Abstract PD9-09: Breast cancer index and assessment of tumor proliferation by molecular grade index (MGI) within distinct HOXB13/IL17BR (H/I) subsets

Abstract

Abstract Background: Previous studies have demonstrated that proliferation- and ER-associated gene expression shows a time-dependent interaction with risk of recurrence. Breast Cancer Index (BCI) is a gene expression-based test that integrates biomarker panels of both proliferation (Molecular Grade Index, MGI), and endocrine response (HOXB13/IL17BR, H/I). BCI has been validated as a significant and independent prognostic factor both for risk of overall (0-10y) and late (>5y) distant recurrence and is predictive of extended endocrine benefit in patients with early-stage, hormone receptor-positive (HR+) breast cancer. In this study, correlative analyses were performed to evaluate molecular measures of proliferation and ER signaling by MGI and H/I that underly recurrence risk across clinical categories in patients receiving BCI testing as part of routine care. Methods: Analysis was performed using the BCI Clinical Database for Correlative Studies, an IRB-approved de-identified database which contains >50 data elements including clinicopathologic and molecular variables from 19,126 clinical cases submitted for BCI testing. Descriptive analyses assessed the distribution of MGI by H/I categories based on time of testing or BCI intervention point (time of diagnosis <1y for early recurrence vs 4-7y post diagnosis for late recurrence), lymph node status (N0 vs. N+), age (<50y vs. ≥50y), tumor size (T1-T3), and grade (1-3) to understand the molecular features that may be associated with recurrence in HR+ disease. Results: Analysis included 18,853 patients (88% ≥50y, 73% N0, 70% pT1, 51% grade 2). Comparative analysis of patients tested with BCI at <1y vs. those recurrence-free and tested at 4-7y post diagnosis showed a similar proportion of patients in the H/I categories (H/I-High: 44%1y, 43% 4-7y, P=0.510). An increased proportion of MGI-High was observed in 4-7y (61%) vs. 1y (53%) (P<0.001). The distribution of MGI categories within H/I-Low and High subsets was also similar based nodal status (N0 vs. N+), age (<50y vs. ≥50y), and tumor size. However, H/I status was inversely proportional to tumor grade (P<0.001): the proportion of H/I-Low decreased with increasing grade (Grade 1: 70%, 2: 59%, 3: 36%), whereas the proportion of H/I-High patients increased (Grade 1: 30%, 2: 41%, 3: 64%). In the H/I-Low subset, as grade increased, the proportion of MGI-Low patients decreased (1: 45%, 2: 23%, 3: 5%), while MGI-High remained relatively consistent across grade (1: 25%, 2: 36%, 3: 31%). In H/I-High patients, MGI-High increased as grade increased (1: 11%, 2: 26%, 3: 59%). Conclusion: BCI functional characterization using MGI for tumor proliferation and H/I for estrogen signaling in this large-scale analysis showed that over half (59%,1y vs. 67%, 4-7y) of endocrine responsive tumors (H/I-High) were also highly proliferative (MGI-High) irrespective of time of testing. Results showed that tumor grade correlated with MGI and H/I status, indicating that a subset of high-grade tumors were highly proliferative as well as endocrine responsive. These findings suggest that proliferation and endocrine signaling are combinatorial molecular drivers of recurrences in HR+ breast cancer. Table 1.Biomarker categorization by H/I and MGI status by time of testing, nodal status, age, tumor size, and grade.H/I-LowH/I-HighPatientsNMGI-Low (%)MGI-High (%)MGI-Low (%)MGI-High (%)Time of testing<1y1278282718264-7y1305725321429Nodal StatusN0950227311428N+344222311631Age<50y475824361129≥50y1409526301529Tumor SizeT1464930311524T2182619321435T319927311527Grade1224245251911239812336152631530531559 Citation Format: Reshma Mahtani, Yuan Yuan, Kari B Wisinski, Jay Morris, Max Salganik, Yi Zhang, Catherine A Schnabel, Vk Gadi. Breast cancer index and assessment of tumor proliferation by molecular grade index (MGI) within distinct HOXB13/IL17BR (H/I) subsets [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 PD9-09.