African American Lung Cancer Patients Research Articles

Abstract 4830: Predicting drug treatment response in African American lung cancer patients who smoke

Abstract Background: Lung cancer is the third most commonly diagnosed cancer in the US and the leading cause of cancer-related death. African Americans (AAs) have higher lung cancer incidence and mortality rates, and lower survival rates, when compared to their European American (EA) counterparts. It is widely known that cigarette smoking is the strongest risk factor for lung cancer development, but it also plays a significant role in clinical outcome. Cigarette smoking after lung cancer diagnosis (up to 30% patients) comes with several risks, including increased secondary tumors and mortality rates (by 20%), as well as poor treatment outcomes (higher radiation and chemotherapy failure and higher drug clearance). There are limited transcriptomic studies that describe molecular characterizations of AA smokers with lung cancer to predict treatment outcomes. Hypothesis: Cigarette smoking leads to greater drug resistance-related gene expression in AA lung cancer patients. Methods: mRNA expression changes in an AA (NCI-H2172) and EA (NCI-H1944) lung cancer cell line pair exposed to liquid cigarette smoke condensate (CSC) were profiled. The cell lines were matched based on age (62 years), sex (female), histology (lung adenocarcinoma, LUAD, the most common subtype), and culture properties (adherent). The CSC was derived from Murty Pharmaceuticals and prepared by smoking University of Kentucky's 3R4F Standard Research Cigarette on an FTC Smoke Machine. A total of 500,000 cells per well were treated for one hour under standard incubation conditions (37°C, pH 7.0, 5% CO2). Cells were pelleted, RNAs were isolated, treated with DNAse-I to remove contaminating genomic DNA, quantified, and sent for bulk mRNA-sequencing (Novogene Co). Three biological replicates and technical triplicates were performed. Partek Flow and Partek Genomics Suite workflows were used to identify population-specific differentially expressed gene (DEG) signatures and pathway enrichment after CSC exposure. DEG were profiled in LUAD tissues from current smokers in an AA and EA TCGA cohort (n = 18 AAs, 86 EAs). Results: Population-specific gene expression changes were discovered (n = 52 AA DEGs, n = 31 EA DEGs; P <0.001). All of the DEGs were mutually exclusive with no overlap. Some pathways were shared between both populations and others were unique. PI3K/Akt/mTOR signaling pathway enrichment was unique in AA LUAD cells and ECM receptor interactions were distinct in EA LUAD cells. AKT2 (which activates mTOR) had significantly higher expression in LUAD tumor tissues from current AA smokers compared to current EA smokers. Conclusion: Population-specific PI3K/Akt/mTOR pathway alterations may help explain drug resistance in LUAD tumors from AA patients. PI3K signaling is considered a significant cause of resistance to chemotherapy, targeted therapy, and immunotherapy. Future Directions: Expose AA and EA LUAD cell lines to CSC and PI3K/Akt/mTOR pathway inhibitors. Citation Format: Mia Ray, Isaiah Osei-Gyening, Kwabena Acheampong, Marisa Riebesell, Khadijah A. Mitchell. Predicting drug treatment response in African American lung cancer patients who smoke [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4830.

Abstract PO-234: Relationship between increased concentrations of circulating chemokines and population differences in tumor biology

Abstract Genetic ancestry is a significant determinant of multiple aspects of tumor biology, immunity, and inflammatory responses. In lung cancer, in addition to increased incidence in African American (AA) men compared with other racial and ethnic groups in the US, differences in tumor biology between AAs and European Americans (EAs) have been identified. Natural selection is a strong driver of gene selection leading to population differences that can be linked to geographic and genetic ancestry. A classic example involves the Duffy antigen receptor for chemokines, also known as DARC. Individuals with African ancestry are more likely to lack DARC expression on their red blood cells (also known as Duffy null), as this confers resistance to malaria. Loss of erythrocyte expression of DARC is associated with increased circulating chemokine levels in the CXCR and CCR families as DARC serves as a dummy chemokine reservoir. Additionally, Duffy null individuals have lower circulating neutrophils, known as benign ethnic neutropenia. However, loss of DARC expression is exclusive to erythrocytes in Duffy null individuals. As venous endothelial cells and tumor cells also express DARC, we questioned whether the increased circulating bioavailability of DARC ligands in AAs led to increased DARC- dependent signaling in the tumor microenvironment (TME) of AA lung cancer patients. DARC expression on tumor cells is associated with increased aggressiveness and invasion, and endothelial cells have been shown to transcytose DARC ligands into the luminal space. As DARC ligands are associated with angiogenesis and granulocyte recruitment, we hypothesized that tumors of AAs would present with increased blood vessel invasion and granulocyte recruitment to the TME. Using the Somalogic multiplex proteomic assay, we observed significantly elevated levels of the ELR+ CXCR chemokines, with the exception of IL-8 (CXCL8), in serum samples from AA healthy control and stage 1 lung adenocarcinoma patients compared with EAs (samples from the NCI-UMD Case-Control Study), We did not find any evidence of increased angiogenesis as measured by CD31 immunohistochemical staining in AA patients (n= 39) compared with EA patients (n= 107). Immune cell composition did not differ between AAs and EAs as measured by CIBERSORT analysis in both healthy controls and patients between AAs and EAs. Therefore, while AAs have significantly higher levels of circulating DARC ligands compared with EAs, they do not appear to contribute to increased DARC-dependent signaling in normal and tumor lung tissue microenvironment in AAs. Citation Format: Sheryse Taylor, Julian Candia, Adriana Zingone, John Tsang, Brid Ryan. Relationship between increased concentrations of circulating chemokines and population differences in tumor biology [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-234.

Race, insurance type, and stage of presentation among lung cancer patients.

The purpose of this study was to determine whether African-American lung cancer patients are diagnosed at a later stage than white patients, regardless of insurance type. The relationship between race and stage at diagnosis by insurance type was assessed using a Poisson regression model, with relative risk as the measure of association. The setting of the study was a large tertiary care cancer center located in the southeastern United States. Patients who were diagnosed with lung cancer between 2001 and 2010 were included in the study. A total of 717 (31%) African-American and 1,634 (69%) white lung cancer patients were treated at our facility during the study period. Adjusting for age, sex, and smoking-related histology, African-American patients were diagnosed at a statistically significant later stage (III/IV versus I/II) than whites for all insurance types, with the exception of Medicaid. Our results suggest that equivalent insurance coverage may not ensure equal presentation of stage between African-American and white lung cancer patients. Future research is needed to determine whether other factors such as treatment delays, suboptimal preventive care, inappropriate specialist referral, community segregation, and a lack of patient trust in health care providers may explain the continuing racial disparities observed in the current study.

Abstract 258: Characterizing cancer gene mutations in non-small cell lung cancer from African American patients

Abstract Background and Hypothesis: Lung cancer is the leading cause of cancer-related deaths in the United States. The reasons for higher incidence and inferior survival rates among African American lung cancer patients have not been adequately defined. We hypothesized that molecular differences, specifically differential incidence of somatic cancer gene mutations, may be a contributing factor to these population-based disparities. Large-scale, high-throughput genomic studies of the major subtype of lung cancer, non-small cell lung cancer (NSCLC), have so far neglected to adequately represent African American patients. Such information holds potential to transform treatment decisions to improve care for subsets of patients and address disparities. Methods: We tested our hypothesis using a MALDI-TOF mass spectrometry approach to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously linked to NSCLC, including oncogenes and tumor suppressor genes. The sample sets investigated included NSCLC specimens from 335 patients of European ancestry and 137 African Americans. For 299 of these 472, DNA from normal matched specimens was available and included in the study, thus totaling 771 samples. Results: There was no significant difference in frequencies for somatic cancer gene coding mutations across populations and gene mutation frequencies were within reported ranges, e.g., KRAS (11%), EGFR (10%) and PIK3CA (2%). However, this study also uncovered a previously unrecognized germ line variant in the DDR2 oncogene. In addition, we found that the frequencies of single nucleotide polymorphisms (SNPs) in STK11, cMet, and NOTCH differ between African American and European ancestry patients. Conclusion: This body of work is among the largest reported on to date comparing somatic cancer gene mutations in African American and European-ancestry patients. The outcomes show that across a broad spectrum of coding mutations, genomic tumor testing could equally benefit both populations. Citation Format: Aliccia Bollig-Fischer, Shirish Gadgeel, Wei Chen, Michele Cote, Ann G. Schwartz, Gerold Bepler. Characterizing cancer gene mutations in non-small cell lung cancer from African American patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 258. doi:10.1158/1538-7445.AM2014-258

Abstract B16: Developing an interpersonal framework for lung cancer decision making in African Americans.

Abstract This study evaluates the applicability of different behavioral constructs to inter-personal healthcare decision-making in African Americans, and applies anthropological methods to explore the patient-caregiver dynamic to elucidate a decision-making framework in lung cancer care. Lung cancer is the leading cause of cancer death in the US; overall mortality rates are estimated at 72% for men and 41% for women. Outcomes are worse for African American patients who are generally diagnosed at younger ages, with more advanced disease and more comorbidities. Medical advances have produced several treatment options, even given low overall survival. As African American patients weigh their options with their families, we need to understand how these conversations affect patient attitudes and influence decisions, including whether to participate in clinical trials. Though several, well-validated scales assess different dimensions of social support and social influence, they fall short of adequately describing the actual dynamic between patients and their family members as they discuss treatment options outside of the doctor's office. We surveyed African American lung cancer patients treated at a county safety-net hospital ≤ 18 months of diagnosis (N=100) to identify a subsample of patients (N=20) who could name a primary caregiver and indicated willingness to participate in subsequent dyadic, ethnographic interviews over three time points. Measured constructs included social support, social constraint, illness perceptions, lack of acceptance/struggle with illness, coping, and family relationships. We report preliminary findings based on survey accrual to date (~25%). Most patients reported low educational attainment (87%), ever smoking (95%) and identified smoking as the primary cause of their illness (80%). A majority reported having quit smoking (60%), more than half since diagnosis (60%). Two-thirds report having someone to help them with appointments and medical adherence, to visit with and talk about their diagnosis (66%) and indicated interest in participating in the ethnographic interview arm. In ethnographic interviews with the patient and a family member or other patient-identified caregiver, several themes have emerged, including poor knowledge of disease; anger or frustration about physician communication style; and uncertainty about disease course and patient prognosis. Patient ability to relate their current treatment plan varied by social class, with lower SES patients expressing greater uncertainty and lack of understanding about treatment received and subsequent options. Late-stage patients lack a clear understanding of lung cancer progression, even as it relates to their own prognosis. Patients report clinician reluctance to discuss prognosis: in at least one case, clinicians avoided answering direct questions about current disease stage. Caregivers indicate vigilance and affective support but express this in a language of instrumental support (e.g. meal preparation, patient appetite). Patients and caregivers express distress regarding lack of information, both what they were told and what they understood, particularly related to mortality and family preparation for end of life. Preliminary findings suggest successful inter-personal patient decision making may be adversely influenced physician communication style. Citation Format: Simon Craddock Lee, Deborah J. Wiebe, Celette Sugg Skinner. Developing an interpersonal framework for lung cancer decision making in African Americans. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B16.

Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer

African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.