Group at the Vall d’Hebron Institute of Oncology (VHIO), which was recently published in the JAMA Network Open journal0.
A collaboration by 22 hereditary cancer units
This work is the result of a multi-centre collaboration by 22 hereditary cancer units in Spain and was supported by the Spanish Medical Oncology Society (SEOM) through a grant from the SEOM Foundation, as well as by the Spanish Metastatic Breast Cancer Association (AECMM) through the Chiara Giorgetti Award.
Under normal conditions, the RAD51C and RAD51D genes are essential for the repair of double-strand DNA breaks via homologous recombination. The presence of pathogenic germline alterations in these genes impacts this repair process and increases the risk of developing breast and ovarian cancer.
Analysis of homologous recombination DNA repair deficiency
“The goal of this study is to reveal the functional and genomic deficiencies in homologous recombination in RAD51C/D pathogenic germline variant carriers with cancer in order to determine whether they could benefit from a targeted therapy process”, explained Dr. Judith Balmaña, a medical oncologist at Vall d’Hebron University Hospital, Head of the VHIO Hereditary Cancer Group and last author of the study. A molecular analysis was conducted on the largest specifically recruited cohort of patients with previously untreated primary breast and ovarian tumours with a pathogenic germline variant in RAD51C/D in order to describe the prevalence of homologous recombination deficiency using various biomarkers and to investigate the role of germline alterations in carcinogenesis.“This work describes the characteristics of the patients with primary breast or ovarian tumours with pathogenic germline variants in RAD51c or RAD51D”, said Sara Torres-Esquiu, a genetic consultant in the Haematology Department at the Vall d’Hebron University Hospital, researcher in the VHIO Hereditary Cancer Group and first author of the study. She went on to say that “it also shows that homologous recombination deficiency in these patients is less frequent than in patients with pathogenic variants in the BRCA1, BRCA2 or PALB2 genes”.
Fewer than 70% presented functional homologous recombination deficiency
The study included 181 patients with a pathogenic variant in RAD51C or RAD51D, the largest such group ever studied. 86.7% were women and 55.8% had been diagnosed with cancer, mainly breast or ovarian cancer. In the untreated breast and ovarian tumours, the prevalence of functional homologous recombination deficiency was below 70%. In half of those cases, this was due to retention of the wild‐type allele with no loss of heterozygosity, which was more frequent in oestrogen receptor positive breast tumours.
“The results of this study suggested that retention of the wild‐type allele and not presenting loss of heterozygosity in these pathogenic variants of RAD51C and RAD51D could indicate that the role of these genetic abnormalities in carcinogenesis is less relevant and could have implications for targeted therapy options” explained Dr. Judith Balmaña.
“We are now considering an analysis of the functional capability of homologous recombination in the tumours of patients with pathogenic germline variants in RAD51C or RAD51D to corroborate the suitability of such targeted therapy as the use of PARP inhibitors” concluded the oncologist.
CRECE-SEOM Project
This work is the seed activity promoted by the CRECE-SEOM Project. It involves creating a nationwide register of carriers of germline genetic variants in genes causing a predisposition to cancer within the Hereditary Cancer Section of the Spanish Medical Oncology Society. This register enables the creation of a clinical research platform for longitudinal and cross-sectional studies.
Reference
Sara Torres-Esquius, MSc; Alba Llop-Guevara, PhD; Sara Gutiérrez-Enríquez, PhD; Marcel Romey, MSc; Àlex Teulé, MD; Gemma Llort, MD; Ana Herrero, MD, PhD; Pilar Sánchez-Henarejos, MD, PhD; Anna Vallmajó, MSc; Santiago González-Santiago, MD; Isabel Chirivella, MD, PhD; Juana Maria Cano, MD, PhD; Begoña Graña, MD, PhD; Sara Simonetti, MD, PhD; Isabela Díaz de Corcuera, MD, PhD; Teresa Ramon y Cajal, MD, PhD; Judit Sanz, PhD; Sara Serrano, MD; Andrea Otero, MSc; Cristina Churruca, MD; Ana Beatriz Sánchez-Heras, MD, PhD; Sonia Servitja, MD, PhD; Carmen Guillén-Ponce, MD, PhD; Joan Brunet, MD, PhD; Carsten Denkert, MD; Violeta Serra, PhD; Judith Balmaña, MD, PhD. Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer. JAMA Netw Open. 2024;7(4):e247811. doi:10.1001/jamanetworkopen.2024.7811
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