The molecular epidemiology, survival and treatment experiences of patients with early onset colorectal cancer

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Early onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) occurring in adults aged 18-49 years, has been observed to be increasing in incidence in the UK, with a 48% increase in incidence in 25-49 year olds reported since the early 1990s. This is in contrast to CRC in older age groups, in which incidence is stable or decreasing. Similar trends have been observed across Europe, North America, Asia and Australasia. The observed increasing incidence of EOCRC internationally is being driven by sporadic cases, with studies showing 15-35% of patients have an identified germline mutation, and the remainder of cases are as yet unexplained in terms of aetiology. Sporadic EOCRCs tend to be left-sided or rectal, and present at more advanced stages compared to CRC in older age groups. Furthermore, the molecular pathogenesis, optimal treatment strategies and outcomes of sporadic EOCRC remain incompletely understood. The main aims of this thesis were to investigate the molecular epidemiology and survival of patients with sporadic EOCRC, and to explore the experience of these patients during cancer treatment.

Firstly, a population-based cohort of patients with stage II and III colon cancer in Northern Ireland (n=652) was used to investigate the proportion of sporadic cancers with microsatellite instability, along with the proportion of cancers with selected somatic mutations (in BRAF, KRAS, NRAS and PIK3CA) across age categories. In addition, cancer-specific survival in patients with sporadic early onset colon cancer compared to older patients was evaluated. Results showed differences in the molecular profile of early onset colon cancer compared to cancers in older age groups. Specifically, early onset colon cancers did not harbour any BRAF or NRAS mutations. EOCRC patients did not have a significantly increased risk of cancer-specific death compared to 60-69 year-old patients.

Secondly, a systematic review and meta-analysis was undertaken, examining the prevalence of microsatellite instability/mismatch repair deficiency and BRAF, KRAS, NRAS, PIK3CA and TP53 mutations in sporadic EOCRC, incorporating the population-based Northern Ireland cohort used in the above study. Thirty-two studies were included, and meta-analysis was performed to calculate pooled estimates of the prevalence of the selected molecular characteristics in sporadic EOCRC. Results demonstrated that the molecular profile in sporadic EOCRC displays differences compared to CRC in older patients, with 10% of seemingly sporadic cases displaying microsatellite instability. BRAF mutations are a rare event in sporadic EOCRC, displaying a lower prevalence than in older age groups, while KRAS, NRAS, PIK3CA and TP53 mutations have a similar prevalence to sporadic CRC in older adults.

Thirdly, data from the Northern Ireland Colorectal Cancer Audit 2018, conducted by the Northern Ireland Cancer Registry, were analysed to investigate treatment of EOCRC, and specifically how this varies between age groups (n=1,097). Descriptive statistics were applied to patient demographics, tumour characteristics and treatment modalities. Results demonstrated that significantly more EOCRC patients received chemotherapy, radiotherapy and combined treatment than older age groups.

A further chapter in this thesis explored the experiences of patients during their treatment for EOCRC, with semi-structured interviews of participants who had received treatment in the UK between 2016 and 2021. Thematic analysis demonstrated five findings:
(i) The impact of treatment on an individual’s health and wellbeing, with physical, psychological and social impacts being described.
(ii) Interaction with healthcare throughout the treatment journey, including the key role of healthcare professionals and administrative challenges within the NHS.
(iii) Support during cancer treatment, with the main sources being family/friends and online support.
(iv) Areas of unmet need were identified, specifically the need for tailored information, along with support in the areas of mental health, sex, intimacy and fertility.
(v) The impact of COVID-19 on treatment experiences, with both positive and negative impacts being described.

Finally, a study was undertaken to investigate the impact of the COVID-19 pandemic on pathological cancer diagnoses in Northern Ireland from 1st March to 12th September 2020. Data from the four Northern Ireland pathology laboratories were used to assess trends in pathological cancer diagnoses overall and by cancer site, sex and age, compared to the same timeframe from 2017 to 2019. Results demonstrated a 23% reduction in cancer diagnoses between 1st March and 12th September 2020 compared to the same time period in the preceding 3 years. Although some recovery occurred in August and September 2020, this revealed inequalities across certain patient groups. Pathological diagnoses of lung, prostate and gynaecological malignancies remained well below pre-COVID-19 pandemic levels. Males and younger/middle-aged adults, particularly the 50–59-year-old patient group, also lagged behind other population demographic groups in terms of returning to expected numbers of pathological cancer diagnoses.

In conclusion, differences in the molecular characteristics of sporadic EOCRC compared to CRC in older adults have implications for our understanding of the molecular pathogenesis of the disease, treatment decisions and prognosis for these young patients. Our findings need to be validated in cohorts with larger sample sizes and germline testing results. Furthermore, patients with EOCRC have unique supportive care needs during treatment and there is a need for more holistic consideration of these individuals, with service improvement particularly required in the areas of tailored information, mental health, sex, intimacy and fertility. With regard to learnings from the COVID-19 pandemic, there is a critical need to protect cancer diagnostic services in the event of any future such pandemics, to maintain timely investigation of potential cancer cases. Targeted public health campaigns may be needed to reduce emerging inequalities in cancer diagnoses following the direct and indirect consequences of the COVID-19 pandemic on diagnoses and healthcare services.

Thesis is embargoed until 31 July 2024.
Date of AwardJul 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsHealth and Social Care (Northern Ireland) Research and Development
SupervisorHelen Coleman (Supervisor), Maurice Loughrey (Supervisor) & Finian Bannon (Supervisor)

Keywords

  • Early onset colorectal cancer
  • cancer epidemiology
  • qualitative research
  • cancer survival
  • COVID-19

Cite this

'