Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the total number of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health. Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advances that benefit NSCLC patients. Druggable driver mutations, which mainly occur in EGFR, KRAS, MET, HER2, ALK, ROS1, RET and BRAF, have been identified in more than a quarter of NSCLC patients. A series of highly selective mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well studied and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However, drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drug resistance are constantly being developed, including inhibitors against new mutants, combination therapy with other pathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histone deacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affecting multiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clinical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with some already under clinical trials. This article focuses on driver mutations and epigenetic alterations in association with relevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance, review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the possibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.     

Genetic Variation in GSTP1, Lung Function,Risk of Lung Cancer,and Mortality

IntroductionGlutathione S-transferase pi 1 metabolizes carcinogens from tobacco smoke in the lung. We tested whether genetically altered glutathione S-transferase pi 1 activity affects lung function and risk for tobacco-related cancer and mortality in the general population.MethodsWe genotyped 66,069 individuals from the white general population for two common functional variants in the glutathione S-transferase pi 1 gene (GSTP1)—amino acid isoleucine 105 changed to a valine (Ile105Val) and amino acid alanine 114 changed to a valine (Ala114Val)—and recorded lung function, lung cancer, tobacco-related cancer, and death as outcomes.ResultsLung function was increased stepwise with the Ile105Val genotype overall (p < 0.01) and among smokers separately (p < 0.01). Adjusted hazard ratios for lung cancer, tobacco-related cancer, and death were reduced stepwise with the Ile105Val genotype (p < 0.02): Ile105Val homozygotes and heterozygotes versus noncarriers had hazard ratios for lung cancer of 0.64 (0.47–0.89) and 0.93 (0.78–1.11), for tobacco-related cancer of 0.74 (0.60–0.92) and 0.92 (0.81–1.04), and hazard ratios for death of 0.87 (0.80–0.95) and 0.94 (0.89–0.99), respectively. Population prevented fractions of lung cancer, tobacco-related cancer, and death due to Ile105Val homozygosity were 4%, 3% and 2%, respectively. The Ala114Val genotype was associated with reduced mortality (p < 0.01) but not with lung function, lung cancer, or tobacco-related cancer.ConclusionGSTP1 Ile105Val was associated with increased lung function, reduced risk for lung cancer and tobacco-related cancer, and reduced all-cause mortality in the general population.     

Histologic Lung Cancer Incidence Rates and Trends Vary by Race/Ethnicity and Residential County

Introduction

Lung cancer incidence is higher among non-Hispanic (NH) blacks than among the NH white and Hispanic populations in the United States. However, national cancer estimates may not always reflect the cancer burden in terms of disparities and incidence in small geographic areas, especially urban-rural disparities. Moreover, there is a gap in the literature regarding rural-urban disparities in terms of cancer histologic type.

Patient Demographic Characteristics and Disease Stage as Drivers of Disparities in Mortality in Prostate Cancer Patients Who Receive Care at a Safety Net Academic Medical Center

IntroductionThe purpose of this study was to examine the effect of patient demographic characteristics and tumor stage at diagnosis on mortality in prostate cancer patients who receive care at a safety net, academic medical center with a diverse patient population.Patients and MethodsEight hundred sixty-nine patients were diagnosed with prostate cancer at our institution between August 2004 and October 2011. Patient demographic characteristics were determined as follows: race and/or ethnicity, primary language, insurance type, age at diagnosis, marital status, income (determined by zip code), and American Joint Committee on Cancer (AJCC) tumor stage. Fisher exact or Pearson χ² test was used to test for differences in categorical variables. Multivariate logistic regression analysis was performed to identify factors related to mortality recorded at the end of follow-up in March of 2012.ResultsMortality was significantly decreased in patients who spoke Haitian Creole (odds ratio [OR], 0.18; 95% confidence interval [CI], 0.04-0.74; P = .017). Distribution of insurance type, age, income, and prostate-specific antigen level differed between English and Haitian Creole speakers. Increased mortality was observed in patients who were single (OR, 1.99; 95% CI, 1.06-3.73; P = .032), older than 70 (OR, 15.5; 95% CI, 3.03-79.45; P = .001), had Medicaid and/or free care (OR, 4.98; 95% CI, 1.72-14.4; P = .003), or had AJCC stage IV cancer (OR, 9.56; 95% CI, 4.89-18.69; P < .001). There was no significant difference in mortality according to race and/or ethnicity or income in the multivariate-adjusted model.ConclusionIn this retrospective study, prostate cancer patients who spoke Haitian Creole had a lower incidence of mortality compared with English speakers. Consistent with similar large-scale studies, being single or having Medicaid and/or free care insurance predicted worse outcomes, reinforcing their roles as drivers of disparities.     

EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer

Introduction

Inherited genetic determinants of lung cancer risk remain relatively elusive. Germline mutations in EGFR and erb-b2 receptor tyrosine kinase 2 (ERBB2) have been previously reported in lung cancers that may be associated with genetic susceptibility to lung cancer.

Genetic Variation in PDCD6 and Susceptibility to Lung Cancer

Lung cancer is the most common type of cancer and one of the leading causes of death in the world. Geneticfactors play an important role in its development. PDCD6, the encoding gene for programmed cell death protein6, may function as a tumor suppressor gene. Non-small cell lung cancer (NSCLC) contributes about 80% tonewly histologically diagnosed lung cancer patients. To explore the relationship between PDCD6 and NSCLC,we examined two single nucleotide polymorphisms(rs3756712 G/T andrs4957014 G/T, both in the intron region)of the PDCD6gene.A hospital-based case-control study was carried out including 302 unrelated NSCLC patientsand 306 healthy unrelated subjects. Significantly increased NSCLC risk was found to be associated with the Tallele of rs4957014 (P=0.027, OR=0.760, 95%CI=0.596-0.970). The genotype and allele frequencies of rs3756712did not shown any significant difference between NSCLC group and controls (P=0.327, OR=0.879, 95%CI=0.679-1.137). In conclusion, we firstly demonstrated the association between the PDCD6 gene and risk of NSCLC ina Chinese Han population.     

Current Drugs and Drug Targets in Non-Small Cell Lung Cancer: Limitations and Opportunities

Lung cancer is a serious health problem and leading cause of death worldwide due to its high incidenceand mortality. More than 80% of lung cancers feature a non-small cell histology. Over few decades, systemicchemotherapy and surgery are the only treatment options in this type of tumor but due to their limited efficacyand overall poor survival of patients, there is an urge to develop newer therapeutic strategies which circumventthe problems. Enhanced knowledge of translational science and molecular biology have revealed that lung tumorscarry diverse driver gene mutations and adopt different intracellular pathways leading to carcinogenesis. Hence,the development of targeted agents against molecular subgroups harboring critical mutations is an attractiveapproach for therapeutic treatment. Targeted therapies are clearly more preferred nowadays over systemictherapies because they target tumor specific molecules resulting with enhanced activity and reduced toxicityto normal tissues. Thus, this review encompasses comprehensive updates on targeted therapies for the drivermutations in non-small cell lung cancer (NSCLC) and the potential challenges of acquired drug resistance facedi n the field of targeted therapy along with the imminent newer treatment modalities against lung cancer.     

Disparities in lung cancer stage, treatment and survival among American Indians and Alaskan Natives

Background

Disparities in lung cancer care and outcomes have been documented for blacks and Hispanics. Less is known about the care received by the American Indian and Alaskan Native population (AI/AN). We sought to evaluate lung cancer outcomes in this population and to asses if potential disparities in survival are explained by differences in stage of disease at diagnosis and type of treatment received.

Methods

We identified patients with potentially resectable (stages I-IIIA) non-small cell lung cancer (NSCLC) from the Surveillance, Epidemiology and End Results registry between 1988 and 2006. Kaplan-Meier curves were used to compare survival of AI/AN patients to those of other racial groups. Cox regression analysis was used to identify potential mediators of the association between AI/AN origin and worse survival.

Results

Five-year lung cancer survival was 47% for AI/AN, 56% for whites, 51% for blacks, 55% for Hispanics and 59% for individuals of other race (p < 0.0001). AI/AN were more likely to be diagnosed with stage IIIA (p < 0.0001) and less likely to undergo resection (p < 0.0001) than whites. In multivariable regression analyses, controlling for patient characteristics and histology, AI/AN race was associated with worse survival than white patients. When stage, treatment and surgery were added to the model, AI/AN origin was no longer significantly associated with worse outcomes.

Conclusions

AI/AN with potentially resectable NSCLC have survival rates comparable to other minority groups and worse than whites. These survival differences are partly explained by advanced stage at diagnosis, and lower rates of treatment.     

Ethnic Variation in Consumption of Traditional Tobacco Products and Lung Cancer Risk in Nepal

Lung cancer is the leading contributor to cancer deaths in the developing world. Within countries, significantvariability exists in the prevalence of lung cancer risk, yet limited information is available whether some of theobserved variability is associated with differences in the consumption pattern of local tobacco products withdiffering potency. We recruited 606 lung cancer cases and 606 controls from the B.P. Koirala Memorial CancerHospital in Nepal from 2009-2012. We estimated odds ratios (ORs) and 95% confidence intervals (CI) for lungcancer risk associated with different tobacco products, using unconditional logistic regression. Unfiltered cigarettestended to be the most frequently used products across ethnic subgroup with about 53.7% of Brahmins, 60.1% ofChettris, and 52.3% of Rai/Limbu/Magar/others. In contrast, about 39.9% of Madishe/Tharu smokers reportedusing bidi compared with only 27.7% who smoked unfiltered cigarettes. Among those who only smoked one typeof product, choor/kankat smokers had the highest lung cancer risk (OR 10.2; 95% CI 6.2-16.6), followed by bidismokers (OR 5.6; 95% CI 3.6-8.7), unfiltered cigarettes (OR 4.9; 95% CI 3.4-7.2), and filtered cigarettes (OR 3.4;95% CI 2.2-5.3). A clear dose-response relationship was observed between increased frequency of smoking andlung cancer risk across all ethnic subgroups. These results highlight the important role of traditional tobaccoproducts on lung cancer risk in the low income countries.     

Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial

IntroductionThe National Lung Screening Trial (NLST) randomized high-risk current and former smokers to three annual screens with either low-dose computed tomography (LDCT) or chest radiography (CXR) and demonstrated a significant reduction in lung cancer mortality in the LDCT arm after a median of 6.5 years' follow-up. We report on extended follow-up of NLST subjects.MethodsSubjects were followed by linkage to state cancer registries and the National Death Index. The number needed to screen (NNS) to prevent one lung cancer death was computed as the reciprocal of the difference in the proportion of patients dying of lung cancer across arms. Lung cancer mortality rate ratios (RRs) were computed overall and adjusted for dilution effect, with the latter including only deaths with a corresponding diagnosis close enough to the end of protocol screening.ResultsThe median follow-up times were 11.3 years for incidence and 12.3 years for mortality. In all, 1701 and 1681 lung cancers were diagnosed in the LDCT and CXR arms, respectively (RR = 1.01, 95% confidence interval [CI]: 0.95–1.09). The observed numbers of lung cancer deaths were 1147 (with LDCT) versus 1236 (with CXR) (RR = 0.92, 95% CI: 0.85–1.00). The difference in the number of patients dying of lung cancer (per 1000) across arms was 3.3, translating into an NNS of 303, which is similar to the original NNS estimate of around 320. The dilution-adjusted lung cancer mortality RR was 0.89 (95% CI: 0.80–0.997). With regard to overall mortality, there were 5253 (with LDCT) and 5366 (with CXR) deaths, for a difference across arms (per 1000) of 4.2 (95% CI: –2.6 to 10.9).ConclusionExtended follow-up of the NLST showed an NNS similar to that of the original analysis. There was no overall increase in lung cancer incidence in the LDCT arm versus in the CXR arm.     

Characteristics and Prediction of Lung Cancer Mortality in China from 1991 to 2013

Objective: To describe and analyze the epidemiological characteristics of lung cancer mortality in China from1991 to 2013, forecast the future five-year trend and provide scientific evidence for prevention and managementof lung cancer. Materials and Methods: Mortality data for lung cancer in China from 1991 to 2013 were usedto describe epidemiological characteristics. Trend surface analysis was applied to analyze the geographicaldistribution of lung cancer. Four models, curve estimation, time series modeling, gray modeling (GM) andjoinpoint regression, were performed to forecast the trend for the future. Results: Since 1991 the mortality rate oflung cancer increased yearly. The rate for males was higher than that for females and rates in urban areas werehigher than in rural areas. In addition, our results showed that the trend will continue to increase in the ensuing5 years. The mortality rate increased from age 45-50 and peaked in the group of 85 years old. Geographicalanalysis indicated that people living in northeast China provinces and the coastal provinces in eastern China hada higher mortality rate for lung cancer than those living in the centre or western Chinese provinces. Conclusions:The standardized mortality rate of lung cancer has constantly increased from 1991 to 2013, and been predictedto continue in the ensuing 5 years. Further efforts should be concentrated on education of the general public toincrease prevention and early detection. Much better prevention and management is needed in high mortalityareas (northeastern and eastern parts of China) and high risk populations (45-50-year-olds).     

Disparities in the Diagnosis and Treatment of Lung Cancer among People with Disabilities

Introduction

Potential disparities in the diagnosis, treatment, and survival of patients with lung cancer with and without disabilities have rarely been investigated.

血清CEA、LDH对肺腺癌靶向治疗的临床疗效及预后的预测价值

目的 探讨血清CEA、LDH对肺腺癌靶向治疗的临床效果与预后的预测作用.方法 选取60例接受表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)进行复治的肺腺癌患者为研究对象,测定患者治疗前后血清CEA、LDH水平,并将其水平与影像学标准评估疗效进行比较,观察其预后情况.结果 治疗前CEA正常组患者的临床治疗有效率13.3%,治疗前CEA升高组患者的临床治疗有效率37.8%,差异有统计学意义(P<0.05);治疗前LDH正常组患者的临床治疗有效率37.5%,治疗前LHD升高组患者的临床治疗有效率25.0%,差异无统计学意义(P>0.05).治疗前CEA≥20.0 ng/mL患者PFS为(8.2±1.3)月,CEA<20.0 ng/mL患者PFS为(5.1±1.0)月,2组PFS差异有统计学意义(P<0.05);治疗前CEA≥20.0 ng/mL患者OS为(16.4±2.0)月,CEA<20.0 ng/mL患者OS为(13.1±1.8)月,2组OS差异有统计学意义(P<0.05).结论 治疗前检测血清中CEA水平对预测肺腺癌靶向治疗效果和预后具有重要的作用.     

2013—2017年黑龙江省肿瘤登记地区肺癌发病与死亡分析

目的 分析2013—2017年黑龙江省肿瘤登记地区肺癌发病、死亡及时间变化趋势,为进一步制定肺癌防控提供依据。方法 计算黑龙江省肿瘤登记地区2013—2017年肺癌的发病（死亡）率、中标发病（死亡）率,标化率采用2000年全国人口普查标准人口和Segi’s世界标准人口构成作为标准。年度变化百分比（APC）使用Joinpoint软件计算。结果 2013—2017年黑龙江省肿瘤登记地区肺癌发病率为63.44/10万,中国人口标化率（中标率）为36.14/10万。其中男性肺癌发病率（78.08/10万）高于女性（49.04/10万）;农村地区肺癌发病率（65.54/10万）高于城市地区（58.20/10万）。2013—2017年黑龙江省肿瘤登记地区肺癌死亡率为57.02/10万,中标率为32.53/10万。其中男性肺癌死亡率（69.92/10万）高于女性（44.40/10万）;农村地区肺癌死亡率（60.68/10万）高于城市地区（48.02/10万）。55岁~年龄组肺癌发病率呈下降趋势（APC=-5.0%, t=-5.1, P<0.05）,70~年龄组肺癌死亡率呈下降趋势（APC=-4.9%, t=-5.0, P<0.05）。结论 黑龙江省是肺癌高发地区,肺癌严重威胁本省居民健康,必须针对本省肺癌流行病学特点进一步加强肺癌防控工作。