Erlotinib-treated Non-small Cell Lung Cancer Research Articles

EGFR Polymorphism and Survival of NSCLC Patients Treated with TKIs: A Systematic Review and Meta-Analysis.

Tyrosine kinase inhibitor- (TKI-) based therapy revolutionized the overall survival and the quality of life in non-small-cell lung cancer (NSCLC) patients that have epidermal growth factor receptor (EGFR) mutations. However, EGFR is a highly polymorphic and mutation-prone gene, with over 1200 single nucleotide polymorphisms (SNPs). Since the role of EFGR polymorphism on the treatment outcome is still a matter of debate, this research analyzed the available literature data, according to the PRISMA guidelines for meta-analyses. Research includes PubMed, Scopus, ISI Web of Science, and 14 of genome-wide association studies (GWAS) electronic databases in order to provide quantitative assessment of the association between ten investigated EGFR SNPs and the survival of NSCLC patients. The pooled HR and their 95% CI for OS and PFS for different EGFR polymorphisms using a random or fixed effect model based on the calculated heterogeneity between the studies was applied. The longest and the shortest median OSs were reported for the homozygous wild genotype and a variant allele carriers for rs712829 (-216G>T), respectively. Quantitative synthesis in our study shows that out of ten investigated EGFR SNPs (rs11543848, rs11568315, rs11977388, rs2075102, rs2227983, rs2293347, rs4947492, rs712829, rs712830, and rs7809028), only four, namely, rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D), and rs4947492, have been reported to affect the outcome of TKI-based NSCLC treatment. Of these, only -216G>T and variable CA repeat polymorphisms have been confirmed by meta-analysis of available data to significantly affect OS and PFS in gefitinib- or erlotinib-treated NSCLC patients.

The T790M resistance mutation in EGFR is only found in cfDNA from erlotinib-treated NSCLC patients that harbored an activating EGFR mutation before treatment

BackgroundLung cancer patients with an activating mutation in the EGFR (epidermal growth factor receptor) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR. The difficulties in obtaining biopsies at progression make it challenging to investigate the appearance of the T790M mutation at progression in large patient cohorts. We have used cell free DNA (cfDNA) from patients treated with erlotinib to investigate if the development of a T790M mutation coincides with the presence of an activating EGFR mutation in the pre-treatment blood sample.MethodsA cohort of 227 NSCLC (non-small cell lung cancer) adenocarcinoma patients was treated with erlotinib irrespective of EGFR-mutational status. Blood samples were drawn immediately before erlotinib treatment was initiated and again at progression. The cobas® EGFR Mutation Test v2 designed for cfDNA was used to identify 42 EGFR mutations.ResultsOf the 227 NSCLC patients, blood samples were available from 144 patients both before erlotinib treatment and at progression (within 1 month before or after clinical progression). One hundred and twenty-eight of the 144 were wild-type EGFR before treatment, and we demonstrate that the T790M mutation was not present at progression in any of these. In contrast, in the 16 patients with an activating EGFR mutation in the pre-treatment blood sample six patients (38%) were identified with a T790M mutation in the progression blood sample.ConclusionThe T790M resistance mutation is only found in the cfDNA of erlotinib-treated NSCLC patients if they have an activating EGFR mutation before treatment.

18F-FDG PET/CT for Very Early Response Evaluation Predicts CT Response in Erlotinib-Treated Non-Small Cell Lung Cancer Patients: A Comparison of Assessment Methods.

The purpose of this study was to determine which method for early response evaluation with 18F-FDG PET/CT performed most optimally for the prediction of response on a later CT scan in erlotinib-treated non-small cell lung cancer patients. Methods:18F-FDG PET/CT scans were obtained before and after 7-10 d of erlotinib treatment in 50 non-small cell lung cancer patients. The scans were evaluated using a qualitative approach and various semiquantitative methods including percentage change in SUVs, lean body mass-corrected (SUL) SULpeak, SULmax, and total lesion glycolysis (TLG). The PET parameters and their corresponding response categories were compared with the percentage change in the sum of the longest diameter in target lesions and the resulting response categories from a CT scan obtained after 9-11 wk of erlotinib treatment using receiver-operating-characteristic analysis, linear regression, and quadratic-weighted κ. Results: TLG delineation according to the PERCIST showed the strongest correlation to sum of the longest diameter (R = 0.564, P < 0.001), compared with SULmax (R = 0.298, P = 0.039) and SULpeak (R = 0.402, P = 0.005). For predicting progression on CT, receiver-operating-characteristic analysis showed area under the curves between 0.79 and 0.92, with the highest area under the curve of 0.92 (95% confidence interval [CI], 0.84-1.00) found for TLG (PERCIST). Furthermore, the use of a cutoff of 25% change in TLG (PERCIST) for both partial metabolic response and progressive metabolic disease, which is the best predictor of the CT response categories, showed a κ-value of 0.53 (95% CI, 0.31-0.75). This method identifies 41% of the later progressive diseases on CT, with no false-positives. Visual evaluation correctly categorized 50%, with a κ-value of 0.47 (95% CI, 0.24-0.70). Conclusion: TLG (PERCIST) was the optimal predictor of response on later CT scans, outperforming both SULpeak and SULmax The use of TLG (PERCIST) with a 25% cutoff after 1-2 wk of treatment allows us to safely identify 41% of the patients who will not benefit from erlotinib and stop the treatment at this time.

BIM and SHP2 expression levels to predict clinical outcome to EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p).

e19078 Background: EGFR mutations are among the most common driver mutations, responding well, albeit transiently, to EGFR TKIs. We were able to identify high levels of BIM mRNA expression as a predictive marker of response, progression free survival (PFS) and overall survival (OS) in erlotinib-treated NSCLC p. The Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is downstream of both EGFR and several other receptor tyrosine kinases (RTK). SHP2 is required for sustained activation of extracellular signal-regulated kinase (ERK) and BIM downregulation. Methods: We assessed the static levels of BIM and SHP2 mRNA expression, by quantitative real time polymerase chain reaction, and correlated our findings with PFS and OS in 30 EGFR-mutant NSCLC p treated with EGFR TKIs like erlotinib, gefitinib or afatinib. Results: Median age 68; 73.3% female; 73.3% never-smokers; 83.3% adenocarcinoma; 80% erlotinib treated; 66.7% response rate to EGFR TKIs. PFS was 22.3 months (m) for p with intermed...

1662P - MCPH1 (BRIT1) and Outcome to Erlotinib in Non-Small-Cell Lung Cancer (NSCLC) Patients (P) Harboring EGFR Mutations

ABSTRACT Background Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with erlotinib can range from a few months (m) to more than two years, but genetic influences on the duration of response remain unclear. The cytotoxic effect of erlotinib has been related to several proteins that regulate DNA damage response (eg, BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in important molecules involved in DNA damage signaling, including BRCA1, MDC1 and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF chromatin remodeling complex during DNA repair. Methods We used the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts, to analyze the expression of 44 selected genes, many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC p. We identified MCPH1 and correlated expression levels with clinical outcomes. Results p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%), 12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%), 21 with L858R mutation (38.2%). PFS was not reached for patients with high MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with low levels (P = 0.01). Median survival was 31 m for p with high levels, not reached for p with intermediate levels and 17 m for p with low levels (P = 0.004). Conclusions The enhanced effect of erlotinib in the presence of elevated MCPH1 could be due to the fact that MCPH1 can interfere with the function of MDC1 and 53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib response. Disclosure All authors have declared no conflicts of interest.

High mRNA expression of LMO4, a BRCA1 downregulator, correlates with better prognosis in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.

e18137 Background: Advanced NSCLC p with EGFR activating mutations show an impressive progression-free survival (PFS) to erlotinib. The co-existence of the EGFR T790M mutation, in conjunction with high BRCA1 mRNA levels, affected PFS to erlotinib (Rosell et al. CCR 2011). LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers, and CtIP can bind to BRCA1 and LMO4. We have assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP and LMO4 levels on outcome. Methods: mRNA expression of LMO4 and CtIP was examined by RT-PCR in the original pretreatment tumor biopsies of 81 NSCLC p with sensitive EGFR mutations. Results: Expression of BRCA1 and LMO4 was successfully assessed in 55 p: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% never-smokers; 81.8% ECOG PS &lt;2; 80% adenocarcinoma; 14.5% BAC; 4.5% LCC; 94.5% stage IV; 63.6% exon 19 deletion; 36.4% L858R mutation; 36.4% T790M; 83.1% showed clinical benefit to erlotinib (CR/PR/SD). BRCA1 expression was correlated with that of CtIP (r=0.31; P=0.01) and LMO4 (r=0.32; P=0.02). There was no correlation between CtIP and LMO4 (r=0.09; P=0.49). PFS for p with high LMO4 levels was not reached while it was 13 months (m) for p with low levels (P=0.006). Overall survival (OS) was not reached for p with high levels of LMO4 and was 31 m for p with low levels (P=0.17). No differences in PFS or OS were observed according to CtIP levels. When BRCA1 and LMO4 expression was analyzed together, PFS was not reached for p with low BRCA1 and high LMO4 levels and was 19 m for p with low levels of both genes (P=0.04). PFS was 8 m for p with high BRCA1 and low LMO4 levels and 18 m for p with high levels of both genes (P=0.03). In the multivariate analysis, BRCA1 and LMO4 expression emerged as markers of PFS (Table). Conclusions: BRCA1 and LMO4 mRNA expression can predict PFS to erlotinib in p with EGFR mutations and could be useful in the development of new therapeutic strategies. [Table: see text]

MCPH1 (BRIT1) and outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) harboring EGFR mutations.

e18131 Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with erlotinib can range from a few months (m) to more than two years, but genetic influences on the duration of response remain unclear. The cytotoxic effect of erlotinib has been related to several proteins that regulate DNA damage response (eg, BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in important molecules involved in DNA damage signaling, including BRCA1, MDC1 and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF chromatin remodeling complex during DNA repair. Methods: We used the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts, to analyze the expression of 44 selected genes, many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC p. We identified MCPH1 and correlated expression levels with clinical outcomes. Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%), 12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%), 21 with L858R mutation (38.2%). PFS was not reached for patients with high MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with low levels (P=0.01). Median survival was 31 m for p with high levels, not reached for p with intermediate levels and 17 m for p with low levels (P=0.004). Conclusions: The enhanced effect of erlotinib in the presence of elevated MCPH1 could be due to the fact that MCPH1 can interfere with the function of MDC1 and 53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib response.

DAB2 interactive protein (DAB2IP) methylation in serum DNA of non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

7593 Background: DAB2IP loss promotes primary tumor growth by activating Ras and drives metastasis through NFkB, serving as a signaling scaffold to coordinately regulate these pathways. DAB2IP is frequently methylated in lung cancer, and methylation in the m2a region is a key regulatory factor for DAB2IP expression in prostate cancer. We examined DAB2IP methylation in cell lines and in serum from erlotinib-treated NSCLC p with EGFR mutations. Methods: In human lung, breast and colorectal cancer cell lines, we analyzed DAB2IP promoter methylation in regions m2a and m2b by methylation-specific PCR (MSP) and bisulfite genomic sequencing. In circulating serum DNA from 152 erlotinib-treated NSCLC p with EGFR mutations, we analyzed methylation in the m2a and m2b promoter regions of DAB2IP by MSP. Methylation status was correlated with clinical outcome. Results: Methylation was detected in the m2a region of 42 (27.63%) p, and in the m2b region in 51 (33.55%) p. There were no major differences in clinical characteristics (age, gender, smoking history, EGFR mutation type, metastatic sites) between p with methylation in the m2a region and p with methylation in the m2b region. Overall progression-free survival (PFS) was 15 months (m), and median survival (MS) 28 m for all 152 p. For the 41 p with bone metastases (mets), PFS was 14 m for 30 p without methylation in the m2a region vs 8 m for 11 p with methylation in the m2a region (P=0.01), and MS was 23 m vs 10 m, respectively (P=0.19). For the 57 p with distant mets but no lung mets, PFS was 18 m for 36 p without methylation in the m2a region vs 10 m for 21 p with methylation in the m2a region (P=0.01), and MS was 24 m vs 16 m, respectively (P=0.03). No differences in either PFS or MS were observed according to the methylation status of the m2b region. Conclusions: Methylation in the m2a region of DAB2IP in serum DNA correlates with PFS and MS to erlotinib in NSCLC p with EGFR mutations with non-lung mets. Surveillance of DAB2IP methylation status in circulating DNA could be a useful tool to predict outcome to erlotinib in EGFR-mutated NSCLC p with non-lung mets.

Mutations of the catalytic subunit a of PI3K (PIK3CA) in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations.

7588 Background: Stage IV NSCLC p with EGFR mutations treated with erlotinib had a median progression-free survival (PFS) of 14 months (m) and median survival (MS) of 27 m in our experience. However, EGFR mutations can only imperfectly predict outcome. PIK3CA mutations occur in several tumors and have prognostic and therapeutic implications. We examined the presence and potential influence of PIK3CA mutations on outcome to erlotinib in NSCLC p with EGFR mutations. Methods: PIK3CA mutation status was assessed in pretreatment paraffin-embedded tumor samples from 118 advanced NSCLC p with EGFR mutations treated with erlotinib. E542K, E545K and H1047R mutations were screened by 5’-nuclease PCR (Taqman) assay and confirmed by standard PCR followed by sequencing. Results: PIK3CA mutations were detected in 6 of 118 patients (5.1%). 84% of p with PIK3CA mutations had adenocarcinomas vs 50% of p with wild-type (wt) PIK3CA (P=0.01). Response rate was 50% for p with mutations vs 70% for p with wt PIK3CA (P=0.03). There were no other differences between p with and without PIK3CA mutations. 2 of the 6 p with PIK3CA mutations had the uncommon L861Q mutation in exon 21 of EGFR. 1 of the 6 p had complete response; 2 had partial response; 3 had progressive disease. There was a non-significant trend towards shorter PFS for the 6 p with PIK3CA mutations (9 vs 16 m; P=0.59). MS was not reached for the 6 p with PIK3CA mutations, while it was 29 m for p with wt PIK3CA (P=0.09). Conclusions: PIK3CA mutations can be present in some EGFR-mutant NSCLC p, with lower response and a trend towards shorter PFS. Treatment with EGFR tyrosine kinase inhibitors plus PIK3CA inhibitors should be tested in this small subset of p with double mutations.

Highlights of This Issue

FK506-binding proteins play important roles in cancer progression. Here, Valentine and coworkers found that a secreted member of the FK506 binding protein family, FKBPL, and a potent peptide derivative, AD-01, act as highly effective inhibitors of angiogenesis in vitro and in vivo. Systemic delivery of AD-01 to tumor-bearing mice greatly reduced tumor vascularization (visualized by intravital microscopy) and effectively inhibited tumor growth. They found that AD-01 acted through a CD44-dependent mechanism to prevent migration of endothelial cells, without affecting proliferation. These findings may open a new approach to antiangiogenic therapy in cancer.CLDN4, a cell tight junction protein, is highly expressed in most ovarian cancers, but is expressed at low levels in normal tissues. Here, Gao and colleagues used the noncytotoxic small molecule C-CPE as a CLDN4- targeted delivery vehicle to selectively open cellular tight junctions and potentiate chemotherapy delivery into ovarian cancer cells. C-CPE sensitized CLDN4-expressing tumor xenografts to low-dose Taxol and suppressed tumor growth without inducing overt toxicity in animals. Further, this treatment was highly specific to CLDN4-positive ovarian cancer cells vs. CLDN4-negative cancer cells or nonneoplastic cells. This therapeutic strategy may have important implications for enhancing efficacy of conventional chemotherapy.EGFR-sensitive mutations predict improved outcome to erlotinib, but the T790M mutation can shorten the duration of response. Here, Rosell and colleagues identified a concomitant EGFR T790M mutation in a high proportion of pretreatment samples from erlotinib-treated nonsmall cell lung cancer patients. They found that, if BRCA1 mRNA expression was low, the T790M mutation did not hamper the effect of erlotinib. However, progression-free survival was significantly shorter in patients with both the T790M mutation and higher levels of BRCA1. These results suggest that initial analysis of the EGFR T790M mutation and BRCA1 mRNA expression could help predict outcome to erlotinib.Efficient predictive biomarkers are needed to enhance the responsiveness and cost-effectiveness of targeted chemotherapy. In this issue, Kim and coworkers describe a novel three-step approach of genome-wide screening, clinical association, and biological validation to identify SNP markers. Using this approach, they identified two candidate markers, LIFR rs3729740 and possibly ISX rs361863, that may help improve the prediction of metastatic colorectal cancer sensitivity to cetuximab regimens. The approach presented here could reduce the cost and time involved in conventional genome-wide association studies, and could be applied to the discovery of chemosensitive markers for new regimens.

Expression of MET, IGF-1R, IL-6/gp130, and AXL in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.

7555 Background: We have observed a 70% response rate (RR) in NSCLC p with EGFR mutations treated with erlotinib. Primary resistance to erlotinib could result from the absence of an EGFR-organized network. Crosstalk and transactivation between other receptor tyrosine kinases, such as EGFR, IGF-1R and MET, is recognized as a mechanism of growth in several tumors. Mutant EGFR could activate the IL-6/gp130 pathway. Overexpression of AXL has been observed in NSCLC and in GIST imatinib-resistant tumors. Methods: The expression of MET, IGF-1R, IL-6/gp130 and AXL was examined by QPCR in the original pretreatment tumor biopsies of 98 NSCLC p with EGFR mutations. Expression levels by terciles were correlated with outcome to erlotinib. Results: There was a good correlation between the expression of IL-6/gp130 and AXL (r = 0.33; p = 0.001). No differences were observed in expression of the four genes according to gender, smoking history, type of EGFR mutation, or other clinical characteristics. The highest tercile of AXL expression was associated with a higher incidence of lung metastases (87.5%; p = 0.02). No other association between any of the genes and metastatic sites (including brain and bone) was observed. Overall RR was 70%, progression-free survival (PFS) was 14 months (m), and median survival (MS) was 27 m. No differences in RR, PFS or MS were observed according to the expression of any of the four genes. Conclusions: The coactivation of other receptor tyrosine kinases seems not to affect the initial outcome to erlotinib in NSCLC p with EGFR mutations. The association of high levels of AXL with lung metastases should be further examined, since AXL expression has been correlated with metastasis to the lung in a breast cancer model. The addition of AXL inhibition could be a novel treatment approach for enhancing the effect of erlotinib in p with EGFR mutations. No significant financial relationships to disclose.

MRNA expression of protein phosphatase 2A/C (PP2A/C) in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.

e18037 Background: EGFR mutations can influence double-strand break (DSB) repair due to impairment of DNA-PKcs/Ku complexes. PP2A enhances Ku and DNA-PK activities, accelerating DSB repair. In addi...

Survivin and CrkL expression in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.

e18063 Background: Survivin inhibits activation of caspas es, and its overexpr ession can lead to resistance to apoptotic stimuli. Enhanced survivin expression has been shown to be related to IGF-1R activity. CrkL is a 39-kDa tyrosine-phosphorylated adaptor protein that is involved in leukemia cell signalling and is an important substrate of Bcr-Abl. Methods: Survivin and CrkL protein expression were ass essed by immunohistochemical (IHC) staining in original pretreatment tumor biopsies of 126 NSCLC p with EGFR mutations, in whom IGF-1R expr ession had previously been examined. IHC was evaluated semiquantitatively and scored according to the percentage of cells showing distinct nuclear and/or cytoplasmic reaction and the intensity of IHC. Tumors with a score of 0 or 1 were defined as negative and those with a score of 2 or 3 were defined as positive. IHC intensity was correlated with outcome to erlotinib. Results: There was no correlation between the expression of survivin and CrkL (p = 0.16). A correlation was observed between survivin and IGF-1R mRNA levels (r = 0.12; p = 0.005). No differences were observed in the expression of the two proteins according to gender, smoking history, PS, type of EGFR mutation, metastatic site, or other clinical characteristics. Overall response rate (RR) was 70%, progr ession-free survival (PFS) was 14 months (m), and median survival (MS) was 27 m. No differenc es in RR were observed according to the expression of either of the proteins. PFS for the 17 p with negative survivin was 24 m vs 14 m for 109 p with positive survivin (p = 0.11). MS was 36 m for p with negative survivin and 27 m for those with positive survivin (p = 0.004). No differences in PFS or MS were observed according to CrkL expr ession. Conclusions: Negative survivin protein expression is observed in a small number of patients with EGFR mutations and confers improved survival. No significant financial relationships to disclose.

Outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) according to the presence of the EGFR T790M mutation and BRCA1 mRNA expression levels in pretreatment biopsies.

7514 Background: The initial pr esence of double EGFR mutations (L858R or exon 19 deletion plus T790M) has been detected in the absence of drug selection and could explain the selection of the T790M mutation as the single drug-resistance mutation during therapy with gefitinib or erlotinib. Experimental evidence shows that the disruption of BRCA1 enhances erlotinib-mediated cytotoxicity. Methods: Pretreatment biopsi es from129 erlotinib-treated NSCLC p with EGFR mutations were re- examined for the presence of the T790M mutation using laser microdissection followed by TaqMan assay in the pr esence of a peptide-nucleic acid clamp. BRCA1 mRNA expression was examined by quantitative PCR. Results: Double mutations were found in 45 p (35%), with no differences between p with and those without T790M in characteristics or initial r esponse to erlotinib (63.6% vs 72.3%, respectively). Median progression-free survival (PFS) was 12 months (m) in p with T790M and 18 m in p without T790M (p = 0.05). PFS was 27 m in p with low BRCA1, 18 m in p with intermediate BRCA1 and 10 m in p with high BRCA1. PFS was also 27 m for p with T790M and low BRCA1, while it dropped to 3 m for p with T790M and intermediate or high BRCA1. The multivariate analysis showed an association between poor PFS and T790M (HR, 3.96; p = 0.001), male sex (HR, 3.18; p = 0.01), brain metastases (HR, 4.55; p = 0.006), intermediate BRCA1 (HR, 4.36; p = 0.008), and high BRCA1 (HR, 5.81; p = 0.001). Conclusions: The high frequency of pretreatment double mutations concurs with a previous report (Mah eswaran et al. NEJM 2008). The strong influence of T790M and BRCA1 levels on erlotinib outcome can lead to novel personalized treatment strategies. No significant financial relationships to disclose.

Wood-Smoke Exposure as a Response and Survival Predictor in Erlotinib-treated Non-small Cell Lung Cancer Patients: An Open Label Phase II Study

Erlotinib, a tyrosine kinase inhibitor, has improved survival and quality of life in patients with non-small cell lung cancer (NSCLC) after first- or second-line chemotherapy. Asian origin, adenocarcinoma histology, female gender, lack of tobacco use, and expression of epidermal growth factor receptor are significant independent predictors of response to Erlotinib. Although tobacco use is considered a major cause of NSCLC, other risk factors such as wood-smoke exposure (WSE) are associated. Almost 3 billion people worldwide rely on solid fuels as their primary source of domestic energy for cooking and heating. In this study, 150 consecutive unselected patients with histologically proven NSCLC with progression after prior first- or second-line chemotherapy and/or poor performance status were treated with Erlotinib 150 mg/d. Clinical and pathologic characteristics were associated with response. Overall response to Erlotinib was observed in 51 patients [34%; 95% confidence interval {95% CI}, 29.9-37.6]. In multivariate analysis, clinical features associated with response to Erlotinib were adenocarcinoma (35 versus 20%; p = 0.05) and WSE (83 versus 13%; p < 0.001). Factors associated with longer progression-free survival in Cox analysis included adenocarcinoma (7.9 versus 2.3 months; p = 0.009), female gender (8.4 versus 5.3 months; p = 0.04), and WSE (17.6 versus 5.3 months; p = 0.006). WSE is associated with better response to Erlotinib and improved progression-free survival in patients with NSCLC. Additional studies in epidermal growth factor receptor signaling pathway in WSE-associated NSCLC are warranted.