RESUMO
Background: World over, less than a quarter of breast cancer diagnoses are in premenopausal women. However, in India premenopausal women constitute half of all women with breast cancer in most hospital case series. Most of these women present at advanced stages with aggressive subtypes of disease and hence the high mortality.The role and utility of detecting androgen receptor (AR) expression in the different sub-types of breast cancer, especially the ones without hormone receptor expression is yet to be firmly established. Evidence from previous studies is suggestive of its beneficial role in hormone receptor positive (HR+) breast cancer. The biological function of AR on the mammary epithelium is determined by the Estrogen receptor (ER) context, in that, it is found to be anti-proliferative in ER positive tumors while it is thought to promote growth in the absence of ER activity. An interesting approach to representing this interplay is as a ratio between AR/ER expressions. As expected, the ratio has been shown to be positively correlated with better outcomes in hormone receptor cancers, mostly in postmenopausal women. The effect of a high ratio in ER negative tumors seems more complicated. In this study, we have evaluated the AR/ER ratio specifically in patients younger than 50 years in whom the estrogenic influence is dominant due to their premenopausal status. Materials and Methods: Tumor samples from patients 50 years or younger were chosen from a larger cohort of 275 patients with median follow up of 72 months. Expression of ER and AR proteins were detected by immunohistochemistry (IHC), and the transcript levels of ESR1 and AR were determined by quantitative PCR. Relative normalized units of their gene expression were used to calculate the AR/ER ratio. A cut-off at the 3rd quartile was used to divide tumors into categories of high and low ratios. Clinical characteristics were compared between the low and high ratio groups along with IHC subtype distribution (HR+, HER2+ and Triple negative (TNBC)). Kaplan Meier curves was used for survival analysis and Cox proportional hazard analysis model was used to calculate the hazard ratio (HR). The results were validated in METABRIC dataset. Results: Eighty-eight (32%) patients were <50 years with a mean age of 43 years. AR/ER ratio ranged between 0.6 to 3.5 with a mean of 1.5. Sixty-six tumors were categorized as low and 22 were high based on the 3Q cut off (1.7). Clinical characters such as age, tumor size, grade, stage of disease was not different between the high and low ratio categories. Distribution of IHC subtypes among each group showed high ratio category had 64% TNBC tumors (p<0.0001). Tumors with high ratio had poor disease-free survival, (HR-2.6(95% CI-1-6.9) p-0.03). Trends in the METABRIC dataset was similar with 411(21%) patients <50 years. Ninety-seven patients with high ratio had significantly poor disease-free survival (HR-1.95 (95% CI-1.3-2.7) p-0.000). Conclusion: Interaction between AR and ER is known to influence the AR activity and our results reiterate prognostic ability of AR/ER ratio even in young patients of breast cancer. Our results suggest androgenic influences on clinical progression of breast cancer in this age group mediated through AR, has to be examined by its level in relation to the activity of ER, particularly in hormone receptor negative breast cancers. Even more importantly, examining these influences in the context of the menopausal status might help identify subgroups of patients most likely to benefit from interventions targeted at AR.
RESUMO
BACKGROUND: The 2010 guidelines by ASCO-CAP have mandated that breast cancer specimens with ≥1% positively staining cells by immunohistochemistry should be considered Estrogen Receptor (ER) positive. This has led to a subclass of low-ER positive (1-10%) breast cancers. We have examined the biology and clinical behavior of these low ER staining tumors. METHODS: We have developed a probabilistic score of the "ER-positivity" by quantitative estimation of ER related gene transcripts from FFPE specimens. Immunohistochemistry for ER was done on 240 surgically excised tumors of primary breast cancer. Relative transcript abundance of 3 house-keeping genes and 6 ER related genes were determined by q-RT PCR. A logistic regression model using 3 ER associated genes provided the best probability function, and a cut-off value was derived by ROC analysis. 144 high ER (>10%), 75 ER negative and 21 low-ER (1-10%) tumors were evaluated using the probability score and the disease specific survival was compared. RESULTS: Half of the low-ER positive tumors were assigned to the ER negative group based on the probability score; in contrast 95% of ER negative and 92% of the high ER positive tumors were assigned to the appropriate ER group (p<0.0001). The survival of the low-ER group was intermediate between that of the high ER positive and ER negative groups (p<0.05). CONCLUSION: Our results suggest that the newly lowered ASCO-CAP criteria for ER positivity, leads to the false categorization of biologically ER negative tumors as ER positive ones. This may have particular relevance to India, where we have a much higher proportion of ER negative tumors in general.