EGFR-mutant Adenocarcinoma Research Articles

Review: Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat®, Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy.

Quality of life in advanced non-small cell lung cancer patients receiving first-line gefitinib monotherapy

9614 Background: Gefitinib is a potential first-line treatment option for patients with advanced non-small cell lung cancer (NSCLC), especially for patients with activating mutations in the EGFR gene. However, little is known about patient-reported health-related quality of life (HRQOL) in this patient population. The aims of this study were to explore the prognostic values of baseline HRQOL for time-to-treatment failure (TTF), as well as the predictors of repeatedly measured posttreatment HRQOL, in advanced NSCLC patients receiving first-line gefitinib. Methods: A total of 106 chemonaive patients with advanced NSCLC were enrolled in a phase II trial. Gefitinib was given at a dose of 250 mg/d. HRQOL was assessed monthly with the EuroQoL instrument (EQ-5D) and the Lung Cancer Symptom Scale (LCSS) questionnaire. Baseline HRQOL and clinical/molecular predictors of TTF were jointly examined by multiple Cox's proportional hazards model. The associations between the clinical/molecular factors and repeatedly measured posttreatment HRQOL were analyzed by fitting marginal linear regression model using the generalized estimating equations (GEE) method. Results: In this prospective study, HRQOL data were obtained from 94 patients. Baseline EQ-5D index (estimated hazard ratio = 0.286, 95% C.I.: 0.135–0.603, p = 0.001) and the presence of L858R EGFR mutation in adenocarcinoma (estimated hazard ratio = 0.520, 95% C.I.: 0.307–0.880, p = 0.015) were retained as independent prognostic factors in the final multiple Cox's proportional hazards model for TTF. According to preliminary GEE analysis of repeatedly measured posttreatment HRQOL, the patients with wild-type EGFR consistently had worse HRQOL in EQ-5D index (p < 0.0001), EQ-5D VAS score (p = 0.0002), and LCSS global score (p < 0.0001), respectively. Conclusions: In advanced NSCLC patients receiving first-line gefitinib, better baseline EQ-5D index and L858R EGFR mutation in adenocarcinoma predict longer TTF. In addition, patients with wild-type EGFR had worse posttreatment HRQOL. No significant financial relationships to disclose.

Significant association between EGFR-mutated lung adenocarcinoma and past illness from gastric cancer or uterine myoma: Its implication in carcinogenesis

The present study investigated the potential difference between EGFR-mutated lung adenocarcinoma (ADC) and KRAS-mutated ADC in relation to past illness and family history. Among the 153 tumors examined, 33 (21.6%) were EGFR-mutated, and 22 (14.4%) were KRAS-mutated. The EGFR-mutated cases showed a significantly higher prevalence of past illness involving the gastric cancer in males (EGFR 3/8 (37.5%), KRAS 0/13 (0.0%), no mutation (NONE) 1/57 (1.8%); Fisher's exact test, P = 0.0064) or uterine myoma in females (EGFR 8/25 (32.0%), KRAS 0/9 (0.0%), NONE 3/41 (7.3%); Fisher's exact test, P = 0.0139). No association between the mutations and family history was found. The EGFR-mutated ADC is therefore likely to develop through a distinct carcinogenetic pathway from the others, but genetic backgrounds seemed unlikely to be determinant predisposing to the EGFR-mutated ADC.

Epidermal Growth Factor Receptor Abnormalities in the Pathogenesis and Progression of Lung Adenocarcinomas

To identify the characteristics and sequence of epidermal growth factor receptor (EGFR) abnormalities relevant to the pathogenesis and progression of lung adenocarcinoma, we performed a precise mapping analysis of EGFR mutation, gene copy number, and total and phosphorylated EGFR protein expression for the same tissue sites. We examined normal bronchial and bronchiolar epithelium (NBE) and tumor tissues obtained from 50 formalin-fixed lung adenocarcinomas, including 24 EGFR-mutant primary tumors with nine corresponding lymph node metastases and 26 wild-type primary tumors. NBE in 12 of 24 (50%) mutant and 3 of 26 (12%) wild-type tumors harbored EGFR mutations; these NBE also showed a lack of EGFR copy number increase and frequent EGFR (69%) and phosphorylated EGFR (33%) overexpression. EGFR mutation and protein overexpression were more frequent in NBE sites within tumors than in NBE sites adjacent to and distant from tumors, suggesting a localized field effect. Sites with high and low EGFR copy numbers were heterogeneously distributed in six of nine primary tumors and in one of eight metastases. EGFR protein overexpression was significantly higher in metastasis sites than in primary tumors. We conclude from our findings that EGFR mutations and protein overexpression are early phenomena in the pathogenesis of lung adenocarcinoma and that EGFR mutation precedes an increase in gene copy number. In EGFR-mutant adenocarcinoma metastases, the higher levels of EGFR overexpression and more homogeneously distributed high gene copy numbers suggest tumor progression. Our findings have important implications for the development of new strategies for targeted chemoprevention and therapy in lung adenocarcinoma using EGFR inhibitors.

EGFR Tyrosine Kinase Domain Mutations Are Detected in Histologically Normal Respiratory Epithelium in Lung Cancer Patients

To determine whether EGFR tyrosine kinase domain mutations are early events in the pathogenesis of lung adenocarcinomas, we tested for the presence of EGFR mutations in histologically normal bronchial and bronchiolar epithelia from lung adenocarcinomas bearing the common EGFR mutations. DNA was extracted from microdissected tissue obtained from 21 tumors with known EGFR mutations, 16 tumors without mutation, and 90 sites of normal bronchial and bronchiolar epithelium from the same surgical specimens. With the use of PCR and direct DNA sequencing, EGFR mutations identical to the tumors were detected in the normal respiratory epithelium in 9 of 21 (43%) patients with EGFR mutant adenocarcinomas but none in patients without mutation in the tumors. The finding of mutations being more frequent in normal epithelium within tumor (43%) than in adjacent sites (24%) suggests a localized field effect phenomenon. Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.

EGFR Mutation Is Specific for Terminal Respiratory Unit Type Adenocarcinoma

We have previously reported that terminal-respiratory-unit (TRU) type adenocarcinoma is a distinct subset of lung adenocarcinoma in terms of molecular pathway for carcinogenesis and phenotypic profiles. This type of cancer shows TRU features, characterized by distinct cellular morphology and the expression of TTF-1 and surfactant proteins. Recently, two groups published novel mutations of the epidermal growth factor receptor (EGFR) that are closely associated with clinical response to gefitinib. The clinicopathologic features of gefitinib responders overlap with those of TRU-type adenocarcinoma, and the characteristics of TRU are likely to correspond to the bronchioloalveolar features reported as a predictor of gefitinib response. We therefore examined the characteristics of EGFR-mutated pulmonary adenocarcinomas with special reference to TRU-type adenocarcinoma. EGFR mutation was detected in 97 of 195 adenocarcinomas, 91 of 149 TRU-type adenocarcinomas and 6 of 46 tumors of other types. Conversely, 91 of 97 EGFR-mutated adenocarcinomas were categorized as TRU-type adenocarcinomas. This type-specific involvement was confirmed by logistic regression model. In addition, EGFR mutation was detected in some cases of atypical adenomatous hyperplasia, a preinvasive lesion of TRU-type adenocarcinoma. These findings further confirm that TRU-type-adenocarcinoma is a distinct adenocarcinoma subset in which a particular molecular pathway is involved.