Smokers who have chronic obstructive pulmonary disorder (COPD) may face nearly twice the risk of getting small cell lung cancer (SCLC)--the deadliest form of lung cancer--than smokers who don't have COPD, according to a large worldwide study led by researchers at the Harvard T.H. Chan School of Public Health.

The study was published online September 24, 2015 in EBioMedicine.

The new study--the largest-ever epidemiologic study of SCLC--is the first to look at how much COPD, a progressive disease that makes it hard to breathe, increases smokers' risk of getting SCLC. Although it's long been known that smoking is a major risk factor for lung cancer, the new study estimates the risk more precisely than before.

"This work suggests that we need to tease out the mechanisms by which COPD may increase lung cancer risk in smokers, and to conduct clinical trials to determine whether treating COPD in former and current smokers lessens that risk," said David Christiani, Elkan Blout Professor of Environmental Genetics at Harvard Chan School and senior author of the study.

SCLC accounts for 15-18% of lung cancers worldwide. Although patients often respond well to initial treatment, they often relapse within a year. Those with limited SCLC live, on average, 14-20 months after diagnosis; those with extensive disease live only 9-11 months after being diagnosed. Given SCLC's high relapse and mortality rate, researchers wanted to know more about possible ways to prevent it.

Researchers analyzed data from 24 case-control studies from the International Lung Cancer Consortium--conducted in North America, Europe, Asia and Oceania--that included 4,346 people with SCLC and 37,942 without the disease. The studies included information on participants' health, gender, age, race, education level, and family history of lung cancer, as well as their smoking history, including how old they were when they started, how many years they smoked, how many cigarettes they smoked each day, and, for former smokers, how long it had been since they quit.

The results showed that:

• Among those who smoked a pack of cigarettes each day, the risk of getting SCLC rose sharply through 50 years of smoking, then less sharply after that. Compared with nonsmokers, smokers' odds of getting the disease ranged from more than four times higher for those who smoked a daily pack for less than 20 years in a row, to nearly 70 times higher for those who did so for 80 years or more.
• Smokers with COPD had a 1.86-fold higher risk of SCLC than smokers without COPD.
• Among smokers, having COPD accounted for 8% of SCLC cases.

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Other Harvard Chan School authors, all from the Department of Environmental Health, included Ruyi Huang, postdoctoral research fellow and lead author; Yongyue Wei, postdoctoral research fellow; Li Su, lab director and researcher; and Ruyang Zhang, postdoctoral research fellow.

This work was supported by the National Institutes of Health and National Cancer Institute (grants CA092824, CA074386, CA090578, ES00002, CA80127, CA84354, CA68384, the Intramural Research Program, CA060691, HHSN261201000028C, P30CA022453, CA167462, DA11386, CA90833, CA77954, CA09142, CA96134, and ES011667); BfS (Bundesamt für Strahlenschutz, Germany) (grant St Sch 1066, 4074, 4074/1); Mayo Clinic Foundation; Canadian Cancer Society Research Institute (grant 020214); FIS/Spain (grant FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604); FICYT/Asturias (grants FICYT PB02-67 and FICYT IB09-133); Roy Castle Lung Cancer Foundation in UK; Ministry of Education, Science, Sports, Culture, and Technology of Japan (grants-in-aid for Scientific Research on Priority and Innovative Areas); Ministry of Health, Labor, and Welfare of Japan [Third-Term Comprehensive 10-Year Strategy for Cancer Control; National Cancer Center Research and Development Fund (23-A-4); Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry of Health, Labor and Welfare; the Bi-national Israel-US Science Foundation; the Baden-Württemberg Ministry of Science Research and Arts Foundation; the Ann Fitzpatrick Alper Research Program for Environmental Genomics of the University of California at Los Angeles Jonsson Comprehensive Cancer Center. Wei is partially supported by the National Natural Science Foundation of China (grant 81402764) and the Natural Science Foundation of Jiangsu, China (grant BK20140907). Zhang is partially supported by the National Natural Science Foundation of China (grant 81402763).

"Associated links among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium," Ruyi Huang, Yongyue Wei, Rayjean J. Hung, Geoffrey Liu, Li Su, Ruyang Zhang, Xuchen Zong, Zuo-Feng Zhang, Hal Morgenstern, Irene Brüske, Joachim Heinrich, Yun-Chul Hong, Jin Hee Kim, Michele Cote, Angela Wenzlaff, Ann G. Schwartz, Isabelle Stucker, John Mclaughlin, Michael W. Marcus, Michael P.A. Davies, Triantafillos Liloglou, John K. Field, Keitaro Matsuo, Matt Barnett, Mark Thornquist, Gary Goodman, Yi Wang, Size Chen, Ping Yang, Eric J. Duell, Angeline S. Andrew, Philip Lazarus, Joshua Muscat, Penella Woll, Janet Horsman, M. Dawn Teare, Anath Flugelman, Gad Rennert, Yan Zhang, Hermann Brenner, Christa Stegmaier, Erik H. F. M. van der Heijden, Katja Aben, Lambertus Kiemeney, Juan Barros-Dios, Monica Pérez-Ríos, Alberto Ruano-Ravina, Neil E. Caporaso, Pier Alberto Bertazzi, Maria Teresa Landi, Juncheng Dai, Hongbing Shen, Guillermo Fernandez-Tardon, Marta Rodriguez-Suarez, Adonina Tardon, Ruyang Zhang, David C. Christiani, EBioMedicine, online September 24, 2015, doi:10.1016/j.ebiom.2015.09.031.

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Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives--not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America's oldest professional training program in public health.