The impact of sex differences on host and tumour prognostic factors in patients with non-small cell lung cancer

Abstract

Epidemiological studies demonstrate that women live longer than men following diagnosis of non-small cell lung cancer (NSCLC) even after controlling for prognostic factors. This study examines the one biological trait all patients have, sex, and seeks to understand and generate new knowledge with respect to the impact of sex on survival. Patient and tumour characteristics of women and men are examined from presentation and diagnosis, to staging, with specific focus on the impact of these factors on outcomes in NSCLC treated surgically with curative intent. The study also explores how to include sex differences in medical research more generally.

Aim and research question The aim is to examine the impact on survival of the association of sex with the following recognised prognostic patient and tumour characteristics: • age • performance status • smoking history • positron emission tomography maximum standardised uptake value • tumour, node, metastasis (TNM) staging

The research question is: “What is the impact of sex on validated and putative prognostic factors in non-small cell lung cancer and how can we translate understandings in sex differences in lung cancer to facilitate a more targeted research and therapeutic approach to improve patient outcomes?” This is answered by sex disaggregated analysis of the prognostic value of host and tumour factors from a detailed clinical dataset, including patient outcomes, and compared to an independent population level validation dataset. Finally, I examine international examples of success in sex differences medical research more broadly, and the policy landscape that is preventing translation of both the findings in lung cancer, and sex differences in health and disease across the health care continuum in Australia.

Method A detailed surgical database was developed from patients treated surgically with curative intent from the Peter MacCallum Cancer Centre and St Vincent’s Hospital Melbourne from 2000-2010. An additional cohort of patients was identified and analysed from the Surveillance, Epidemiology and End Results (SEER) database, the US population level database. The SEER database was matched to the Melbourne cohort with respect to surgical treatment with curative intent and date of surgery, to ensure continuity with clinical protocols. Extensive clinical data were collected to allow analyses of the impact of sex differences on prognostic variables in three key areas: 1. Host factors (sex, age, smoking and performance status) 2. The maximum standardised uptake value on Positron Emission Tomography 3. TNM staging

The patient outcome was disease specific five-year survival. During this research, a new edition of TNM staging was developed resulting in two different editions of TNM staging being used, with the 7th edition in chapter 3 and 4 and 8th edition in chapter 5. Data were analysed with IBM SPSS Statistics software (SPSS) version 21 (Chapter 4), version 22 (Chapter 3) and versions 25 and R (Chapter 5).

Findings There are biological differences between women and men in the disease process in early NSCLC. These differences span elements from patient characteristics to survival outcomes. Irrespective of the parameter examined, male sex was a consistent negative prognostic factor. However, the prognostic value of previously identified tumour and host characteristics was equally valid for men and women. Whilst the finding of poorer survival in men with NSCLC is not new, researchers and clinicians have assumed that this was because women are less likely to smoke; due to ethnicity (there is a distinct variant of NSCLC which is less aggressive and occurs more commonly in women of Asian descent); because women are more likely than men to get adenocarcinoma, with its better survival profile compared with squamous cell cancer; and that women are likely to seek treatment at an earlier stage. The research presented in this thesis demonstrates that these assumptions do not fully explain the observed survival differences. Whilst the observations are correct superficially, the causality is false. Survival differences between men and women persist irrespective of ethnicity, histology and disease stage. These findings have important implications for research design, translation, clinical guidelines and practice.

Significance A better understanding of the impact of patient and tumour sex on tumour characteristics has the potential to improve understanding of the biology of lung cancer and may lead to different staging and treatment approaches. Understanding the impact of sex on patient response to treatment may improve patient outcomes for men and women by improving selection of therapies tailored to each sex. In addition, novel targets for therapeutics may be identified.

This thesis presents a comprehensive delineation of the differences in survival between men and women with NSCLC. These differences raise important questions with respect to the accuracy and efficacy of TNM staging when applied to clinical decision-making for both sexes and indicate that current therapeutic decision-making driven by stage should be reviewed. There is a significant possibility that the oncological community may be over-treating women and under-treating men. Publications from this study may provide direction for future clinical trials, redefine staging, assist in changing clinical practice by more accurate prediction of tumour behaviour, and support the move to individualised treatment.