Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort

Abstract

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.

Evolution of HER2-low expression from primary to recurrent breast cancer

“…However, our finding suggests that the evolution of HER2-low expression from primary to recurrent tumor within the same breast cancer subtype involves a not negligible proportion of HER2-negative breast cancer patients, thus surely deserving to be further deepened. In our study, as expected, and consistently with available evidence 15 , 17 , HER2-positive phenotype in either primary tumors or recurrent lesions was the most stable, with less than 5% of the total cases showing HER2 positivity gain or loss.…”

“…However, a thorough evaluation of HER2-low evolution from primary to recurrent breast cancer is still lacking. In particular, it has been consistently demonstrated the phenomenon of both HR and HER2 status discordance between primary and recurrent breast cancer 15 – 17 , and biopsy of sites of locoregional relapse/distant metastasis is currently endorsed by international breast cancer guidelines 8 , 18 , 19 . Focusing on HER2 status, HER2 discordance has so far been investigated by dichotomizing cases between HER2-positive vs HER2-negative or, as recently reported, by considering the evolution from primary to metastatic disease of IHC-based scores in HER2-low primary breast cancer 20 .…”

Breast Cancer Heterogeneity

“…The most relevant evidence of temporal heterogeneity is the discordance in terms of ER, PR and HER2 expression that could emerge between primary tumors and their matched metastatic lesions. Discordant expression rates can be observed in a not irrelevant quota of patients and varies from 9–30% for ER, 15–45% for PR and 4–16% for HER2 expressions, and can affect tumor behavior and treatment response [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. According to PAM50 gene expression, breast primary tumors shift toward unfavorable subtypes in metastases, with a worse prognosis associated with a change from luminal primary tumor to non-luminal distant metastasis [ 58 ].…”

Circulating Tumor Cell Assay to Non-Invasively Evaluate PD-L1 and Other Therapeutic Targets in Multiple Cancers

“…Discordance in tumor characteristics, predominantly the receptor status, of primary and metastatic breast cancer is largely due to tumor progression and evolution, the choice of adjuvant therapies and sites of metastasis [10][11][12]. As clinically relevant discordances in hormone receptor (ER, estrogen receptor; PR, progesterone receptor) and human epidermal growth factor receptor 2 (HER2) status impact prognosis, subsequent therapy choices and patient management [11,[13][14][15], it warrants biopsy and retesting of the metastatic lesions for these markers [16][17][18][19]. However, biopsies of metastases or serial biopsies in case of disease progression are cumbersome, expensive, restricted to the most accessible metastatic site and do not account for intra-tumor and inter-metastatic heterogeneity.…”