Abstract P3-08-06: A novel integrated, clinical-pathologic and genomic classification method segregates early from late relapsing invasive ductal luminal breast cancers (IDLBC) of the METABRIC study
Authors: W Hackl, D Pinet, D Demanse
Journal: Cancer Research (2019)

Abstract Background and Objectives Endocrine therapy is one of the most effective anti-cancer treatments for HR-positive breast cancers. However, in a significant proportion of patients the disease will relapse irrespective of the treatment modality (SERM, SERD, AI). Despite the progress made with multigene signatures for molecular classification of luminal breast cancers, predicting sensitivity towards endocrine modalities remains challenging. With the help of invasive ductal luminal breast cancers (IDLBC) from the METABRIC study we have developed an integrated clinical-pathologic and genomic classification method, identifying three distinct groups (IDLBC1, -2 and -3) [1, 2]. The 3 groups differ by DNA damage load, predominant lesion type, characteristic lesion patterns and oncogenic driver mechanisms [1, 3]. Here we present characteristic gene expression profiles of IDLBCs and discuss their biologic and clinical implications. Methods Gene expression profiles based on cDNA microarray data of 1.104 IDLBCs on the METABRIC study were examined (EGAS00000000083) [3]. To identify differentially expressed genes across IDLBC1-3 groups (52%, 23%, 25%), we compiled a gene list (N=2034) from 34 gene signatures reported to be predictive of ER, PR, GATA3, FOXA1 and/or AR signalling. A multiclass significance analysis of microarrays with 100 iterations and a false discovery rate of 0.05 was used to extract differentially expressed genes. Results Of 2034 steroid receptor signalling associated genes 36 exhibited differential expression in the IDLBC1/2 and -3 groups. The IDLBC1/2 specific set included 2 ER-associated genes (WLS, SPARCL1), 1 FOXA1-associated gene (NTN4) and 2 PR-associated genes (ZBTB16, CRY2). The IDLBC3 overexpressed set included 31 genes, amongst them regulators of mitotic fidelity, as well as effectors of centromere and kinetochore functioning. Eight of these genes have been reported as ER-associated (POLR2H, ECE2, SCL7A5, KIF11, FAM83D, GPSM2, MASTL, POLE2). Additional IDLBC3 hallmarks included high proliferation activity, defect apoptosis, epithelial-mesenchymal-transformation (EMT), BRCA-ness, multiple-drug resistance (MDR) and early relapse. The estimated relapse-free-survival rate at 5 years in the IDLBC3 group was 77% [95%CI 72; 82], significantly lower than in IDLBC1/2 tumours (91% [95%CI 89; 93]) and comparable to triple negative IDLBCs on the METABRIC study (70% [95%CI: 65; 76]). Conclusions We have shown that our integrated classification method has the potential to segregate early relapsing luminal breast cancers (IDLBC3) from tumours with favourable prognosis (IDLBC1/2). The data presented here and in the abstract by Demanse et al [4] provide also an intuitive hypothesis why IDLBC3 tumours are sensitive towards Letrozole but not Tamoxifen. Prospective clinical studies will be required to validate this hypothesis and to demonstrate the value of the IDLBC classification approach. References 1. Demanse, manuscript in preparation (2018) 2. Pereira, Nat Commun (2016) 3. Curtis, Nat (2012) 4. Demanse, SABCS, abstract submitted (2018) 5. Loi SABCS, Oral Presentation (2016) 6. Luen, JAMA Oncology (2018) Citation Format: Hackl W, Pinet D, Demanse D. A novel integrated, clinical-pathologic and genomic classification method segregates early from late relapsing invasive ductal luminal breast cancers (IDLBC) of the METABRIC study [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 P3-08-06.