ER+ Breast Cancer Prognostic

About

Approximately 12.9% of US women will develop invasive breast cancer over the course of their lifetime. There are currently over 3.8 million breast cancer survivors in the United States, and the American Cancer Society estimates that over 280,000 new cases of invasive breast cancer will be diagnosed in 2021. While the death rates have decreased in recent years, breast cancer is still the second leading cause of cancer death in women. Breast cancer is a heterogeneous disease, so determining an accurate and specific prognosis is essential to ensure that breast cancer patients receive the most effective course of treatment. A prognosis is usually based on a combination of clinical characteristics (eg: tumor size and grade, patient age) and histopathologic features. The majority of breast cancers express the estrogen receptor (ER+) and are responsive to endocrine therapies which impair estrogen signaling. Tamoxifen, a selective estrogen receptor modulator (SERM), has been the standard of care for ER+ patients for more than 30 years. Tamoxifen has decreased recurrence rates by nearly half and has reduced mortality by about one-third. However, approximately one quarter of women treated with tamoxifen relapse within 10 years of treatment. These data demonstrate that resistance to endocrine therapy continues to be an important clinical concern and that ER status is insufficient to predict treatment response. To date, several multigene expression profiling assays have been developed as prognostic tools for ER+ patients, including OncotypeDX, Prosigna and Mammaprint. While these tests stratify ER+ patients, their primary role is to identify individuals who do not need chemotherapy and they are not normally used to influence endocrine therapy decisions. There is an urgent need for improved prognostic tests due to risk of recurrence and limitations of current tests. Such tests should have robust biomarkers capable of predicting patient response to endocrine therapy to enable improve treatment and maximize survival. Recent studies have demonstrated that the expression and activation of the glucocorticoid receptor (GR) has a direct impact on the regulation of many ER target genes, due to the crosstalk between GR and ER as transcriptional activators. The coactivation of these receptors leads to the recruitment of GR to ER DNA binding sites, which can have either cooperative or antagonistic gene-specific outcomes. In ER+ breast cancer cells which express GR, the activation of GR in addition to ER results in the increased expression of pro-differentiation genes, which is associated with improved relapse-free survival in ER+ breast cancer patients. GR also impedes estrogen-stimulated cell growth by directly blocking the recruitment of transcriptional coactivators to ER-bound enhancers, repressing estrogen-activated gene transcription. Overall, it appears that GR promotes a more indolent phenotype in ER+ breast cancer via the modulation of ER-directed gene transcription. The loss of this modulation could result in increased cell survival and proliferation, even in response to ER-targeted therapies. For example, low GR expression has been associated with worse patient outcomes in ER+ breast cancers. It has been established that GR protein is frequently decreased in breast tumors and that lower GR expression is associated with higher tumor grade. Researchers at Queen’s University have identified that methylation of the GR gene (NR3C1) promoter is a common event which results in the downregulation of GR in breast cancer. While the GR promoter is not methylated in ordinary mammary tissue, it is methylated in approximately 15% of breast tumors, most of which are ER+4. A multiplexed bisulfite sequencing assay has been developed for detecting GR promoter methylation as a prognostic tool for use in ER+ breast cancer patients5. This next-generation sequencing (NGS) approach can detect GR promoter methylation with a limit of detection as low as 1% tumor cells5. By applying this assay to an established clinical trial cohort, our researchers discovered that the methylation of specific NR3C1 promoter regions can have positive or negative prognostic value in ER+ patients. This may be explained by region C methylation being inversely correlated with methylation in other regions, including region U. These data support the idea that decreased methylation across the NR3C1 promoter is associated with better outcomes in ER+ patients. GR was also investigated as a marker in an independent cohort assembled by Kaplan‑Meier plotter. ER+ patients with low GR‑expressing tumors exhibited an increased risk of breast cancer‑related death compared to those with high GR expression. Decreased GR expression was also found to be detrimental in ER+ patients treated with tamoxifen, as it was marginally associated with poor overall survival and significantly associated with increased relapse risk. Therefore, our multiplex bisulfite sequencing assay could be used to determine GR expression in ER+ tumors and predict treatment response. Additionally, this assay could also be used as a companion diagnostic for selective estrogen receptor degraders (SERDs) by identifying patients who are unlikely to respond to SERM treatment due to altered GR expression.