Abstract PD14-09: APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD)
Authors: Chumsri Saranya , Raskina Kira , Sammons Sarah , Alder Laura , Danziger Natalie , Schrock Alexa B , McGregor Kim , Sokol Ethan 
Published: March 2022

Background: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including BC. In our clinical experience, HR+HER2- BC with an APOBEC signature do poorly on standard of care (SOC) first line endocrine therapy (ET) + CDK4/6 inhibitor (CDK4/6i) and need additional treatment options. Here we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival (OS) on SOC and immune checkpoint inhibitors (ICI).Methods: Hybrid capture-based comprehensive genomic profiling (CGP) results from 29,833 formalin-fixed paraffin-embedded tissue biopsies of all BC subtypes were analyzed. For outcomes (TTD and OS), this study used a de-identified nationwide (US-based) BC clinico-genomic database (CGDB, ~800 sites of care, 1/2011 - 12/2020). HR+HER2- metastatic BC pts who received first line ET + CDK4/6i were included (CGDB cohort).TTD was defined as the difference between the first and last drug episode within a given line of treatment (LOT). LOT were derived based on FH algorithms. OS was defined as the time from LOT start to the date of death or data cutoff. Log-rank test and Cox model were used to evaluate the difference in outcomes. To reduce the impact of confounding variables (Age at Dx, Stage at Dx, Tumor Type, Metastases sites, TMB group (≥10 vs &lt;10), SOC treatment group, PIK3CA), inverse probability of treatment weighting (IPTW) was used. Eligible pts from Mayo Clinic and Duke University were HR+HER2- mBC with sequencing data from FMI between 9/2013-7/2020. Clinical data were manually extracted from Mayo and Duke EHR. Results: Of all 29,833 BC samples in the CGP cohort, 7.9% were APOBEC+ with high rate in invasive lobular carcinoma (ILC) 16.7% vs. 4.9% in invasive ductal carcinoma (IDC) and metastatic lesions 9.7% vs. 4.3% from breast. APOBEC+ samples had a higher median TMB 12.5 vs. 2.5 mut/Mb. In CGDB, 857 HR+HER2- BC met inclusion criteria; 69 (8%) pts were APOBEC+ and 788 (9.2%) were APOBEC-. APOBEC+ pts had significantly shorter TTD on SOC ET+CDK4/6i than APOBEC- pts, 7.8 (95% CI 4.3-14.6) vs. 12.4 (95% CI 11.2-14.1) months (p=0.0036). APOBEC+ pts also had noticeably shorter OS compared to APOBEC- pts, 32.4 (95%CI 19.8-47.4) vs. 40.5 (95%CI 36.9-45.7) months (p=0.06).Cox regression results indicate that the relative risk of shorter TTD for the APOBEC+ vs the APOBEC- was 1.6 (95%CI 1.03-2.39). Also, APOBEC+ pts had almost twice the risk that APOBEC- pts had of death (HR=1.96, 95%CI 1.2-3.3). In CGDB, there were 10 APOBEC+ pts who received ICI, 9/10 had evaluable TTD data, 4/9 were still on treatment as of Dec 2020. 5/9 received ICI monotherapy, 4 pts received ICI + chemotherapy. TTD ranged from 0.3 to 11.3 mo, 1 pt’s TTD was &gt; 6 mo. In Mayo and Duke cohort, there were 6 pts, 5/6 received ICI + chemotherapy. The TTD was 0.9-40.5 months with longest 2 pts receiving 5-FU plus ICI (11 and 40.5 months). To better understand the ICI treatment landscape, TTD in HR+HER2- hTMB MSS APOBEC- CGDB cohort (N=6) was analyzed: 5/6 had evaluable treatment data, 4/5 finished ICI treatment, 1 pt’s TTD was &gt; 3 mo, 0/5 had TTD &gt; 6 mo. Conclusions: APOBEC+ occurs in ~7% of BC and is more common in ILC and metastatic lesions. APOBEC+ HR+HER2- pts had shorter TTD and OS on SOC ET+CDK4/6i relative to APOBEC- pts. However, TTD on ICI tended to be longer in APOBEC+ pts, but our data is limited, and more research is needed.

CGDB APOBEC+ vs. APOBEC- with SOC 1st lineAPOBEC+ (N=69)APOBEC- (N=788)p adjusted (FDR)*Age at Dx, Median (IQR)59.0 (53.0, 65.0)56.0 (47.0, 65.0)0.102Stage at Dx0.067- 0-III52 (75.4%)505 (64.1%)- IV11 (15.9%)245 (31.1%)- Not documented6 (8.7%)38 (4.8%)Metastasis free interval, yrs, Median (IQR)5.2 (3.0, 10.5)5.1 (2.8, 9.3)0.734Tumor Grade0.104- Grade 12 (2.9%)49 (6.2%)- Grade 234 (49.3%)259 (32.9%)- Grade 311 (15.9%)163 (20.7%)- Not documented22 (31.9%)317 (40.2%)Tumor Type0*- IDC7 (10.1%)251 (31.9%)- ILC30 (43.5%)138 (17.5%)- Other /Not documented32 (46.4%)399 (50.6%)Metastases sites0.734- Bone-only17 (24.6%)169 (21.5%)- CNS11 (15.9%)104 (13.2%)- Visceral41 (59.4%)514 (65.3%)TMB, Median (IQR)11.3 (8.8, 18.8)2.5 (1.3, 3.8)0*MSI0.946- MSI-H0 (0.0%)4 (0.5%)- MSI-I0 (0.0%)1 (0.1%)- MSS68 (98.6%)728 (97.2%)- Not documented1 (1.4%)16 (2.1%)BRCA5 (7.2%)45 (5.7%)0.734PIK3CA46 (66.7%)341 (43.3%)0.001*Treatments0.005*- AI + CDK4/6i31 (44.9%)510 (64.7%)- Fulvestrant + CDK4/6i38 (55.1%)278 (35.3%)

Citation Format: Saranya Chumsri, Kira Raskina, Sarah Sammons, Laura Alder, Natalie Danziger, Alexa B Schrock, Kim McGregor, Ethan Sokol. APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-09.