Predictive value of DNA repair gene expression for response to neoadjuvant chemotherapy in breast cancer

Abstract

Genome-wide analysis using microarrays has revolutionized breast cancer (BC) research. A substantial body of evidence supports the clinical utility of the 21-gene assay (Oncotype DX) and 70-gene assay (MammaPrint) to predict BC recurrence and the magnitude of benefit from chemotherapy. However, there is currently no genetic tool able to predict chemosensitivity and chemoresistance to neoadjuvant chemotherapy (NACT) during BC treatment. In this study, we explored the predictive value of DNA repair gene expression in the neoadjuvant setting. We selected 98 patients with BC treated with NACT. We assessed DNA repair expression in 98 formalin-fixed, paraffin-embedded core biopsy fragments used at diagnosis and in 32 formalin-fixed, paraffin-embedded post-NACT residual tumors using quantitative reverse transcription-polymerase chain reaction. The following genes were selected: BRCA1, PALB2, RAD51C, BRCA2, ATM, FANCA, MSH2, XPA, ERCC1, PARP1, and SNM1. Of 98 patients, 33 (33.7%) achieved pathologic complete response (pCR). The DNA expression of 2 genes assessed in pre-NACT biopsies (PALB2 and ERCC1) was lower in pCR than in non-pCR patients (P=0.005 and P=0.009, respectively). There was no correlation between molecular subtype and expression of DNA repair genes. The genes BRCA2 (P=0.009), ATM (P=0.004), FANCA (P=0.001), and PARP1 (P=0.011) showed a lower expression in post-NACT residual tumor samples (n=32) than in pre-NACT biopsy samples (n=98). The expression of 2 genes (PALB2 and ERCC1) was lower in pCR patients. These alterations in DNA repair could be considered suitable targets for cancer therapy.

Figure 1. Estimated 5-year disease-free survival by pathologic complete response (pCR) (Kaplan-Meier method). The number of patients at risk at each follow-up time is shown below the graph.

Figure 2. Estimated 5-year overall survival by pathologic complete response (pCR) (Kaplan-Meier method). The number of patients at risk at each follow-up time is shown below the graph.

Figure 3. DNA repair gene expression of PALB2 and ERCC1 genes in pre-neoadjuvant chemotherapy biopsies by pathologic complete response (pCR). Data are reported as medians (interquartile range). P<0.05 between groups for the two genes (Mann-Whitney test).

Figure 4. DNA expression of repair genes in post-NACT residual tumors and pre-NACT biopsies. NACT: neoadjuvant chemotherapy. Data are reported as medians (interquartile range). P<0.05 between groups for the four genes (Mann-Whitney test).