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1.  Common genetic variants in cell cycle pathway are associated with survival in stage III–IV non-small-cell lung cancer 
Carcinogenesis  2011;32(12):1867-1871.
Cell cycle progression contributes to the cellular response to DNA-damaging factors, such as chemotherapy and radiation. We hypothesized that the genetic variations in cell cycle pathway genes may modulate treatment responses and affect survival in patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 374 single-nucleotide polymorphisms (SNPs) from 49 cell cycle-related genes in 598 patients with stages III–IV NSCLC treated with first-line platinum-based chemotherapy with/without radiation. We analyzed the individual and combined associations of these SNPs with survival and evaluated their gene–gene interactions using survival tree analysis. In the analysis of survival in all the patients, 39 SNPs reached nominal significance (P < 0.05) and 4 SNPs were significant at P <0.01. However, none of these SNPs remained significant after correction for multiple comparisons at a false discovery rate of 10%. In stratified analysis by treatment modality, after adjusting for multiple comparisons, nine SNPs in chemotherapy alone and one SNP in chemoradiation remained significant. The most significant SNP in chemotherapy group was CCNB2:rs1486878 [hazard ratio (HR) = 1.69, 95% confidence interval (CI), 1.25–2.30, P = 0.001]. TP73: rs3765701 was the only significant SNP in chemoradiation group (HR = 1.87; 95% CI = 1.35–2.59, P = 1.8 × 10−4). In cumulative analysis, we found a significant gene-dosage effect in patients receiving chemotherapy alone. Survival tree analysis demonstrated potential higher order gene–gene and gene–treatment interactions, which could be used to predict survival status based on distinct genetic signatures. These results suggest that genetic variations in cell cycle pathway genes may affect the survival of patients with stages III–IV NSCLC individually and jointly.
doi:10.1093/carcin/bgr217
PMCID: PMC3220611  PMID: 21965272
2.  Optimal chemotherapy treatment for women with recurrent ovarian cancer 
Current Oncology  2007;14(5):195-208.
Question
What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy?
Perspectives
Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy.
Outcomes
Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada.
Results
Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer.
In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials.
In eight of the thirteen trials in which 35%–100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038; hazard ratio: 1.23; 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001).
Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.
Practice Guideline
Target Population
This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy. As a general categorization within what is actually a continuum, “platinum sensitivity” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy, and “platinum resistance” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped. “Platinum-refractory disease” refers to a lack of response or to progression while on platinum-based chemotherapy.
Recommendations
Although the body of evidence that informs the clinical recommendations is based on randomized trial data, those data are incomplete. Based on the available data and expert consensus opinion, the Gynecology Cancer dsg makes these recommendations:
Systemic therapy for recurrent ovarian cancer is not curative. It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. All suitable patients should be offered the opportunity to participate in randomized trials, if available.
In the absence of contraindications, combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy. As compared with carboplatin alone, the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival.
If combination platinum-based chemotherapy is not indicated, then a single platinum agent should be considered. Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile.
If a single platinum agent is not being considered, then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin are seen as reasonable treatment options.
Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy.
For patients with platinum-refractory or platinum-resistant disease, the goals of treatment should be to improve quality of life by extending the symptom-free interval, by reducing symptom intensity, and by increasing progression-free interval, and, if possible, to prolong life.
With non-platinum agents, monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options.
No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence. Many treatment options have shown modest response rates, but their benefits over best supportive care have not been studied in clinical trials.
PMCID: PMC2002482  PMID: 17938703
Chemotherapy; drug therapy; ovarian cancer; ovarian neoplasms; practice guideline; systematic review
3.  Genetic Variations in Multiple Drug Action Pathways and Survival in Advanced-Stage Non-small Cell Lung Cancer Treated with Chemotherapy 
Purpose
Variations in genes related to anticancer drugs' biologic activity could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, i.e., glutathione metabolism, DNA repair, cell cycle, and EGFR, were systematically investigated to examine their association with survival in advanced-stage NSCLC treated with chemotherapy.
Experimental Design
A total of 894 tagging single-nucleotide polymorphisms (tagSNPs) in 70 genes from the four pathways were genotyped and analyzed in a 1076-patient cohort. Association with overall survival was analyzed at single-SNP and whole-gene levels within all patients and major chemotherapy agent combination groups.
Results
A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway) (HR=1.45, 95% CI=1.20–1.70 and HR=1.25, 95% CI=1.05–1.50, respectively). In stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by MAP3K1 variant (HR=1.38, 95% CI =1.11–1.72) and a protective effect by RAF1 (HR=0.64, 95% CI=0.5–0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR=0.54, 95% CI=0.38–0.77; HR=0.67, 95% CI=0.52–0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR=1.91, 95% CI=1.30–2.80; HR=1.83, 95% CI=1.27–2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis.
Conclusion
Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced-stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations.
doi:10.1158/1078-0432.CCR-10-2877
PMCID: PMC3124814  PMID: 21636554
non-small cell lung cancer; survival; single-nucleotide polymorphisms; pathway; chemotherapy
4.  Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.
Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.
The following reports can be publicly accessed at the MAS website at: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer: An Evidence-Based Analysis
Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis
Objective
The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa®) or erlotinib (Tarceva®) in patients with advanced non-small cell lung cancer (NSCLC).
Clinical Need: Target Population and Condition
With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer deaths in Ontario. Those with unresectable or advanced disease are commonly treated with concurrent chemoradiation or platinum-based combination chemotherapy. Although response rates to cytotoxic chemotherapy for advanced NSCLC are approximately 30 to 40%, all patients eventually develop resistance and have a median survival of only 8 to 10 months. Treatment for refractory or relapsed disease includes single-agent treatment with docetaxel, pemetrexed or EGFR-targeting TKIs (gefitinib, erlotinib). TKIs disrupt EGFR signaling by competing with adenosine triphosphate (ATP) for the binding sites at the tyrosine kinase (TK) domain, thus inhibiting the phosphorylation and activation of EGFRs and the downstream signaling network. Gefitinib and erlotinib have been shown to be either non-inferior or superior to chemotherapy in the first- or second-line setting (gefitinib), or superior to placebo in the second- or third-line setting (erlotinib).
Certain patient characteristics (adenocarcinoma, non-smoking history, Asian ethnicity, female gender) predict for better survival benefit and response to therapy with TKIs. In addition, the current body of evidence shows that somatic mutations in the EGFR gene are the most robust biomarkers for EGFR-targeting therapy selection. Drugs used in this therapy, however, can be costly, up to C$ 2000 to C$ 3000 per month, and they have only approximately a 10% chance of benefiting unselected patients. For these reasons, the predictive value of EGFR mutation testing for TKIs in patients with advanced NSCLC needs to be determined.
The Technology: EGFR mutation testing
The EGFR gene sequencing by polymerase chain reaction (PCR) assays is the most widely used method for EGFR mutation testing. PCR assays can be performed at pathology laboratories across Ontario. According to experts in the province, sequencing is not currently done in Ontario due to lack of adequate measurement sensitivity. A variety of new methods have been introduced to increase the measurement sensitivity of the mutation assay. Some technologies such as single-stranded conformational polymorphism, denaturing high-performance liquid chromatography, and high-resolution melting analysis have the advantage of facilitating rapid mutation screening of large numbers of samples with high measurement sensitivity but require direct sequencing to confirm the identity of the detected mutations. Other techniques have been developed for the simple, but highly sensitive detection of specific EGFR mutations, such as the amplification refractory mutations system (ARMS) and the peptide nucleic acid-locked PCR clamping. Others selectively digest wild-type DNA templates with restriction endonucleases to enrich mutant alleles by PCR. Experts in the province of Ontario have commented that currently PCR fragment analysis for deletion and point mutation conducts in Ontario, with measurement sensitivity of 1% to 5%.
Research Questions
In patients with locally-advanced or metastatic NSCLC, what is the clinical effectiveness of EGFR mutation testing for prediction of response to treatment with TKIs (gefitinib, erlotinib) in terms of progression-free survival (PFS), objective response rates (ORR), overall survival (OS), and quality of life (QoL)?
What is the impact of EGFR mutation testing on overall clinical decision-making for patients with advanced or metastatic NSCLC?
What is the cost-effectiveness of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the first-line setting?
What is the budget impact of EGFR mutation testing in selecting patients with advanced NSCLC for treatment with gefitinib or erlotinib in the second- or third-line setting?
Methods
A literature search was performed on March 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2004 until February 28, 2010 using the following terms:
Non-Small-Cell Lung Carcinoma
Epidermal Growth Factor Receptor
An automatic literature update program also extracted all papers published from February 2010 until August 2010. Abstracts were reviewed by a single reviewer and for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists, until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
The inclusion criteria were as follows:
Population: patients with locally advanced or metastatic NSCLC (stage IIIB or IV)
Procedure: EGFR mutation testing before treatment with gefitinib or erlotinib
Language: publication in English
Published health technology assessments, guidelines, and peer-reviewed literature (abstracts, full text, conference abstract)
Outcomes: progression-free survival (PFS), Objective response rate (ORR), overall survival (OS), quality of life (QoL).
The exclusion criteria were as follows:
Studies lacking outcomes specific to those of interest
Studies focused on erlotinib maintenance therapy
Studies focused on gefitinib or erlotinib use in combination with cytotoxic agents or any other drug
Grey literature, where relevant, was also reviewed.
Outcomes of Interest
PFS
ORR determined by means of the Response Evaluation Criteria in Solid Tumours (RECIST)
OS
QoL
Quality of Evidence
The quality of the Phase II trials and observational studies was based on the method of subject recruitment and sampling, possibility of selection bias, and generalizability to the source population. The overall quality of evidence was assessed as high, moderate, low or very low according to the GRADE Working Group criteria.
Summary of Findings
Since the last published health technology assessment by Blue Cross Blue Shield Association in 2007 there have been a number of phase III trials which provide evidence of predictive value of EGFR mutation testing in patients who were treated with gefitinib compared to chemotherapy in the first- or second-line setting. The Iressa Pan Asian Study (IPASS) trial showed the superiority of gefitinib in terms of PFS in patients with EGFR mutations versus patients with wild-type EGFR (Hazard ratio [HR], 0.48, 95%CI; 0.36-0.64 versus HR, 2.85; 95%CI, 2.05-3.98). Moreover, there was a statistically significant increased ORR in patients who received gefitinib and had EGFR mutations compared to patients with wild-type EGFR (71% versus 1%). The First-SIGNAL trial in patients with similar clinical characteristics as IPASS as well as the NEJ002 and WJTOG3405 trials that included only patients with EGFR mutations, provide confirmation that gefitinib is superior to chemotherapy in terms of improved PFS or higher ORR in patients with EGFR mutations. The INTEREST trial further indicated that patients with EGFR mutations had prolonged PFS and higher ORR when treated with gefitinib compared with docetaxel.
In contrast, there is still a paucity of strong evidence regarding the predictive value of EGFR mutation testing for response to erlotinib in the second- or third-line setting. The BR.21 trial randomized 731 patients with NSCLC who were refractory or intolerant to prior first- or second-line chemotherapy to receive erlotinib or placebo. While the HR of 0.61 (95%CI, 0.51-0.74) favored erlotinib in the overall population, this was not a significant in the subsequent retrospective subgroup analysis. A retrospective evaluation of 116 of the BR.21 tumor samples demonstrated that patients with EGFR mutations had significantly higher ORRs when treated with erlotinib compared with placebo (27% versus 7%; P=0.03). However, erlotinib did not confer a significant survival benefit compared with placebo in patients with EGFR mutations (HR, 0.55; 95%CI, 0.25-1.19) versus wild-type (HR, 0.74; 95%CI, 0.52-1.05). The interaction between EGFR mutation status and erlotinib use was not significant (P=0.47). The lack of significance could be attributable to a type II error since there was a low sample size that was available for subgroup analysis.
A series of phase II studies have examined the clinical effectiveness of erlotinib in patients known to have EGFR mutations. Evidence from these studies has consistently shown that erlotinib yields a very high ORR (typically 70% vs. 4%) and a prolonged PFS (9 months vs. 2 months) in patients with EGFR mutations compared with patients with wild-type EGFR. Although having a prolonged PFS and higher respond in EGFR mutated patients might be due to a better prognostic profile regardless of the treatment received. In the absence of a comparative treatment or placebo control group, it is difficult to determine if the observed differences in survival benefit in patients with EGFR mutation is attributed to prognostic or predictive value of EGFR mutation status.
Conclusions
Based on moderate quality of evidence, patients with locally advanced or metastatic NSCLC with adenocarcinoma histology being treated with gefitinib in the first-line setting are highly likely to benefit from gefitinib if they have EGFR mutations compared to those with wild-type EGFR. This advantage is reflected in improved PFS, ORR and QoL in patients with EGFR mutation who are being treated with gefitinib relative to patients treated with chemotherapy.
Based on low quality of evidence, in patients with locally advanced or metastatic NSCLC who are being treated with erlotinib, the identification of EGFR mutation status selects those who are most likely to benefit from erlotinib relative to patients treated with placebo in the second or third-line setting.
PMCID: PMC3377519  PMID: 23074402
5.  DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy  
Journal of Clinical Oncology  2011;29(31):4121-4128.
Purpose
Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy.
Patients and Methods
All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy.
Results
We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma.
Conclusion
We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy.
doi:10.1200/JCO.2010.34.3616
PMCID: PMC3675702  PMID: 21947825
6.  Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Background
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
Methods
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
Results
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
Conclusion
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
doi:10.1093/jnci/djr075
PMCID: PMC3096796  PMID: 21483023
7.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
Question
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Perspectives
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
Methodology
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
Results
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
PMCID: PMC2880902  PMID: 20567625
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
8.  The Use of Pharmacogenomics for Selection of Therapy in Non-Small-Cell Lung Cancer 
INTRODUCTION
Performance status (PS) is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer (NSCLC), although pharmacogenomic markers may also correlate with outcome. The aim of our study was to correlate clinical and pharmacogenomic measures with overall survival.
METHODS
This was an IRB approved, retrospective study in which the medical records of 50 patients with advanced NSCLC from 1998–2008 were reviewed, and gender, race, PS, and chemotherapy regimens were documented. Stromal expression of pharmacogenomic markers (VEGFR, ERCC1, 14-3-3σ, pAKT, and PTEN) was measured. Clinical factors and pharmacogenomics markers were compared to overall survival using a Cox proportional hazards model.
RESULTS
Forty patients received platinum-based therapy. Median age was 65 years. Improved PS, female gender, and gemcitabine therapy were significantly associated with longer overall survival (P = 0.004, P = 0.04, and P = 0.003, respectively). Age was not associated with survival. Caucasians had better overall survival in comparison to African Americans with median survival of 14.8 months versus 10.4 months (P = 0.1). Patients treated with platinum-based therapy had better survival of 15 months versus 8 months for non-platinum based therapy (P = 0.01). There was no significant association between any of the pharmacogenomics markers and overall survival other than in patients treated with platinum, in whom ERCC1 negativity was strongly associated with longer survival (P = 0.007).
CONCLUSION
ERCC1 negativity with platinum therapy, gemcitabine therapy, good PS, and female gender all correlated with improved overall survival in patients with advanced NSCLC.
doi:10.4137/CMO.S18369
PMCID: PMC4259862  PMID: 25520568
pharmacogenomics; selection of therapy; non-small-cell lung cancer
9.  Chemotherapy Outcomes by Histologic Subtypes of Non-Small cell Lung Cancer: Analysis of the Southwest Oncology Group Database for Antimicrotubule-Platinum Therapy 
Clinical lung cancer  2013;14(6):627-635.
Histological subtyping has been advocated to select chemotherapy for patients with advanced stage non-small-cell lung cancer (NSCLC). Data from four randomized trials (S9308, S9509, S9806 and S0003) administering an antimicrotubular agent (a taxane or vinorelbine) plus platinum in patients receiving first line treatment for advanced stage NSCLC were analyzed. Of 1146 patients included in this analysis there was no difference in OS or PFS by histological subtype. Since the great majority of advanced NSCLC patients continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted.
Objectives
Histologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non-small-cell lung cancer (NSCLC). To determine if histologic subtype was associated with efficacy for the commonly used antimicrotubular (AMT) agents, paclitaxel, docetaxel and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database.
Methods
Data from 4 randomized trials (S9308, S9509, S9806 and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan-Meier.
Results
Of 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%) and 165 had NSCLC not otherwise specified (NOS)(14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies.
Conclusions
This pooled analysis from 4 SWOG trials employing an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted.
doi:10.1016/j.cllc.2013.06.010
PMCID: PMC4122504  PMID: 23910067
Chemotherapy outcomes; Histology; Lung cancer
10.  Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Purpose
Genetic variation may influence chemotherapy response and overall survival in cancer patients.
Experimental design
We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA).
Results
Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population.
Conclusion
In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients.
doi:10.1158/1078-0432.CCR-12-1202
PMCID: PMC3723686  PMID: 22872573
11.  Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy 
Background
Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and cooper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy.
Methods
From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival.
Results
Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P < 0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P = 0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P < 0.01).
Conclusion
This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.
doi:10.1016/j.lungcan.2011.06.011
PMCID: PMC3319119  PMID: 21788094
Human copper transporter 1; Cisplatin; ATP7A; ATP7B; Non-small cell lung cancer; Prognosis
12.  XRCC3 Thr241Met Polymorphism and Clinical Outcomes of NSCLC Patients Receiving Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(8):e69553.
Introduction
X-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.
Methods
A systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.
Results
A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR  = 1.509, 95% CI: 1.099–2.072, Pheterogeneity  = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR  = 0.939, 95% CI:0.651–1.356, Pheterogeneity  = 0.112) or PFS (MetMet vs. ThrThr, HR  = 0.960, 95% CI: 0.539–1.710, Pheterogeneity  = 0.198). Additionally, no evidence of publication bias was observed.
Conclusions
This systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.
doi:10.1371/journal.pone.0069553
PMCID: PMC3734199  PMID: 23940523
13.  Survival Following Surgery with or without Adjuvant Chemotherapy for Stage I–IIIA Non-Small Cell Lung Cancer: An East Asian Population-Based Study 
The Oncologist  2012;17(10):1294-1302.
The survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I–IIIA non-small cell lung cancer is examined. The lower risk for death provided by adjuvant chemotherapy among the Asian population is comparable with that found in the literature based mainly on data from white patients.
Background.
Asian ethnicity is associated with a distinct molecular etiology, treatment response, and survival outcome among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I–IIIA NSCLC.
Methods.
This study recruited patients aged ≥18 years with histologically proven stage IA–IIIA NSCLC registered in the Taiwan Cancer Registry database in January 2004 to December 2007. Platinum-containing adjuvant chemotherapy had to be started within 90 days of the primary surgery. Kaplan–Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time.
Results.
This study included 2,231 patients with stage IA–IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group for both stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival outcome of stage II (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.39–0.94; p = .024) and IIIA (HR, 0.71; 95% CI, 0.52–0.96; p = .029) patients. Among these patients, those who received adjuvant chemotherapy had a superior overall survival outcome for both genders, for the subgroup of patients aged ≥70 years, and for those with adenocarcinoma.
Conclusion.
Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC.
doi:10.1634/theoncologist.2012-0082
PMCID: PMC3481895  PMID: 22826374
Non-small cell lung cancer; Adjuvant chemotherapy; Asian ethnicity; Survival; Comparative effectiveness
14.  Effect of Polymorphisms in XPD on Clinical Outcomes of Platinum-Based Chemotherapy for Chinese Non-Small Cell Lung Cancer Patients 
PLoS ONE  2012;7(3):e33200.
Purpose
Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Experimental Design
353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg156Arg, Asp312Asn, Asp711Asp and Lys751Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing.
Results
Variant genotypes of XPD Asp312Asn, Asp711Asp and Lys751Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp312Asn, Asp711Asp and Lys751Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10−4, log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0–1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS.
Conclusions
Our study provides evidence for the predictive role of XPD Asp312Asn, Asp711Asp and Lys751Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.
doi:10.1371/journal.pone.0033200
PMCID: PMC3315552  PMID: 22479369
15.  SIRT1 Expression Is Associated with the Chemotherapy Response and Prognosis of Patients with Advanced NSCLC 
PLoS ONE  2013;8(11):e79162.
Aim
The role of Sirtuin 1 (SIRT 1) in carcinogenesis is controversial. This study was to explore the association between the SIRT1 expression and the clinical characteristics, the responsiveness to chemotherapy and prognosis in Non-small cell lung cancer (NSCLC).
Methods
We enrolled 295 patients with inoperable advanced stage of NSCLC, namely, stage III (A+B) and IV NSCLC. All patients had received platinum-based chemotherapy after diagnosis and the chemotherapy response were evaluated. All patients were followed up for overall survival (OS) and progression free survival (PFS). In vitro, H292 cells were tranfected with SIRT1 small interfering RNA (siRNA). The cell biological behaviors and chemosensitivity to cisplatin treatment were studied. The in vivo tumorgenesis and metastasis assays were performed in nude mice.
Results
We found that the SIRT1 expressions were significantly associated with the tumor stage, tumor size and differentiation status. Patients with high SIRT 1 expressions had a significantly higher chance to be resistant to chemotherapy than those with low SIRT 1 expression. Patients with high expression of SIRT1 had significantly shorter OS and DFS than those with low expression. Cox analyses confirmed that the SIRT 1 expression was a strong predictor for a poor OS and PFS in NSCLC patients underwent Platinum-based chemotherapy. In vitro studies revealed that the reduced expression SIRT 1 by siRNA technique significantly inhibited cell proliferation, migration and invasion. More importantly, SIRT1 si-RNA significantly enhanced the chemosensitivity of H292 cells to cisplatin treatment. The in vivo tumorgenesis and metastasis assays showed that SIRT1 knockdown dramatically reduced the tumor volume and the metastatic ability in nude mice.
Conclusion
Collectively, our data suggest that the SIRT1 expression may be a molecular marker associated with the NSLCLC clinical features, treatment responsiveness and prognosis of advanced NSCLC.
doi:10.1371/journal.pone.0079162
PMCID: PMC3818418  PMID: 24223900
16.  A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer 
PLoS Medicine  2006;3(12):e467.
Background
Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence.
Methods and Findings
In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK).
Conclusions
Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.
Meta-analysis of several lung cancer gene expression studies yields a set of 64 genes whose expression profile is useful in predicting survival of patients with early-stage lung cancer and possibly informing treatment decisions.
Editors' Summary
Background.
Lung cancer is the commonest cause of cancer-related death worldwide. Most cases are of a type called non-small cell lung cancer (NSCLC) and are mainly caused by smoking. Like other cancers, how NSCLC is treated depends on the “stage” at which it is detected. Stage IA NSCLCs are small and confined to the lung and can be removed surgically; patients with slightly larger stage IB tumors often receive chemotherapy after surgery. In stage II NSCLC, cancer cells may be present in lymph nodes near the tumor. Surgery plus chemotherapy is the usual treatment for this stage and for some stage III NSCLCs. However, in this stage, the tumor can be present throughout the chest and surgery is not always possible. For such cases and in stage IV NSCLC, where the tumor has spread throughout the body, patients are treated with chemotherapy alone. The stage at which NSCLC is detected also determines how well patients respond to treatment. Those who can be treated surgically do much better than those who can't. So, whereas only 2% of patients with stage IV lung cancer survive for 5 years after diagnosis, about 70% of patients with stage I or II lung cancer live at least this long.
Why Was This Study Done?
Even stage I and II lung cancers often recur and there is no accurate way to identify the patients in which this will happen. If there was, these patients could be given aggressive chemotherapy, so the search is on for a “molecular signature” to help identify which NSCLCs are likely to recur. Unlike normal cells, cancer cells divide uncontrollably and can move around the body. These behavioral differences are caused by changes in their genetic material that alter their patterns of RNA transcription and protein expression. In this study, the researchers have investigated whether data from several microarray studies (a technique used to catalog the genes expressed in cells) can be pooled to construct a gene expression signature that predicts the survival of patients with stage I NSCLC.
What Did the Researchers Do and Find?
The researchers took the data from seven independent microarray studies (including a new study of their own) that recorded gene expression profiles related to survival time (less than 2 years and greater than 5 years) for stage I NSCLC. Because these studies had been done in different places with slightly different techniques, the researchers applied a statistical tool called distance-weighted discrimination to smooth out any systematic differences among the studies before identifying 64 genes whose expression was associated with survival. Most of these genes are involved in cell adhesion, cell motility, cell proliferation, and cell death, all processes that are altered in cancer cells. The researchers then developed a statistical model that allowed them to use the gene expression and survival data to calculate risk scores for nearly 200 patients in five of the datasets. When they separated the patients into high and low risk groups on the basis of these scores, the two groups were significantly different in terms of survival time. Indeed, the gene expression signature was better at predicting outcome than routine staging. Finally, the researchers validated the gene expression signature by showing that it predicted survival with more than 85% accuracy in two independent datasets.
What Do These Findings Mean?
The 64 gene expression signature identified here could help clinicians prepare treatment plans for patients with stage I NSCLC. Because it accurately predicts survival in patients with adenocarcinoma or squamous cell cancer (the two major subtypes of NSCLC), it potentially indicates which of these patients should receive aggressive chemotherapy and which can be spared this unpleasant treatment. Previous attempts to establish gene expression signatures to predict outcome have used data from small groups of patients and have failed when tested in additional patients. In contrast, this new signature seems to be generalizable. Nevertheless, its ability to predict outcomes must be confirmed in further studies before it is routinely adopted by oncologists for treatment planning.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030467.
US National Cancer Institute information on lung cancer for patients and health professionals.
MedlinePlus encyclopedia entries on small-cell and non-small-cell lung cancer.
Cancer Research UK, information on patients about all aspects of lung cancer.
Wikipedia pages on DNA microarrays and expression profiling (note that Wikipedia is a free online encyclopedia that anyone can edit).
doi:10.1371/journal.pmed.0030467
PMCID: PMC1716187  PMID: 17194181
17.  PI3K/PTEN/AKT/mTOR Pathway Genetic Variation Predicts Toxicity and Distant Progression in Lung Cancer Patients Receiving Platinum-based Chemotherapy 
Summary
Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08 – 13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20 - 0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45 - 0.97), 0.52 (95% CI: 0.35 - 0.77), and 0.62 (95% CI: 0.42 - 0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly two-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.
doi:10.1016/j.lungcan.2010.04.008
PMCID: PMC2952281  PMID: 20447721
lung cancer; chemotherapy; platinum-agents; AKT; clinical outcomes
18.  Prognostic value of ERCC1 mRNA expression in non-small cell lung cancer, breast cancer, and gastric cancer in patients from Southern China 
Abstract: Background: Excision repair cross complementation group 1 (ERCC1) is a nucleotide excision repair pathway gene which provides protection against platinum-based chemotherapy-induced DNA damage. Methods: ERCC1 mRNA expression was quantified by quantitative real-time reverse-transcription PCR in paraffin-embedded non-small cell lung cancer (NSCLC; n = 357), gastric cancer (n = 106), and breast cancer (n = 363) tissues. Survival curves were generated by Kaplan-Meier analysis; Cox proportional multivariate regression analysis was applied. Results: ERCC1 mRNA expression was significantly higher in breast cancer than gastric cancer or NSCLC (both P < 0.0001), but not significantly different in NSCLC and gastric cancer (P = 0.119). In NSCLC, the low ERCC1 group had significantly longer disease free survival (DFS) than the high ERCC1 group (29.1 vs. 21.0 months, P < 0.0001); in the surgery alone and postoperative platinum-containing chemotherapy subgroups, DFS was significantly longer for the low ERCC1 groups than high ERCC1 groups (30.2 vs. 25.1 months, P = 0.018; 27.0 vs. 19.4 months, P < 0.0001, respectively). In gastric cancer patients receiving surgery alone, the low ERCC1 group had significantly longer overall survival than the high ERCC1 group (47.54 vs. 27.47 months, P = 0.018). Conclusions: High ERCC1 mRNA expression of the NSCLC tumor tissues was associated with poor disease-free survival (DFS), in both the surgery alone and postoperative platinum-containing chemotherapy subgroups. Meanwhile, low ERCC1 mRNA expression had significantly longer overall survival in gastric cancer patients receiving surgery alone. Therefore, ERCC1 expression was a prognostic factor and predictive marker in NSCLC, and gastric cancer after surgery alone, but was not a prognostic factor in breast cancer.
PMCID: PMC4314004
ERCC1; mRNA; expression; prognostic factor; NSCLC; gastric cancer; breast cancer
19.  Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy †, ‡ 
Purpose
Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate SNPs/genes, we performed a genome-wide association study (GWAS) for cisplatin cytotoxicity using lymphoblastoid cell lines (LCLs), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
Experimental Design
GWAS for cisplatin were performed with 283 ethnically diverse LCLs. 168 top SNPs were genotyped in 222 small cell and 961 non-small cell lung cancer (SCLC, NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.
Results
Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the four top SNPs and 8 genes for which expression was correlated with three SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.
Conclusions
This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer.
doi:10.1158/1078-0432.CCR-11-1133
PMCID: PMC3167019  PMID: 21775533
Lung cancer; cisplatin; pharmacogenomics; lymphoblastoid cell lines; GWAS
20.  Biomarkers of TGF-β Signaling Pathway and Prognosis of Pancreatic Cancer 
PLoS ONE  2014;9(1):e85942.
Background
Transforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.
Method
We examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.
Results
The expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).
Conclusion
Our data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.
doi:10.1371/journal.pone.0085942
PMCID: PMC3896410  PMID: 24465802
21.  Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer 
The Oncologist  2012;17(12):1551-1561.
Thirteen tag SNPs at the CASP8 and CASP10 loci in patients with advanced NSCLC were genotyped in a two-stage analysis consisting of a discovery set and an independent validation set. These SNPs were evaluated for their association with toxicity outcomes with platinum-based chemotherapy.
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens.
doi:10.1634/theoncologist.2011-0419
PMCID: PMC3528388  PMID: 22843554
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
22.  Prognostic Value of EGFR Mutation and ERCC1 in Patients with Non-Small Cell Lung Cancer Undergoing Platinum-Based Chemotherapy 
PLoS ONE  2013;8(8):e71356.
Background
In order to improve the outcome of patients with non-small cell lung cancer (NSCLC), a biomarker that can predict the efficacy of chemotherapy is needed. The aim of this study was to assess the role of EGFR mutations and ERCC1 in predicting the efficacy of platinum-based chemotherapy and the outcome of patients with NSCLC.
Methods
We conducted a retrospective study to analyze the relationships between EGFR mutations or ERCC1 expression and progression-free survival (PFS) in patients with NSCLC who received platinum-based chemotherapy. EGFR mutation status was determined using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method, and immunohistochemistry was used to examine the expression of ERCC1 in tumor samples obtained from the patients.
Results
Among the NSCLC patients who received platinum-based chemotherapy, the median PFS was significantly better in those who had never smoked and those with exon 19 deletion, and the median overall survival (OS) was significantly better in those who had never smoked, those with exon 19 deletion, and women. Cox regression analysis revealed that exon 19 deletion and having never smoked were significantly associated with both PFS and OS. Subset analysis revealed a significant correlation between ERCC1 expression and EGFR mutation, and ERCC1-negative patients with exon 19 deletion had a longer PFS than the other patients; ERCC1-positive patients without exon 19 deletion had a shorter PFS than the other patients.
Conclusions
Our results indicate that among NSCLC patients receiving platinum-based chemotherapy, those with exon 19 deletion have a longer PFS and OS. Our findings suggest that platinum-based chemotherapy is more effective against ERCC1-negative and exon 19-positive NSCLC.
doi:10.1371/journal.pone.0071356
PMCID: PMC3734014  PMID: 23940741
23.  Genetic Variations in the Regulator of G-Protein Signaling Genes Are Associated with Survival in Late-Stage Non-Small Cell Lung Cancer 
PLoS ONE  2011;6(6):e21120.
The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients.
doi:10.1371/journal.pone.0021120
PMCID: PMC3117866  PMID: 21698121
24.  Correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer 
OncoTargets and therapy  2014;7:1185-1193.
Background
The purpose of this research was to investigate the relationship between epidermal growth factor receptor (EGFR) mutations and the response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).
Methods
A total of 266 patients with stage IIIB or IV NSCLC who received platinum-based doublet therapies as first-line chemotherapy were investigated retrospectively, and their clinical data were assessed according to EGFR mutation.
Results
EGFR mutations were identified in 45.5% of patients. There was no significant difference in response rate between EGFR mutation carriers and EGFR wild-type carriers (P=0.484). Among the patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, however, those with EGFR mutations responded better to treatment than EGFR wild-type patients (46.2% versus 20.8%, P=0.043). The disease control rate associated with pemetrexed-based treatments was higher than for vinorelbine-based therapies in EGFR mutation patients (P=0.001). EGFR mutation was found in patients with longer progression-free survival and median survival time, and improved 1-year and 2-year overall survival when compared with EGFR wild-type patients (6.1 versus 5.0 months, P=0.004; 18.9 versus 13.8 months, P=0.001; 81.0% versus 63.4%, P=0.002; and 33.9% versus 22.8% P=0.044, respectively). Patients with the EGFR exon 19 mutation had longer progression-free survival than those with EGFR exon 21 mutation (P=0.007). Multivariate analysis showed that the response to first-line chemotherapy and the presence of EGFR mutations were independent prognostic factors in patients with advanced NSCLC.
Conclusion
Our data showed that the presence of EGFR mutations meant longer survival times for patients with advanced NSCLC who received platinum-based doublet first-line chemotherapy, especially in those with the exon 19 deletion mutation. Among KRAS wild-type patients, those with EGFR mutation responded better to first-line chemotherapy than EGFR wild-type patients.
doi:10.2147/OTT.S63665
PMCID: PMC4085297  PMID: 25061320
non-small cell lung cancer; chemotherapeutic agents; epidermal growth factor receptor mutation; targeted therapy; prognosis
25.  Associations of Polymorphisms in DNA Repair Genes and MDR1 Gene with Chemotherapy Response and Survival of Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(6):e99843.
Objectives
We aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1) rs11615, xeroderma pigmentosum group D (XPD/ERCC2) rs13181, X-ray repair cross complementing group 1 (XRCC1) rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1) rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1) rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC) in a Chinese population.
Materials and Methods
A total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis.
Results
BRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95%CI = 0.204−0.794, p = 0.008) and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95%CI = 0.244−0.934, p = 0.030) were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402−0.948, p = 0.028) in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020) and smoking (p = 0.037) were associated with increased risks of death in early stage NSCLC patients after surgery.
Conclusions
Polymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with NSCLC.
doi:10.1371/journal.pone.0099843
PMCID: PMC4059653  PMID: 24933103

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