Breast cancer biological characterization - Evaluation of the prognostic and/or predictive role of clinical, pathological and molecular biomarkers to dissect breast cancer heterogeneity: focus on estrogen-low breast cancer

Background Although 1% is the recommended cutoff for defining triple-negative breast cancer (TNBC), growing evidence suggests that 10% cutoff may better recapitulate TNBC. Conversion to TNBC at relapse is associated with poor survival. We primarily aim to assess the prognostic impact of phenotypic conversion to estrogen receptor (ER)-low BC in patients experiencing relapse. Methods Relapsing BC patients from two Institutions were included. Patients were categorized in: TNBC (ER=0%, HER2-0/low), ER-low (ER=1-9%, HER2-0/low), Luminal-like (ER=10-100%, HER2-0/low), HER2+. Overall survival (OS) and post-relapse survival (PRS) were adopted as endpoints. Results 877 patients were included. The proportion of ER-low tumors was 2.6% on primary BC and 2.7% on relapse. When assessing the prognostic impact of primary BC phenotype, TNBC and ER-low subtypes showed similar and significantly poorer OS and PRS as compared to Luminal-like and HER2+ subtypes. In particular, median OS [mos] was: TNBC 68.6 vs ER-low 47.6 vs Luminal-like 125.4 vs HER2+ 121.4, p<0.001. PRS analysis described the same phenomenon (p<0.001). Superimposable findings were observed when considering the prognostic impact of tumor phenotype at relapse (OS, p<0.001; PRS, p<0.001). At relapse, 6.4% of TNBC (n=6), 2.5% of Luminal-like (n=10) and 1.9% of HER2 BC cases (n=3) converted to ER-low phenotype, with a total conversion rate to ER-low BC of 2.8%. Among Luminal-like primary BC patients, those converting to ER-low phenotype at relapse showed the worst survival outcome as compared to those with stable Luminal-like disease or evolving to either TNBC or HER2+ BC at relapse. In detail, median OS (mos) was: concordant Luminal-like 131.3 vs conversion to HER2+ 129.9 vs conversion to TNBC 75.9 vs conversion to ER-low 50.6, p<0.001. Superimposable findings were observed for PRS. Conclusions ER-low BC was associated with unfavorable prognosis, similar to TNBC and significantly poorer than Luminal-like and HER2+. Luminal-like BC patients converting to ER-low phenotype experienced the worst survival rates, even worse than those converting to TNBC, possibly due to the limited access to TNBC treatment algorithms. Our study supports the assimilation of ER-low BC to TNBC.