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Title: DNA repair biology signatures to predict carboplatin (C) vs docetaxel (D) benefit in advanced TNBC Authors:  Holly Tovey - The Institute of Cancer Research (United Kingdom) [presenting]
Maggie Cheang - The Institute of Cancer Research (United Kingdom)
Abstract: In the TNT Trial no improved response rate (RR) to C over D in aTNBC was observed, but it was in BRCA1/2 mutated patients (pts). We hypothesise tumours with other aberrant DNA damage response (DDR) characteristics have higher RR to C than D. We tested the predictive value of DDR related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 \& DDIR) on 192 treatment-naive primary tumours (PT) by total RNA-sequencing. Paired PT and recurrent (REC) signature scores were compared. PT-REC pairs were available from 12 pts who received chemotherapy (CT) between PT \& REC. CIN70 increased from PT to REC, DDIR (non-significantly) \& PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. DDIR predicted response to D in pts who received CT before trial entry. PARPi7 predicted response to D in CT naive pts. In CT naive pts, high CIN70 tumours suggested higher C RR as hypothesised. In conclusion, in this trial of aTNBC, DDIR high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDIR score. The hypothesised CIN70 treatment interaction was observed in CT naive pts. Our results suggest care is required in the application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT.