Tracking endocrine resistance in estrogen-receptor positive breast cancer in ctDNA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14550-e14550
Author(s):  
Magdalena Meissner ◽  
Rachel Butler ◽  
Angela Claire Casbard ◽  
Margherita Carucci ◽  
Tracie-Ann Madden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Initial Period ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Gene Panel ◽  
Comparable Efficacy ◽  
Liquid Biopsies ◽  
Estrogen Receptor Positive

e14550 Background: Endocrine therapy is the standard of care treatment for patients with estrogen-receptor positive advanced breast cancer, owing to improved tolerability and comparable efficacy to that of cytotoxic chemotherapy. Half of such cancers will progress through first line therapy (primary endocrine resistance) and half will progress after an initial period of disease control (secondary or acquired endocrine resistance). A significant challenge is to test for and identify biomarkers which can guide the likely success of endocrine therapy as a single agent or in combination with small molecule inhibitors.This is particularly challenging where metastatic deposits reside at sites where biopsy is difficult. Potential biomarkers indicative of resistance to endocrine therapy have been identified and can be detected in circulating tumour DNA (ctDNA). CtDNA is shed from tumours and is detectable in a cancer patient’s bloodstream. Information on mutational profiles can guide an oncologist in the selection of targeted therapy in addition to hormonal therapy. Methods: We have analysed formalin-fixed paraffin-embedded(FFPE) tumour samples and longitudinal liquid biopsies from 19 patients who were treated with fulvestrant in combination with a novel inhibitor of the PIK3CA/AKT pathway with next-generation sequencing using a targeted 44-gene panel. Mutations identified using this technique were tracked during the course of treatment using droplet-digital PCR(ddPCR). Results: 57 samples were tested using a 44-gene panel; 19 FFPE tumour samples and matched ctDNA samples were obtained prior therapy and ctDNA samples at disease progression. Mutations detected in PIK3CA, AKT1, ESR1and TP53 genes were trackable in longitudinal ctDNA samples using ddPCR. The association between ctDNA dynamics and outcome will be presented. Conclusions: Multiple mutations that enable the early detection of treatment failure and resistance can be tracked in ctDNA. Investigating the clinical utility of ctDNA is paramount.

scholarly journals Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor–Positive Breast Cancer

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Emily Smart ◽  
Svetlana E Semina ◽  
Jonna Frasor
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Signaling Pathway ◽  
Endocrine Resistance ◽  
Dimethyl Fumarate ◽  
Therapy Resistance ◽  
Molecular Characteristics ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

Abstract The majority of breast cancers are diagnosed as estrogen receptor–positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

scholarly journals Detection of ESR1 Mutations Based on Liquid Biopsy in Estrogen Receptor-Positive Metastatic Breast Cancer: Clinical Impacts and Prospects

2020 ◽  
Vol 10 ◽  
Author(s):  
Hao Liao ◽  
Wenfa Huang ◽  
Wendi Pei ◽  
Huiping Li
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Liquid Biopsy ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Favorable Prognosis ◽  
Sequencing Technologies ◽  
Estrogen Receptor Positive ◽  
Almost All

Endocrine therapy is the main treatment option for estrogen receptor-positive (ER+) breast cancer (BC). Compared with other clinical subtypes, ER+ BC patients usually have a more favorable prognosis. However, almost all ER+ BCpatients develop endocrine resistance and disease progression eventually. A large number of studies based on liquid biopsy suggest that ESR1 mutations may play a key role in this process. For patients with ER+ metastatic BC (MBC), ESR1 is an important prognostic factor and may associate with the resistance to endocrine therapy, like aromatase inhibitors. The advances of sequencing technologies allow us to conduct longitudinal monitoring of disease and unveil the clinical implications of each ESR1 sub-clone in ER+ MBC. Moreover, since the ESR1-related endocrine resistance has not been fully addressed by existing agents, more potent cornerstone drugs should be developed as soon as possible. Herein, we reviewed the recent progress of detecting ESR1 mutations based on liquid biopsy and different sequencing technologies in ER+ MBC and discussed its clinical impacts and prospects.

scholarly journals Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Esmael Besufikad Belachew ◽  
Dareskedar Tsehay Sewasew
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Therapeutic Modality ◽  
Breast Cancers ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

scholarly journals Nuclear Mechanisms Involved in Endocrine Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jürgen Dittmer
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Standard Treatment ◽  
Current Knowledge ◽  
Endocrine Resistance ◽  
Estrogen Receptor Α ◽  
Cyclin Dependent Kinase ◽  
Druggable Targets ◽  
Positive Breast Cancer

Endocrine therapy is a standard treatment offered to patients with ERα (estrogen receptor α)-positive breast cancer. In endocrine therapy, ERα is either directly targeted by anti-estrogens or indirectly by aromatase inhibitors which cause estrogen deficiency. Resistance to these drugs (endocrine resistance) compromises the efficiency of this treatment and requires additional measures. Endocrine resistance is often caused by deregulation of the PI3K/AKT/mTOR pathway and/or cyclin-dependent kinase 4 and 6 activities allowing inhibitors of these factors to be used clinically to counteract endocrine resistance. The nuclear mechanisms involved in endocrine resistance are beginning to emerge. Exploring these mechanisms may reveal additional druggable targets, which could help to further improve patients’ outcome in an endocrine resistance setting. This review intends to summarize our current knowledge on the nuclear mechanisms linked to endocrine resistance.

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