Variables beyond gender differences contribute to ‘invisible epidemic’ of lung cancer in women

Patricia Rivera, MD, FCCP
Patricia Rivera, MD, FCCP

Lung cancer is more than an epidemic for women. While smoking prevalence is declining among both men and women, lung cancer mortality among women is up. Lung cancer kills more women each year than breast cancer.

“The data on whether or not tobacco exposure is more carcinogenic to women are conflicting, but observations about sex differences in lung cancer are well accepted,” said Patricia Rivera, MD, FCCP, Professor of Medicine at the University of North Carolina at Chapel Hill. “Adenocarcinomas are more common in women, they are younger at diagnosis, and women who have never smoked are at higher risk for lung cancer than men who have never smoked.”

Dr. Rivera discussed the epidemiology and biology of lung cancer in women in the session Addressing an Invisible Epidemic: Lung Cancer in Women on Tuesday. The roots of sex differences in lung cancer, she said, are unclear.

Some studies suggest that women may have lower odds of quitting smoking than men. Other studies show different results by country.

Julie Barta, MD
Julie Barta, MD

Multiple nicotine replacement therapy trials found that women have lower quit rates than men. But the odds were reversed for varenicline, with women showing better results compared to men. Vaping studies are similarly mixed.

The mixed signals likely stem from study design, said Julia Barta, MD, Assistant Professor of Pulmonary and Critical Care Medicine at the Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University Sidney Kimmel Medical College. Treatment groups and survey populations are seldom balanced by sex, and sociocultural factors are seldom evaluated.

“A conceptual framework encompassing biological, social, cultural, environmental, and psychosocial factors in smoking cessation can help identify and develop strategies to more effectively address tobacco use,” Dr. Barta said. “Clinical trials need to be designed with gender-specific outcomes in mind.”

The epidemiology and biology of lung cancer in women also needs greater attention to sex-based differences. Male/female smoking differences do not explain the higher incidence of lung cancer among mid-adult women compared to men. Biological studies suggest differences in genetic mutations, DNA adduct formation, P450 enzyme activity, biotransformation of carcinogens, sex steroid signaling, and decreased DNA repair capacity in women.

Mary M. Pasquinelli, DNP, APRN, FNP-BC, CTTS
Mary M. Pasquinelli, DNP, APRN, FNP-BC, CTTS

“There are multiple pathways by which estrogen may be involved in lung tumor development through downstream signaling,” Dr. Rivera said. “We need more data.”

Poorly understood biological differences between men and women may also affect lung cancer screening.

Studies suggest that women may be more susceptible to lung carcinogens and develop lung cancer after lower cigarette exposure than men, said Mary M. Pasquinelli, DNP, APRN, FNP-BC, CTTS, Pulmonary and Thoracic Medical Oncology Nurse Practitioner at the University of Illinois Hospital and Health Science System. But the US Preventive Screening Services Task Force (USPSTF) lung cancer screening eligibility criteria are based solely on age and smoking history.

The USPSTF attempted to ease gender disparities in its 2013 screening criteria by reducing age and smoking history thresholds in 2021.

Dr. Pasquinelli was the lead author on CREST, a retrospective study comparing USPSTF vs PLCOm2012 criteria in 883 lung cancer patients with a history of smoking treated at the University of Illinois at Chicago from 2010 to 2019. The study found that the 2013 USPSTF criteria understated risk in women by 10% and by 6% in the 2021 revision.

Anne V. Gonzalez, MD, MSc, FCCP
Anne V. Gonzalez, MD, MSc, FCCP

“The USPSTF shows a gender/sex disparity,” she said. “We recommend including the PLCOm2012 model into the USPSTF screening guidelines.”

Sex also matters in lung cancer treatment outcomes. Multiple studies show women have a lung cancer survival advantage over men whether treated or untreated, but the reasons are unclear. Female gender is a significant prognostic factor for patients treated with EGFR tyrosine kinase inhibitors, while there is no gender difference in ALK inhibitor outcomes. And women taking anti-PD1 inhibitors are significantly less likely to improve compared to men.

“Lung cancer is clearly an important women’s health issue,” said Anne V. Gonzalez, MD, MSc, FCCP, Associate Professor of Respiratory Medicine at McGill University Health Center in Canada. “Differences in treatment outcomes must be examined systematically. Sex/gender is a determinant in its own right, not a simple variable.”

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