Abstract P4-14-02: Analysis of DRFI and OS of HR-positive, HER2-negative breast cancer patients treated on the BIG1-98 study, classified according to a novel, integrated, clinical-pathologic and genomic classification method

Abstract

Abstract Background and Objectives HRpos, HER2neg early breast cancer is molecularly heterogeneous. Classifications that integrate genetic, genomic and clinical-pathologic data (nodal status, tumour size, tumour differentiation, Ki-67 status, PR expression) are lacking. In a previous study we have defined three different molecular groups of invasive ductal luminal breast cancer (IDLBC) using clinical prognostic variables, gene expression, copy number variation and mutation data from the METABRIC series [1, 2] and showed that IDLBC groups (IDLBC1, -2, -3) had distinct prognostic outcomes [3, 4]. The 3 groups differ by DNA damage load, predominant lesion type, characteristic lesion patterns, oncogenic driver mechanisms and time to first recurrence. Here we evaluated the prognostic and predictive value of these groups on patients treated on the BIG1-98 study. Methods We used our predefined subgroups (IDLBC1, -2, -3) to classify patients in the BIG1-98 set [5, 6]. A weighted Cox proportional hazards regression model was used to assess the association between IDLBC subtype, treatment on OS and DRFI endpoints in the BIG1-98 study. Weighted chi-squared tests were used for categorical variables and weighted t-tests for mutational burden. All statistical computations were carried out in R v.3.2.3. Results Five hundred thirty eight breast cancers (ductal 75%, lobular 17%, 8% other) were included in this study. The DNA damage burden of IDLBC1 or -2 type tumours was significantly lower compared to IDLBC3 (mean lesion numbers: 9, 11, 18.5). IDLBC1 type tumours (48%) harboured mainly oncogenic point mutations (predominantly PIK3CA 51%, MAP3K1 27%, NCOR1 22%, FANCD2 20%). IDLBC2 (34%) and IDLBC3 type tumours (18%) were both mutated (PIK3CA 53% vs 38%, GATA3 12% vs 30%, TP53 10% vs 37%, CDH1 20% vs 8%), 8p11-12 (IDLBC3 38% vs IDLBC2 21% or IDLBC1 5%, p value < 0.001) and/or 11q13-14 amplified (IDLBC3 46% vs IDLBC2 28% or IDLBC1 2%, p value < 0.001). Consistent with the higher DNA damage load patients with IDLBC3 type tumours had significantly shorter distant recurrence free intervals (DRFI) (HR (95% CI) 2.35 [1.99; 2.78] p-value= <2e-16) and significantly shorter OS compared to IDLBC1 or -2 (HR (95% CI) 2.55 [2.2; 2.96] p-value= <2e-16). Patients with IDLBC1 or -2 type tumours seemed to have the same survival regardless of hormonal treatment assignment. However, the IDLBC3 group derived greater magnitude of benefit from Letrozole compared to Tamoxifen (HR (95% CI): DRFI 0.85 [0.66; 1.09] vs. 0.53 [0.35; 0.79] interaction p-value=0.03, OS 0.98 [0.8; 1.21] vs 0.34 [0.25; 0.47], interaction p-value=2.5e-09). Conclusions We have validated our integrated clinical-pathologic and genomic classification method on an independent dataset of HRpos, HER2neg early stage breast cancer. Our classification also suggests differing magnitude of benefit for adjuvant Letrozole benefit. Prospective clinical studies will be required to validate and corroborate this novel classification approach.