Determinants of colorectal cancer progression and the interplay between biology and therapeutics

Abstract

Recurrence of colorectal cancer (CRC) remains a key challenge in modern oncology. Surgery is the mainstay of cure for both early and advanced disease. In early CRC systemic treatments have a role in controlling disease recurrence, albeit that knowledge of which patients derive benefit is imperfect. In advanced disease limited to the liver, systemic therapy is used to both downsize colorectal liver metastases (CRLM) and control micrometastases, although the majority of patients develop recurrence. This thesis utilises the datasets and biobanks of two clinical trials to further understanding of disease recurrence in both the early and more advanced settings.
The FACS trial affords a cohort in which to both explore the characteristics of recurrence and evaluate the effect of pathological markers on disease recurrence after resection of stage I-III CRC. Stage is shown to influence survival even after recurrence suggesting that the stages of primary CRC represent different disease biology rather than simply points in the timeline of disease progression.
The characteristics of progressive disease in resectable CRLM are evaluated in the New EPOC study with a particular focus on the earlier disease progression with the addition of epidermal growth factor receptor (EGFR) blockade with cetuximab to chemotherapy and surgery. The pattern of disease progression seen is strongly suggestive of a failure of control of micrometastatic disease. Furthermore, the detriment with the addition of cetuximab persists despite restriction to an all RAS wild-type population. Additional analyses of AREG/EREG and miR-31-3p expression, and primary tumour location, fail to identify a subgroup that benefited from the addition of cetuximab. The ligand and microRNA analyses do however enable the identification of a subgroup of patients with a poorer outcome. While the mechanism of this differential effect requires investigation, these data support a biological explanation rather than, for example, inadequate surgery being responsible.
Lastly, the mature analyses of New EPOC demonstrate cetuximab to not only have accelerated disease progression, but also suggest it may have led to the development of a more aggressive disease genotype and phenotype. Subgroup analyses afford reassurance that inadequate surgery was not responsible for the study outcome, but also intriguingly suggest that the detriment with cetuximab appears to have predominantly occurred in patients with favourable characteristics

More information

Identifiers

Catalogue record

Export record