Evaluation of Discordance Rate of HER2, ER, PR Receptors Status between Primary Breast Cancer and Distant Metastasis or Locoregional Recurrences

Abstract

B reast cancer is the most common diagnosed cancer in females and the second cause of cancer related death in females worldwide, with more than 1.4 million new cases and about 450.000 breast cancer related death annually. The management of recurrent breast cancer requires evidence-based approaches, historically ER, PR, and HER2,where available from the primary cancer, have been used to direct subsequent therapy, assuming no change in the biological features of the recurrent disease compared with the original primary, this approach is no longer considered tenable, some recent guidelines support reassessment of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor type 2 (HER2) receptor in tumor tissue at the time of diagnosis of relapse to tailor appropriate therapy for each patient, this is based largely on retrospective evidence that loss of ER in recurrent breast cancer is an established predictor for poor response to endocrine therapy despite of its primary status. If therapy-predictive markers continue to change throughout tumor progression, then investigating metastatic lesions via biopsy would provide additional important information on the nature of the radiologically verified lesions, including marker expression, which would enable better management of patients with metastatic disease. A growing body of evidence indicates a lack of concordance in receptor status between primary and recurrent tumors in up to 40% of the cases. The differences between primary tumors and metastatic tumors in the biological markers could be a result of sampling errors (pre-analytical), analytical errors, genetic drift occurring during tumor progression or intratumoral heterogeneity wherein the clone with the more aggressive phenotype starts the micrometastatic process from the beginning, moreover, adjuvant treatments (endocrine treatment, chemotherapy and targeted therapy) might also interfere with this process, by selecting resistant clones. The prognostic impact of discordance between receptors expression in primary and metastatic breast cancer is doubtful, as most of the retrospective studies concluded that discordant cases have poor survival rates, but on the contrary some prospective trials did not highlight detrimental effects of discordance on patient’s outcomes, so more research is required to adequately assess this point. The important question in this topic is whether there is a significant rate of biomarkers drift justify the need for recurrent tumor biopsy and re-testing the biological markers as a standard, and the impact of the biopsy results in the management of patients with recurrent breast cancer (the predictive value). Another interesting question is the prognostic value of concordance/ discordance in the ER, PR and HER2 and if the phenotypic drift throughout the disease progression reflect a bad prognostic criteria. In conclusion, our study evaluated the discordance rates of HER2 and hormonal receptors (ER and PR) between primary breast cancer and matched recurrent tumors (locoregional or systemic recurrences), and assessed the DFS in the concordant and discordant group of patients, also we evaluated the effect of the adjuvant therapy (endocrine, chemotherapy and targeted therapy) on the receptors changes (selective pressure of the adjuvant therapy in the tumor cells), and we also evaluated the effect of the patients and primary tumors characteristics on the receptors discordance, lastly we evaluated the impact of biological markers discordance on the management of the recurrent breast cancer patients. In the current study we found a significant discordance rates in the ER and PR between primary breast cancer and matched locoregional or systemic recurrences, while there was no significant discordance rate in the HER2 between primary and recurrent breast cancer tumors. We also showed that in most of the cases with receptors discordance, the incidence of ER, PR and HER2 loss (receptors changed from positive to negative) was more likely than receptors gain (receptors changed from negative to positive) with a significant difference between receptors loss and gain. Survival analysis revealed that there was no significant difference in the DFS between the patients with receptors discordance and those with receptors concordance. Our results suggested that adjuvant hormonal therapy led to down regulation of the hormonal receptors throughout the disease progression, specially ER (ER changed from positive in the primary breast tumor to negative in the recurrent tumor after adjuvant hormonal therapy). On the other hand there was no impact of the adjuvant chemotherapy (anthracycline based) and the receptors discordance rates. Regarding the patient’s characteristics, there was no significant impact of the patient’s age or menopausal status on the rate of receptors discordance. Also the primary tumor’s characteristics (primary tumor stage, pathological type and tumor grade), did not influence the rate of receptors discordance. Our study revealed that the recurrent tumor biopsy and re-assessment of biomarkers (ER, PR and HER2) had impact on patient’s management and led to change in the treatment plan in 17.7% of the patients. These findings together with the findings of the previous studies, raised the role of the biopsy from locoregional or metastatic tumors and re-testing ER, PR and HER2 in patients with recurrent breast cancers, as there is impact of the recurrent biopsy and biomarkers results on the patient management and outcomes, and for better understanding of the biological behavior of the recurrent disease and tailoring the treatment according to the recurrent tumor characteristics, and also as a prognostic marker for the recurrent disease.