UCLA

Background: The burden of disease attributable to illicit drug use is increasing each year as illicit drug use has become a global epidemic. The International Agency for Research on Cancer (IARC) classified opium consumption as a Group 1 carcinogen in October, 2020. However, it is unclear if smoking other illicit drugs affects the risk and survival of lung cancer and upper aerodigestive tract (UADT) cancers. In addition, while some studies have assessed the effect of candidate genetic polymorphisms on lung and UADT cancers development and progression, few epidemiologic studies have explored the potential interactions between genetic polymorphisms and illicit drug smoking on cancer susceptibility and survival.

Objective and Specific Aims: The overall objective of this dissertation is to examine the associations of illicit drug smoking, genetic polymorphisms of cell cycle control, DNA repair, inflammation, and stem cell genes, and their interactions on susceptibility and survival of lung and UADT cancers. The specific aims were: 1) To estimate the magnitude of association between illicit drug smoking, including marijuana, opium, PCP, and crack cocaine, with risk and survival of lung and UADT cancers (marijuana for cancer survival only); 2) To verify and estimate the association between cocaine use and risk and survival of HNC, and to explore the potential interaction between cocaine use and major risk factors of HNC (e.g., tobacco use and alcohol consumption) on risk and survival of HNC, using a pooled data set from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium; 3) To estimate the associations between genetic polymorphisms of cell cycle control, DNA repair, inflammation, and stem cell genes, and risk and survival of lung and UADT cancers, and to explore the potential interaction between genetic polymorphisms and illicit drug smoking on risk and survival of lung and UADT cancers.

Study Design and Population: Aims 1 and 3 were based on a population-based case-control study conducted in Los Angeles County between 1999 and 2004. The study included 611 incident cases of lung cancer, 601 cases of UADT cancers, and 1,040 controls. Epidemiologic data including drug smoking histories were collected in face-to-face interviews; 88% of participants provided buccal cell samples for genotyping. Follow-up data were retrieved from the Los Angeles County Cancer Registry. For Aim 2, the pooled analysis was conducted by pooling individual-level data on cocaine use from three case-control studies with 1,639 cases and 2,506 controls from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Follow-up data were gathered by the INHANCE team from each individual study.Statistical Methods: In Aims 1 and 3, for cancer susceptibility analyses, odds ratios (OR’s) and 95% confidence intervals (CI’s) were estimated using unconditional logistic regression models. Models were adjusted for age, sex, race/ethnicity, education, tobacco use status, and alcohol consumption status. For survival analyses, hazard ratios (HR’s) and 95% CI’s were estimated using Cox proportional hazards models, adjusting for the above-stated covariates, tumor stage at diagnosis, and treatment. In addition, semi-Bayes ‘shrinkage’ adjustments were applied in Aim 3, and semi-Bayes adjusted OR’s and HR’s with their corresponding 95% posterior intervals (PI’s) were estimated. A polygenic risk score (PRS) was also constructed in Aim 3 to assess the effect of individual’s genetic background on cancer susceptibility and survival. In Aim 2, OR’s and HR’s with their corresponding 95% CI’s were estimated using hierarchical logistic regression models and Cox proportional hazards models to account for between-study heterogeneities. In all aims, additive and multiplicative interactions were assessed by computing the relative excess risk due to interaction (RERI) and the ratio of odds ratios (ROR) or hazard ratios (RHR) with their corresponding 95% CI’s.

Results:Aim 1. Adjusting for potential confounders, ever vs. never crack cocaine smoking was positively associated with the risk of UADT cancers (OR = 1.56, 95% CI: 1.05, 2.33), and a dose-response relationship was observed for lifetime smoking frequency (p for trend = 0.024). High cumulative use (> median; 6 times) vs. never crack cocaine smoking was associated with the risk of UADT cancers (OR = 1.81, 95% CI: 1.07, 3.08) and lung cancer (OR = 1.58, 95% CI: 0.88, 2.83). A positive association was also observed between heavy phencyclidine (PCP) smoking and the risk of UADT cancers (OR = 2.29, 95% CI: 0.91, 5.79). Little associations were observed between opium smoking and the risk of lung cancer or UADT cancers. No clear associations were detected between illicit drug smoking and the survival of lung and UADT cancers. Aim 2. Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine inhalation and head and neck cancer (HNC) (ORever vs. never = 1.35, 95% CI: 0.96, 1.90). In stratified analyses, while we did not detect associations between cocaine inhalation and HNC risk among never tobacco or alcohol users due to the limited sample size, the positive association was observed among tobacco users and alcohol drinkers. ORs for high cumulative cocaine use (> 18 times) vs. never were 1.66 (95% CI: 1.03, 2.69) among tobacco users and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers. A weak association was found for heavy (> 100 times) cocaine use with HNC overall survival (HR>100 vs. never = 1.42, 95% CI: 0.92, 2.19). No clear interaction was detected on any scale, while the positive association between heavy cocaine use and HNC survival was observed among tobacco users (HR>100 vs. never = 1.40, 95% CI: 0.89, 2.18) and alcohol drinkers (HR>100 vs. never = 1.48, 95% CI: 0.96, 2.30). In stratified analyses by cancer sites, oral cavity cancer patients who had high cumulative use had an increased hazard of death with an HR of 2.10 (95% CI: 1.06, 4.17). Additionally, among oropharyngeal cancer patients, heavy cocaine use was associated with an increased hazard of death with an HR of 2.53 (95% CI: 1.13, 5.67). Aim 3. After applying semi-Bayes adjustments, associations with risk and survival of lung and UADT cancers were identified with single nucleotide polymorphisms (SNPs) from four major pathways, including cell cycle control, DNA repair, inflammation, and stem cell regulation. Associations were observed for 1) cell cycle control genes: CCND1 rs3862792, CDC25B rs932529, HUS1 rs1056663, RCHY1 rs2126852, and WWOX rs12828; 2) DNA repair genes: BRCA2 rs206118, BRIP1 rs2048718, ERCC6 rs2228529, EXO1 rs1776177, GAPDH rs1136666, LIG1 rs20580, MLH1 rs1799977, MSH5 rs4711279, NEIL3 rs17064587, RAD51 rs1801320, SMUG1 rs3087404, TDG rs11111861, and XRCC3 rs1799794; 3) inflammation genes: CRP rs1205, CSF2 rs25882, IL10 rs1800871, and IL-1B rs1143627; 4) stem cell genes: CTBP2 rs374053, OCT4 rs13409 and rs3130932, and REX1 rs6815391. Additionally, while subject to random error, interactions were observed between crack cocaine smoking and HUS1 rs1056663 and OCT4 rs13409 on the survival of lung and UADT cancers. The polygenic risk score (PRS) was associated with risk and cancer-specific survival of lung (ORQ4 vs. Q1 = 2.63, 95% CI = 1.69, 4.08, P for trend < 0.001; HRQ4 vs. Q1 = 2.04, 95% CI = 1.41, 2.95, P for trend < 0.001) and UADT (ORQ4 vs. Q1 = 2.28, 95% CI = 1.55, 3.33, P for trend < 0.001; HRQ4 vs. Q1 = 3.27, 95% CI = 1.72, 6.21, P for trend < 0.001) cancers with dose-response relationships. No interactions were observed between the PRS and crack cocaine smoking on risk or survival of both cancers.

Conclusion and Public Health Implications: We observed possible positive associations between illicit drug smoking and risk and survival of UADT cancers, especially the association of cocaine inhalation with risk and survival of HNC. We also observed associations between genetic polymorphisms of candidate genes and risk and survival of lung and UADT cancers; some associations could be modified by crack cocaine smoking. Our findings could build preliminary grounds for the concern that illicit drug smoking is positively associated with the development and progression of lung and UADT cancers. Further, our findings add to the body of evidence that genetic polymorphisms of candidate genes may affect the development and progression of lung and UADT cancers, and provide more opportunities for 1) personalized risk and prognostic prediction and individualized therapy and 2) targeted preventive intervention and clinical therapy at population level.