• Evaluation of the Effectiveness of Chemotherapy on Metastatic Breast Cancer and HRD Biomarkers and Pathogenicity of BRCA1/2 in this Disease with Focusing on the Usefulness of Exome Sequencing
  • Ali Ahmadi,1,*
    1. M.Sc. Student, Department of Genetics, Faculty of Advanced Technologies and Science in Medicine, Islamic Azad University Tehran Medical Science, Tehran, Iran


  • Introduction: Breast cancer (BC) is the most common cancer diagnosed in women worldwide. In 2023, there were about 43,700 deaths (43,170 women and 530 men) due to breast cancer in the United States. Worldwide breast cancer is the fifth leading cause of death. Women with BRCA1 or BRCA2 gene mutations are at risk for breast and ovarian cancer and often undergo surgery to remove both of their ovaries. Mutations in the BRCA1 and BRCA2 genes account for 50% of inherited BC and up to 10% of BC. Triple negative BC (TNBC) accounts for 15% of BC in the early stages and is associated with poor long-term results compared to other BC subtypes. TNBC is enriched for BRCA germline mutations and is the basis for the use of molecular testing as a biomarker to identify patients. Identification of unclassified BRCA variants of unknown importance (VUSs) Clinical usefulness of molecular testing limits the risk issues associated with computation VUS are mainly undesirable types that lack of experimental and clinical data cannot be categorically classified as pathogenic. The American College of Genetics and Medical Genomics (ACMG) says that efforts should be made to resolve the classification of this variant as pathogenic or benign. While the role of BRCA1/2 genes in familial breast and ovarian cancer is well established. With the development of poly (ADP-ribose) polymerase (PARP) inhibitors, the exact relationship between BRCA1/2 genes and triple-negative sporadic breast cancer/high-grade serous carcinoma (TNBC/HGSC) needs further investigation. The aim of this study was to determine a specific clinical pathway for VUS carriers and to investigate the biomarkers of genomic instability and their relationship with the prevalence of BRCA1/2 and CNA somatic spot mutations.
  • Methods: This interventional study with narrative review approach was conducted in 2023 by searching keywords such as Chemotherapy, Metastatic Breast Cancer, HRD Biomarkers, Exosome and BRCA1/2 in valid databases such as: Scopus, Science Direct, Web of Science, and PubMed.
  • Results: Metastatic breast cancer (MBC) is often managed with platinum-based chemotherapy during the course of the disease. The benefits of these treatments in the advanced stages of the disease and in non-triadic negative subtypes are not known. Because homologous recombinant deficiency (HRD) can provide information about tumor susceptibility، BRCA tumor suppressor genes maintain DNA integrity and allow double-stranded DNA breaks to be repaired by the homologous recombinant (HR) system. Disruption of BRCA protein activity due to pathogenic types of loss of function (LoF) can compromise the effectiveness of the repair system and lead to an increased risk of cancer. Harmful BRCA changes have been associated with an increased risk of various types of cancer, including ovaries, pancreas, prostate, and melanoma. Genetic testing for BRCA genes represents a targeted strategy with clinical management of BC and pathways to prevent relatives of patients. The findings of VUS should be interpreted as non-informational and should not directly affect cancer management. Individual screening and prevention strategies are useful in such cases, overall response rate, disease control rate, PFS and PFS2/PFS1 ratios were evaluated to assess the effectiveness of platinum-based chemotherapy. BRCA1 c.5057A>C (p.His1686Pro) was also detected during oncological evaluations in this study. This mistaken change is located in exon 16 of the BRCA1 gene and has resulted in the replacement of histidine to proline at the amino acid position p.1686 with a 46% allele frequency. The BRCA1 variant c.5057A>C (p.His1686Pro) is annotated in the original public database as a rare VUS (rs730882166). In a single-center study, BRCA1/2 mutation status, HRD score and signature level 3 were reported by multivariate analysis, only the absence of liver metastases independently was associated with better PFS in platinum-based chemotherapy. The exome tumor sequencing method to quantify HRD should be systematically investigated and more valid and standardized before its clinical use. Further studies are needed to confirm these results to guide the use of platinum in MBC.
  • Conclusion: With multivariate analysis, only the absence of liver metastases independently was associated with better PFS in platinum-based chemotherapy. However, the exome tumor sequencing method to quantify HRD must be systematically investigated and validated and standardized before its clinical use. Further studies are needed to confirm these results to guide the use of platinum in MBC.
  • Keywords: Chemotherapy, Metastatic Breast Cancer, HRD Biomarkers, Exosome and BRCA1/2