Abstract
The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC). HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed. In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE(+)) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2-1.5; P = 0.000005] when compared with HAGE(-) cases. Patients who received ACT and expressed mRNA-HAGE(+) were at a lower risk of death than those who were mRNA-HAGE(-) (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE(+) had a 2-fold death risk increase (P = 0.018) compared with HAGE(-). HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted.
Highlights
Of the 1.38 million newly diagnosed breast cancer cases each year, 12% are defined as being triple negative (TNBC; refs. 1, 2)
The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response and associated with prolonged survival
Recent studies suggest that clinical outcomes in triple-negative breast cancers (TNBC) are influenced by immune responses to the tumor [4,5,6,7], and data have revealed that the basal-like, immunomodulatory, and mesenchymal stem-like molecular subtypes, are characterized by (i) tumor-infiltrating lymphocytes (TIL) with high PD1 and PDL1 expression, (ii) elevated expression of genes that are involved in T-cell function, immune transcription, IFN response, and antigen processing [8] and (iii) high pathologic complete response rate and favorable clinical outcome after anthracycline combination Neo-adjuvant chemotherapy (ACT) (AC-Neo-ACT; refs. 6–8)
Summary
Of the 1.38 million newly diagnosed breast cancer cases each year, 12% are defined as being triple negative (TNBC; refs. 1, 2). Research efforts to discover specific prognostic and predictive molecular signatures that can guide individualized therapy for this subgroup of breast cancer patients are urgently needed [3]. Recent data suggest that some patients with TNBC may benefit from immune-based therapies [4, 5] such as immunostimulating therapies that might act synergistically when combined with chemotherapy, and tumor vaccines targeting cancer-specific antigens (CSA) that might be highly expressed in TNBC [5, 9]. There is a general lack of information underpinning the expression of CSAs in breast cancer, especially in the TNBC subtype
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