Abstract P4-02-05: Apocrine morphology and LAR molecular subtype predict prognosis of TNBC patients with residual disease after neoadjuvant chemotherapy
Authors: 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 
Published: May 2019

Abstract
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.