scholarly journals Evaluating the effects of RAS and CK2 Inhibitors in ESR1 Mutated Breast Cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Camilo Suescum ◽  
Harikrishna Nakshatri
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast ◽  
Ras Signaling ◽  
Breast Cancers ◽  
Metastatic Progression ◽  
Estrogen Receptor Positive ◽  
Signaling Inhibitors ◽  
Esr1 Mutation ◽  
Ck2 Inhibitors

Background and Hypothesis: Estrogen Receptor alpha (ESR1) is rarely mutated in primary breast cancers but is frequently mutated in metastasis that can appear after many years of anti-estrogen therapy. Mutations to ESR1 can result in estrogen-independent activity of ESR1 causing anti-estrogen to become ineffective. Previous work on this project has led to the hypothesis that RAS pathway activation in metastatic cancer cells as a result of ESR1 mutation leads to elevated CK2 activity which ultimately results in metastatic progression. Therefore, we hypothesize that the use of RAS signaling inhibitors or CK2 inhibitors have efficacy in blocking or reducing the metastatic progression of metastatic breast cancers with hyperactive RAS pathways. Experimental Design or Project Methods: The estrogen receptor positive, anti-estrogen sensitive breast cancer cell line MCF-7 and the same cell line genomically modified to replace wild type ESR1 to breast cancer metastasis enriched Y537S or D538G ESR1 mutation were used in this study. Cells were treated with various concentrations of the RAS pathway inhibitor Salirasib or CK2 inhibitor Silmitasertib and cell proliferation rates were measured using bromodeoxyuridine incorporation ELISA. Results: Thus far, the use of RAS signaling inhibitors or CK2 inhibitors have not shown efficacy in decreasing the proliferation rates of modified ESR1 MCF-7 cells. While there is a general trend of growth inhibition by these inhibitors at a higher concentration, there is no significant difference between the ESR1 mutant expressing cells and their respective controls.  Conclusion and Potential Impact: This study will establish the feasibility of using RAS signaling inhibitors or CK2 inhibitors in the treatment of metastatic estrogen receptor-positive breast cancer. Future studies testing the effects of these drugs either alone or in combination with the clinically used anti-estrogen Fulvestrant for not only primary tumor growth but also metastasis in clinically relevant in vivo models may ultimately lead to clinical translation.  Finally, demonstrating efficacy in these types of drugs may fuel the further refinement of drugs targeting these pathways to treat metastatic breast cancer.

scholarly journals Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer

2021 ◽  
pp. JCO.20.02272
Author(s):  
Aditya Bardia ◽  
Virginia Kaklamani ◽  
Sharon Wilks ◽  
Amy Weise ◽  
Donald Richards ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Once Daily ◽  
Estrogen Receptor Positive ◽  
Heavily Pretreated ◽  
Esr1 Mutation

PURPOSE This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor–positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

scholarly journals In Silico Discovery of Mitosis Regulation Networks Associated with Early Distant Metastases in Estrogen Receptor Positive Breast Cancers

2013 ◽  
Vol 12 ◽  
pp. CIN.S10329 ◽  
Author(s):  
Yuriy Gusev ◽  
Rebecca B. Riggins ◽  
Krithika Bhuvaneshwar ◽  
Robinder Gauba ◽  
Laura Sheahan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
In Silico ◽  
Expression Profiles ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Mitotic Checkpoint ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

The aim of this study was to perform comparative analysis of multiple public datasets of gene expression in order to identify common genes as potential prognostic biomarkers. Additionally, the study sought to identify biological processes and pathways that are most significantly associated with early distant metastases (<5 years) in women with estrogen receptor-positive (ER+) breast tumors. Datasets from three published studies were selected for in silico analysis of gene expression profiles of ER+ breast cancer, using time to distant metastasis as the clinical endpoint. A subset of 44 differently expressed genes (DEGs) was found common to all three studies and characterized by mitotic checkpoint genes and pathways that regulate mitotic spindle and chromosome dynamics. DEG promoter regions were enriched with NFY binding sites. Analysis of miRNA target sites identified significant enrichment of miR-192, miR-193B, and miR-16–1 targets. Aberrant mitotic regulation could drive increased genomic instability leading to a progression towards an early onset metastatic phenotype. The relative importance of mitotic instability may reflect the clinical utility of mitotic poisons in metastatic breast cancer, including poisons such as the taxanes, epothilones, and vinca alkaloids.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

scholarly journals Practice-Changing Interventions in the Systemic Management of Breast Cancer

2020 ◽  
Vol 18 (7.5) ◽  
pp. 941-944
Author(s):  
William J. Gradishar
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Targeted Agents ◽  
Her2 Positive ◽  
Nccn Guidelines ◽  
Estrogen Receptor Positive ◽  
Treatment Paradigm

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.

A phase 1b study of chemoimmunotherapy with pegylated liposomal doxorubicin and pembrolizumab in estrogen receptor-positive, endocrine-resistant breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1049-1049
Author(s):  
Alberto A. Gabizon ◽  
Nathan Cherny ◽  
Rut Isacson ◽  
Areen Abu Remilah ◽  
Alberto Gabizon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Liposomal Doxorubicin ◽  
Safety Information ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Skin Toxicity ◽  
Pharmacokinetic Analysis ◽  
Estrogen Receptor Positive ◽  
Phase 1B

1049 Background: This is a single center phase 1b study of a regimen of pembrolizumab (PBZ) and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer. PLD was chosen as chemotherapy component because it is mildly myelosuppressive and non-immunosuppressive and contains doxorubicin, a strong immunogenic cell death inducer. Methods: Patients with estrogen receptor positive, HER2 negative, metastatic breast cancer, whose disease progressed on hormonal and biological therapy and up to 2 chemotherapy lines were eligible for enrollment. PLD, 30 mg/m2, and PBZ, 200 mg flat dose, were infused on day 1 of every 3-week cycles. The main study objectives were safe dose clearance, characterization of dose-limiting toxicities (DLT), tumor response, and pharmacokinetic analysis of PLD and PBZ during the first 3 cycles of treatment in a 1st cohort of 6 patients and a 2nd confirmatory cohort of 6-9 patients. Patients with partial response (PR) or stable disease (SD) continued on the extended phase of the study consisting of 9 additional cycles during which further safety information was collected. All patients were followed-up for survival. Results: 12 patients were recruited (median age 61 y, range 45-91). 9 patients had received prior doxorubicin treatment. 82 treatments have been administered (median: 7, range 2-13). Overall, treatment was well tolerated. DLT including infusion reactions, grade ≥2 myelosuppression, hair loss and mucocutaneous toxicity were not observed in the first 3 cycles. Subsequently, skin toxicity (grade 2-3 palmar-plantar erythema) was observed forcing treatment delays of 1-2 weeks. Except for 2 cases of subclinical hypothyroidism, there were no other apparent PBZ-related side-effects. There was no evidence of cardiac toxicity. There were 2 early deaths (days 25 and 45) probably related to disease progression. Upon reevaluation on week 9, we observed: 2 patients with PD, 4 with SD, 2 with PR (15+ and 5+ mth), 1 with no measurable disease, and 1 early to evaluate. Three out of 5 patients responded well to post-study chemotherapy with durable improvement or stabilization (range, 5 to 11+ mth). Median follow-up is 14 mth. Median survival has not been reached with 4 deaths and a longest survivor of 19+ mth. Median progression-free survival is 6.0 mth. The clearance of PLD was slow with high Cmax, long T½ and small Vd. There was a significant increase in the AUC of PLD between the 1st and 3rd cycle (median: 2,649 vs 3,422 mg*h/l, p = 0.039). Analysis of PBZ plasma levels is ongoing. Conclusions: The combination of PLD and PBZ is well tolerated and feasible for extended treatment. Dose interval of PLD should be lengthened to 4 weeks after 2-3 cycles to prevent skin toxicity. The late appearance of skin toxicity is probably related to a delay in PLD clearance after 2 treatment cycles with PLD and PBZ. Clinical trial information: NCT03591276 .

scholarly journals Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 684 ◽  
Author(s):  
Nadiia Lypova ◽  
Lilibeth Lanceta ◽  
Alana Gipson ◽  
Stephanie Vega ◽  
Rodolfo Garza-Morales ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Viral Entry ◽  
Metastatic Breast ◽  
Receptor Expression ◽  
Type I ◽  
Development Of Resistance ◽  
Estrogen Receptor Positive ◽  
Entry Receptor ◽  
Resistant Cells

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer.

Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial.

1997 ◽  
Vol 15 (7) ◽  
pp. 2494-2501 ◽  
Author(s):  
C A Russell ◽  
S J Green ◽  
J O'Sullivan ◽  
H E Hynes ◽  
G T Budd ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Response Time ◽  
Treatment Failure ◽  
Metastatic Breast ◽  
Megestrol Acetate ◽  
Phase Iii ◽  
Time To Treatment Failure ◽  
Estrogen Receptor Positive

PURPOSE A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen. PATIENTS AND METHODS Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm. RESULTS Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash. CONCLUSION With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.

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