scholarly journals Novel strategies to improve the endocrine therapy of breast cancer

2017 ◽  
Author(s):  
Aurelio Bartolome Castrellon
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptors ◽  
Endocrine Therapy ◽  
Targeted Therapies ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Estrogen Therapy ◽  
Endocrine Treatment ◽  
Intrinsic Resistance ◽  
First Line

Endocrine therapy (ET) constitutes the usual first-line of therapy for patients in the treatment of metastatic hormone receptorpositive breast cancer. Unfortunately, not all patients respond to first-line endocrine treatment due to intrinsic resistance, while others may initially respond but eventually progress with secondary acquired resistance leading to disease progression. Mechanisms of resistance to anti-estrogen therapy include, loss of expression for estrogen or progesterone receptor, upregulation of epidermal receptor growth factor 2, increased receptor tyrosine kinase signaling, leading to activation of various intracellular pathways that are involved in signal transduction such as PI3K/AKT/mammalian target of rapamycin, and others. Growing understanding of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of resistance. These insights have led to the development of targeted therapies that may prove to be effective options for the treatment of breast cancer and may overcome hormone therapy resistance. In this review we summarize some of the mechanisms of endocrine resistance, selected clinical trials of ET and targeted therapies, which might interfere with estrogen receptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent ET.

scholarly journals Endocrine Therapeutic Strategies for Patients with Hormone Receptor-positive Advanced Breast Cancer

2017 ◽  
Vol 13 (02) ◽  
pp. 127
Author(s):  
Peter Schmid ◽  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Endocrine Therapy ◽  
Cancer Biology ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Progression Free Survival ◽  
Endocrine Treatment ◽  
Receive Combination Therapy ◽  
Mutational Status

Endocrine treatment constitutes the therapeutic backbone for patients with oestrogen and/or progesterone receptor-positive breast cancer unless there is visceral crisis or suspected or known endocrine resistance. Whether all patients who are suitable for endocrine therapy should receive combination therapy or whether there remains a role for single-agent endocrine therapy is yet to be determined. Cancer biology (ESR1 mutational status) and disease pattern determine the choice of single-agent endocrine treatment. Possibly, patients with low disease burden, slow progression and presumed endocrine sensitivity might still be considered for single-agent endocrine therapy, whereas patients with more aggressive disease including visceral metastases might benefit from combination therapy. Improved guidance on selection and sequencing of treatments should become available once overall survival (OS) and progression-free survival (PFS) data have been reported from the ongoing trials in breast cancer, principally, FALCON (NCT01602380), PALOMA-2 (NCT01740427) and MONALEESA-2 (NCT01958021), which include different patient groups and, probably, different endocrine sensitivity.

scholarly journals MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sanne Løkkegaard ◽  
Daniel Elias ◽  
Carla L. Alves ◽  
Martin V. Bennetzen ◽  
Anne-Vibeke Lænkholm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Predictive Marker ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Minichromosome Maintenance ◽  
Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

scholarly journals Navigation through inter- and intratumoral heterogeneity of endocrine resistance mechanisms in breast cancer: A potential role for Liquid Biopsies?

Tumor Biology ◽  
2017 ◽  
Vol 39 (11) ◽  
pp. 101042831773151 ◽  
Author(s):  
Florian Reinhardt ◽  
André Franken ◽  
Tanja Fehm ◽  
Hans Neubauer
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Potential Role ◽  
Endocrine Resistance ◽  
Resistance Mechanisms ◽  
Intratumoral Heterogeneity ◽  
Endocrine Treatment ◽  
Liquid Biopsies ◽  
Hormone Receptor Positive

The majority of breast cancers are hormone receptor positive due to the expression of the estrogen and/or progesterone receptors. Endocrine therapy is a major treatment option for all disease stages of hormone receptor–positive breast cancer and improves overall survival. However, endocrine therapy is limited by de novo and acquired resistance. Several factors have been proposed for endocrine therapy failures, which include molecular alterations in the estrogen receptor pathway, altered expression of cell-cycle regulators, autophagy, and epithelial-to-mesenchymal transition as a consequence of tumor progression and selection pressure. It is essential to reveal and monitor intra- and intertumoral alterations in breast cancer to allow optimal therapy outcome. Endocrine therapy navigation by molecular profiling of tissue biopsies is the current gold standard but limited in many reasons. “Liquid biopsies” such as circulating-tumor cells and circulating-tumor DNA offer hope to fill that gap in allowing non-invasive serial assessment of biomarkers predicting success of endocrine therapy regimen. In this context, this review will provide an overview on inter- and intratumoral heterogeneity of endocrine resistance mechanisms and discuss the potential role of “liquid biopsies” as navigators to personalize treatment methods and prevent endocrine treatment resistance in breast cancer.

Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 524-524
Author(s):  
Jane Bayani ◽  
Elizabeth Kornaga ◽  
Cheryl Crozier ◽  
Gun Ho Jang ◽  
Irina Kalatskaya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Endocrine Therapy ◽  
Targeted Therapies ◽  
Copy Number ◽  
Targeted Sequencing ◽  
Phase Iii ◽  
Current Therapy ◽  
Endocrine Treatment ◽  
The Impact

524 Background: Hormone receptor positive breast cancer is a therapeutic challenge. Despite optimal anti-endocrine therapies, most breast cancer deaths follow a diagnosis of early luminal cancer. To understand the impact of multiple aberrations in the context of current therapy, we assessed the prognostic ability of genomic signatures as a putative stratification tool to targeted therapies. Methods: This a priori study is based on molecular pathways which might predict response to targeted therapies. DNA from 420 patients from the phase III TEAM pathology cohort were used. Patients with a distant recurrence within 5 years were matched by clinical variables to those disease-free at follow up. Copy number analysis was performed using the Affymetrix Oncoscan Assay. Targeted sequencing was performed in a subset of samples for genes based on signaling cassettes mined from the ICGC. Pathways were identified as aberrant if there were copy number variations (CNVs) and/or mutations in any of the pre-determined pathway genes: 1) CCND1/CCND2/CCND3/CDK4/CDK6; 2) FGFR1/FGFR2/FGFR2/FGFR4; and 3) AKT1/AKT2/PIK3CA/PTEN. Kaplan-Meier and log-rank analyses were used for DFS between groups. Hazard ratios were calculated using the Cox proportional hazard models adjusted for age, tumour size, grade, lymph node and HER2 status. Results: 390/420 samples passed informatics QC filters. For the CCND/CDK pathway, patients with no CNV changes experienced a better DFS (HR = 1.7, 95% CI 1.3-2.3, p < 0.001). For the FGFR/FGF pathway, a similar outcome is seen among patients without CNVs (HR = 1.5, 95% CI 1.1-2.0; p = 0.005). For AKT/PIK3CA, a decrease in DFS was seen in those with aberrations (HR = 1.4, 95% CI 1.0-1.8, p = 0.03). Conclusions: We demonstrated that CNVs of genes within CDK4/CCND, PIK3CA/AKT and FGFR pathways are independently linked to high risk of relapse following endocrine treatment, with implications for identifying those patients who are at high-risk for recurrence despite optimal anti-endocrine therapy and linking molecular features driving these cancers to targeted therapies.

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.

MONARCH 3: A randomized phase III study of anastrozole or letrozole plus abemaciclib, a CDK4/6 inhibitor, or placebo in first-line treatment of women with HR+, HER2-locoregionally recurrent or metastatic breast cancer (MBC).

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. TPS624-TPS624
Author(s):  
Matthew P. Goetz ◽  
Masakazu Toi ◽  
Suzanne Klise ◽  
Martin Frenzel ◽  
Nawel Bourayou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Single Agent ◽  
Metastatic Breast ◽  
Adjuvant Endocrine Therapy ◽  
Phase Iii ◽  
Type I ◽  
First Line ◽  
Phase Iii Study

TPS624 Background: Abemaciclib (LY2835219), a cell cycle inhibitor of CDK4/CDK6, demonstrated a clinically manageable safety profile and single-agent anti-tumor activity in MBC; all tumor responses were observed in hormone receptor positive (HR+) disease (Tolaney SM, Rosen LS, Beeram M, et al. San Antonio Breast Cancer Symposium, 2014, Abstract P5-19-13). Non-steroidal aromatase inhibitors (NSAI, letrozole and anastrazole), approved in the first-line setting for postmenopausal women with HR+ MBC, are being evaluated in combination with abemaciclib for safety and tolerability in a phase Ib study (NCT02057133) and in the present study (NCT02246621) to assess clinical efficacy. Methods: MONARCH 3 is a randomized, double-blind, placebo-controlled, phase III study of abemaciclib + NSAI vs placebo + NSAI in locoregionally recurrent (not amenable to curative treatment) breast cancer or MBC, with no prior systemic therapy in this disease setting. Patients will be randomized 2:1, and stratified by nature of disease (visceral vs bone-only metastases vs other) and prior (neo)adjuvant endocrine therapy (aromatase inhibitor vs other vs none). Abemaciclib 150 mg or placebo will be given continuously PO every 12 hours until progression, along with anastrozole 1 mg or letrozole 2.5 mg once daily at the investigator’s discretion, and assessments will occur every 28 days. Postmenopausal women with HR+, HER2- disease, a disease-free interval > 12 mos after completion of (neo)adjuvant endocrine therapy, ECOG PS ≤ 1, adequate organ function, and measurable disease or nonmeasurable bone-only disease (RECIST v1.1) are eligible. The primary endpoint is progression-free survival (PFS); a key secondary endpoint is overall survival (OS). The study has 80% power to detect an increase in PFS of approximately 40% (hazard ratio = 0.714). Assuming a median PFS of 10 mos in the control arm, this corresponds to a 4-mo increase in the median PFS. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%. Enrollment began November 2014; planned enrollment is 450 patients. Clinical trial information: NCT02246621.

scholarly journals Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer – Proceedings from breast cancer expert group meeting

2021 ◽  
Vol 15 (S10) ◽  
Author(s):  
Shaheenah Dawood ◽  
Maria Konstantionva ◽  
Rebecca Dent ◽  
Florencia Perazzo ◽  
Sung-Bae Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Registry ◽  
Single Agent ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Treatment Selection ◽  
Evidence Based ◽  
First Line ◽  
Clinical Questions ◽  
Breast Cancer Registry

Abstract Purpose The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 − mBC. Design A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 − mBC. Results Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 − mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 − mBC. Conclusion The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 − mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 − mBC.

scholarly journals Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer

2020 ◽  
Author(s):  
Maryam Soleimani ◽  
Simone Borgoni ◽  
Emre Sofyalı ◽  
Pernette J. Verschure ◽  
Stefan Wiemann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Endocrine Therapy ◽  
Proportional Hazards ◽  
Endocrine Resistance ◽  
Therapy Resistance ◽  
Cox Proportional Hazards ◽  
Endocrine Treatment ◽  
Endocrine Therapy Resistance ◽  
Cox Proportional Hazards Models

Abstract Background: Estrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance. Methods: We used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N=552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N=210 and N=172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen. Results: We identified 132, 9 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 171, 50 and 160 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. Single-locus signatures for the ER+/HER2- and TAM cohorts were conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were identified in both survival and T47D signatures. Conclusions: We identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance.

Long-duration chemotherapy, switch to endocrine therapy, or watch only? A single-center retrospective study of metastasis breast cancer with ER/PR(+) and CerbB2(-).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11589-e11589
Author(s):  
Huang Jian ◽  
zhan-Hong Chen ◽  
Wenming Cao ◽  
Wei-Wu Ye ◽  
Huang Ping ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
Endocrine Therapy ◽  
Single Agent ◽  
First Line ◽  
Long Duration ◽  
Significant Difference ◽  
One Year ◽  
Line Chemotherapy ◽  
Better Than

e11589 Background: To evaluate the efficiency of long-duration chemotherapy used Capecitabine or switch to endocrine therapy in metastasis breast cancer (MBC) patients with ER/PR(+) and CerbB2(-). Methods: We retrospective analysis 112 patients of our center from 01/Jan/2009 to 30/April/2012, who with ER/PR(+) and CerbB2(-) MBC. All these patients accepted capecitabine -based regimen as first-line or 2nd-line chemotherapy. Three regimens included long-duration chemotherapy(LC) used capecitabine, switch to endocrine therapy(STET) or watch only(WO) were given after capecitabine-based regimen. We compared the differences among these three regimens. Results: 70/112 were first-line chemotherapy,52/112 were 2nd-line chemotherapy. All these patients used capecitabine-based regimen (include single-agent or in combination with another chemotherapy drug), and the response were: CR, PR, SD≥24 weeks. 29 patients were LC,28 patients were STET and 55 patients were WO after capecitabine-based regimen. The median progression-free survival (mPFS) was 7 months, one year survival rate was 32.0%, response rate(RR) was 35.7% in all these patients. The mPFS were 22 months, 12 months and 5 months in LC group, STET group and WO group respectively. The one year survival rate were 67.6%,46.5% and 5.1% in these three groups respectively. WO group was significantly worse than LC and STET groups on mPFS (p<0.0001) and one year survival rate (p<0.05). LC group and STET group was no significant difference in mPFS(p=0.1832) and one year survival rate (p=0.5012). The RR were 51.7%, 39.3% and 25.5% in these three groups respectively. LC group was significantly better than WO group (p=0.0287). No significant difference between LC and STET groups (p=0.4287) or STET groups and WO group (p=0.2145). Conclusions: Long-duration treatment is better than watch only(WO).Patients with ER/PR(+) and CerbB2(-) MBC used capecitabine-based regimen (include single-agent or in combination with another chemotherapy drug), and the response were: CR, PR, SD≥24 weeks maybe get more benefits from long-duration chemotherapy used capecitabine. A multicenter prospective study is going on.

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