Single nucleotide polymorphisms of 8 inflammation‐related genes and their associations with smoking‐related cancers

Tobacco smoke and its metabolites are carcinogens that increase tissue oxidative stress and induce target tissue inflammation. We hypothesized that genetic variation of inflammatory pathway genes plays a role in tobacco‐related carcinogenesis and is modified by tobacco smoking. We evaluated the association of 12 single nucleotide polymorphisms of 8 inflammation‐related genes with tobacco‐related cancers (lung, oropharynx, larynx, esophagus, stomach, liver, bladder, and kidney) using 3 case‐control studies from: Los Angeles (population‐based; 611 lung and 553 upper aero‐digestive tract cancer cases and 1,040 controls), Taixing, China (population‐based; 218 esophagus, 206 stomach, 204 liver cancer cases, and 415 controls), and Memorial Sloan‐Kettering Cancer Center (hospital‐based; 227 bladder cancer cases and 211 controls). After adjusting for age, education, ethnicity, gender, and tobacco smoking, IL10 rs1800871 was inversely associated with oropharyngeal cancer (CT+TT vs. CC adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.50–0.95), and was positively associated with lung cancer among never smokers (TT vs. CT+CC aOR: 2.5, 95% CI: 1.3–5.1) and inversely with oropharyngeal cancer among ever smokers (CT+TT vs. CC aOR: 0.63, 95% CI: 0.41–0.95). Among all pooled never smokers (588 cases and 816 controls), TNF rs1799964 was inversely associated with smoking‐related cancer (CC vs. CT+TT aOR: 0.36, 95% CI: 0.17–0.77). Bayesian correction for multiple comparisons suggests that chance is unlikely to explain our findings (although epigenetic mechanisms may be in effect), which support our hypotheses, suggesting that IL10 rs1800871 is a susceptibility marker for oropharyngeal and lung cancers, and that TNF rs1799964 is associated with smoking‐related cancers among never smokers.     

Cyclooxygenase‐2 gene polymorphisms reduce the risk of oral premalignant lesions

BACKGROUND:

Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase‐2 gene (COX‐2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single‐nucleotide polymorphisms of COX‐2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.

METHODS:

The authors conducted a case‐control study that included 147 patients with OPL and a group of 147 healthy, matched controls. The effects of 3 potentially functional COX‐2 polymorphisms on the risk of OPL were evaluated: the ?765 G→C polymorphism (rs20417), the exon 10 +837 T→C polymorphism (rs5275), and the exon 10 ?90 C→T polymorphism (rs689470).

RESULTS:

The variant‐containing genotypes of COX‐2 exon 10 +837T→C variant were associated with a significantly reduced risk of OPL (odds ratio [OR], 0.48; 95% confidence interval [95% CI], 0.28‐0.80). This protective effect also was significant in men, younger individuals, ever smokers, and ever drinkers. Consistently, a common halotype WMW (in the following order: ?765G→C, exon 10 +837T→C, and exon 10 ?90C→T; w, widetype; M, variable allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon 10 +837T→C, both were associated with a reduced risk of OPL (WMW: OR, 0.55; 95% CI, 0.33‐0.93; WWW/WMW: OR, 0.44; 95% CI, 0.22‐0.89). In addition, using never smokers with the variant‐containing genotypes as the reference group, interaction effects were observed between specific COX‐2 variants and tobacco smoking in the modulation of OPL risk.

CONCLUSIONS:

Overall, the current results provided the first epidemiologic evidence indicating that potentially functional polymorphisms of the COX‐2 gene may have an impact on individual susceptibility to OPLs. Cancer 2009. © 2009 American Cancer Society.     

An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy

Platinum‐based chemotherapy (PBC) in combination with the 3^rd generation drugs is the first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3–4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum‐induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two‐phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)_adj=1.61 and 2.35, 95% confidence interval (CI)=1.11–2.33 and 1.25–4.41, and P_adj=0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57–0.65 vs. 0.55–0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.     

A TGF‐β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16‐associated oropharyngeal cancer

TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site may alter TGF‐β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF‐β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer‐free controls in the non‐Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF‐β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never‐smokers (OR, 165.9; 95% CI, 28.6–960.4) or never‐drinkers (OR, 196.0; 95% CI, 28.2–1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3–87.0 vs. OR, 6.0; 95% CI, 1.7–17.9, respectively). The significant associations between this polymorphism and HPV16‐associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF‐β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16‐associated oral cancer, particularly in OPSCC subjects who are never‐smokers, never‐drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.     

Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes

Laryngeal cancer is known to be associated with smoking and high alcohol consumption. Nucleotide excision repair (NER) plays a key role in repairing DNA damage induced by these exposures and might affect laryngeal cancer susceptibility. In a population‐based case‐control study including 248 cases and 647 controls, the association of laryngeal cancer with 14 single nucleotide polymorphisms (SNPs) in 8 NER genes (XPC, XPA, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. For genotyping, sequence specific hybridization probes were used. Data were evaluated by conditional logistic regression analysis, stratified for age and gender, and adjusted for smoking, alcohol consumption and education. Pro‐carriers of ERCC6 Arg1230Pro showed a decreased risk for laryngeal cancer (OR = 0.53, 95% CI 0.34–0.85), strongest in heavy smokers and high alcohol consumers. ERCC5 Asp1104His was associated with risk in heavy smokers (OR = 1.70, 95% CI 1.1–2.5). Val‐carriers of RAD23B Ala249Val had an increased cancer risk in heavy smokers (OR = 1.6, 95% CI 1.1–2.5) and high alcohol consumers (OR = 2.0, 95% CI 1.1–3.4). The combined effect of smoking and alcohol intake affected risk, at high exposure level, for ERCC6 1230Pro carriers (OR = 0.47, 95% CI 0.22–0.98) and RAD23B 249Val carriers (OR = 2.6, 95% CI 1.3–4.9). When tested for gene–gene interaction, presence of 3 risk alleles in the XPC‐RAD23B complex increased the risk 2.1‐fold. SNPs in the other genes did not show a significant association with laryngeal cancer risk. We conclude that common genetic variations in NER genes can significantly modify laryngeal cancer risk. © 2009 UICC     

Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double‐positive lung cancer

Patients with epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non‐functional exon 3‐containing isoform over the functional exon 4‐containing isoform, impairing TKI‐induced, BIM‐dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion‐containing NSCLC cells to EGFR‐TKI. In the present study, we determined the safety of vorinostat‐gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR‐mutated NSCLC with the BIM deletion, pretreated with EGFR‐TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1‐7, and gefitinib 250 mg was given daily on days 1‐14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose‐limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression‐free survival was 5.2 months (95% CI: 1.4‐15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA‐containing exon 4 over mRNA‐containing exon 3, acetylated histone H3 protein, and proapoptotic BIM_EL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double‐positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment.     

Detection of EGFR and KRAS mutations in fine‐needle aspirates stored on Whatman FTA cards

BACKGROUND:

The aims of this study were to compare the quality of DNA recovered from fine‐needle aspirates (FNAs) stored on Whatman FTA cards with that retrieved from corresponding cell blocks and to determine whether the DNA extracted from the cards is suitable for multiple mutation analyses.

METHODS:

FNAs collected from 18 resected lung tumors and cell suspensions from 4 lung cancer cell lines were placed on FTA Indicating Micro Cards and further processed to produce paired formalin‐fixed paraffin‐embedded (FFPE) cell blocks. Fragment analysis was used for the detection of EGFR exon 19 deletion, and direct sequencing for detection of EGFR exon 21 L858R mutation and exon 2 deletion of KRAS. Corresponding FFPE tissue sections from 2 resection specimens were also tested.

RESULTS:

Analyses were successful with all FNAs and lung cancer‐derived cell lines collected on cards. Polymerase chain reaction failed in 2 cell blocks. For FNAs collected on cards, 5 cases showed EGFR and 3 showed KRAS mutations. Eleven cases were wild type. With cell blocks, 4 cases were found to harbor KRAS and 4 harbored EGFR mutations. All lung cancer‐derived cell lines tested positive for their respective mutations, and there was complete agreement between card and cell block FNA samples for EGFR exon 21. For EGFR exon 19, 1 of 18 cases showed discordant results between the card and cell block, and for KRAS 1 of 17. The two resection specimens tested gave concordant results with the FTA card.

CONCLUSIONS:

Storage of cytologic material on FTA cards can maximize and simplify sample procurement for multiple mutational analyses with results similar to those from cell blocks. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

Safety and efficacy of first‐line dacomitinib in Japanese patients with advanced non‐small cell lung cancer

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first‐line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28‐d cycles, in patients with EGFR‐activating mutation–positive (EGFR‐positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non‐small cell lung cancer (NSCLC). The primary endpoint was progression‐free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307‐0.961]; 2‐sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0‐31.3] mo, 9.3 [95% CI, 7.4‐14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first‐line dacomitinib in Japanese patients with EGFR‐positive advanced NSCLC.     

Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer

BACKGROUND:

The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single‐nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer.

METHODS:

The authors identified patients with advanced‐stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum‐based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty‐two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross‐complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis.

RESULTS:

In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine‐guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression‐free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42‐0.95; P = .03). The XPC (rs1124303) guanosine‐thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24‐0.94; P = .03). The XPC poly(AT) (PAT) (?/+)/(?/?) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36‐0.89; P = .01). The XPF/ERCC4 (rs12926685) cytidine‐thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41‐0.95; P = .03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS.

CONCLUSIONS:

The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum‐based chemotherapy. Cancer 2012;. © 2011 American Cancer Society.     

Hypoxia induces gefitinib resistance in non‐small‐cell lung cancer with both mutant and wild‐type epidermal growth factor receptors

Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non‐small‐cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild‐type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor‐α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia‐inducible factor‐1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild‐type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR‐mutant NSCLC through the activation of wild‐type EGFR mediated by the upregulation of TGFα. The presence of wild‐type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib.     

Variation in PAH‐related DNA adduct levels among non‐smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotype

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never‐smokers. We tried to find a model to explain the relationship between variation in PAH‐related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never‐smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by 32 P‐postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10⁸ nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non‐risk‐allele genotype, and was higher in the MPO homozygote risk‐allele genotype. The sum of risk alleles in these genes significantly correlated with the log‐adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non‐smokers in this population had PAH‐related DNA adduct levels three to four times higher than smokers and occupationally‐exposed groups in previous studies, with large inter‐individual variation which could best be explained by a combination of Phase I genes and NER capacity.     

ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor‐naïve Japanese patients with EGFR mutation‐positive non‐small‐cell lung cancer

Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non‐small‐cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR‐TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation‐positive NSCLC. Epidermal growth factor receptor‐TKI‐naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open‐label, single‐arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end‐point was to determine the safety of ASP8273 300 mg; the secondary end‐point was antitumor activity defined by RECIST version 1.1. Thirty‐one patients (12 men and 19 women; median age, 64 years [range, 31‐82 years]) with EGFR mutation‐positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment‐emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post‐baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once‐daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI‐naïve Japanese patients with EGFR mutation‐positive NSCLC.     

Driver mutations determine survival in smokers and never‐smokers with stage IIIB/IV lung adenocarcinomas

BACKGROUND:

The authors previously demonstrated that never‐smokers with stage IIIB/IV nonsmall cell lung cancer (NSCLC) lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and sex. In this study, the authors hypothesized that smoking‐dependent differences in the distribution of driver mutations may explain differences in prognosis between these subgroups.

METHODS:

In total, 293 never‐smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for epidermal growth factor receptor (EGFR) mutations and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and rearrangements in anaplastic lymphoma kinase (ALK) between 2009 and 2010 were investigated. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan‐Meier method. Group comparison was performed with log‐rank tests and Cox proportional hazards methods.

RESULTS:

Although the overall incidence of these mutations was nearly identical (55% never‐smokers vs 57% current/former smokers; P = .48), there were significant differences in the distribution of mutations between these groups for EGFR mutations (37% never‐smokers vs 14% former/current smokers; P < .0001), KRAS mutations (4% never‐smokers vs 43% former/current smokers; P < .0001), and ALK rearrangements (12% never‐smokers vs 2% former/current smokers; P < .0001). Among never‐smokers and former/current smokers, the prognosis differed significantly by genotype. Patients who had KRAS mutations had the poorest survival. Smoking status, however, had no influence on survival within each genotype.

CONCLUSIONS:

Never‐smokers and former/current smokers with lung adenocarcinomas were not homogeneous subgroups. Each was made up of individuals whose tumors had a unique distribution of driver mutations, which were associated with different prognoses, irrespective of smoking history. Cancer 2012. © 2012 American Cancer Society.     

Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L

IntroductionAbout 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted.MethodsChemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366).ResultsBetween August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45–74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%–). The overall response rate was 81.5% (95% CI: 63.3%–91.3%), median PFS was 18.6 months (95% CI: 12.0–24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo–not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each).ConclusionsThis prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.     

Mortality risk in former smokers with breast cancer: Pack‐years vs. smoking status

It is unclear why successful quitting at time of breast cancer diagnosis should remove risk from a significant lifetime of smoking. Studies concluding this may be biased by how smoking is measured in many epidemiological cohorts. In the late 1990s, a randomized trial of diet and breast cancer outcomes enrolled early‐stage female breast cancer survivors diagnosed within the previous 4 years. Smoking history and key covariate measures were available at study entry for 2,953 participants. Participants were followed for an average of 7.3 years (96% response rate). There were 10.1% deaths (83% from breast cancer). At enrollment, 55.2% were never smokers, 41.2% former smokers and 4.6% current smokers. Using current smoking status in a Cox regression, there was no increased risk for former smokers for either all‐cause mortality [hazard ratio (HR) = 1.11; 95% confidence interval (CI) = 0.87–1.41; p‐value = 0.42) or breast cancer mortality. However, when we categorized on extensive lifetime exposure, former smokers with 20+ pack‐years of smoking (25.8%) had a significantly higher risk of both all‐cause (HR = 1.77; 95% CI = 1.17–2.48; p‐value = 0.0007) and breast cancer‐specific mortality (HR = 1.62; 95% CI = 1.11–2.37; p‐value = 0.01). Lifetime smoking exposure, not current status, should be used to assess mortality risk among former smokers.     

DNA repair gene polymorphisms and tobacco smoking in the risk for colorectal adenomas

DNA damage is thought to play a critical role in the development of colorectal adenoma. Variation in DNA repair genes may alter their capacity to correct endogenous and exogenous DNA damage. We explored the association between common single-nucleotide polymorphisms (SNPs) in DNA repair genes and adenoma risk with a case-control study nested in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 1338 left sided, advanced colorectal adenoma cases and 1503 matched controls free of left-sided polyps were included in the study. Using DNA extracted from blood, 3144 tag SNPs in 149 DNA repair genes were successfully genotyped. Among Caucasians, 30 SNPs were associated with adenoma risk at P < 0.01, with four SNPs remaining significant after gene-based adjustment for multiple testing. The most significant finding was for a non-synonymous SNP (rs9350) in Exonuclease-1 (EXO1) [odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.11-1.51, P = 0.001)], which was predicted to be damaging using bioinformatics methods. However, the association was limited to smokers with a strong risk for current smokers (OR = 2.15, 95% CI = 1.27-3.65) and an intermediate risk for former smokers (OR = 1.45, 95% CI = 1.14-1.82) and no association for never smokers (OR = 0.98, 95% CI = 0.76-1.25) (P(interaction) = 0.002). Among the top findings, an SNP (rs17503908) in ataxia telangiectasia mutated (ATM) was inversely related to adenoma risk (OR = 0.75, 95% CI = 0.63-0.91). The association was restricted to never smokers (OR = 0.55, 95% CI = 0.40-0.76) with no increased risk observed among smokers (OR = 0.89, 95% CI = 0.70-1.13) (P(interaction) = 0.006). This large comprehensive study, which evaluated all presently known DNA repair genes, suggests that polymorphisms in EXO1 and ATM may be associated with risk for advanced colorectal adenoma with the associations modified by tobacco-smoking status.     

Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

BACKGROUND:

The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype‐specific subsets of never‐smokers with nonsmall cell lung cancer (NSCLC).

METHODS:

The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never‐smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing.

RESULTS:

Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression‐free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40‐0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07‐10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65‐10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes.

CONCLUSIONS:

To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never‐smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype‐specific subsets can lead to successful treatment with appropriate kinase inhibitors. Cancer 2012;. © 2011 American Cancer Society.     

Polymorphisms in tissue inhibitors of metalloproteinases‐2 and ‐3 and breast cancer susceptibility and survival

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases which are involved in normal cellular processes and also in cancer development and progression. The purpose of this study was to evaluate polymorphisms in the TIMP‐2 and TIMP‐3 genes for their associations with breast cancer susceptibility and survival. Using data from the Shanghai Breast Cancer Study, 19 SNPs for each gene were evaluated for associations with breast cancer risk among 1,062 cases and 1,069 controls; associations with disease‐free and overall survival were evaluated among the cases. For TIMP‐2, women with the rs7501477 TT genotype were 3 times more likely to be breast cancer cases than women with the CC genotype (OR: 2.9, 95% CI: 1.2–7.0). For TIMP‐3, women with the rs9609643 AA genotype were 60% less likely to be breast cancer cases than women with the GG genotype (OR: 0.4, 95% CI: 0.2–1.0), whereas women with the rs8136803 TT genotype were 5 times more likely to be cases than women with the GG genotype (OR: 5.1, 95% CI: 1.1–24.3). Further, breast cancer cases with rs8136803 TT were almost 4 times more likely to have decreased disease‐free survival (HR: 3.9, 95% CI: 1.4–10.6) and had a trend toward decreased overall survival (HR: 1.9, 95% CI: 0.6–6.1). An important study limitation was that these 3 SNPs (rs7501477, rs9609643, rs8136803) had low minor allele frequencies which resulted in small numbers of homozygote individuals. Genetic variation in the TIMP‐2 and TIMP‐3 genes may contribute to individual differences in breast cancer susceptibility and survival. © 2009 UICC     

XRCC3 haplotypes and risk of gliomas in a Chinese population: A hospital‐based case‐control study

In mammalian cells, X‐ray repair cross‐complementing group3 (XRCC3) plays an important role in the DNA double‐strand breaks (DSBs) repair by homologous recombination. Genetic polymorphisms in the XRCC3 gene may potentially affect the repair of DSBs and thus confer susceptibility to gliomas. In this study, we used a haplotype‐based approach to investigate whether 4 tagging single nucleotide polymorphisms of the XRCC3 gene are associated with risk of gliomas in 771 glioma patients and 752 cancer‐free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the unconditional logistic regression, and haplotype associations were estimated using Haplo.Stat. After adjustment for age and sex, the variant G allele of rs861530 and T allele of rs3212092 were significantly associated with an increased risk of gliomas (AG/GG versus AA: adjusted OR = 1.44, 95% CI = 1.15–1.80, p = 0.001 and CT/TT versus CC: adjusted OR = 1.66, 95% CI = 1.12–2.46, p = 0.013, respectively). Consistent with these results, XRCC3 haplotype “GGCC” containing rs861530 G allele and haplotype “AGTC” containing rs3212092 T allele were also significantly associated with an elevated risk of gliomas compared with the common haplotype “AGCC” (adjusted OR = 1.35, 95% CI = 1.14–1.58, p = 0.000 and adjusted OR = 1.67, 95% CI = 1.11–2.52, p = 0.015, respectively). Our results suggest that common genetic variants in the XRCC3 gene may modulate glioma risk. © 2009 UICC     

Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists

Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case-control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (OR(GC) = 1.1, OR(CC) = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/Gy(GG) = 1.0, 95% CI = <0, 6.0; EOR/Gy(GC/CC) = 5.9, 95% CI = 0.9, 14.4; p(het) = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/Gy(AA) = 9.1, 95% CI = 2.1-21.3; EOR/Gy(AC/CC) = 0.6, 95% CI = <0, 4.6; p(het) = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.