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.
Background In patients with triple-negative breast cancer (TNBC), tumor-infiltrating lymphocytes (TILs) have been reported to be associated with improved survival. Lehmann et al. identified 6 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), mesenchymal stem like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR)], and we previously reported that TNBC subtype is a predictor of pathologic complete response (pCR). Recently, the IM gene expression signature has been shown to be indicative of the presence of TILs and has been incorporated into TNBC subtyping as a modifier of the other groups rather than a separate subtype. However, the association between TNBC subtype and the presence of TILs is not known. We hypothesized that the BL2 and LAR subtypes, which have low pCR rates, have low rates of immune infiltration. Inflammatory breast cancer (IBC) is an aggressive cancer that is frequently triple-negative. The association between IBC and the presence of TILs also is not known. In this study, we analyzed the association between TNBC molecular subtype and the IM signature and determined whether the IM signature differed between patients with IBC and non-IBC. Methods We retrospectively analyzed 88 patients with TNBC from the World IBC Consortium dataset for whom IBC status was known (IBC, n=39; non-IBC, n=49) and tumor gene expression data were available. TNBC specimens were classified using the TNBCtype algorithm (Insight Genetics, Inc., TN, USA), which uses a 101-gene signature. For each tumor, the TNBCtype algorithm reports the TNBC molecular subtype (BL1, BL2, M, MSL, or LAR) and the IM status, which is described as positive (IM+) or negative (IM-). Recently, Fisher's exact test was used to analyze differences in subtype distribution between the IM+ and IM- tumors. Results The subtype distribution differed significantly between the IM+ and IM- tumors IM signature in TNBC subtypesSubtypeTotal (n=88)IM+ (n=32)IM- (n=56)BL13015 (50)15 (50)BL2202 (100)M808 (100)MSL3113 (42)18 (58)LAR121 (8)11 (92)Not determined53 (60)2 (40) (p=0.0087). The majority of IM+ cases occurred in the BL1 and MSL subtypes. No IM+ cases were observed in the BL2 or M subtypes, and only 1 was observed in the LAR subtype. IM+ cases occurred at roughly the same frequency in patients with IBC (33%) and non-IBC (37%, p=0.73). Conclusions TNBC molecular subtypes differ in their degree of immune infiltration, and most IM+ TNBCs are of the BL1 and MSL subtypes. Our finding that the proportion of IM+ cases was not different between IBC and non-IBC indicates that TILs are recruited to the tumor microenvironment similarly in IBC and non-IBC tumors. Further, Pietenpol et al recently showed that the MSL signature represents normal stromal cells rather than tumor cells by performing laser-capture microdissection of TNBC specimen. Validation studies are needed to corroborate and further expand upon our findings. Citation Format: Harano K, Wang Y, Lim B, Seitz RS, Morris SW, Bailey DB, Hout DR, Skelton RL, Ring BZ, Masuda H, Rao AUK, Woodward WA, Reuben JM, Ueno NT. Rates of immune infiltration in patients with triple-negative breast cancers by molecular subtype and in patients with inflammatory and non-inflammatory breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-14.
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Background: TNBC molecular subtype classification updated by Lehmann et al. includes 4 subtypes: basal-like 1 and 2 (BL1), (BL2), mesenchymal (M), and luminal androgen receptor (LAR), and as a modifier of these subtypes, an Immunomodulatory (IM) gene expression signature. However, molecular subtypes have not been linked to morphological features of TNBC. Apocrine carcinoma has been proposed as a TNBC category that expresses androgen receptor. LAR-subtype TNBC has a poor response to neoadjuvant systemic therapy (NST). We hypothesized that defining the apocrine-featured TNBC by morphology and molecular subtype predict the prognosis of patients with residual disease after NST. Methods: We created the Pan-Pacific TNBC Consortium dataset, which contains paired samples of matched pre and post-NST TNBC tumors from 4 institutions. All patients received NST and didn't have a pathological complete response (pCR). Three pathologists examined hematoxylin and eosin-stained slides of 86 pre-NST samples and determined (1) the presence of apocrine differentiation, (2) the level of tumor-infiltrating lymphocytes (TILs), (3) the histological grade (HG), and (4) the rate of necrosis. These morphological features were compared among the subtypes. For a sample to be considered apocrine positive, apocrine differentiation had to be identified by 2 or more pathologists. Fisher's exact test was used to test the association of subtypes and morphological features. The log-rank test was used to compare disease-free survival (DFS). Results: Twelve of 24 (50%) apocrine-positive tumor samples were LAR subtype, and12 of 17 (70%) LAR-subtype tumor samples exhibited apocrine differentiation. The other subtypes showed following: BL1, 11/44 (25%); BL2, 0/7 (0%); M, 1/10 (10%); unclassified, 0/8 (0%). The median follow-up time was 22 months. In all populations, 2-year DFS rates were higher in patients with apocrine-positive tumors than in those whose tumors did not exhibit apocrine differentiation (P = .027; 2-year DFS, 85% vs 54%). The LAR subtype was also associated with lower HG, although LAR tumors had a similar prognosis to the other subtypes. In the combined analysis of subtypes and apocrine differentiation, patients with apocrine-positive LAR tumors had a higher 2-year DFS rate than did those with apocrine-negative LAR tumors (P = .044; 2-year DFS, 88% vs. 30%). However, patients with apocrine-positive BL1 tumors had no better DFS than did those with apocrine-negative BL1 tumors (P = .133). TIL levels and the presence of the IM signature were positively associated (P = .01), and apocrine differentiation positivity tended to be negatively associated with TIL level (P = .06). Neither TIL level nor IM signature was associated with survival. Conclusion: Apocrine differentiation was associated with the LAR subtype of TNBC and better prognosis in patients who did not have a pCR. The LAR subtype alone did not predict DFS; however, LAR tumors with apocrine differentiation had a better prognosis than did LAR tumors without apocrine differentiation. Using a combination of morphologic and genomic testing may be helpful in determining the prognosis of patients with apocrine-positive TNBC tumors who have residual disease after NST. Citation Format: Masuda H, Miura S, Harano K, Wang Y, Hirota Y, Matsunaga Y, Lim B, Lucci A, Parinyanitikul N, Lee HJ, Gong G, Rao A, Seitz RS, Morris SW, Hout DR, Nakamura S, Tripathy D, Harada O, Krishnamurthy S, Ueno NT. Apocrine morphology and LAR molecular subtype predict prognosis of TNBC patients with residual disease after neoadjuvant chemotherapy [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 P4-02-05.
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