Cumulative copy number imbalances after neoadjuvant chemotherapy residual breast tumor is an independent predictor of relapse

Abstract Background: Identifying breast cancer patients after neoadjuvant chemotherapy (NAC) at greatest risk of recurrence would enhance selection of patients who may benefit from novel adjuvant treatments. Patients. 243 stage I-III breast cancer patients who underwent NAC with ≥10% residual tumor cellularity were identified from the MD Anderson Cancer Center and Ben Taub General Hospital, Harris County hospital. Tumor DNA was isolated for DNA copy number using OncoScan CNV FFPE, Affymetrix. Median follow-up was 67.8 months. Continuous residual cancer burden (RCB) scores with CNI data were available for 152 cases. To test if CNIs covering large regions were associated with recurrence after adjusting for prognostic variables and study site, data were summed to a chromosome-arm level. Eleven chromosome arms with false discovery rate <0.05 for breast cancer recurrence were identified. A stepwise multivariable model including age at diagnosis, tumor subtype, histologic grade, pre- and post-treatment stage, study site, and the 11 chromosomal arms were used to fit a parsimonious multivariate model for recurrence. Minimizing the Akaike Information Criterion yielded a final model with post-stage and a 5-arm CNI (5A-CNI) indicator including 2q, 3q, 4q, 10p, and 18p. Tumors were classified on 5A-CNI as 0 [no CNI], 1 [1- 2] and 2 [> 2]. Results. The study population included 76 non-Hispanic White, 89 Hispanic, and 68 African American patients with a mean age of 49.1 years. 105 patients were classified as 5A-CNI-0, 97 as 5A-CNI-1 and 41 as 5A-CNI-2. A higher 5A-CNI score was associated with tumor grade, ER-negative tumors (p<0.002) and tumor subtype (p=0.014). For 5A-CNI scores of 0, 1 and 2, recurrence rates of 14%, 34% and 58.5% were observed, respectively. In the final multivariable model adjusted for post-stage, RCB and study site, when compared to 5A-CNI-0, the hazard of recurrence was elevated for 5A-CNI-1 (HR= 2.27 [95% CI, 1.01-5.1]) and 5A-CNI-2 tumors (HR=7.43 [95% CI, 2.85-19.39]). Further, while the sample size is limiting, of 10 patients who were RCB3 and 5A-CNI-2, 9 relapsed (90%) during follow-up compared to only 6 of 43 (14%) of RCB3 patients with 5A-CNI-0 (p<10-6). For patients with RCB1 or 2, relapse did not differ by 5A-CNI score. Neither race nor ethnicity were found to be independently associated with recurrence or tumor subtype. However, African American, followed by Hispanic patients, were more likely than non-Hispanic White patients to be classified as 5A-CNI-2 (p=0.013). Table 1.Significant difference in distribution of 5 arm CNI classifier by Race/Ethnicity in Study Sample (p =0.013).5A-CNI012Non-Hispanic Whiten=44; 57.9%n=25; 32.9%n=7; 9.2%Hispanicn=32; 36%n=42; 47.2%n=15; 16.9%African Americann=28; 41.2%n=23; 33.8%n=17; 25% Conclusion. The 5A-CNI score in post NAC tumor identifies a patient population with very poor prognosis independent of current clinical prognostic factors including RCB. Validation of these findings may lead to a post NAC genomic test that identifies patients who would benefit from additional treatment Further investigation of the nature of the association between the 5A-CNI score and race/ethnicity, which appears independent of tumor subtype, is warranted. Citation Format: Thompson PA, Brewster A, Tsavachidis S, Armstrong G, Do K-A, Ha M-J, Gutierrez C, Symmans F, Bondy M. Cumulative copy number imbalances after neoadjuvant chemotherapy residual breast tumor is an independent predictor of relapse [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-06.