Genetic and functional homologous repair deficiency as biomarkers for platinum sensitivity in TNBC: A case report

Abstract

Triple-negative breast cancer is the most aggressive subtype of mammary carcinoma. In the early stage, neoadjuvant chemotherapy (NAC) is the standard of care for prognostic stratification and the best adjuvant treatment strategy. A 30-year-old female presented in the emergency room because of a gigantic right breast associated with an ulcerated lump at the upper quadrants. The right axillary nodes were palpable. An ultrasound was performed, showing the ulcerated neoformation with enlarged right axillary lymph nodes observed to level III. A core biopsy of the breast lesion was performed, and the pathological examination revealed a nonspecial type, grade 3, invasive, triple-negative breast cancer. No distant disease was found in the PET-CT scan. A germline genetic panel by next-generation sequencing identified a likely pathogenic variant in RAD51D (c.898C>T). Assessment of the functionality of the DNA homologous recombination repair pathway by RAD51 foci in the tumor revealed a profile of homologous recombination deficiency. NAC consisting of weekly carboplatin and paclitaxel followed by dose-dense doxorubicin/cyclophosphamide was performed with a complete metabolic response achieved in the PET-CT scan. The patient underwent a modified radical mastectomy plus axillary lymphadenectomy with a pathological complete response in the breast and axilla and remains disease-free after 2 years of follow-up. We report a young female with a triple-negative breast cancer stage cT4bN3M0 and a hereditary pathogenic mutation in RAD51D. The tumor was highly proliferative and homologous recombination-deficient by RAD51. The patient received platinum-based NAC, achieving a pathologic complete response. More effort should be made to identify predictive functional biomarkers of treatment response, such as RAD51 foci, for platinum sensitivity.

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

“…In ARIEL2, Swisher et al showed that mutations in RAD51C/D were associated with genomic HRD (based on high genomic LOH) and response to the PARP inhibitor rucaparib in 5 of 7 patients (71.4%) with relapsed high-grade ovarian cancer, reaching a median progression-free survival similar to patients with mutated BRCA1/2 . Similarly, one study showed a high sensitivity to DNA-damaging chemotherapy in a patient with breast cancer with a RAD51D germline PV and functional HRD . Overall, prior clinical trials in breast cancer or ovarian cancer have analyzed the efficacy of platinums and PARP inhibitors for patients with germline RAD51C/D PVs observing a wide range of treatment responses .…”

“…Similarly, one study showed a high sensitivity to DNA-damaging chemotherapy in a patient with breast cancer with a RAD51D germline PV and functional HRD. 25 Overall, prior clinical trials in breast cancer or ovarian cancer have analyzed the efficacy of platinums and PARP inhibitors for patients with germline RAD51C/D PVs observing a wide range of treatment responses. 26 , 27 Some studies have reported the presence of gsLOH 26 but lack of concordance with HRD by GIS, and others do not report biallelic inactivation or HRD status.…”