Lung Cancer in Non-smokers

Introduction

Lung cancer is the most common cause of cancer death worldwide, and is predicted to be diagnosed in over 200,000 new patients in the US this year [1]. While smoking is undoubtedly the most significant cause, recent reports have highlighted a significant increase in cases of lung cancer among non- (and never-) smokers [2,3]. So, how significant is this? What do we know about the causes of lung cancer in non-smokers, and how close are we to being able to predict and prevent it?

The lung cancer epidemic

Lung cancer was practically unknown in the early years of the 20th century. Popularisation of smoking tobacco led to the epidemic of cancer diagnoses the Western world has experienced over the last 50 years. Over 80% of lung cancer occurs in people who are (or have been) smokers. Although the number of new cases is levelling off in many Western Countries, the epidemic is now spreading to emerging nations such as China, as the impact of more tobacco smoking is seen [4].  Despite advances in treatment, the outlook for many with lung cancer remains poor. Early detection undoubtedly helps, but even for the ‘earliest’ tumours 5-year survival is only 45-50%. For more advanced tumours 5-year survival is around 10% [5].

Among the large numbers of smokers, there have always been a small number of non-smokers who develop lung cancer; while many of these cancers have been attributable to the inhalation of second-hand smoke (SHS), lung cancer in non-smokers was recognised as a specific entity in the 2000s.

The suggestion that lung cancer in non-smokers is increasing comes from two reports. The first is a paper from the UK that showed that in a major cancer treatment centre, both the proportion and absolute number of cases has significantly increased over a 7-year period [2]. This is important since theoretically the proportion could increase as tumours in smokers start to fall thanks to the effects of smoking cessation programs, but a rise in absolute numbers is harder to explain. In this study, most tumours (in both groups) were detected on incidental imaging, as a screening program does not exist in the UK. A second study, this one from the US, looked at the proportion of diagnoses in non-smokers over a 25-year timespan across several cancer treatment centres. They found that the proportion of cases in non-smokers has risen from 8% to 14% over this time [3].

Causes and risk factors for lung cancer

Years of research have proven beyond reasonable doubt that smoking tobacco causes lung cancer. Tobacco is just one of a long list of proven carcinogens found in the smoke from cigarettes, cigars and other tobacco products [6]. As well as markedly increasing the risk in smokers, tobacco smoke also increases the risk in non-smokers through the inhalation of second-hand smoke [7].

Due to the overwhelming prevalence of lung cancer in smokers, investigations into other risk factors—among both smokers and non-smokers—are few. However, some have been done, and shed light onto possible causes.

Radon exposure has been shown to be a significant risk factor. Radon is a naturally occurring gas, whose concentration varies hugely depending on the locality, and can also accumulate in poorly ventilated buildings or mines. For example, a large study across Canada found that for every year living in a high radon exposure area, the odds ratio of an individual developing lung cancer increases by 11% [8].

Evidence for additional risk factors often comes from studies in countries where smoking is less common. A history of lung cancer in a first degree relative seems to increase the risk, as does long-standing exposure to smoke from burning fuel for heating or cooking in poorly ventilated houses. In some cases, previous lung disease (such as tuberculosis or emphysema) also seems to increase the risk [9,10].

As with many conditions, there is a drive to understand any environmental or lifestyle factors (aside from smoking) which might increase the risk. Many lifestyle traits which might increase risk are more common among smokers (such as reduced exercise and poor diet), making this analysis extremely difficult. However, a recent meta-analysis has shown that eating large amounts of red meat might be an additional contributing factor [11]. Similarly, a recent study across Europe has linked particulate air pollution with lung cancer in smokers, although it is not yet clear whether this also applies to non-smokers [12].

There has also long been a question about whether smoking cannabis also increases the risk of lung cancer as cannabis smoke shares many potential carcinogens with those of tobacco. These agents have been shown to cause cancer in animal models [13]. In addition, smoking cannabis tends to lead to more tar and higher levels of retained carbon monoxide in smokers. Again, many users also smoke tobacco, so separating the risk from cannabis is challenging. A report in 2015 brought together several studies from North America, Oceania and Europe to attempt to quantify the risk. They looked at over 1500 cases of cancer and around 2500 controls and found that cannabis use was not a significant risk factor for lung cancer, although they could not rule out adverse effects from long-term use [14].

Recent studies have also identified genetic differences which may predispose to lung cancer, in both smokers and non-smokers. While not absolute, such genetic ‘markers’ may prove to be useful in identifying individuals at greater risk of cancer who may benefit from screening programs. Certain genetics variations, most commonly some EGF receptors—so-called ‘driver’ genes—are also increasingly being detected in tumours, especially those in non-smokers [15]. Interestingly, while increasing the risk for a non-smoker, some of these seem to have a reduced impact if the person has smoked [16]. Genome-wide analysis techniques have also identified novel genetic foci (SNPs or abnormal repeats), which seem to be linked to increased risk of lung cancer with a high degree of reliability [17]. It has been suggested that these might provide targets for future screening programs.

Lung Cancer in non-smokers

Unpicking the differences between lung cancers in smokers and non-smokers can be challenging. Data derived from large databases rarely provides an accurate smoking history, and personal recollections tend to underestimate its frequency. However, many reports have found that lung cancer in non-smokers is more common in women, may occur at a slightly younger age, and has a different histological profile [18]. Many studies report that lung cancer in non-smokers tends to be diagnosed at a later stage, perhaps relating to the close medical follow-up for smokers due to other health problems (such as heart disease). Survival and prognosis for non-smokers is not entirely clear; some studies have shown improved survival, while other have found no difference from the smoking population. Similarly, some investigators report improved survival for women non-smokers, while other do not [19].

There is a recognition that we can ‘explain’ a greater proportion of lung cancer in non-smokers in Asia and the developing world than we can in the West, and that more needs to be done to understand its causes. It seems that at the moment, the difficulties of extracting a clear smoking history, and separating non-smokers from smokers in any analysis, means that the findings remain cloudy.

Screening for lung cancer

Lung cancer is common, and early detection and treatment significantly improves the chances of survival. Lung cancer should therefore be an ideal target for a screening program. To be successful, a screening program needs to deliver a reliable diagnosis in a minimally invasive manner for a sensible price. To be sustained by public funding, this then needs to demonstrably translate into improved survival for patients [20].

Repeated attempts to develop such a screening program for lung cancer have been challenging; among the most major problems are that lungs are buried deep within us and not easily seen. For this reason, screening tends to produce better results (be more cost effective with a lower risk/benefit ratio) when it focuses on people at high risk of cancer. A large American study published in 2011 looked at using low-dose CT scans in a high-risk population. This national trial recruited over 50,000 people over a 2-year period. The tumours that were detected were more likely to be low stage, and partly because of this, they demonstrated a survival improvement of 20% [21]. In light of this, the American Cancer Society recommended a screening program for lung cancer be made available to people between the ages of 55-74 years with a strong smoking history (at least 30 pack years—one pack year is one pack per day for a year), who are still smoking or have stopped less than 15 years ago [22]. Even for this defined group, screening with CT has not been universally adopted. A screening program has not been instituted in the UK; a review in the respected Cochrane library in 2013 concluded that more evidence was needed to demonstrate the cost-effectiveness of screening before its adoption could be recommended [23].

Extensive research has been done to try and identify surrogate markers of lung cancer. Such a marker would ideally be able to detect cancer without the need for invasive testing, or at least identify those more at risk who might benefit from CT screening. Tests utilising screening of sputum, blood, or using fibreoptic scopes to inspect the lungs internally have all been suggested [24]. To date, none has proven sufficiently reliable to translate into a practical screening tool. Recently identified genetic markers hold promise for the near future, but are not yet available [17].

Summary

Smoking remains the leading cause of lung cancer, and the leading cause of lung cancer-related deaths worldwide. The importance of ongoing legislation and support to reduce the number of smokers, and prevent people starting smoking are crucial. For non-smokers, advances in the understanding of the genetic and environmental factors which predispose to lung cancer hold promise that a screening program maybe developed in the near future. There is no doubt that a need exists for a robust and reliable screening tool to help improve the outlook for this devastating disease.

References:

1: American Cancer Society – Key Statistics for Lung Cancer. Accessed Dec 2017
https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html

2: Increasing frequency of non-smoking lung cancer: Presentation of patients with early disease to a tertiary institution in the UK. Cufari ME, Proli C, De Sousa P, et al. Eur J Cancer. 2017 Oct;84:55-59. doi: 10.1016/j.ejca.2017.06.031.

3: Proportion of Never-Smoker Non-Small Cell Lung Cancer Patients at Three Diverse Institutions. Pelosof L, Ahn C, Gao A, et al. J Natl Cancer Inst. 2017 Jan 28;109(7). doi: 10.1093/jnci/djw295.

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