lung cancer risk

Menopause and other reproductive factors may play a role in lung cancer risk.

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An older woman wearing a blue knit cap drinks coffee on a beach
Researchers say menopause and age of first child birth may be factors in determining a woman’s risk of lung cancer.
  • Women who do not smoke are at a greater risk of lung cancer than male non-smokers.
  • Sex hormones may mediate these gender disparities in lung cancer incidence, but the evidence showing an association between sex hormone-related reproductive factors and lung cancer risk has been contradictory.
  • A large study involving more than 273,000 women, however, did find an association between reproductive factors, such as age at menopause and first childbirth, and lung cancer risk.
  • Experts say the study underscores the importance of considering reproductive factors while screening for lung cancer.

While smoking is a risk factor for lung cancer, women are at a higher riskTrusted Source of lung cancer incidence than men after accounting for smoking status.

Scientists say that hormones may contribute to these sex differences in susceptibility to lung cancer.

However, evidence supporting a role for factors associated with reproductive health, especially those involving changes in sex hormone levels, in the causation of lung cancer has been inconsistent in the past.

Now, researchers who conducted a large study published in the journal Chest report that reproductive factors, such as early age at menopause and first childbirth, are associated with an increased risk of lung cancer.

Dr. Wael Harb, a hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast and Saddleback Medical Centers in California who was not involved in the study, told Medical News Today that these findings could help improve lung cancer screening.

“Identifying reproductive factors that may contribute to lung cancer risk in women could lead to early interventions or screening strategies tailored to this population,” Harb said. “This has the potential to reduce the burden of lung cancer among women.”

“This research adds to the existing body of knowledge by providing insights into the complex relationship between reproductive factors and lung cancer, potentially paving the way for further investigations and advancements in the field,” he added.

Sex differences in lung cancer incidence

Smoking is a risk factor for all lung cancers, but women show an increased susceptibility to lung cancer even after adjusting the data for smoke exposure.

Numerous studies in the past have examined the association between sex-specific reproductive factors and lung cancer risk to understand the basis of the higher incidence of lung cancer in women.

Specifically, these studies have examined the potential role of reproductive factors, such as age at the onset of menstruation (menarche), age at menopause, and the use of hormone replacement therapy and oral contraceptives, in influencing lung cancer risk. These reproductive factors influence the length and duration of exposure to sex hormones, such as estrogen and progesterone.

Experts note that one of the shortcomings of past studies is their small sample size. Moreover, these studies have involved different study populations or deployed different study designs, precluding the possibility of drawing meaningful conclusions.

Impact of reproductive factors on lung cancer risk

In the present study, researchers from China used data from the UK Biobank, a large database containing medical, genetic, and lifestyle information from more than half a million United Kingdom residents.

Using the database, the researchers analyzed health and genetic data obtained from 273,190 women between 2006 and 2010.

The researchers obtained self-reported data from these participants on reproductive factors, including age at menarche (first menstrual period) and menopause, use of hormone replacement therapy and oral contraceptive pills, age at first live birth, and surgical removal of ovaries or the uterus.

The researchers also calculated reproductive lifespan by subtracting the age at menarche from that at menopause.

Menarche before 12 years of age was categorized as early menarche, whereas menopause before 47 years was classified as early menopause.

The researchers tracked the incidence of lung cancer in this group of women over an average follow-up period of 12 years. Upon analyzing the data, the researchers reported that participants who were older and were smoking at the end of the follow-up period were more likely to have lung cancer.

Women who had an earlier onset of menarche or menopause were also at increased risk of lung cancer. Women with a reproductive lifespan shorter than 36 years had a higher likelihood of lung cancer incidence than those with a normal reproductive lifespan of 36 to 39 years.

Surgical removal of the ovaries that produce the sex hormones estrogen and progesterone was also associated with elevated lung cancer incidence. Such an association was absent in women who had undergone a surgical removal of the uterus.

In addition, use of hormonal replacement therapy was associated with a greater likelihood of lung cancer. However, this association disappeared after adjusting for factors such as age, race, body-mass index, and smoking status.

Lastly, the risk of lung cancer was higher in women who had their first live birth before 26 years of age than those who had a firstborn between 26 and 30 years of age.

Together, experts say these results suggest a role for the disruption of sex hormone levels in mediating lung cancer.

In a follow-up analysis, the researchers examined whether these reproductive factors were associated with specific subtypes of lung cancer.

Partially consistent with previous studiesTrusted Source, the present research found that early age of menopause onset, shorter reproductive lifespan, and younger age at first childbirth was associated with the risk of non-small cell lung cancer, including adenocarcinomas. This association was more pronounced in women who were currently smoking or had a history of smoking.

Strengths and limitations of the lung cancer study

The strengths of the study included the large sample size and a long follow-up period of 12 years.

Harb also noted that the study adjusted their analysis for variables, such as smoking and environmental exposures, while examining the association between reproductive factors and lung cancer risk.

A shortcoming of the study included the use of self-reported data on reproductive factors, making it susceptible to bias. The study involved primarily women of European descent and the findings may not be generalizable to other populations.

Implications of the lung cancer research

Dr. Michael Gieske, the director of Lung Cancer Screening at St. Elizabeth Healthcare in California who wasn’t involved in the study, told Medical News Today that the findings could play an important role in risk assessment for lung cancer.

“We know that lung cancer is due to more than age and smoking history with many other risk factors in consideration,” Gieske said. “Accordingly, we are looking at genetic markers and other causes and predilections for lung cancer so that we will ultimately be able to save many more lives from lung cancer through expanded evidence-based screening.”

“AI algorithms incorporating risk factors… will be a growing part of the overall risk assessment for all types of cancer in the near future,” he added. “This science, along with improving biomarker capabilities will transform the way we approach cancer screening.”

AI Model Detects Future Lung Cancer Risk Based on CT Scans

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An artificial intelligence tool for lung cancer risk assessment being developed by researchers at MIT’s Abdul Latif Jameel Clinic for Machine Learning in Health, Mass General Cancer Center (MGCC), and Chang Gung Memorial Hospital (CGMH) takes a personalized approach to assessing each patient’s risk of lung cancer based on CT scans. The deep-learning model named Sybil is described in a new paper published in the Journal of Clinical Oncology.

“It’s the biggest cancer killer because it’s relatively common and relatively hard to treat, especially once it has reached an advanced stage,” says Florian Fintelmann, MGCC thoracic interventional radiologist and co-author on the new work. “In this case, it’s important to know that if you detect lung cancer early, the long-term outcome is significantly better. Your five-year survival rate is closer to 70%, whereas if you detect it when it’s advanced, the five-year survival rate is just short of 10%.”

Although there has been a surge in new therapies introduced to combat lung cancer in recent years, the majority of patients with lung cancer still succumb to the disease. Low-dose computed tomography (LDCT) scans of the lung are currently the most common way patients are screened for lung cancer with the hope of finding it in the earliest stages, when it can still be surgically removed. Sybil takes the screening a step further, analyzing the LDCT image data without the assistance of a radiologist to predict the risk of a patient developing a future lung cancer within six years.

Jameel Clinic, MGCC, and CGMH researchers demonstrated that Sybil obtained C-indices of 0.75, 0.81, and 0.80 over the course of six years from diverse sets of lung LDCT scans taken from the National Lung Cancer Screening Trial (NLST), Mass General Hospital (MGH), and CGMH, respectively — models achieving a C-index score over 0.7 are considered good and over 0.8 is considered strong. The ROC-AUCs for one-year prediction using Sybil scored even higher, ranging from 0.86 to 0.94, with 1.00 being the highest score possible.

Despite its success, the 3D nature of lung CT scans made Sybil a challenge to build. Co-author Peter Mikhael, an MIT PhD student in electrical engineering and computer science, and a iliate of Jameel Clinic and the MIT Computer Science and Artificial Intelligence Laboratory (CSAIL), likened the process to “trying to find a needle in a haystack.” The imaging data used to train Sybil was largely absent of any signs of cancer because early-stage lung cancer occupies small portions of the lung — just a fraction of the hundreds of thousands of pixels making up each CT scan. Denser portions of lung tissue are known as lung nodules, and while they have the potential to be cancerous, most are not, and can occur from healed infections or airborne irritants. 

To ensure that Sybil would be able to accurately assess cancer risk, Fintelmann and his team labeled hundreds of CT scans with visible cancerous tumors that would be used to train Sybil before testing the model on CT scans without discernible signs of cancer.

MIT electrical engineering and computer science PhD student Jeremy Wohlwend, co-author of the paper and Jameel Clinic and CSAIL a iliate, was surprised by how highly Sybil scored despite the lack of any visible cancer. “We found that while we [as humans] couldn’t quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer,” he recalls. “Knowing [Sybil] was able to highlight which side was the most likely side was really interesting to us.”

Co-author Lecia V Sequist, a medical oncologist, lung cancer expert, and director of the Center for Innovation in Early Cancer Detection at MGH, says the results the team achieved with Sybil are important “because lung cancer screening is not being deployed to its fullest potential in the U.S. or globally, and Sybil may be able to help us bridge this gap.”

Lung cancer screening programs are underdeveloped in regions of the United States hardest hit by lung cancer due to a variety of factors. These range from stigma against smokers to political and policy landscape factors like Medicaid expansion, which varies from state to state.

Moreover, many patients diagnosed with lung cancer today have either never smoked or are former smokers who quit over 15 ago — traits that make both groups ineligible for lung cancer CT screening in the United States.

“Our training data consisted only of smokers because this was a necessary criterion for enrolling in the NLST,” Mikhael says. “In Taiwan, they screen nonsmokers, so our validation data is expected to contain people who didn’t smoke, and it was exciting to see Sybil generalize well to that population.”

“An exciting next step in the research will be testing Sybil prospectively on people at risk for lung cancer who have not smoked or who quit decades ago,” says Sequist. “I treat such patients every day in my lung cancer clinic and it’s understandably hard for them to reconcile that they would not have been candidates to undergo screening. Perhaps that will change in the future.”

There is a growing population of patients with lung cancer who are categorized as nonsmokers. Women nonsmokers are more likely to be diagnosed with lung cancer than men who are nonsmokers. Globally, over 50% of women diagnosed with lung cancer are nonsmokers, compared to 15 to 20% of men.

MIT Professor Regina Barzilay, a paper co-author and the Jameel Clinic AI faculty lead, who is also a member of the Koch Institute for Integrative Cancer Research, credits MIT and MGH’s joint e orts on Sybil to Sylvia, the sister to a close friend of Barzilay and one of Sequist’s patients. “Sylvia was young, healthy and athletic — she never smoked,” Barzilay recalls. “When she started coughing, neither her doctors nor her family initially suspected that the cause could be lung cancer. When Sylvia was finally diagnosed and met Dr Sequist, the disease was too advanced to revert its course. When mourning Sylvia’s death, we couldn’t stop thinking how many other patients have similar trajectories.”

COPD increases lung cancer risk in smokers

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Former smokers have a higher risk of small cell lung cancer (SCLC), which, in some cases, is partially mediated by chronic obstructive pulmonary disease (COPD), according to a large, multinational study.

Compared to non-smokers, former and current smokers had a significantly higher risk of SCLC (odds ratio [OR], 6.21, 95 percent CI, 5.21-7.41 and OR, 26.72, 95 percent CI, 22.54-31.68, respectively; p<0.001).

Smokers who have COPD had a 1.86 times higher risk of SCLC (95 percent CI, 1.61-2.16; p<0.001) than smokers without COPD. Among former smokers, COPD indirectly mediated the risk of SCLC (OR, 1.03; p<0.001), though this only occurred in less than 10 percent of cases. [EBioMedicine 2015;doi:10.1016/j.ebiom.2015.09.031]

A longer period of cessation greatly reduced the risk of SCLC in a dose-response manner (OR, 0.57, 95 percent CI, 0.45-0.73 for individuals who had quit for 5-9 years versus OR, 0.11, 95 percent CI, 0.09-0.14; p<0.001 for those who had quit for more than 20 years).

Previous studies have shown that even after years of cessation, the risk of SCLC remains higher than that of non-smokers, which has been attributed to irreversible lung damage. [Resp Res 2013;14:97]

The association between COPD and overall lung cancer is well-established, and newer studies have demonstrated the link between cigarette smoking and concurrent COPD and NSCLC. [Ann Intern Med 1987;106:512-518; Int J Cancer 2014;134:961-970]

To investigate the impact of smoking and the specific role of COPD on SCLC risk, researchers analyzed data from 24 studies from the International Lung Cancer Consortium (ILCCO) that included 4,346 patients with SCLC and 37,942 without the disease.

According to the researchers, SCLC has a high mortality and relapse rate, which raises the need for preventive measures. This is the largest study investigating the link between multiple smoking risk factors, COPD and SCLC risk, as well as the first to look into COPD as a mediator between smoking and SCLC.

Study limitations include potential underdiagnosis of COPD leading to overestimation of smoking patterns. The use of corticosteroids or statins which improve COPD and reduce lung cancer risk may also have distorted the results. Researchers called for further investigation into the role of genetics and the pathways by which COPD, smoking and lung cancer are connected in order to enable early diagnosis of SCLC.

No association between lung cancer risk in women and reproductive history or hormone use

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The Women’s Health Initiative Studies, a large prospective study of lung cancer, found no strong associations between lung cancer risk and a wide range of reproductive history variables and only revealed weak support for a role of hormone use in the incidence of lung cancer.

In the United States 40% of the 160,000 deaths from are women. In men 90% of lung cancer deaths are associated with tobacco usage; however in women this number is around 75-80%. Female never-smokers are more likely to develop lung cancer than male never-smokers and the histological subtype of lung cancer is different between men and women. Women have a better prognosis with a 5-year survival rate of 20% compared to 15.4% for men. Given these gender differences there is a need to understand the potential role of reproductive factors and hormone use in determining lung cancer risk in women.

The Women’s Health Initiative Observational Study and Clinical Trials enrolled a geographically and ethnically diverse cohort of 161,808 postmenopausal women age 50-79 years between 1993 and 1998 at 40 centers across the United States. Reproductive history, oral contraceptive use, and hormone therapy replacement was evaluated in the 160,855 women eligible to be included in the analysis. Incident lung cancer was observed in 2,467 and the median follow-up was 14 years.

The results published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that with previous use of estrogen plus progestin (< 5 years) were at a slightly reduced risk for lung cancer. Increasing age at menopause trended towards reduced risk whereas increasing number of children trended towards increased risk. Those who were age 20-29 at the birth of their first child had reduced risk of non-small cell lung cancer (NSCLC), but not all lung cancer. Risk estimates for hormone therapy usage and previous surgery to remove both ovaries varied with tobacco exposure history.

The authors conclude “our study does not support the idea that reproductive history independently contributes to lung cancer risk, and recapitulates the inconsistent findings within epidemiologic literature on lung cancer risk and reproductive history measures. Likewise, the epidemiologic literature is also inconsistent with regard to the role of hormone use in lung cancer risk and the overall results presented by our study suggest that oral contraceptives and hormone therapy use are not associated with risk of lung cancer.” The lead author Ann G. Schwartz, Deputy Center Director, Karmanos Cancer Institute, Wayne State University and member of IASLC, cautions that “questions remain about estrogen and lung that will not easily be answered by studies focusing on  use and