Changes In Clinically Used Biomarkers Expression Throughout Breast Tumor Progression

Background: Clinically used biological markers carried out in the primary tumor are usually used to make therapy decisions for breast cancer patients.This study was designed to assess biomarkers like estrogen receptor(ER),progesterone receptor(PR),Ki67 and human epidermal growth factor receptor 2(HER2)expression and molecular subtype in primary tumors,the corresponding involved lymph node and asynchronous relapses.Methods: 273 tissue blocks of primary tumors,involved axillary lymph nodes(N=212)and asynchronous relapses(N=61)were included in our hospital.The samples were evaluated by two independent pathologists according to ER,PR,Her-2and Ki67 by immunohistochemistry(IHC)and fluorescence in situ hybridization(FISH).Expression of ER?PR?HER-2 and Ki67 and molecular subtypes in primary tumors was compared with involved axillary lymph nodes and asynchronous relapses.Also,the expression of these biomarkers in different pars within primary tumors were compared.Results:(1)Of the 212 breast cancer patients,discordance rates in primary tumors and the corresponding lymph nodes metastases were 18.4%% for ER,24.5% for PR,14.6% for HER-2,and 19.9% for Ki67(ER:P=0.01<0.05,PR:P=0.00<0.05,HER-2:P=0.71>0.05,Ki67:P=0.11>0.05).88 patients(41.5%)had a change in molecular subtype during tumor progression: 65 cases for luminal A/B,8 cases for HER-2positive and 15 cases for triple negative(P=0.00<0.05).(3)Of 63 breast cancer patients,discordance rates between primary tumors and asynchronous relapses were 36.0%(22/61)?31.2%(19/61)?16.4%(10/61)?? 11.5%(7/61)respectively.(PR:P=0.40,HER-2:P=0.84,Ki67:P=0.06>0.05).19 patients(41.5%)had a change in molecular subtype during tumor progression: 13 cases for luminal A/B,3 cases for HER-2 positive and 3 cases for triple negative(P=0.17>0.05).a.Of 19 breast cancer patients with local recurrence,biomarkers expression changed in 6 cases for ER,7 cases for PR,4 cases and 4 cases for HER-2 and Ki67(PR:P=0.02<0.05).b.Of 42 breast cancer patients with distant metastases,biomarkers expression changed in 16 cases for ER,12 cases for PR,6 cases and 3 cases for HER-2and Ki67(ER:P=0.02<0.05?PR:P=0.41,HER-2:P=0.14,Ki67:P=0.42>0.05).(4)Of 53 breast cancer patients,discordance rates between the different parts within primary tumors were 28.3%(15/53)?34.0%(18/53)?15.1%(8/53)?? 16.9%(9/53)(ER:P=0.12,PR: P=0.03<0.05,HER-2:P=0.10,Ki67:P=0.74>0.05)?(2)Of 53 breast cancer patients,discordance rates for biomarkers between different parts within primary tumors(the central and marginal parts)were 30.2%(16/53)?34.0%(18/53)?32.1%(17/53)?? 16.9%(9/53)respectively(ER:P=0.12,PR:P=0.03<0.05 HER-2:P=0.10,Ki67:P=0.74).In the meantime,we also compared the difference between the marginal part of the original primary tumor and the corresponding lymph nodes metastases.Discordance rates were 37.7%(20/53),33.9%(18/53),13.2%(7/53)? 20.8%(11/53),(ER:P=0.02<0.05,PR:P=0.22,HER-2:P=0.18,Ki67:P=0.21>0.05).Conclusions: Expression of these biomarkers and molecular subtypes are not stable throughout tumor progression.These therapy-predictive biomarkers alter in clinically significant frequencies throughout the tumor progression.Therapeutical and prognostic information for individual patients appears to be available from the analysis of biomarker expression in the corresponding involved lymph nodes.The study supports biomarker analysis also in asynchronous relapses and within the primary tumors.Biomarkers investigation at relapses may potentially improve patient clinical management and prognosis.