Plasma TP53 as an indicator of poor survival in neoadjuvant-treated triple negative breast cancer: A prospective study and meta-analysis.

Abstract

e12594 Background: A proportion of triple negative breast cancer (TNBC) patients with pathologic complete response (pCR) will eventually experience disease recurrence. It is crucial to identify the few high-risk patients needing treatment intensification and those at risk of overtreatment. Methods: We prospectively isolated circulating tumor DNA (ctDNA) from pre/post-NAC plasma samples and then analyzed by duplex sequencing of our own designed panel combined driver and resistance-related genes between March 2016 to April 2022 in patients with TNBC. Kaplan-Meier analysis with a Log-rank test and the Cox proportional hazard regression model were used for the univariate and multivariable survival analysis. Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). A systematic literature search and meta-analysis was performed to further investigate the prognosis value of TP53 detection in ctDNA on breast cancer patients. Results: Before NAC, 53 of the 95 TNBC patients had detectable ctDNA (55.79%), which decreased after NAC (19/64, 29.69%). The median follow-up was 38.53 months (range 6.03-90.30 months). TP53 (36/95, 37.89%), BRCA2 (9/95, 9.47%) and PI3KCA (7/95, 7.37%) were the most frequently mutated genes pre-NAC. While post-NAC, TP53 (8/64, 12.50%), BRCA2 (5/64, 7.81%) and BRCA1 (4/64, 6.25%) were the most frequently mutated genes. Resistance gene mutations were almost undetectable. Pre/Post-NAC TP53 detection and its conversion status (no clearance after NAC vs. negative from baseline) were independent prognosis factors adjusted by age, tumor size and node status in event free survival (EFS) ( P =0.055, P =0.035, P =0.0008), distant disease-free survival (DDFS) ( P =0.017, P =0.017, P =0.003) and overall survival (OS) ( P =0.016, P =0.066, P =0.023). We made a contrast of the predictive efficiency of traditional clinical variables (age, tumor size and nodal status) combined pCR vs. TP53 conversion status through establishing time-dependent ROC curves. The predictive power were improved in TP53 conversion status combined clinical model in predicting EFS at 1 (AUC=0.82 vs 0.77), 3 (AUC=0.81 vs 0.76) and 5 years (AUC=0.69 vs 0.61), DDFS at 1 (AUC=0.79 vs 0.69), 3 (AUC=0.81 vs 0.76) and 5 years (AUC=0.70 vs 0.60) and OS at 1 (AUC=0.83 vs 0.88), 3 (AUC=0.86 vs 0.79) and 5 years (AUC=0.69 vs 0.64). The meta-analysis including six studies reported data of baseline TP53 detection and survival also demonstrated that plasma pre-NAC TP53 detection in ctDNA was significantly associated with a poor survival (HR = 2.42; P = 0.044). No enough studies were available for prognostic analysis of post-NAC and TP53 conversion status. Conclusions: Customized ctDNA tests are much less valuable than TP53 tests alone. Pre/Post-NAC TP53 detection and its conversion status were independent factor of shorter survival.