Ernst Wynder was born in Herford, Germany in 1922. He and his parents were Jews who fled Germany in 1938, coming to the U.S., and he enrolled as an undergraduate at NYU. When the war started, he received citizenship and enlisted in the army. Because of his knowledge of German, he was sent back to Europe where he was assigned to intelligence duties.

When the war ended, he enrolled at Washington University at St. Louis, where he ultimately received his MD degree. During a summer research project, he studied smoking behavior among lung-cancer patients in New York City and realized that it was unusually high. In medical school, starting in 1947, he worked with Evarts Graham, a renowned thoracic surgeon, and collected data on 605 male patients with lung cancer, focusing on their smoking histories. Their investigation discovered that 97% smoked.

At that time, that might have been as far as most researchers would have gone. Most clinical studies pre-1950 consisted of either case reports or case series, descriptions of a large number of cases, such as we are discussing here. It might have sufficed to simply say that 97% of a sample of 605 lung cancer patients smoked, and to let it go at that.

But Wynder and Graham made use of what was then a totally novel methodologic tool—a control group. That sounds clichéd now, but in 1949 it was revolutionary. It was one of the first uses of the case-control study, now a commonplace experimental design in medical research. They collected and interviewed an additional 780 male patients of similar age who did not have lung cancer as a comparison or control group. In this population, the proportion of smokers was 85.4%. Wynder and Graham also showed that the percentage of heavy smokers was much higher in the lung cancer group than the control group.

The rate of smokers even in the control group may seem relatively high. However, one must recall that smoking was very common at that time among adult men, so a smoking rate over 80% in the general male population is not surprising. Equally important is that Wynder did not draw his control group from an ideal source. The controls were actually other patients seen in the pulmonary clinics at Washington University and the other participating hospitals. Thus, most of them also had tobacco-related diseases, such as emphysema and chronic bronchitis, and therefore the prevalence of smoking in the control group was higher than it might have been in a truly healthy population. If the study were conducted today, an epidemiologist would draw a control group from, for example, an orthopedic clinic where one would not expect an unusually elevated smoking rate.

Nonetheless, this study was published in May of 1950 in the Journal of the American Medical Association and drew the first widespread recognition of the possible link between tobacco and lung cancer. Multiple studies rapidly followed from others and within the next 15 years, despite intense opposition by the tobacco industry, it became well established that tobacco was responsible for the lung cancer incidence and mortality. A reasonable estimate is that heavy cigarette smoking raises one’s risk tenfold.

This led to the Surgeon General’s Report on Tobacco and Cancer that was released in 1964 and precipitated the decline in cigarette smoking (at least in men). It takes a while for the cessation in smoking to reduce lung cancer incidence and mortality, so lung cancer mortality actually peaked in about 1985 at roughly 82 deaths/100,000 in males and has now fallen to about 46/100,000, reflecting the decline in smoking rates to below 15%.

The lung cancer incidence and mortality rates lag behind the tobacco cessation rates, so we are likely to see a continued drop in mortality among males for the foreseeable future. In addition, it is also important to note that at least some of the improvement in mortality over the last decade or so can be credited to improvements in treatment with precision medicine and targeted therapies and immunotherapy making significant gains.

While there is good news in lung cancer in the U.S., the bad news is that the tobacco companies have targeted the international scene to compensate. Smoking rates have zoomed skyward in India, China and Africa, and remain elevated in the European Union. Thus, global rates of lung cancer are increasing and therefore lung cancer has now risen to become the number one cancer worldwide.

Two final points on this. Both Wynder and Sir Richard Doll, the British epidemiologist mostly credited with establishing the link between cigarettes and lung cancer, were nominated on a number of occasions for the Nobel Prize in Medicine, but never won. Was there a cancer discovery that was more impactful in our time? But laboratory discoveries always had the inside track over epidemiology with the Nobel committee.

Finally, I would note that Ernst himself was a very heavy smoker before making his scientific insights—there is always hope for repentance.

Next week an unusual approach to encourage smoking cessation in “Thoughts on Cancer.”

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.