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ERCC1 Is a Predictor of Anthracycline Resistance and Taxane Sensitivity in Early Stage or Locally Advanced Breast Cancers.

ABSTRACT: Genomic instability could be a beneficial predictor for anthracycline or taxane chemotherapy. We interrogated 188 DNA repair genes in the METABRIC cohort (n = 1980) to identify genes that influence overall survival (OS). We then evaluated the clinicopathological significance of ERCC1 in early stage breast cancer (BC) (mRNA expression (n = 4640) and protein level, n = 1650 (test set), and n = 252 (validation)) and in locally advanced BC (LABC) (mRNA expression, test set (n = 2340) and validation (TOP clinical trial cohort, n = 120); and protein level (n = 120)). In the multivariate model, ERCC1 was independently associated with OS in the METABRIC cohort. In ER+ tumours, low ERCC1 transcript or protein level was associated with increased distant relapse risk (DRR). In ER-tumours, low ERCC1 transcript or protein level was linked to decreased DRR, especially in patients who received anthracycline chemotherapy. In LABC patients who received neoadjuvant anthracycline, low ERCC1 transcript was associated with higher pCR (pathological complete response) and decreased DRR. However, in patients with ER-tumours who received additional neoadjuvant taxane, high ERCC1 transcript was associated with a higher pCR and decreased DRR. High ERCC1 transcript was also linked to decreased DRR in ER+ LABC that received additional neoadjuvant taxane. ERCC1 based stratification is an attractive strategy for breast cancers.

SUBMITTER: Abdel-Fatah TMA

PROVIDER: S-EPMC6721618 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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ERCC1 Is a Predictor of Anthracycline Resistance and Taxane Sensitivity in Early Stage or Locally Advanced Breast Cancers.

Abdel-Fatah Tarek M A TMA Ali Reem R Sadiq Maaz M Moseley Paul M PM Mesquita Katia A KA Ball Graham G Green Andrew R AR Rakha Emad A EA Chan Stephen Y T SYT Madhusudan Srinivasan S

Cancers 20190810 8

Genomic instability could be a beneficial predictor for anthracycline or taxane chemotherapy. We interrogated 188 DNA repair genes in the METABRIC cohort (n = 1980) to identify genes that influence overall survival (OS). We then evaluated the clinicopathological significance of ERCC1 in early stage breast cancer (BC) (mRNA expression (n = 4640) and protein level, n = 1650 (test set), and n = 252 (validation)) and in locally advanced BC (LABC) (mRNA expression, test se ...[more]

PMID: 31405143

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Project description:CONTEXT:Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE:To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN, SETTING, AND PATIENTS:Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. MAIN OUTCOME MEASURES:Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). RESULTS:Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. CONCLUSION:A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Project description:BackgroundChemotherapy is associated with decreased quality of life (QOL), fatigue, depression, and weight gain in patients with breast cancer. Weight gain is associated with poorer prognosis. Yoga improves QOL, fatigue, and mood in women with breast cancer but its effect on treatment-related weight gain has not been studied. The aim of this trial was to determine the feasibility of personalized yoga therapy in women receiving treatment for early-stage or locally advanced breast cancer and assess its impact on weight gain.MethodsThirty women were randomized 1:1 to receive yoga therapy by a certified yoga therapist during treatment or a control group. Participants in the yoga arm were asked to complete three 30 minute yoga sessions weekly (which included movement, breath work, mindfulness, and relaxation) throughout adjuvant or neoadjuvant chemotherapy (N = 29) or endocrine (N = 1); the control arm received breast cancer treatment without yoga. For comparability between participants randomized to yoga therapy, the single patient treated with endocrine therapy was excluded from the analysis. Primary outcomes were feasibility and weight change. Additional outcomes were mood, fatigue, QOL, serum tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) as immune mediator biomarkers.ResultsMean age was 51.6 years, 75.9% were white and 24.1% were people of color, reflecting the cancer center population. 80% had stage II-III disease. Enrollment was completed in 9 months. Compliance was lower than predicted; however, participants participated in on average 1.7 yoga sessions/week for a mean 15.6 weeks duration. There were no adverse events. Control arm participants gained on average 2.63% body weight during treatment while yoga participants lost 0.14% body weight (weight change = -0.36 in yoga arm vs. 2.89 in standard of care arm, Wilcoxon rank sum test P = .024). Control participants reported increased fatigue and decreased QOL, while yoga participants reported no change in QOL. No significant change in TNF-alpha or CRP was noted in either arm.ConclusionThis feasibility study suggests that personalized yoga therapy is beneficial for QOL and weight maintenance among women undergoing chemotherapy for early-stage or locally advanced breast cancer. Weight maintenance associated with yoga therapy may be of clinical significance in this population given the poorer prognosis associated with weight gain in breast cancer survivors.Trial registrationNIH Clinicaltrials.gov #NCT03262831; August 25, 2017. https://clinicaltrials.gov/ct2/show/NCT03262831.

Dataset Information

ERCC1 Is a Predictor of Anthracycline Resistance and Taxane Sensitivity in Early Stage or Locally Advanced Breast Cancers.

Publications

ERCC1 Is a Predictor of Anthracycline Resistance and Taxane Sensitivity in Early Stage or Locally Advanced Breast Cancers.

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