Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib

Satouchi, Miyako; Negoro, Shunichi; Funada, Yasuhiro; Urata, Yoshiko; Shimada, Temiko; Yoshimura, Sho; Kotani, Yoshikazu; Sakuma, Takashi; Watanabe, Hiroshi; Adachi, Shuji; Takada, Yoshiki; Yatabe, Yasushi; Mitsudomi, Tetsuya

doi:10.1038/sj.bjc.6603710

Cited by 40 publications

(41 citation statements)

References 29 publications

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“…The incidence of EGFR mutations in this study (15%) was consistent with Western (13) and other Korean data (11,12), although lower than that reported in the previous studies from Taiwan and Japan (14,15). Our result should be interpreted with caution because it represents only a small group of patients with advanced NSCLC, and the patients had unfavorable clinical characteristic.…”

Section: Discussionsupporting

confidence: 78%

Epidermal growth factor-receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung

Hong¹,

Kim²,

Park³

et al. 2008

JCO

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Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.

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Section: Discussionsupporting

confidence: 78%

Epidermal growth factor-receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung

Hong¹,

Kim²,

Park³

et al. 2008

JCO

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“…(4,(10)(11)(12)20,22,24,26,27,(32)(33)(34)(35)(36) The prevalence of EGFR mutations in our Japanese cohort was low (18%) compared with values determined previously for East Asian populations. Given that most previous studies examined only individuals treated with EGFR TKI, patient selection based on clinical predictors might have led to an increase in the proportion of subjects with adenocarcinoma histology, a factor known to be associated with EGFR mutations.…”

Section: Discussionmentioning

confidence: 88%

Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non‐small cell lung cancer

et al. 2008

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Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC. (Cancer Sci 2008; 99: 2455-2460) T he epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family and has been implicated in the proliferation and survival of cancer cells. Aberrant expression of EGFR has been detected in many human epithelial malignancies, including non-small cell lung cancer (NSCLC).(1,2) This receptor has therefore been identified as a promising target for anticancer therapy, and several agents have been synthesized that inhibit its tyrosine kinase activity. EGFR tyrosine kinase inhibitors (TKI) have been evaluated most extensively in individuals with NSCLC, and they have had a substantial impact on the treatment of this disease by offering additional therapeutic options for patients with advanced NSCLC. (3)(4)(5)(6) Somatic mutations in the tyrosine kinase domain of EGFR have been detected in a subset of NSCLC patients who respond to EGFR TKI (7)(8)(9) and have been shown to be closely associated with sensitivity to these drugs.(10-14) Indeed, we and others have prospectively demonstrated a high response rate to EGFR TKI therapy in NSCLC patients with EGFR mutations. (15)(16)(17)(18)(19)(20)(21) An increased copy number of the EGFR gene, as revealed by fluorescence in situ hybridization (FISH), has also emerged as an effective molecular marker of EGFR TKI sensitivity in NSCLC. (22)(23)(24) We previously showed that EGFR mutation and EGFR amplification are associated in human NSCLC cell lines and that endogenous EGFR expressed in such cell lines positive for both of these EGFR alterations are activated constitutively.(25) However, the relationship between EGFR mutation and FI...

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“…Two well conducted retrospective reports from the Dana-Farber/Harvard Cancer Center (DF/HCC) [52] and the Memorial Sloan-Kettering Cancer Center [53] combining 32 (22 exon 19 deletions, and 10 L858R) and 34 patients (23 exon 19 deletions, and 11 L858R), respectively, indicated that the response rates, progression-free and overall survival of gefitinib or erlotinib treated individuals was superior in exon 19 deletions than the L858R mutation patients [52,53]. Two retrospective East Asian cohorts did not show significant differences in survival between the gefitinib-treated L858R and exon 19 deletions [25,28,50], and a recent Japanese retrospective report actually described an improved survival for L858R-bearing patients after gefitinib therapy [54].…”

Section: Discussionmentioning

confidence: 99%

Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers

et al. 2007

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Purpose-Epidermal growth factor receptor (EGFR) mutations have been found in the majority of gefitinib-responsive non-small cell lung cancer (NSCLC) patients from retrospective studies. We sought to compile the available phase II and prospective trials of this EGFR tyrosine kinase inhibitor (TKI) to better understand the efficacy and safety of selecting patients to receive gefitinib based on their genotype.Design-We searched published trials involving EGFR-mutant patients and gefitinib. Five reports were identified (published between June 2006 and April 2007) in which gefitinib was given in a prospective manner to EGFR mutation positive patients at a dose of 250 mg a day. Responses were determined by RECIST and toxicities by NCI-CTC.Results-A total of 101 patients were pooled from these studies. 59 received gefitinib as their first line of therapy and 42 after having received chemotherapy. The combined rate of complete and partial response (CR+PR) in the 99 measured patients was 80.8% (80/99) and only 7.1% (7/99) had progressive disease as best response. The response rate (CR+PR) for exon 19 deletion and L858R patients were 80.3% (53/66) and 81.8% (27/33), respectively. The median progression-free survival ranged from 7.7 to 12.9 months. Overall survival had not been reached in 4/5 reports and was 15.4 months in one of them. Gefitinib administration was safe (<50% of patients developed grade 1-2 skin rash or diarrhea) and interstitial lung disease was only reported in 2 patients (2%), without deaths.Conclusions-Gefitinib monotherapy leads to objective responses in most patients with EGFR mutations. Both L858R and deletion 19 mutations derived similar clinical benefits. Small molecule TKIs are the new treatment paradigm for EGFR-mutant NSCLC.

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Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib

Cited by 40 publications

References 29 publications

Epidermal growth factor-receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung

Epidermal growth factor-receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung

Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non‐small cell lung cancer

Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers

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