Abstract GS3-05: Classification of triple negative breast cancer (TNBC) by DNA damage immune response (DDIR) signature and homologous recombination deficiency (HRD) status: Analysis of SWOG S9313 adjuvant trial
Authors: Stecklein Shane R , Barlow William , Pusztai Lajos , Timms Kirsten , Kennedy Richard , Badve Sunil , Gökmen-Polar Yesim , Porter Peggy , Linden Hannah , Tripathy Debu , Hortobagyi Gabriel N , Godwin Andrew K , Thompson Alastair , Hayes Daniel , Sharma Priyanka 
Published: February 2021

Abstract
Introduction/Aims: DDIR signature, HRD, and stromal tumor infiltrating lymphocytes (sTIL) have each been associated with favorable outcomes in early stage TNBC. We assessed the overlap between these markers and created prognostic categories based on their combined use in a prospective trial of TNBC patients uniformly treated with adjuvant doxorubicin (A) and cyclophosphamide (C) on the SWOG S9313 trial. Methods: SWOG S9313 trial accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC, with no difference in outcomes between the two arms. 425 centrally determined TNBC cases from S9313 were identified. DDIR signature (score ≥ 0.3681 = DDIR+, Almac Diagnostic Services), HRD status (score ≥ 42 = HRD+, Myriad Genetics), and sTIL were assessed. Gene expression data (Xcel™ array) was subjected to claraT V3.0.0 biological signature analysis (Almac Diagnostic Services), and co-expression cluster analysis was used to identify signatures associated with DDIR and HRD status. The impact of dual classification by DDIR and HRD status (Group 1: DDIR+/HRD+, Group 2: DDIR+/HRD-, Group 3: DDIR-/HRD+, Group 4: DDIR-/HRD-) on disease free survival (DFS) and overall survival (OS) was examined using Cox regression with adjustment for randomized treatment assignment and nodal status. Results: For the 425 patients, median age was 45 years, 33% were node-positive, and 5-year DFS and OS were 74% and 82%, respectively. DDIR and HRD status was available for 89% each, sTIL% was available for 99%, and all three markers were available for 77% (328/425) of patients. 60% were DDIR+ and 65% HRD+. Among DDIR- tumors, 58% were HRD+. sTIL% was associated with DDIR status (P&lt;0.0001) but not with HRD status (P=0.75). The proportion of patients in each group, median sTIL%, and 5-year DFS and OS for each group are outlined in Table 1. DFS and OS were similar for Groups 1, 2, and 3 but significantly lower for Group 4. As expected, cluster analysis showed that immune response signatures dominated Groups 1 and 2 regardless of HRD status. Group 3 tumors were characterized by over-representation of genomic instability signatures, a paucity of immune-related signatures, and low sTIL infiltration. Despite this immune-depleted phenotype, the 5-year OS for Group 3 was similar to that of the immune-enriched DDIR+ groups. Signatures associated with epithelial-mesenchymal transition, mast cell infiltration, and xenobiotic metabolism were over-represented in Group 4. Conclusions: Forty percent of patients with early stage TNBC demonstrate immune-deplete (DDIR-) phenotype, and within this phenotype, more than half demonstrate HRD+ status. HRD+ status within the immune-deplete phenotype predicts for better DFS and OS with adjuvant AC, probably due to underlying genomic instability and increased sensitivity to DNA damaging chemotherapy. Sixty percent of early stage TNBC patients demonstrate an immune-enriched (DDIR+) phenotype, and this phenotype is associated with improved survival with adjuvant AC chemotherapy regardless of HRD status. These findings provide important insights for patient selection and stratification in ongoing and future trials assessing DNA damaging therapy (e.g. PARPi, anthracyclines, platinum agents), immunotherapy, and their combinations in TNBC.
Table 1Immune-Enriched GroupsImmune-Deplete GroupsGroup 1 DDIR+/HRD+ N=137 (42%)Group 2 DDIR+/HRD- N=59 (18%)Group 3 DDIR-/HRD+ N=77 (23%)Group 4 DDIR-/HRD- N=55 (17%)5-year DFS82%74%74%56%P=0.001 (Group 1 vs 4); P=0.006 (Group 2 vs 4); P=0.016 (Group 3 vs 4); P=NS (Groups 1 vs 2, 1 vs 3, and 2 vs 3)5-year OS88%86%83%69%P=0.001 (Group 1 vs 4); P=0.003 (Group 2 vs 4); P=0.026 (Group 3 vs 4); P=NS (Group 1 vs 2, 1 vs 3, and 2 vs 3)Median sTIL (%)20%20%5%5%P&lt;0.0001 (Group 1 vs 3); P&lt;0.0001 (Group 2 vs 3); P=NS (Group 1 vs 2, 3 vs 4)
Citation Format: Shane R Stecklein, William Barlow, Lajos Pusztai, Kirsten Timms, Richard Kennedy, Sunil Badve, Yesim Gökmen-Polar, Peggy Porter, Hannah Linden, Debu Tripathy, Gabriel N Hortobagyi, Andrew K Godwin, Alastair Thompson, Daniel Hayes, Priyanka Sharma. Classification of triple negative breast cancer (TNBC) by DNA damage immune response (DDIR) signature and homologous recombination deficiency (HRD) status: Analysis of SWOG S9313 adjuvant trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-05.