Homologous recombination deficiency predicts response to platinum-based neoadjuvant chemotherapy in early-stage triple-negative breast cancer patients: Secondary analysis of the neocart randomized clinical trial.
Authors: Zhang Liulu , Wu Zhiyong , Li Jie , Lin Ying , Liu Zhenzhen , Cao Yin , Zhang Gangling , Zhang Yi , Chen Yuanqi , Gao Hong-Fei , Yang Mei , Yang Ciqiu , Zhu Teng , Cheng Min-Yi , Ji Fei , Li Jieqing , Wang Kun 
Published: June 2022

e12606

Background: We recently performed the NeoCART trial to compare six cycles of docetaxel plus carboplatin (DCb) with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel (EC-D) in the neoadjuvant setting of triple-negative breast cancer (TNBC). The present study assessed the homologous recombination deficiency (HRD) score, stromal tumor-infiltrating lymphocytes (TILs), and Ki67 as predictors of pathological complete response (pCR) in the NeoCART trial cohort. Methods: Participants in the NeoCART trial (NCT03154749) were randomly assigned, at a 1:1 ratio, to an experimental DCb for 6 cycles (DCb group) or an EC for 4 cycles followed by docetaxel for 4 cycles group (EC-D group). Pretherapeutic formalin-fixed, paraffin-embedded tumor tissues were assessed retrospectively for DNA extraction and sequencing. Sequencing was performed using the Illumina HiSeq4000 platform. The HRD score was calculated based on the genome-wide allele-specific copy number result, and it was composed of three parts: 1) loss of heterozygosity (LOH): the number of segments >=15 Mb in length (but not covering the entire chromosome), mCN =0 and tCN > 0; 2) telomeric allelic imbalance (TAI): the number of segments with allelic imbalances (mCN!= tCN - mCN) extending to the telomeric end of a chromosome; 3) large-scale state transitions (LST), the number of chromosomal breaks between adjacent segments of at least 10 Mb, with a distance between them not larger than 3 Mb. Results: The primary and secondary endpoints, including pCR, event-free survival, overall survival, breast-conserving surgery rates, and treatment-related toxicities, were published previously. HRD testing was attempted on baseline FFPE tumor samples for 54 patients in the NeoCART cohort and was successfully completed for 43 patients (79.6%). It was unavailable for 11 patients due to inadequate tissue or the quality filter. Patients with HRD measurable tumors received DCb in 22 cases and EC-D in 21 cases. TP53 (93.0%), PIK3CA (27.9%), PTEN (11.6%), ATRX (9.3%), NF1 (9.3%), PIK3R1 (9.3%) and PKHD1 (9.3%) were the most frequently mutated genes. No significant association between BRCA1/2 mutation status and pCR was observed in the general population or the two treatment arms. Patients in the DCb group who achieved pCR had a higher HRD score (p =0.04), higher stromal TILs (p =0.02), and a higher Ki67 index (p =0.04) than non-pCR patients. RCB 0/1 was associated with higher stromal TILs (P =0.05) and a higher Ki67 index (P =0.008). However, no correlation between HRD score and pCR was observed in the EC-D group. Conclusions: PCR in TNBC patients correlated with a higher HRD score, higher stromal TILs, and a higher Ki67 index on carboplatin-based neoadjuvant chemotherapy regardless of BRCA status. Clinical trial information: NCT03154749.