Résumé
Background: Microarrays studies identified the subtype of luminal androgen receptor (LAR) among triple-negative breast cancer (TNBC). This subgroup is distinct of basal-like tumors and is characterized by the lack of ER, CK5/6 expression but the expression of genes that are usually expressed by ER+ luminal tumors like androgen receptor (AR). Using immunohistochemistry (IHC) AR is expressed in 8-58% of TNBC and its prognostic value is controverted.
The aspartic protease cathepsin D (cath-D) is overproduced and hypersecreted by breast cancer (BC) cells and is often described as a marker of poor prognosis. We have already shown that cath-D is a tumor-specific extracellular target in TNBC suitable for antibody-based therapy.
We aimed at evaluating co-expression AR/cath-D-associated profiles and its prognostic value in a large retrospective series of patients with non-metastatic TNBC with a long follow-up.
Patients and methods: AR and cath-D expression were evaluated by IHC in tissue microarrays of 147 patients with non-metastatic TNBC treated in our center between 2002 and 2012. Positivity threshold was set at ≥1% nuclear staining for AR. In tumor epithelial BC with vesicular and peripheral membrane labeling, cath-D signal was scored as absent (0%), low (<20%), moderate (20-50%) or high (>50%). Tumors were defined as cath-D+ for staining ≥ 20%. Basal-like phenotype (CK5/6 and/or EGFR+), lymphocytic infiltration, PD-L1 expression and macrophages infiltration were also assessed.
Results: Median age was 61.6 years (range 30.2-98.6). 53.1% of tumors were classified pT1 and 61.2% pN0. We found 86.2% of ductal carcinomas, 6.9% of lobular carcinomas and 6.9% of other histological types. SBR grade 1-2 represented 11% of tumors. A basal-like phenotype was observed in 61.6% of cases. Adjuvant chemotherapy (ACT) was delivered in 68% of patients.
72.8% of patients had AR+ tumors. Among the 142 patients with available AR/cath-D co-expression 62.7% had AR+ and cath-D+ tumors. AR+/cath-D+ tumors exhibited more frequently: lymph node invasion (p=0.04), less frequently macrophages infiltration (p=0.04) and a trend of lower nuclear grade (1/2) (p=0.06) than others TNBC. There was no significant difference regarding basal-like phenotype, lymphocytic infiltration or PD-L1 expression.
With a median follow-up of 5.4 years, there was a trend for a lower relapse-free survival (RFS) for patients with AR+/cath-D+ tumors (p=0.09): 3-years RFS were 67.4% (CI 95% [54.1-77.6]) and 81.9% (CI 95% [68.0-90.1]) for AR+/cath-D+ and the others TNBC, respectively. 5-years RFS were 57.6% (CI 95% [43.0-69.7]) and 71.4% (CI 95% [55.4-82.5]) for AR+/cath-D+ and the others TNBC, respectively. Tumor size, nodal status and ACT were also statistically correlated to RFS. In univariate analysis, age (p=0.01), tumor size (p=0.002), nodal status (p=0.004), ACT (p=0.004) were significantly associated with overall survival (OS). There was a trend for AR/cath-D co-expression (p=0.086). In multivariate analyses, tumor size (p=0.002), ACT (p<0.001) and AR/cath-D co-expression (p<0.001) were independent prognostic factors.
Conclusions: In this series, almost 63% of TNBC had an AR/cath-D co-expression with distinct clinicopathological characteristics. AR+/cath-D+ co-expression independently predicted OS. Patients with AR+/cath-D+ tumors tended to have higher risk of late recurrences than patients with others TNBC. These biomarkers could be useful to identify a specific subgroup of TNBC with worse prognosis and could have therapeutic implications: anti-androgens are under investigation; pre-clinical studies are ongoing with anti-cath-D antibodies.
Citation Format: Hanane Mansouri, Lindsay Alcaraz, Caroline Mollevi, Aude Mallavialle, William Jacot, Florence Boissière-Michot, Joelle Simony-Lafontaine, Valérie Laurent-Matha, Pascal Roger, Emmanuelle Liaudet-Coopman, Séverine Guiu. Prognostic value of androgen receptor and cathepsin D co-expression in non-metastatic triple-negative breast cancer and correlation with other biomarkers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-11.