Sex-based differences in lung cancer

Lung cancer remains one of the most ominous health threats worldwide, capturing the concern of scientists, physicians, and the general public alike. In what promises to be a pivotal discovery for how we understand and potentially treat this disease, a recent retrospective study from the Division of Pulmonology at the Medical University of Vienna, Austria, indicates that women might carry a disproportionately higher risk for developing lung cancer than men do, even when their exposure to cigarette smoke is substantially lower.

This remarkable finding has generated vigorous discussion in oncology circles, fueling new hypotheses about the biological, molecular, and perhaps even hormonal underpinnings that differentiate how lung cancer manifests and progresses in men and women. The findings, which derive from a cohort of 286 consecutive patients diagnosed between 2020 and 2022, provide a fresh look at a century-old question: Do women and men exhibit distinct susceptibilities to lung cancer, and if so, what does that mean for future diagnostics, treatments, and potentially even public health policies?

The quest to understand why one group may be at higher risk than the other isn’t new. Historically, there have been waves of research offering conflicting conclusions on whether women might be inherently more susceptible to lung cancer, particularly in its adenocarcinoma form, than men who smoke comparably. Some of these controversies date back decades, when smoking habits, environmental exposures, and even diagnostic technologies differed substantially from what we have today. But the pressing need to answer these questions has only grown more urgent, given the major changes in recent years: improved diagnostic tools, widespread adoption of immunotherapy, and rapidly evolving molecular-targeted agents that have transformed the lung cancer treatment landscape.

The data from this Austrian study are striking. Although roughly equal numbers of men (152) and women (134) were included in the final analysis, a clear discrepancy emerged in cumulative tobacco exposure. The typical female patient had smoked around 35 pack-years, whereas the typical male patient had smoked closer to 45 pack-years. Though these numbers might seem close to those not steeped in the epidemiology of smoking-related illnesses, they are significant for researchers. In simplest terms, it means that for every 35 “packs per day x year” ratio in a woman, the average man had consumed about 10 more “packs per day x year.” Yet the disease rates were not lower among women, pointing to the possibility that female patients may more easily transition from risk to actual disease at a lower threshold of tobacco exposure.

The timing of these findings is critical, not just because smoking patterns have changed over generations, but also because the last decade has witnessed an unprecedented rise in molecular testing, lung cancer screening programs, and the adoption of sophisticated treatments that specifically target genetic alterations in tumors. These targeted therapies, which focus on specific driver mutations such as EGFR (Epidermal Growth Factor Receptor) or KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog), have revolutionized treatment strategies and, in some instances, have extended survival well beyond what was possible with traditional chemotherapy.

Against this backdrop, the difference in cancer susceptibility—seemingly favoring higher risk in women—has prompted renewed interest in the notion that biological sex, including hormones like estrogen and its receptor subtypes, may shape both the emergence and progression of lung tumors. Estrogen receptor (ER) expression, particularly ERβ, has been implicated in lung carcinogenesis. Various studies preceding this Austrian cohort have shown that lung cancer cells may sometimes exhibit higher ER expression, and that this phenomenon appears more frequent in female patients, suggesting that the interplay of hormones could be partly responsible for the heightened vulnerability.

In parallel, the question arises as to whether this phenomenon might also intensify the impact of smoking. Some researchers suspect that estrogen pathways could exacerbate the carcinogenic effects of cigarette smoke, thereby accelerating tumor formation in female lungs. This synergy, if conclusively proven, would deepen our understanding of why the threshold for turning risk into reality appears lower in women, but it would also potentially guide more nuanced approaches to lung cancer prevention and screening.

The current study from Vienna found another interesting twist in the molecular landscape: Women appear to harbor a higher fraction of treatable driver mutations compared to men. While both sexes had roughly equal rates of genetic alterations overall (around 72–74%), women were more likely to test positive for so-called “actionable” mutations. This categorization includes mutations for which targeted therapies—specialized drugs that either inhibit or otherwise modulate the activity of the mutant proteins—are available.

This was particularly evident for EGFR, KRAS (in its newly discovered targetable subtypes), and HER-based mutations. Since these mutations are predominantly (though not exclusively) associated with adenocarcinoma, which was indeed the most frequent histologic subtype seen in both sexes in this study, the data underscore an important therapeutic angle. While men and women displayed similar overall rates of adenocarcinoma, the presence of targetable mutations in women suggests that female patients could, in theory, enjoy a substantial benefit from these genetically tailored drugs.

This leads naturally to questions about how we should structure routine molecular testing. Historically, the guidance for whether to test tumors for these mutations varied according to factors like smoking history and histological subtype. Yet in light of findings that indicate nearly equal rates of significant driver mutations, and a higher prevalence of potentially actionable variations in women, there is a growing argument for broad, universal molecular profiling of all newly diagnosed lung cancers, regardless of the patient’s age, sex, or prior smoking history.

On a practical level, the utility is clear: If even a fraction of patients can receive targeted therapy that extends their life and improves quality of living, it would be negligent not to order the tests. Indeed, universal molecular profiling is already gaining ground in many comprehensive cancer centers, reflecting the contemporary precision medicine approach.

But the new data do not stop at genetic predisposition. The study’s timeframe—between April 2020 and December 2022—captured a new era in lung cancer treatment, where immunotherapy has entered the mainstream. Designed to unleash the immune system against malignant cells by blocking inhibitory checkpoints such as PD-1 (Programmed Death-1) or PD-L1 (Programmed Death-Ligand 1), immunotherapy has significantly reshaped oncological care. Some previous research had hinted that women might not respond as robustly as men to immunotherapy alone, although they might benefit more from chemo-immunotherapy combinations.

Interestingly, in this Austrian cohort, the distribution of PD-L1 expression levels—an important biomarker to guide immunotherapy decisions—was comparable between men and women, as was the proportion of patients who exceeded the 50% threshold for PD-L1 positivity. In other words, the raw data regarding PD-L1 expression did not suggest a marked difference that might otherwise explain any sex-based discrepancies in response to immunotherapy. That said, PD-L1 expression is merely one piece of a very intricate puzzle. Other biological mechanisms are undoubtedly at play.

Still, for clinicians who are making day-to-day decisions about who might benefit from checkpoint inhibitors, these findings serve as a gentle reminder that PD-L1 status alone, even stratified by sex, is far from definitive in predicting treatment responses. The complexities surrounding immunotherapy response also mirror broader complexities in lung cancer staging at presentation. One might assume that women’s heightened awareness of bodily changes or historically better engagement with healthcare systems would produce earlier diagnoses and thus lower-stage disease. However, the Austrian analysis found that comparable proportions of men and women were diagnosed at advanced stages—namely stages IIIB, IIIC, and IV.

The reasons could be multifaceted: the nature of the tumor itself, differences in symptomatology, or possibly limitations or delays in seeking medical attention, which might differ among subsets of men and women. Another factor might be the relative novelty of lung cancer screening programs. Low-dose CT (computed tomography) scans, proven to detect lung cancer at earlier stages, are still being rolled out unevenly across the globe. In some regions, access is robust, while in others, it is minimal or absent. The experiences of Austrian patients may reflect a particular healthcare structure or screening availability that could differ drastically from, say, the United States, China, or other parts of Europe. Large-scale generalizations therefore require caution, but the findings that advanced disease was prevalent in both men and women at diagnosis underscore that both sexes remain vulnerable to late detection under current protocols.

Nevertheless, it remains striking how the incidence patterns have changed over the last few decades, especially in certain regions. Historically, squamous cell carcinoma was the leading subtype of lung cancer, often overshadowing adenocarcinomas, particularly among men. But epidemiological data from the past 10 to 20 years has shown a shift: Adenocarcinoma is now predominant, especially in more developed countries. The reasons behind this shift are believed to involve changes in the composition and design of cigarettes, including filters and tobacco blends, as well as changing lifestyles and environmental exposures.

Some also attribute it to the increased prevalence of female smokers in certain age brackets during critical periods, although epidemiological patterns can vary widely from one country to another. For example, in some parts of Asia, the incidence of EGFR-mutant lung cancer is exceptionally high, even among never-smokers; these patterns have also influenced how globally minded clinicians think about testing and targeted therapy.

Importantly, while adenocarcinoma dominates in these new data, it does not necessarily imply universal improvements in survival outcomes. The Austrian researchers found that the overall median survival was about 23.4 months for the entire cohort (men and women included). Encouragingly, while a slight survival benefit emerged for women, it was not statistically significant within this particular group. Previous large-scale studies had suggested that women might enjoy slightly longer survival than men, particularly after adjusting for known prognostic factors, but these findings are not always replicated in smaller, single-center cohorts.

One potential explanation for the lack of a significant survival gap in this study could be the relatively small sample size or the limited follow-up duration. Another possibility is that improvements in individualized therapies may be narrowing any historical advantage women might have had. If both sexes now receive prompt and personalized treatments—targeted therapies when actionable mutations are present, and immunotherapies for high PD-L1 expression or in combination with chemotherapy—some of those earlier disparities might disappear. Or it might simply be that a larger number of patients would be required to generate a statistically significant difference in survival by sex.

From a public health perspective, these novel findings and the controversies they stir carry major implications. For one, it may prompt calls for more vigilant lung cancer screening in women, even those with lower pack-year histories of smoking. Given the possibility that women transition to malignancy at a lower overall exposure, current guidelines that focus on heavy long-term smokers might miss a subgroup of women who smoke less yet remain at high risk.

Another public health angle concerns outreach and education, particularly among younger women who might underestimate their risk if they casually compare themselves to male peers or older smokers. That said, the study also highlights a critical point for clinicians and regulators: Biology is a key factor. If it turns out that women are more prone to certain molecular changes, or if their hormonal environment accelerates tumor growth, then “one-size-fits-all” screening thresholds might miss a significant fraction of female patients who present at advanced stages.

The era of precision medicine suggests that the next logical step is to refine screening guidelines not just by age or smoking history, but also by incorporating genetic markers, family history, and perhaps other biological signals that are known to differ between women and men. Equally important is the consideration that certain viruses, notably human papillomavirus (HPV) subtypes 16 and 18, might play a contributory role in some lung cancers. Previous studies have hinted at a higher detection rate of HPV in female lung cancer patients, potentially adding one more piece to the puzzle of sex-specific vulnerabilities. Future research may well delve deeper into this area, examining whether HPV positivity correlates with specific histological subtypes or certain molecular profiles in women.

The intriguing question is whether HPV’s known oncogenic properties, so clearly established in cervical and oropharyngeal cancers, could also be fueling lung cancer in a subset of women. If validated, these discoveries could open new doors for prevention—perhaps a greater push for HPV vaccination programs or guidelines for HPV screening in individuals at risk for lung cancer.

But for all the attention on difference in biology, the interplay of environment, culture, and behavior must not be lost. Even as these new findings indicate a stronger vulnerability among women, men continue to represent a large share of lung cancer morbidity and mortality. Smoking remains the overriding risk factor for lung cancer in both sexes. Even among never-smokers, environmental exposures—ranging from secondhand smoke to radon or air pollution—pose real threats.

The advent of widespread immunotherapy, combined with more nuanced chemotherapies and targeted therapies, has boosted survival rates, but the disease remains notoriously lethal. Therefore, efforts to reduce smoking in the population, mitigate harmful environmental exposures, and promote early screening remain the cornerstones of controlling this cancer’s global toll.

The authors of the Austrian study themselves acknowledge limitations. As a single-center retrospective analysis, results might not generalize perfectly to other populations, ethnicities, or healthcare systems. The timing of the study—from 2020 to 2022—also intersects with the global COVID-19 pandemic, which arguably could have affected patients’ willingness or ability to seek medical care for new respiratory symptoms, possibly shifting the distribution of stages at presentation in unpredictable ways.

In addition, the fact that about two-thirds of patients underwent molecular testing is already relatively high in a real-world setting, but not universal. It is possible that broader testing might have turned up an even greater diversity of mutations, or differently distributed ones. Moreover, the period of follow-up might be too short to capture a full survival picture, particularly for those patients who received targeted therapies with the potential for prolonged disease control.

Nonetheless, the study provides a timely snapshot that is uniquely situated in the era when immunotherapy and targeted therapies are no longer experimental but standard of care in many contexts. While additional research is needed to confirm and expand upon these findings, they add momentum to a growing body of evidence suggesting that female sex itself is an important risk factor or risk modifier for lung cancer, well beyond the scope of mere lifestyle choices like smoking.

This opens up compelling avenues for further inquiry. One natural step is to conduct prospective studies—potentially multinational in scope—to see if these Austrian findings hold across different ethnic groups, healthcare systems, and screening protocols. Another is to explore deeper synergy between sex hormones and known oncogenic drivers. Researchers could, for instance, focus on how the presence of certain hormone receptor subtypes in tumor cells correlates with the presence or absence of specific driver mutations, and how these interactions change the tumor microenvironment in ways that may favor or thwart immunotherapy.

If researchers find strong mechanistic ties between hormones and driver mutations, it could lead to entirely new combination therapies involving, for example, estrogen receptor antagonists plus EGFR inhibitors in certain patients, or the addition of immunomodulatory agents that specifically target hormone-mediated pathways. There is an inherent excitement in seeing this possibility: that a synergy of biological factors, which are more pronounced in one sex, could be therapeutically exploited to improve outcomes for both.

At the same time, the data highlight that men, while often associated with heavier smoking and historically higher lung cancer incidence rates, still exhibit equally advanced disease and carry significant loads of genetic mutations. In some men, actionable driver mutations remain the key to unlocking better prognoses through targeted therapies. For them, universal molecular profiling is just as important and should be pursued. The real revelation might be that while men and women harbor different distributions of mutations, nobody should be excluded from advanced testing on the basis of sex alone.

When it comes to immunotherapy, the lack of a visible difference in PD-L1 expression between men and women might be a subtle hint that the differences in immunotherapy response, if they exist, are mediated by more complex immunological or hormonal pathways not captured by PD-L1 alone. It reminds us how, even with all the advances in biomarker-driven therapy, we still have an incomplete picture of why some patients thrive on checkpoint inhibitors and others see little benefit. A deeper dive into the tumor microenvironment—including T-cell infiltration, levels of other immune checkpoints, and potential epigenetic or microbiome influences—may eventually yield the robust biomarkers that truly predict immunotherapy success.

That lines up with a broader push in oncology to look beyond single metrics like PD-L1 and adopt integrative profiling approaches (also known as multi-omics) that evaluate genomic, transcriptomic, proteomic, and even metabolomic data in tandem.

Ultimately, the main message shining through this new wave of research, epitomized by the Austrian study, is that lung cancer is a complex, multifactorial disease deeply intertwined with genetic, hormonal, behavioral, and environmental components. And sex, in all its biological and sociocultural dimensions, is a far more important variable than was once appreciated. We can no longer view lung cancer as a monolith. Even within specific histological subtypes, the underlying drivers, the molecular pathways, and the patient’s prognosis can vary greatly, necessitating a precision medicine approach.

While we must remain vigilant against the threat that lung cancer poses to both men and women, emerging data make it clear that risk mitigation, early detection, and treatment strategies might benefit from a nuanced awareness of these sex-based differences. If women indeed require less cumulative tobacco exposure to reach a similar or higher risk threshold, they should be approached with screening and prevention protocols that reflect that reality.

Similarly, the higher likelihood of actionable mutations in female patients means that thorough molecular testing is not a luxury but a necessity to ensure that each patient can be directed to the therapy that offers the best chance of success. We will need to reconcile these findings with existing guidelines, many of which were developed in eras or populations where men were the predominant focus for lung cancer screening. Doing so could facilitate earlier detection in populations that were previously overlooked.

And given the shifting demographic trends in smoking and lung cancer incidence worldwide, it is likely that these conversations will become more pressing in the years to come. In addition to these clinical and public health dimensions, the current discussions reinforce the importance of promoting more female-led research, encouraging women’s enrollment in clinical trials, and ensuring that large trials specifically look for sex-based differences in outcomes—whether for chemotherapy, immunotherapy, or targeted therapies. Only by rigorously analyzing these parameters can we be certain that we are not missing critical information that could enhance patient outcomes.

Indeed, if we continue to uncover robust evidence of distinct biological pathways shaping tumor genesis and progression in women, we may see the field move toward more specialized approaches in drug development, staging, and even risk assessment. Ultimately, lung cancer stands as both a significant health crisis and a fascinating scientific frontier. The revelations from Vienna are sure to inspire a new generation of questions and research projects, shining a light on the interplay between sex, smoking, tumor biology, and evolving therapy paradigms.

While it is not the first study to propose that women might be more susceptible to lung cancer or that they may respond differently to certain treatments, the timing and focus of this investigation, reflecting a patient population diagnosed in the early 2020s, offer an updated snapshot that complements the historical data. The field must now grapple with these findings, replicate them in larger cohorts, and translate them into actionable steps for improving patient outcomes.

If we succeed, future patients may benefit from gender-informed screening, personalized treatments for targeted mutations, and perhaps even new lines of therapy that exploit hormonal or immune-based vulnerabilities in the tumor. As science progresses, the ultimate objective remains constant: to minimize lung cancer’s devastating burden on both men and women across the world.

Though controversies remain, the suggestion that female patients could be at greater risk, potentially at lower exposure levels to carcinogens like tobacco, should serve as a clarion call. Whether we learn to harness these biological differences to tailor therapy more effectively or refine our screening protocols to detect cancer earlier, such insights can only bring us closer to the day when lung cancer is less likely to claim the title of the world’s deadliest malignancy.

The findings, thus, remind us that every angle—be it sex-based genetics, environmental exposures, hormonal milieu, or immunological factors—must be explored with vigor and care. The future of lung cancer research looks both challenging and bright: If we can leverage discoveries like these, we may yet transform lung cancer from a near-certain killer into a disease that is both preventable and, for many, treatable with high rates of long-term survival.

The quest to understand all these nuances continues, and each new study, including this one, represents an important piece of the evolving puzzle that is lung cancer.

Subject of Research: Sex-based differences in lung cancer susceptibility and molecular genetics in the 2020s
Article Title : Sex-based differences in lung cancer susceptibility and molecular genetics in the 2020s
News Publication Date : 30 January 2025
Article Doi References : https://doi.org/10.1016/j.heliyon.2025.e42089
Image Credits : Figures and graphical abstract courtesy of the authors and Heliyon
Keywords : Lung cancer, Sex-based differences, Lung cancer susceptibility, Adenocarcinoma, EGFR mutation, KRAS mutation, Immunotherapy, Targeted therapy, Estrogen receptor, Smoking

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