ER and PI3K Independently Modulate Endocrine Resistance in ER-Positive Breast Cancer: Figure 1.

e22033 Background: We demonstrated that pCR is correlated with increasing HER2-FISH ratio, while disease-free survival (DFS) with pCR and ER-positivity in HER2-positive breast cancer treated with trastuzumab (SABCS 2008). It is known that quantitative HER2-FISH ratio correlates with ER levels and HER2-positivity imparts a higher grade in ER-positive BC. Collectively, we hypothesized that combined ER (≥10) and a HER2 ratio cut-point may subdivide HER2-positive BC into pCR predictive subtypes.Methods: Of the 80 HER2-positive (IHC3+/FISH+) BC, quantitative HER2 FISH ratio (widely spread over 1–18.3) and ER correlation was noted (r=0.34, p=0.002). Moreover, HER2 ratio (>4) correlated with higher Ki-67 (r= 0.5, p=0.01) and grade (p trend=0.05) in ER-positive subtype, inferring a biologic cut-point. Results: Of patients with stage I-IV BC treated neoadjuvantly (92% trastuzumab-based), pCR was 0% (0/13) in ER-positive-low-HER2 compared to 77% (10/13, p=0.0001), 75% (24/32, p<0.0001) and 37.5% (3/8, p=0.043) in ER-positive-high-HER2, ER-negative-high-HER2 and ER-negative-low-HER2, respectively. DFS was 100, 90, 80% and 60% (logrank-trend p<0.05) in these 4 subtypes (excluding stage IV), respectively, at a median follow-up of 38 months (range 6–72). In ER-negative subtypes, DFS was 97% and 29% (logrank p=0.0001) in patients with or without pCR; of the six with RT, 0% DFS was noted in four with HER2-negative/HER2-reduced (HER2-R) RT, compared to 100% in the two with unchanged HER2 (p=<0.05, logrank test). In ER-positive subtypes, DFS is 95% overall, and 100% in patients with RT; 7 of 10 tested RT were HER2- R. Conclusions: pCR is crucial and high in ER-negative-high-HER2 and is crucial (but low) in ER-negative-low-HER2-positive BC for improved outcome. Improved DFS is associated with high pCR in ER-positive-high-HER2 BC, but is independent of the low pCR in ER-positive-low-HER2-subtype. Thus, combined HER2 and ER offer improved prediction. In hypothesis generating analysis, HER2-R may underlie relapse in ER-negative subtypes (HER2-basal-transitional-residual), while it may be beneficial in ER-positive subtypes (luminal-B- A-transitional) by reducing HER2-pathway mediated endocrine resistance. [Table: see text]

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Antiestrogenic Effects of the Novel Sphingosine Kinase-2 Inhibitor ABC294640

Endocrinology ◽

10.1210/en.2010-0420 ◽

2010 ◽

Vol 151 (11) ◽

pp. 5124-5135 ◽

Cited By ~ 70

Author(s):

James W. Antoon ◽

Martin D. White ◽

William D. Meacham ◽

Evelyn M. Slaughter ◽

Shannon E. Muir ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Resistance ◽

Sphingosine Kinase ◽

Hek293 Cells ◽

Sphingolipid Metabolism ◽

Cancer Drug ◽

The Novel ◽

Er Positive ◽

Cancer Tumor ◽

Positive Breast Cancer

Alterations in sphingolipid metabolism have been shown to contribute to the development of endocrine resistance and breast cancer tumor survival. Sphingosine kinase (SK), in particular, is overexpressed in breast cancer and is a promising target for breast cancer drug development. In this study, we used the novel SK inhibitor ABC294640 as a tool to explore the relationship between SK and estrogen (E2) receptor (ER) signaling in breast cancer cells. Treatment with ABC294640 decreased E2-stimulated ERE-luciferase activity in both MCF-7 and ER-transfected HEK293 cells. Furthermore, the inhibitor reduced E2-mediated transcription of the ER-regulated genes progesterone receptor and SDF-1. Competitive receptor-binding assays revealed that ABC294640 binds in the antagonist ligand-binding domain of the ER, acting as a partial antagonist similar to tamoxifen. Finally, treatment with ABC294640 inhibited ER-positive breast cancer tumor formation in vivo. After 15 d of treatment with ABC294640, tumor volume was reduced by 68.4% (P < 0.05; n = 5) compared with control tumors, with no marked weight loss or illness. Taken together, these results provide strong evidence that this novel SK inhibitor, which had not previously been known to interact with E2 signaling pathways, has therapeutic potential in treating ER-positive breast cancer via inhibition of both SK and ER signaling.

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ER-positive breast cancer cells are poised for RET-mediated endocrine resistance

PLoS ONE ◽

10.1371/journal.pone.0194023 ◽

2018 ◽

Vol 13 (4) ◽

pp. e0194023 ◽

Cited By ~ 5

Author(s):

Sachi Horibata ◽

Edward J. Rice ◽

Chinatsu Mukai ◽

Brooke A. Marks ◽

Kelly Sams ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Endocrine Resistance ◽

Er Positive ◽

Positive Breast Cancer

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Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.584 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 584-584

Author(s):

Emre Koca ◽

Polly Ann Niravath ◽

Joe Ensor ◽

Tejal Amar Patel ◽

Xiaoxian Li ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Phase Ii Trial ◽

Endocrine Resistance ◽

Newly Diagnosed ◽

Open Label ◽

Hormone Receptor Positive ◽

Open Label Phase ◽

Er Positive ◽

Positive Breast Cancer

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.

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Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

Breast Care ◽

10.1159/000405017 ◽

2015 ◽

Vol 10 (3) ◽

pp. 168-172 ◽

Cited By ~ 15

Author(s):

Katrin Almstedt ◽

Marcus Schmidt

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Hormone Receptor ◽

Endocrine Resistance ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Hormone Receptor Positive ◽

Study Results ◽

Er Positive ◽

Positive Breast Cancer

Breast cancer is a heterogeneous disease with different molecular subtypes. Most tumours are hormone receptor positive (luminal subtype) with potential endocrine responsiveness. Endocrine therapy is commonly used in these patients. Disease progression caused by endocrine resistance represents a significant challenge in the treatment of breast cancer. To understand the mechanisms of resistance of long-term oestrogen-deprived breast cancer cells, it is important to focus on cross-talk between steroid receptor signalling and other growth factor receptors and intracellular pathways. (Pre-)clinical trials showed that co-targeting these pathways can restore endocrine sensitivity. The focus of the current review is on the intracellular PI3K/AKT/mTOR signalling pathway and cyclin-dependant kinases (CDKs) in oestrogen receptor (ER)-positive breast cancer. Study results clearly show that both inhibition of the PI3K/AKT/mTOR pathway and CDK4/6 are promising ways to improve the efficacy of endocrine treatment in ER-positive breast cancer patients with comparably few side effects. Further clinical trials are needed to identify the patient population who would benefit most from a dual inhibition.

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RADICAL trial: A phase Ib/IIa study to assess the safety and efficacy of AZD4547 in combination with either anastrozole or letrozole in ER positive breast cancer patients progressing on these aromatase inhibitors (AIs).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1059 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1059-1059 ◽

Cited By ~ 9

Author(s):

Michael Seckl ◽

Philip David Badman ◽

Xinxue Liu ◽

Iain R. MacPherson ◽

Ishtiaq Husain Zubairi ◽

...

Keyword(s):

Breast Cancer ◽

Disease Progression ◽

Tumour Size ◽

Retinal Pigment ◽

Endocrine Resistance ◽

Pharmacokinetic Data ◽

Safety And Efficacy ◽

Phase Ib ◽

Er Positive ◽

Positive Breast Cancer

1059 Background: Patients with metastatic ER positive breast cancer invariably experience disease progression whilst taking AIs. Fibroblast growth factor receptor inhibitors (FGFRI) such as AZD4547 can reverse endocrine resistance in breast cancer cells. Consequently, we designed the RADICAL trial to test the safety and efficacy of AZD4547 combined with letrozole (L) or anastrozole (A). Methods: Patients with prior disease progression on either AI were initially recruited to a Phase Ib study which showed that L 2.5mg or A 1mg daily continuously could be safely combined with AZD4547 80mg twice daily on a 1wk on/1 wk off schedule. Pharmacokinetic data showed no significant interactions. Subsequently, 52 patients progressing on these AIs were recruited, either continuing, or, if other therapies had subsequently been given, restarting their prior AI together with AZD4547. Primary endpoint was change in tumour size (RECIST v 1.1) at 12 weeks compared to baseline. Results: Enrolled patients had previously received a median of 4 (range: 1-11) systemic therapies, including endocrine treatments with a median of 2 (range: 1-6). The mean tumour size change at 12 and 28 weeks was 7% (95%CI: -4%, 17%) and 8% (95%CI: -4%, 20%), respectively. Clinical benefit assessed by partial response (PR) or stable disease (SD) occurred in 36.5% (1 PR and 18 SD) and 25% (2 PR and 11 SD) of patients at 12 and 28 weeks, respectively. The median progression free survival was 3.1 months (95%CI: 2.4-5.4). Most adverse events (AEs) were G1/2 (95.3%). 11 (21%) patients developed asymptomatic AZD4547-induced retinal pigment epithelial detachment, all resolved and 1 and 6 were able to continue on study medication at full and half dose, respectively. Among 34 G3/4 AEs, only 6 were probably/possibly related to AZD4547. Out of 13 unrelated serious AEs, 2 were fatal. Conclusions: Combined AZD4547 with L or A appears to be safe and shows anti-tumour activity in advanced ER+ patients resistant to these AIs. Development of a biomarker to select patients for this therapy will facilitate future studies. Clinical trial information: NCT01791985.

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The NFκB pathway and endocrine-resistant breast cancer

Endocrine Related Cancer ◽

10.1677/erc.1.00977 ◽

2005 ◽

Vol 12 (Supplement_1) ◽

pp. S37-S46 ◽

Cited By ~ 99

Author(s):

Y Zhou ◽

S Eppenberger-Castori ◽

U Eppenberger ◽

C C Benz

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Tyrosine Kinases ◽

Inflammatory Responses ◽

Endocrine Resistance ◽

Molecular Evidence ◽

Normal Mammary Gland ◽

Breast Cancers ◽

Er Positive ◽

Positive Breast Cancer

Endocrine therapy with an estrogen receptor (ER)-targeted antiestrogen, such as tamoxifen, or estrogen ablation by aromatase inhibitors is clinically indicated for the management of all forms of ER-positive breast cancer. However, 30–50% of ER-positive breast cancer cases fail to benefit clinically from endocrine therapy alone, and recent molecular evidence suggests that ‘crosstalk’ pathways originating from activated receptor tyrosine kinases and/or other proliferative and survival signals may be contributing to this endocrine resistance. Molecular identification and validation of candidate ER crosstalking pathways will likely lead to clinically important prognostic markers and targets for the application of novel therapeutics in combination with standard endocrine agents. This review focuses on a critical survival and proliferation pathway involving activation of nuclear factor-κB (NFκB), a family of ubiquitously expressed transcription factors that for nearly two decades have been known to be critical regulators of mammalian immune and inflammatory responses, and more recently have been associated with chemotherapy resistance. With the demonstration that activation of NFκB is absolutely required for normal mammary gland development, NFκB involvment in human breast cancers was initially explored and linked to the development of hormone-independent (ER-negative) breast cancer. Newer clinical evidence now implicates NFκB activation, particularly DNA-binding by the p50 subunit of NFκB, as a potential prognostic marker capable of identifying a high-risk subset of ER-positive, primary breast cancers destined for early relapse despite adjuvant endocrine therapy with tamoxifen. Furthermore, initial preclinical studies suggest that treatment strategies designed to prevent or interrupt activation of NFκB in cell-line models of these more aggressive, ER-positive breast cancers can restore their sensitivity to such standard endocrine agents as tamoxifen.

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A Novel Group of Genes that Causes Endocrine Resistance in Breast Cancer Identified by Dynamic Gene Expression Analysis

10.21203/rs.3.rs-1047808/v1 ◽

2021 ◽

Author(s):

Arvand Asghari ◽

Katherine Wall ◽

Michael Gill ◽

Natascha Del Vecchio ◽

Farnaz Allahbakhsh ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Endocrine Resistance ◽

Gene Mutations ◽

Therapeutic Approaches ◽

Resistance Development ◽

Development Of Resistance ◽

Er Positive ◽

Underlying Causes ◽

Positive Breast Cancer

Abstract Breast cancer (BC) is the most common type of cancer and the second leading cancer-related cause of death in women worldwide. Endocrine therapy is an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer; however, in many cases, tumor regrowth occurs after the therapy and the tumor becomes unresponsive anymore. While some gene mutations contribute to the resistance in some patients, the underlying causes of the resistance to endocrine therapies are mostly undetermined. In this study, we utilized our recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes that can be crucial to the development of resistance in BC. The expression of these genes is not only altered in cell models during the endocrine resistance development but also significantly changed in endocrine-resistant patients. Surprisingly, this group of genes was also identified as a group of key candidate genes in triple-negative breast cancer (TNBC), suggesting that endocrine resistance and TNBC share the same mechanisms during their development. Our findings explain some of the genetic underlying reasons for endocrine resistance and provide the potential to develop novel common therapeutic approaches against endocrine-resistant BC and TNBC.

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