Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes

Abstract

PurposeWomen with breast tumors with higher expression of AR are in general known to have better survival outcomes while a high AR/ER ratio is associated with poor outcomes in hormone receptor positive breast cancers mostly in post menopausal women. We have evaluated the AR/ER ratio in the context of circulating androgens specifically in patients younger than 50 years most of whom are pre-menopausal and hence have a high estrogenic hormonal milieu.MethodsTumor samples from patients 50 years or younger at first diagnosis were chosen from a larger cohort of 270 patients with median follow-up of 72 months. Expression levels of ER and AR proteins were detected by immunohistochemistry (IHC) and the transcript levels by quantitative PCR. Ciculating levels of total testosterone were estimated from serum samples. A ratio of AR/ER was derived using the transcript levels, and tumors were dichotomized into high and low ratio groups based on the third quartile value. Survival and the prognostic significance of the ratio was compared between the low and high ratio groups in all tumors and also within ER positive tumors. Results were further validated in external datasets (TCGA and METABRIC).ResultsEighty-eight (32%) patients were ≤50 years, with 22 having high AR/ER ratio calculated using the transcript levels. Circulating levels of total testosterone were higher in women whose tumors had a high AR/ER ratio (p = 0.02). Tumors with high AR/ER ratio had significantly poorer disease-free survival than those with low AR/ER ratio [HR-2.6 (95% CI-1.02–6.59) p = 0.04]. Evaluation of tumors with high AR/ER ratio within ER positive tumors alone reconfirmed the prognostic relevance of the high AR/ER ratio with a significant hazard ratio of 4.6 (95% CI-1.35–15.37, p = 0.01). Similar trends were observed in the TCGA and METABRIC dataset.ConclusionOur data in pre-menopausal women with breast cancer suggest that it is not merely the presence or absence of AR expression but the relative activity of ER, as well as the hormonal milieu of the patient that determine clinical outcomes, indicating that both context and interactions ultimately influence tumor behavior.

Androgen Receptor driven gene score identifies tumors with Epithelial to Mesenchymal Transition features in triple negative breast cancer

“…Of the 165 tumors, only 60 tumors were positive for AR protein (36%). As reported earlier (33), Kaplan Meier survival analysis between AR positive and negative tumors showed no significant difference in survival between the two groups, indicating that AR protein alone is not a good prognostic marker in our cohort. Disease free survival in the tumors with high AR driven gene score however was significantly better (mean survival time of 86.13 vs 72.69 months, log rank p=0.032) when compared to the AR low tumors, clearly demonstrating it to be a better prognostic indicator than the AR protein (Figure 2).…”

“…The estimation of total testosterone in serum samples of the selected breast cancer patients was done by a chemiluminescence based immunoassay method using the Abbott Architect ci8200 (Integrated) & i2000 (Immunoassay) instrument, detailed methodology described in our previous publication (33). The serum samples were collected prior to surgery or following surgery from 154 breast cancer patients.…”

“…Immunohistochemistry for AR was done on each of the tumor sections as per standard protocol using the Ventana BenchmarkXT staining system (Ventana Medical Systems, Tucson, AZ, USA), the detailed methodology is described in our previous publication (33), Primary antibody for AR(Clone AR 441, DAKO, dilution at 1:75) was used with positive and negative controls run for each batch. Two pathologists scored the staining for AR protein independently and arrived at a final score.…”

Modulating the Activity of Androgen Receptor for Treating Breast Cancer

“…Moreover, independent studies focused on different AR/ERα ratios also observed similar results. For instance, patients with a higher AR/ERα ratio value have a poorer prognosis, shorter disease-specific survival (DSS) and a higher risk of tumor aggression in breast cancer clinical studies [ 100 , 101 ]. Although activation of AR has been shown to suppress ERα+ve breast cancer by counteracting the activity of ERα, we should bear in mind that AR could have an oncogenic effect, especially in those patients with higher values of AR/ERα ratio.…”

Breast cancer relapses considering molecular biological characteristics

“…The risk of LR in BC patients with ER + and PR + was less than 53%, and ER + and PR ess than 25%, compared to the ER-negative and PR-negative. However, HER-2-positive tumors are aggressive and resistant to chemotherapy (in patients with IIA-B – III stadium), which leads to a decrease in 5-year survival rates and a three-fold increase in 10-year survival rates [ 18 ].…”