Prognostic and predictive value of estrogen receptor 1 expression in completely resected non-small cell lung cancer

Abstract

Adjuvant chemotherapy (ACT) leads to a modest improvement in survival among patients with completely resected non-small cell lung cancer (NSCLC) but molecular predictors are still rare. Publicly available gene microarray, clinical and follow-up data from two different studies on early-stage NSCLC were used to determine the expression of estrogen receptor 1 (ESR1). Expression values were calculated against clinical and survival data in a training set (n 5 138) and a test set (subpopulation from the adjuvant JBR.10 study) allowing the determination of the prognostic effect of ESR1 in the observational arm as well as the predictive effect of ESR1 regarding ACT. Data were well balanced in terms of ESR1 expression. ESR1 high expression was of significant positive prognostic value in the training set and this could be confirmed in the test set cohort (hazard ratio for overall survival 0.248, 95% confidence interval: 0.088-0.701; p 5 0.008). Additionally, ESR1 low tumors showed a benefit from ACT in terms of 5-year survival (33.3% observation arm and 77.8% ACT arm; p 5 0.003), whereas patients with ESR1 high tumors did not have any benefit from ACT (test of interaction p 5 0.024). ESR1 is an independent positive prognostic factor for survival in early-stage NSCLC patients. Patients with ESR1 high tumors did not benefit from ACT.Non-small cell lung cancer (NSCLC) represents more than 80% of all lung tumors and radical surgery remains the cornerstone of treatment for early stages. However, 30-70% of patients undergoing resection develop recurrence and die of their disease. 1,2Based on the results of several randomized phase III trials and a meta-analysis adjuvant cisplatin-based chemotherapy is now accepted as the standard of care for the management of stage II to IIIA completely resected NSCLC with a modest improvement of 5-year overall survival (OS) ranging from 4 to 15%.2-5 Recently, for three of the studies long-term follow-up results were published. 6-8 Only the JBR.10 study, a North American Intergroup phase III trial of adjuvant cisplatin plus vinorelbine, demonstrated significantly better longterm survival for patients in stage II after a median follow-up of 9.3 years. 7 As chemotherapy is associated with significant early and late toxicity, prognostic and predictive markers of patient's outcome are of utmost importance.Estrogen receptor is the prototype of a predictive biomarker. Its expression, as detected by immunohistochemistry, is used to decide on the adjuvant therapy with tamoxifen or aromatase inhibitors in human breast cancer. Several studies have shown that tumors with high expression of estrogen receptor (ESR) show an improved response to antiestrogens or aromatase inhibitors.9,10 Both ESRs and aromatase, the enzyme that synthesizes 17-b-estradiol, are expressed by lung tumors as well. These findings suggest a role of steroid hormones in their growth control.11 This hypothesis is further supported by results from the Women's Health Initiative Trial.12 In this randomized, double-blind, placebo-controlle...

Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis via cytochrome P450 1B1

“…Therefore, the upregulation of ERα at 26 weeks likely plays a role in lung carcinogenesis. Our data are consistent with a recent report which showed ERα expression in the early stage of NSCLC [29]. Our study further suggests that ERα and CYP1B1 may function together to promote lung carcinogenesis.…”

Prognostic value of estrogen receptors mRNA expression in non-small cell lung cancer: A systematic review and meta-analysis

“…Five of these studies were carried out in Europe and one was conducted in the USA. Four of them took the median levels of ESR1 mRNA expression as cut-off points to differentiate the positive (≥median) and negative (<median) status [12][13][14], the other two studies considered the highest two tertiles as positive and the lowest tertile as negative status [16]. All included ESR1 studies directly reported unadjusted HRs and their 95%CIs, whilst only three of them provided adjusted HRs and their 95% CIs.…”

Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer

“…On the other hand, there were some new studies on RNA expression of ERs in NSCLC [35,36] . Brueckl et al [35] reported that ER-α high expression was of significant positive prognostic value and patients with ER-α high tumors did not have any benefit from adjuvant chemotherapy.…”

“…Brueckl et al [35] reported that ER-α high expression was of significant positive prognostic value and patients with ER-α high tumors did not have any benefit from adjuvant chemotherapy. Atmaca et al [36] demonstrated that ER-α mRNA expression was an independent prognostic factor in metastatic NSCLC.…”