QRT-PCR-based DNA Homologous Recombination Associated 4-Gene Score Predicts Pathologic Complete Response to Platinum-Based Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

BackgroundCumulative evidences suggested the addition of platinum agents as neoadjuvant chemotherapy (NACT) could improve pathologic complete response (pCR) in triple-negative breast cancers (TNBC). Previous studies showed DNA homologous recombination deficiency (HRD) was a potential biomarker predicting pCR in ER-negative breast cancer. It would be helpful to personalize the use of platinum agents if a predictive biomarker for platinum sensitivity could be developed. Therefore, we tried to develop a HRD gene expression score to predict tumor sensitivity to platinum-based NACT in TNBC.MethodsA retrospective cohort of 127 TNBC patients from 2012 to 2017 was included in this study. All of them were diagnosed and received platinum-based NACT in Fudan University Shanghai Cancer Center. Clinical data and pathological data of the patients were collected and reviewed. By using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the expression level of eight HRD associated genes was analyzed from the formalin-fixed paraffin-embedded core needle biopsy samples which obtained before NACT. A random forest model was built to estimate the weight of each gene expression level and clinical-pathological factors. Samples were randomized into the training set and validation set with different splitting percentage from 50%:50% to 90%:10%. The training set was used to modulate parameters and select the best model using 5-fold cross validation. The performance of the final model was evaluated in the validation set. ResultsA 4-gene (BRCA1, XRCC5, PARP1, RAD51) expression signature scoring system was developed. TNBC with higher score had nearly quadruple likelihood to achieve pCR to platinum-based NACT compared with a lower score [odds ratio (OR)=3.878; P<0.001]. At the cut-off value of -2.644, the 4-gene score system showed high sensitivity in predicting pCR in breast (93.0%) and pCR in both breast/axilla (91.8%), while, at the cut-off value of -1.969, the 4-gene score showed high specificity for pCR in breast (85.7%) and pCR in both breast/axilla (80.8%). 4-gene score was positively correlated with Ki-67≥40% (P=0.002), but negatively correlated with positive lymph nodes counts (P=0.003). ConclusionThe qRT-PCR-based 4-gene score can be used as an effective predictor of pCR to platinum-based NACT in TNBC.