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    • Functional studies revealed that these ESR mutations lead to

    2020-03-30

    Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of estrogen, conferring resistance against several endocrine agents. Recent studies reported that the occurrence of ESR1 mutations is rare in ER+ primary breast cancers, however these mutations are frequently reported in ER+ recurrent breast cancers pretreated with endocrine therapy [15]. Darwinian theory could potentially explain this disease-related event; ESR1 mutations are selected and enriched during longstanding endocrine therapy. As a result, the subpopulation of resistant clones will grow and account over time for a larger fraction of the tumor mass [24], [25]. Based on ongoing preclinical trials, ESR1 mutation has an effect on the response to endocrine therapy, [22], [23]. Therefore, screening for ESR1 mutations may in the future allow for more individualized treatment controlling ER signaling before the occurrence of wide spread disease. In this study, we investigated the application of ddPCR analysis for detection of ESR1 mutations using archived plasma samples. EROS1 designed to determine the frequency rate of ESR1 mutation with NVP-CGM097 synthesis ER+ recurrent breast cancer refractory to hormonal therapy.
    Materials and methods
    Results
    Discussion Breast tumors are characteristically heterogeneous tumors at the cellular, molecular, and genetic/epigenetic levels. The potential for both spatial and temporal heterogeneity in ER expression is still not well understood. ESR1 mutation expression can fluctuate over time; some NVP-CGM097 synthesis that stain negative at a point of time may express detectable ESR1 mutations at another tome. Resistance in cancer cells to endocrine therapy can be divided into two basic patterns, de novo and acquired resitance [16]. ESR1 mutations are rarely a cause of primary resistance; but breast cancers that show a good initial response to endocrine therapy but thereafter regrow or recur which reflect acquired resistance to endocrine therapy, 15 consistent with our findings. The incidence of ESR1 mutations in breast cancers has been reported to be as low as less than 1% in primary cancers, but as high as 11%–55% in ER+ metastatic tumors [17]. More recent studies using ddPCR techniques show that ESR1 mutations could be found in approximately 2.5%−7% of primary breast cancers, 1 and ultrasensitive detection of rare ESR1 mutations may represent an important biomarker for early detection of endocrine-resistance disease. The 19% resistance mutation rate among recurrent cancers found in our study probably represents an underestimation, given the fluctuating ER expression and ambiguous DNA findings from 29% of our sample population. It should be noted that the analysis was retrospective and the storage-time factor might have an effect on ER analysis. Dynamic ER assessment through longitudinal analysis of plasma samples would be expected to display an even higher sensitivity. It should be noted that we assessed seven different ESR1 mutations. There may be other mutations or aberrations that could also contribute to hormone-resistance in recurrent breast cancer. Association between ESR1 mutation status and type of endocrine therapy is an interesting subject. Longstanding endocrine therapy could provoke the occurrence of ER mutation according to Darwinian theory. One of the key findings of this work is the high prevalence of ER mutation in patients treated with TAM and AIs. Despite the interesting finding, the analysis of ER-medication interaction is limited by the small sample size (n = 21). Our study was not designed to address the impact of ER mutation on clinical outcome and retrospective response to endocrine therapy. Exposure time to endocrine therapy and absolute time are important cofactors in development of acquired ER mutation in hormone sensitive breast cancer. Until now, no study has examined the time needed for the development of acquired resistance. In the current study, 19% patients with recurrent breast cancer developed ER mutation after 5–10 years of the diagnosis of the primary disease (Graphic 1). The correlation between time factor and risk for development ER mutation has significant impact on clinical outcome especially in young age patients who may develop disease relapse within short period after the primary disease.