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.

Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer: Sequencing of chemotherapy and endocrine therapy.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 164-164
Author(s):  
Nicole M. Engel-Nitz ◽  
Yanni Hao ◽  
Jaqueline Willemann Rogerio ◽  
James D. Turnbull ◽  
Gabriel Gomez Rey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Advanced Cancer ◽  
Index Date ◽  
Initial Diagnosis ◽  
Advanced Breast ◽  
Endocrine Treatment ◽  
Breast Cancer Patients

164 Background: National Comprehensive Cancer Network breast cancer guidelines suggest sequencing of systemic therapy. This study examined sequencing of endocrine and chemotherapy treatments to better understand real-world treatment patterns for HR+/HER2- advanced breast cancer. Methods: A proprietary clinical cancer database with physician-reported clinical data on patients with breast cancer was linked to medical and pharmacy claims (2008-2012) from a national US health plan. Study patients had HR+ and HER2- status. Advanced cancer cohorts were defined: stage III (SIII) or IV (SIV) at initial diagnosis, or developed metastases following initial diagnosis (MET). Index date was the first date of advanced cancer diagnosis or date of metastases following initial diagnosis. Health plan enrollment for 3 months pre- and ≥ 3-months post- index date was required; patients who died within 3 months after index date and were continuously enrolled were retained. A 3-month baseline period assessed prior treatment; a variable follow-up (until disenrollment or 31 Oct 2012) assessed patterns of endocrine and chemotherapy treatments following index date. Results: A total of 954 breast cancer patients met study inclusion criteria and were HR+/HER2- with ≥ 3 months of continuous enrollment after index date, with 369 of the 954 (38.68%) SIII, 117 (12.26%) SIV, and 469 (49.16%) MET patients. In the study population, 83.65% were treated with endocrine therapy, starting an average of 179 days after index date. A total of 80.29% were treated with chemotherapy, starting an average of 53 days following the index date; 65% of patients initiated chemotherapy after index date without prior endocrine treatment. Rates varied by cohort: 90% of SIII, 57% of SIV, and 48% of MET patients had no evidence of endocrine treatment prior to initiating chemotherapy. Conclusions: This study found large proportions of HR+/HER2- advanced breast cancer patients initiated chemotherapy without prior endocrine therapy. Further investigation of patient characteristics and outcomes by therapy sequencing patterns will help illuminate the extent to which patterns adhere to NCCN guidelines.

A phase III, open label, prospective, randomized, multicenter, neoadjuvant study of chemotherapy versus endocrine therapy in premenopausal patient with hormone responsive, HER2 negative, breast cancer (KBCSG 012).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 517-517
Author(s):  
hee Jeong Kim ◽  
Woo Chul Noh ◽  
Eun Sook Lee ◽  
Leesu Kim ◽  
Yongsik Jung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Neoadjuvant Endocrine Therapy ◽  
Premenopausal Breast Cancer ◽  
Ki 67 ◽  
Initial Biopsy

517 Background: Neoadjuvant endocrine therapy has shown efficacy in hormone-responsive postmenopausal breast cancer patients. We aimed to assess the efficacy and safety of cytotoxic chemotherapy versus endocrine therapy for hormone-responsive lymph node-positive premenopausal breast cancer patients in a neoadjuvant setting. (NCT01622361). Methods: In this phase 3, randomized, double blind, parallel group, multicenter study, we enrolled premenopausal women with estrogen receptor (ER)-positive, HER2-negative, and lymph node-positive premenopausal breast cancer patients. Patients were randomized to either 24 weeks of neoadjuvant chemotherapy with adriamycin plus cyclophosphamide (AC) followed by taxane (T) or neoadjuvant endocrine therapy with zoladex and tamoxifen. Results: 187 patients were randomly assigned to chemotherapy (n=95) or endocrine therapy (n=92), and 174 patients completed the 24 week neoadjuvant treatment period (n=87, both). More patients in the chemotherapy group had a complete or partial response than did those in endocrine therapy arm on both caliper (chemotherapy 83.9% vs endocrine therapy 71.3%, OR 0.476 95% CI 0.228 to 0.994) and MRI (chemotherapy 83.7% vs endocrine therapy 52.9%, OR 0.219, 95% CI 0.107 to 0.447). Three patient on chemotherapy group (3.4%) and 1 patients (1.15%) on endocrine treatment group showed complete pathologic response. In the patients who had breast cancer with low Ki 67 expression (<20%) on initial biopsy, clinical response on caliper were shown similar on both treatment group (HR 0.958, 95%CI 0.296 to 3.101). Five patients who had no tumor on the breast or lymph node after 24 week neoadjuvant endocrine therapy had higher ER score (all allred score >6), all low grade (1or 2) low Ki 67(≤20%) expression (4/5 patients) on initial biopsy specimen. Conclusions: In premenopausal breast cancer patients, 24 weeks neoadjuvant chemotherapy showed better clinical response than endocrine therapy. Low Ki 67 expression could be a parameter of the endocrine treatment. Clinical trial information: NCT01622361.

Association of Obesity and Luminal Subtypes in Prognosis and Adjuvant Endocrine Treatment Effectiveness Prediction in Chinese Breast Cancer Patients

2021 ◽  
Author(s):  
Siyi Zhu ◽  
Yiwei Tong ◽  
Weiguo Chen ◽  
Xiaosong Chen ◽  
Kunwei Shen
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Clinicopathological Characteristics ◽  
Obese Group ◽  
Treatment Modalities ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
The Impact

Abstract Purpose Our purpose was to evaluate the influence of obesity on clinicopathological characteristics of breast cancer. Secondly we wanted to explore the effect of obesity on the performance of endocrine therapy in Chinese breast cancer patients. Methods Patients with luminal/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer were included and categorized into the non-obese (BMI < 28 kg/m²) and obese (BMI ≥ 28 kg/m²) groups according to body mass index (BMI). Clinicopathological characteristics and treatment modalities were compared among two groups. Furthermore, the interaction of adjuvant endocrine therapy and efficacy between non-obese and obese groups were analyzed. Results A total of 2875 patients were included: 2598 in the non-obese group and 277 in the obese group. A higher rate of patients with comorbidities (OR: 2.83, 95%CI 2.13–3.74, P < 0.001) or PR positive tumor (OR: 1.63, 95%CI 1.03–2.58, P = 0.037) were identified in the obese group. Obesity was not associated with disease recurrence (P = 0.839) or overall survival (P = 0.140) in the whole population. Subgroup analysis did show an association with worse relapse-free survival (RFS, HR 3.48, 95%CI 1.31–9.22, P = 0.012) and overall survival (OS, HR 4.67, 95%CI 1.28–16.95, P = 0.019) in luminal A breast cancer. These results could not be reproduced in the luminal B subtype with a RFS (HR 0.78, 95%CI 0.41–1.49, P = 0.454) or OS (HR 1.17, 95%CI 0.50–2.74, P = 0.727). Furthermore, obesity didn’t impact endocrine therapy effectiveness, neither in Tamoxifen nor aromatase inhibitor group (RFS: interact P = 0.381; OS: interact P = 0.888). Conclusion The impact of obesity on prognosis interacted with luminal subtype status in Chinese breast cancer patients, which was not related with endocrine treatment modality.

scholarly journals Spore Powder ofGanoderma lucidumImproves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Hong Zhao ◽  
Qingyuan Zhang ◽  
Ling Zhao ◽  
Xu Huang ◽  
Jincai Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Ganoderma Lucidum ◽  
Endocrine Treatment ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Cancer Related Fatigue

The fatigue prevalence in breast cancer survivors is high during the endocrine treatment. However, there are few evidence-based interventions to manage this symptom. The aim of this study was to investigate the effectiveness of spore powder ofGanoderma lucidumfor cancer-related fatigue in breast cancer patients undergoing endocrine therapy. Spore powder ofGanoderma lucidumis a kind of Basidiomycete which is a widely used traditional medicine in China. 48 breast cancer patients with cancer-related fatigue undergoing endocrine therapy were randomized into the experimental or control group. FACT-F, HADS, and EORTC QLQ-C30 questionnaires data were collected at baseline and 4 weeks after treatment. The concentrations of TNF-α, IL-6, and liver-kidney functions were measured before and after intervention. The experimental group showed statistically significant improvements in the domains of physical well-being and fatigue subscale after intervention. These patients also reported less anxiety and depression and better quality of life. Immune markers of CRF were significantly lower and no serious adverse effects occurred during the study. This pilot study suggests that spore powder ofGanoderma lucidummay have beneficial effects on cancer-related fatigue and quality of life in breast cancer patients undergoing endocrine therapy without any significant adverse effect.

scholarly journals Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nindo B. Punturi ◽  
Sinem Seker ◽  
Vaishnavi Devarakonda ◽  
Aloran Mazumder ◽  
Rashi Kalra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Protein Trafficking ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Treatment Resistance ◽  
Predictive Marker ◽  
Endocrine Treatment ◽  
Breast Cancer Patients

AbstractResistance to endocrine treatment occurs in ~30% of ER+ breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER+/HER2− patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER+/HER2− breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL- cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER+/HER2− patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER+/HER2− breast cancer patients.

Neuropsychological sequelae of tamoxifen and exemestane after AC-chemotherapy in postmenopausal women with early breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 566-566 ◽  
Author(s):  
C. M. Schilder ◽  
P. C. Eggens ◽  
W. Boogerd ◽  
F. S. van Dam ◽  
S. B. Schagen
Keyword(s):  
Breast Cancer ◽  
Cognitive Functioning ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Cognitive Functions ◽  
Daily Life ◽  
Endocrine Treatment ◽  
Healthy Controls ◽  
Breast Cancer Patients ◽  
Cognitive Complaints

566 Background: Cognitive deficits and cognitive complaints in daily life have been associated with adjuvant chemotherapy in breast cancer survivors. The role of endocrine treatments with respect to these cognitive problems is unclear. Because estrogen deficiency may have adverse effects on certain cognitive functions, it is plausible that endocrine treatments affect cognitive functioning in addition to chemotherapy. The current aim was to investigate whether cognitive functioning of breast cancer patients treated with AC-chemotherapy and endocrine therapy differs from healthy controls and to examine possible distinctive effects between tamoxifen and exemestane. Methods: Postmenopausal breast cancer patients from the TEAM-trial, randomized to receive tamoxifen (n=30) or exemestane (n=51), underwent neuropsychological testing and were interviewed regarding cognitive complaints in daily life 1.5–4 years post AC- chemotherapy. At the time of testing, all patients still received their assigned endocrine treatment. Depression was measured with the Hopkins Symptom Checklist (HSCL), fatigue with the Multidimensional Fatigue Inventory (MFI). Healthy controls (n=48) underwent the same assessment. Results: After controlling for age and IQ, both tamoxifen and exemestane users scored significantly lower on ‘information processing speed’ than healthy controls (Reaction times; p = .023 and p = .008). Tamoxifen users scored significantly lower on ‘mental flexibility’ (Stroop Card 3; p = .007) and ‘category fluency’ (p = .<0001) than healthy controls. A significant higher proportion of both tamoxifen and exemestane users reported memory problems in daily life compared to healthy controls (27.6 and 25.5% versus 6.3%, p = .02). Reported cognitive complaints did not correlate with test scores but with fatigue and depression. Conclusions: These results suggest that endocrine treatments combined with AC-chemotherapy have an effect on certain cognitive functions and provide indications for distinctive cognitive effects of different types of endocrine therapy. No significant financial relationships to disclose.

scholarly journals Clinical Observation and Retrospective Analysis of the Effect of Comprehensive Treatment on Hepatic Hemangiomas in HR Positive Breast Cancer Patients

2021 ◽  
Author(s):  
Linyan Tan ◽  
Manting Hu ◽  
Wenjing Sun ◽  
Saijun Huang ◽  
Yue Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Endocrine Treatment ◽  
Comprehensive Treatment ◽  
Axillary Lymph ◽  
Breast Cancer Patients ◽  
Size Change ◽  
Significant Difference ◽  
Hepatic Hemangiomas

Abstract Objective: To retrospectively assess the size change of hepatic hemangiomas（HH） in hormone receptor positive (HR+) breast cancer patients after comprehensive treatment. Methods: Totally 364 confirmed invasive breast cancer cases with HH were diagnosed at the Breast Cancer Center of Yunnan Cancer Hospital in 2013-2018 by abdominal color Doppler ultrasound (ADUS) + contrast enhanced ultrasound (CEUS) and at least one upper abdominal CT imaging examination. Follow-up was 6-78 months, and changes in location, number and size of HH at different treatment stages were compared between the HR+ and 85 HR- groups. Subgroup analysis of patients receiving chemotherapy and endocrine therapy was also performed. Results: Totally 323 patients were enrolled, including 238 HR+ (73.7%) and 85 HR- (26.3%) cases. Changes in the longest diameter were similar in both groups (P=0.556), and size change of HH was not associated with axillary lymph node metastasis of breast cancer (P>0.05). HH showed no change during chemotherapy but was significantly enlarged after chemotherapy (P<0.01). There was no significant difference between the tamoxifen (TAM; endocrine drug) only and combination or sequential endocrine treatment (P>0.05) groups. Only the aromatase inhibitor group showed statistical significance (P<0.05) in the AI (letrozole, anastrozole and exemestane) group at the t1 time point. Conclusion: During chemotherapy and endocrine therapy for breast cancer patients with HH, the size of HH changes in some patients, while others develop new HH. No significant effect on size change of HH was observed in this study.

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