Small cell lung cancer (SCLC) is an aggressive disease with dismal survival rates and limited therapeutic options. SCLC development is strongly associated with exposure to tobacco carcinogens. However, additional genetic and environmental risk factors that contribute to SCLC pathogenesis are beginning to emerge. Here, we specifically assess disparities pertaining to SCLC in Black populations. In contrast to non–small cell lung cancer, preliminary data suggest that Black individuals may actually be at a lower risk of developing SCLC relative to white individuals. This difference remains unexplained but urgently needs to be verified in larger data sets, because it could provide important new insights and approaches to understanding this recalcitrant tumor. Importantly, little biological information exists on SCLC in Black individuals, and few patient-derived preclinical SCLC models from diverse ancestries are available in the laboratory. Unfortunately, we note strikingly low numbers of Black participants in clinical trials testing new treatments for SCLC. Evidence further indicates that care for patients with SCLC may vary between communities with a large fraction of Black patients and those without. Together, these observations underscore the need to better investigate genetic, environmental, and socioeconomic factors associated with SCLC development, preclinical research, clinical care, and outcomes.
Racial and ethnic minorities in the United States continue to experience health-care disparities. Black individuals are disproportionately affected by cancer generally, having elevated cancer mortality rates relative to other racial groups despite advances in treatment (1). Even after adjusting for contributing socioeconomic factors, Black individuals experience poorer cancer outcomes (1). In particular, lung cancer, which is the leading cause of cancer death in the United States, has striking racial disparities, with Black individuals having the highest 5-year age-adjusted mortality rate (40.1 per 100,000 persons) among common racial and ethnic categories (2). Notably, Black men have a 15% higher incidence and 18% higher death rate from lung cancer relative to white men (1). Multiple factors likely contribute to this survival difference, including that 16% of lung cancer cases are detected early in Black individuals versus 20% in white individuals (1). Normalizing for stage and adjusting for socioeconomic factors, Black individuals are still less likely to receive curative-intent therapies compared with white individuals (1). We believe two critical steps to addressing lung cancer disparities in Black individuals are ensuring that this community is well represented in cutting-edge clinical and translational research studies, and that this community receives care equivalent to their white counterparts. In this review, we will specifically assess cancer disparities in the United States, and use the terms Black individuals/African Americans and white individuals/European Americans interchangeably, as they were reported in the primary referenced literature. We focus on several aspects of the most lethal histology of lung cancer, small cell lung cancer (SCLC), in Black patients, including aspects of basic science investigation, translational research, and clinical care.
SCLC is characterized by high-grade neuroendocrine features, a strong predilection for early metastasis, and rapid acquisition of chemotherapy resistance. SCLC represents 10% to 15% of lung cancer cases, killing approximately 31,000 patients every year in the United States (reviewed in ref. 3). SCLC development is strongly associated with tobacco use, with the vast majority of patients having a smoking history (3). In sharp contrast to non–small cell lung cancer (NSCLC), there have been few therapeutic advances and no improvement in overall survival (3).
Most patients (∼70%) present with extensive-stage (i.e., metastatic) SCLC (ES-SCLC) at diagnosis, and, even with current treatments, the majority of patients (>95%) succumb to the disease within 1 year (3). The mainstay of treatment for patients with SCLC depends on stage and includes radiotherapy, platinum–etoposide chemotherapy combinations, and, within the last 2 years, PD-1/PD-L1 immune-checkpoint inhibitors. Few patients receive surgical resection. The addition of PD-L1 inhibitors to first-line systemic therapy with platinum–etoposide has been the only major systemic treatment breakthrough in more than three decades. As a testament to the abysmal outcomes in patients with ES-SCLC, these PD-L1 targeting agents, in combination with platinum-based cytotoxic chemotherapy, extend median overall survival (OS) by only 2 months, from ∼10 months with chemotherapy alone to ∼12 months with chemotherapy plus PD-L1 blockade (NCT02763579 and NCT03043872). This is in stark contrast to NSCLC, where substantial improvements in survival have been achieved over the past few decades due to the development of several targeted therapies and the advent of immunotherapy (3). Notably, these advances in treatment of NSCLC have depended on a combination of extensive preclinical research efforts and a broad array of clinical trials reflecting different strategies for unique patient populations. Both preclinical studies and clinical trials must reflect the diversity of disease, with representation of the spectrum of genotypes, genders, races, and ethnicities to optimally shape treatment options for patients with lung cancer.
Disparities in SCLC Among Black Individuals
Epidemiologic studies have demonstrated that there are notably higher rates of lung cancer in Black men compared with their white counterparts (85.4 vs. 74.3 per 100,000 men; ref. 1). Although Black men have slightly higher rates of cigarette smoking than white men (1), cigarette smoking, including the type of tobacco and inhalation pattern, may not fully explain the increased rate of lung cancer in Black men. A meta-analysis of lung cancer in individuals who never smoked reported higher incidence and mortality in African American men than in counterparts of European descent (4).
Interestingly, the higher incidence of lung cancer in Black men is exclusive to NSCLC (Fig. 1A). Comparative transcriptomic analyses have identified differences in gene-expression patterns between African American and European American NSCLC tumor samples that could contribute to the differential risk observed. For example, tumors from European Americans were enriched in cell-cycle and proliferation pathways compared with tumors from African Americans (5). This study also revealed population-specific differences in drug sensitivity between the two cohorts evaluated, further underscoring potential differences in underlying tumor biology. In contrast to NSCLC, Black men actually have lower incidence of SCLC compared with white men (7.1 vs. 9.0 per 100,000; Fig. 1B; SEER database, https://seer.cancer.gov/explorer/). This observation may reflect genetic and epigenetic differences between SCLC tumors from Black individuals and SCLC tumors from white individuals. To the best of our knowledge, similar studies have not been performed in SCLC to date; however, such studies could identify key differences with biological implications for understanding SCLC development across racial and ethnic groups. Below, we will review molecular, preclinical, and clinical factors that may address our knowledge gaps surrounding these disparities in SCLC.
Limited Genetic and Genomic Analyses of SCLC in Black Individuals
One approach to investigate genetic factors leading to SCLC development and clinical outcomes in Black individuals is through genome-wide association studies (GWAS). Unfortunately, GWAS in Black patients with lung cancer in general, and SCLC in particular, are quite limited (reviewed in ref. 6). As a result, studies aimed at identifying the causative factors leading to the lower incidence of SCLC in Black men remain challenging to execute. The development of lung cancer, specifically SCLC, could be affected by differences in nicotine addiction. However, we have not found GWAS investigating SNPs in genes coding for subunits of the nicotinic acetylcholine receptor or molecules involved in the metabolism of nicotine (e.g., CYP2A6) examining SCLC as an outcome. Furthermore, given the limited and nonrepresentative GWAS data sets in lung cancer, it is also very challenging to study biological factors leading to differences in response to and toxicity from chemotherapy as well as OS. As an example, a GWAS investigating response to cisplatin, which is an alkylating agent commonly used to treat SCLC, found that lymphoblastoid cell lines from white individuals were more sensitive to cisplatin than those from Black individuals. However, the validation study in actual patients with SCLC did not include Black patients (7). Data from lung cancer in general (6) suggest that there may be shared and distinct genetic factors that contribute to SCLC development in Black individuals and other groups. Unfortunately, however, GWAS related to SCLC in Black patients are too few to identify possible genetic risk factors that may be unique to this population.
Paucity of SCLC Preclinical Models Derived from Black Patients
Given the observed differences in both incidence and survival of SCLC in Black individuals, there is a need to incorporate Black samples into SCLC research models. Having a diverse range of representative samples in preclinical research and clinical trials increases the generalizability of results and may improve health outcomes in particular for populations. These are vital steps toward eliminating health inequities between racial and ethnic minority groups and their white counterparts. Herein, we assess the current representation of preclinical models derived from Black individuals in the SCLC field.
Cell Line Models
Due to the paucity of SCLC tumor tissue availablefor research studies, patient-derived cell lines have been an essential tool for preclinical studies aimed at enhancing our understanding of SCLC biology and developing novel therapies (https://discover.nci.nih.gov/SclcCellMinerCDB/). Analyses of SCLC cell lines from publicly available data sets—the Cancer Cell Line Encyclopedia (CCLE; https://portals.broadinstitute.org/ccle), Genomics of Drug Sensitivity in Cancer (GDSC; https://www.cancerrxgene.org/), and the SCLC cBioPortal for Cancer Genomics (https://www.cbioportal.org/)—indicate that less than 9% of these cell lines are classified as Black (Fig. 1C). In total, only 10 unique cell lines are derived from Black patients out of the 111 unique cell lines in these data sets (Fig. 1D). As a result, research utilizing these data sets likely does not accurately depict tumor biology associated with Black patients with SCLC. Notably, the average age of cell line acquisition (most were acquired at time of diagnosis) is lower for Black patients (51.2 years of age, n = 9) compared with white patients (56.7 years of age, n = 71) and Asian patients (56.4 years of age, n = 8), suggesting that Black individuals experience SCLC at a younger age. A recent study reported a similar observation, with Black patients diagnosed with ES-SCLC being younger (52.5% being 40–65 years of age) compared with white patients (46.7%) and patients from other race groups (40.5%; ref. 8).
Circulating tumor cell patient-derived explants (CDX) and patient-derived xenograft (PDX) models have advanced SCLC preclinical studies, allowing for in vivo investigation of SCLC pathogenesis, exploration of acquired drug resistance, and development of novel targeted therapies (3). Analyses of racial and ethnic diversity in CDX and PDX model–based studies highlight a tremendous area of missed investigative opportunity. In two large-scale studies from the United States (34 CDX/PDX models) and the United Kingdom (39 CDX), race/ethnicity was not readily available (9, 10). This same trend persisted in other CDX/PDX studies, with most (13/14 studies) not citing racial or ethnic patient information.
In the largest collection of primary SCLC tumors published thus far, none (0%) of the 108 tumors for which race/ethnicity was provided are from Black patients (Fig. 1E; ref. 11). In the Memorial Sloan Kettering Cancer Center integrated mutation profiling of actionable cancer targets (MSK-IMPACT) database, only 11 of 352 tumors (3.125%) for which information is available are reported as being from Black patients. None of the 153 tumors available through the SCLC cBioPortal database are from Black individuals. Thus, in total, 1.49% (n = 11/737) of tumors for which racial information has been detailed are from Black individuals (Fig. 1E). This number is likely insufficient to draw any conclusions regarding possible differences in subtypes, gene expression, or genetic alterations. Thus, preclinical models to study SCLC in Black patients are extremely limited.
SCLC Disparities Persist in the Clinic
The most recent advances in SCLC treatment have emerged predominantly in the form of the PD-L1 immune-checkpoint inhibitors atezolizumab (NCT02763579) and durvalumab (NCT03043872), which were approved by the FDA in March 2019 and March 2020, respectively, for first-line treatment in ES-SCLC in combination with traditional platinum–etoposide chemotherapy. Nivolumab (August 2018, NCT01928394) and pembrolizumab (June 2019, NCT03066778) were granted accelerated FDA approvals for second- and third-line treatment of recurrent metastatic SCLC. When assessing the demographics of participants included in these practice-changing, large-scale clinical trials, substantial inequities in participant race/ethnicity are apparent. Only 3 of 403 (0.7%) participants in the IMpower133 trial (atezolizumab), 5 of 537 (0.9%) participants in the CASPIAN trial (durvalumab), 4 of 109 (4%) participants in the CheckMate 032 trial (nivolumab), and 1 of 435 (0.22%) participants in the KEYNOTE 604 trial (pembrolizumab) were Black (Fig. 1F). Another large-scale trial assessing various imaging modalities in patients receiving chemoradiotherapy reported only 2 of 539 patients as Black (NCT00433563; Fig. 1F). These disparities in clinical trials that define new treatments are particularly sobering given well-documented disparities in the clinical treatment of SCLC in Black patients. In particular, a study using the real-world SEER-MEDICARE data set to analyze systemic chemotherapy use in patients with SCLC between 1985 and 2005 reported that Black patients were less likely to receive chemotherapy than their white counterparts (47.5% vs. 50.2%; OR 0.88, P = 0.002 in a multivariable logistic regression model) and that Black patients had significantly inferior survival (12). An additional study of 82,592 patients diagnosed with ES-SCLC from 2004 to 2016 in the National Cancer Data Base reported similar findings, with Black patients being less likely to receive chemotherapy compared with white patients (OR 0.85, P = 0.0004; ref. 8). Despite receiving poorer treatment, Black patients had better one-year survival compared with white patients (8.3 months vs. 8.0 months; ref. 8).
Physicians and Investigators May Influence Disparities in Lung Cancer
Factors contributing to the substantial disparities in lung cancer observed in Black individuals include genetic, socioeconomic, and environmental influences, higher smoking rates, decreased access to care, inequitable treatment in clinic, and lower enrollment in clinical trials (13). Another important factor is provider bias. One study reported that African American individuals who smoke and interacted with racially discordant physicians were less accurate in their perception of lung cancer risk than those who interacted with a racially concordant physician (13). It was also reported in a study that health-care providers gave Black patients significantly less information than their white counterparts during lung cancer consultations (14). Another study reported an absence of systematic training among clinical and research personnel regarding recruitment of minorities into clinical trials (15). In contrast, Black researchers were more likely to investigate racial and ethnic differences in their research and to be trained in recruiting minorities (15). Taken together, these data underscore the importance of cultural competency training for providers and the urgent need to support Black scientific investigators, clinicians, and clinical investigators with focused interests in lung cancer.
Conclusions and Recommendations
We believe that mitigating factors that prevent Black individuals from having similar lung cancer outcomes as white individuals include (i) incorporating Black samples into preclinical research models, (ii) increasing access to care, (iii) ensuring equal treatment delivery, (iv) increasing enrollment in clinical trials, and (v) enhancing the number of Black investigators, clinicians, and—importantly—SCLC patient advocates. The first step is to clearly identify and disseminate the racial disparities knowledge gaps in both clinical and basic molecular/cell biological understanding of lung cancer in general and SCLC in particular for Black individuals. The next steps are to both pinpoint the multiple opportunities that exist for further research in and treatment of SCLC in Black patients and identify “advocates” for filling these knowledge gaps at academic institutions, in general clinical practice, and at the NCI level. The NCI-sponsored SCLC U24 Consortium (U24CA213274), which serves as the central hub for many SCLC U01 grants, the NCI special program of research excellence (“SPOREs”) in lung cancer, the new NCI racial disparities SPOREs, and grants targeting racial disparities are important clinical translational efforts that include clinical and basic laboratory investigators, NCI staff, and patient advocates. These efforts need to be extended to national and international organizations dealing with cancer care and lung cancer, such as the American Society of Clinical Oncology (ASCO), the American Association for Cancer Research (AACR), the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society, and other relevant professional organizations. Extensive efforts also need to be reflected in our training of young clinicians and investigators in these areas and recruitment of Black patient advocates to provide a bridge both to the patients and to the clinical and laboratory investigators addressing these issues. Additional steps should be aimed at disseminating pertinent and easily digestible health information to Black patients and identifying and partnering with important members of the broad health-care team who participate in that process (e.g., social workers, community churches, nurse navigators). Studies aimed at understanding Black individuals' attitudes toward clinical trials and identifying existing barriers that prevent participation must be included in these efforts. In addition, we must ensure that other key stakeholders such as regulatory agencies, funders and sponsors of trials, research institutions, investigators, providers, and trial management staff are keeping disparities on the forefront of trial design and execution. Furthermore, trust between the Black and medical communities must also be reestablished due to the history of unethical medical and research practices—James Marion Sims's experiments on slaves, the Tuskegee Syphilis Study, and theft of HeLa cells—to which Black individuals have been subjected. Finally, we urgently need a consolidated database of Black patients with SCLC, their clinically and molecularly annotated tumors, and available preclinical models that will stimulate and facilitate research in this important area. These are critical first steps toward improving outcomes for Black patients with SCLC.
P.L. Thomas reports grants from NIH during the conduct of the study. J.D. Minna reports grants from NIH and personal fees from NIH and University of Texas Southwestern Medical Center during the conduct of the study. C.M. Rudin reports personal fees from AbbVie, Amgen, AstraZeneca, Bicycle, Celgene, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, Earli, and Harpoon outside the submitted work. J. Sage reports grants from Stemcentrx/AbbVie outside the submitted work; in addition, J. Sage has a patent for Forty Seven Inc./Gilead licensed. C.M. Lovly reports grants from NIH/NCI, Lung Cancer Foundation of America, and IASLC during the conduct of the study; personal fees from Pfizer, Eli Lilly/Loxo, Novartis, AstraZeneca, Genentech, Roche, Ariad, Takeda, Blueprints Medicine, Cepheid, Foundation Medicine, and Syros outside the submitted work. No disclosures were reported by the other authors.
Numerous epidemiological, preclinical, and clinical research studies are cited in this In Focus article. The authors are extremely grateful to all of the patients who generously donated their time and tissue samples to make these studies possible. Through their generous donations, these patients also shared their trust with the cancer research community that ensuing studies would affect their care and the care of others battling SCLC. The authors wish to honor and celebrate these contributions, without which no advances in SCLC would be possible. The authors are also extremely grateful to the investigators who contributed to additional studies in the SCLC field but were not highlighted due to space constraints. The authors thank Luc Girard for preclinical model database analyses and James Mungin Jr. and Samantha Beik for reviewing and editing the manuscript. The authors wish to acknowledge Dr. Adi Gazdar, an internationally renowned expert in SCLC biology, along with Sylvia Stephenson, a lab technician at the NCI-Navy Branch, who codeveloped many of the SCLC cell lines described in the text. Lastly, P.L. Thomas would like to thank the AACR, the Minorities in Cancer Research council, and the NCI Center to Reduce Cancer Health Disparities for selecting her to be a recipient of the 2020 Minority Scholar in Cancer Research Award. This work was supported by the NIH (grant numbers U54CA217450, U01CA224276, P30CA086485, UG1CA233259, S21MD000104, R35CA231997, U24CA213274, U01CA213338, and P50CA070907) and the Lung Cancer Foundation of America/International Association for the Study of Lung Cancer Lori Monroe Scholarship.