Abstract P4-08-06: Impact of molecular subtypes on long-term outcomes in triple-negative breast cancer (TNBC) patients treated with adjuvant AC chemotherapy on SWOG S9313

Abstract

Introduction: TNBC is heterogeneous disease with several molecularly defined subtypes (Lehman et al), each of which may be predictive of response to chemotherapy. TNBC molecular subtypes are associated with varied pathological responses to neoadjuvant chemotherapy. However, subtype specific long-term outcomes for TNBC patients treated with uniform adjuvant chemotherapy are not known. Aims: To characterize long-term outcomes of TNBC molecular subtypes (TNBCtypes) in patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) on S9313 Methods: SWOG 9313 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 (J Clin Oncol 2007). From this trial we identified 425 (14%) patients with centrally determined TNBC for whom tissue was available. Microarray profiling was performed on genomic RNA extracted from pre-treatment FFPE tissue. A 101-gene expression model which has shown to reproduce the classification provided by the original 2188-gene algorithm (Ring et al) was applied to the microarray profiling to generate the following TNBCtypes–Basal-Like 1 (BL1), Basal-Like 2 (BL2), Mesenchymal (M), mesenchymal stem–like (MSL), and luminal androgen receptor (LAR). Immunomodulatory +/- (IM) status was assigned independent of the subtypes. Sequencing of BRCA1/2 from tumor DNA was also performed. The subtypes were tested for prognostic effect on DFS and OS using Cox regression model with adjustment for nodal status. Results: For 425 TNBC patients, the median age was 45 years, 33% were node-positive and 10-year DFS and OS = 66.3% and 74.1%, respectively. A total of 381/424 (89.7%) cases could be classified into TNBCtypes with distribution as follows: BL1=24%, BL2=8%, M=24%, MSL=11%, LAR=9%, unclassified (UNL) =24%. No association between TNBCtypes and race or nodal status was noted. Compared to other subtypes LAR subtype was associated with older age at diagnosis (median age 53 vs 45, p<0.001). Overall 24% of samples were IM+ and 25% demonstrated deleterious tBRCA1/2 mutation. DFS, tBRCA1/2 mutation and IM+ status distribution across different subtypes are provided in the table. All subtypes except for LAR demonstrated a drop in hazard function for recurrence after 5 years. 5 year DFS (%)10 year DFS (%)DFS HR (95% CI), p valueDeleterious tBRCA1/2 mutationIM+ statusBL184.5%77.5%141%60%BL281.3%70.5%1.59 (0.81-3.13) p = 0.1816%12%M69.2%61.2%2.06 (1.25-3.40) p = 0.00528%0%MSL54.8%50.0%2.38 (1.33-4.28) p = 0.00418%7%LAR74.3%53.8%2.24 (1.22-4.14) p = 0.0112%8%UNL76.4%71.8%1.36 (0.80-2.33) p = 0.2620%30% Conclusions: In the presence of adjuvant AC, TNBC molecular subtypes have varied prognosis, with BL1 subtype demonstrating the best prognosis and MSL and LAR subtypes demonstrating the worst prognosis. LAR subtype is associated with older age at diagnosis and continued elevated hazard function for recurrence after year 5. tBRCA1/2 mutations are distributed across all subtypes with the highest prevalence in BL1 and M subtypes. IM+ status was infrequently noted in non-BL1 subtypes. These findings underscore TNBC heterogeneity and the need to account for this heterogeneity in prospective clinical trials. Citation Format: Sharma P, Barlow WB, Hout DR, Seitz RS, Bailey DB, Godwin AK, Pathak H, Timms KM, Solimeno C, Linden HM, Porter P, Tripathy D, Hortobagyi GN, Thompson A, Pusztai L, Hayes DF. Impact of molecular subtypes on long-term outcomes in triple-negative breast cancer (TNBC) patients treated with adjuvant AC chemotherapy on SWOG S9313 [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 P4-08-06.

A Population-Based Analysis of Breast Cancer Incidence and Survival by Subtype in Ontario Women

“…Inherent bias toward the selection of generally healthy patients who present for treatment to a cancer centre likely resulted in longer mos, albeit the very small sample size that represented a limitation in that retrospective study. A different distribution of molecular tnbc subtypes in the various studies (something that was not assessed in our study) might also contribute to differences in reported clinical outcomes 45 .…”

“…In addition, mos could be calculated only for women with stage iv disease and those for whom relapse or recurrence could not be assessed. Given the variation in the natural history of bca, it would be of great interest to examine, at a future date, early and late recurrence by disease subtype in Canadian women 24,[44][45][46] .…”