Gender-related disparities in non-small cell lung cancer

Abstract

Epidemiological studies clearly outline some disparities in cancer onset, progression as well as prognosis and therapeutic response between sexes. In particular, in lung cancer, the leading cause of cancer death, at least in Western countries, a gender disparity appears now to emerge, especially for non-small cell lung cancer (NSCLC). Such a disparity is apparently due to a variety of mechanisms, ranging from genetic and epigenetic differences to gender-specific lifestyle as well as to behavioral causes and, clearly, to sex hormones activity. Here we briefly recapitulate gender differences in terms of risk factors, histopathological features and pathogenetic mechanisms in NSCLC, and hypothesize that a gender-oriented pharmacology could beneficially impact on innovative therapeutic strategies.

Introduction

Cancer epidemiology clearly outlines disparities in tumor onset, progression as well as prognosis and therapeutic response between males and females. Such a different behavior can be attributed to a variety of mechanisms, ranging from genetic and epigenetic differences, responsible for gender-related protective factors, to gender-specific lifestyle and behavioral causes.

Lung cancer represents the leading cause of cancer death, at least in Western countries [1], [2]. In this context, epidemiological studies have highlighted the key role of chemical carcinogenesis – environmental, occupational or “unnecessary” – in lung cancer development [1], [3]. As a matter of fact, lung cancer is directly correlated with tobacco smoke, which is considered responsible for the great majority of lung cancer deaths. Cigarette smoke contains about 5000 different chemical agents, and 80 of these are well-known carcinogens (www.cdc.gov/tobacco). Clinically, it is classified as “small cell lung cancer” (SCLC) and “non-small cell lung cancer” (NSCLC), the latter one, histopathologically subclassified as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, being by far the most frequent (>85% of the total cases) [1].

In spite of the big efforts of both experimental and clinical biomedical research, lung cancer continues to often display a dismal prognosis, essentially attributable to the high percentage of recurrence and to its enormous metastatic capability [1]. The only parameter positively related to patient’s survival is the early diagnosis, feasible, so far, through diagnostic imaging instruments (essentially spiral computed tomography) [4], an approach not univocally recognized as a convincing one [5]. As many cancers, lung cancer is able to survive quiescently in the patient’s body for decades, in spite of the immune surveillance or in equilibrium with it (cancer dormancy) [6], [7], very often in the absence of clinical symptoms. Obviously, dormant cancers represent a serious threat, because they can “wake up” at any time and become a full-blown clinically manifest cancer when it could be too late in order to set up an effective therapy. Five-year survival rates for those who are diagnosed with a localized cancer is ∼50%, while it drops to ∼15% for cancers with regional spread and down to ∼2% in the case of metastatic disease. Over 75% of the patients that are diagnosed with lung cancer present with either regional or metastatic disease, which makes the prognosis for those patients definitely poor. These data, which have remained substantially unchanged for the last two decades, do not take into account patient’s sex.