Colorectal cancer (CRC) accounts for approximately 10% of all cancers and it is the second most frequent cause of death from cancer. Patients who have been diagnosed with metastatic colorectal cancer (mCRC) since the onset of the disease account for 20% of the total, while up to 50% of the patients who have been diagnosed with this type of cancer in a localised form eventually develop metastasis. Although the prognosis for these patients has improved significantly over the last 20 years, with the implementation of more effective treatments, it is still an incurable disease in most cases.
Furthermore, the treatment of these patients is a medical challenge, as although we have managed to identify various molecular targets that are susceptible to treatment, with the aim of developing personalised treatments, the complexity of the metastatic illness itself means that an approach using precision medicine is required, in which the therapy includes knowledge of the genetic alterations of the tumours, the protein expression profile or the tumour microenvironment, among others, in order to achieve control over the illness and a notable improvement in the long-term survival rate and quality of life of these patients.
An article published recently in A Cancer Journal for Clinicians, which is co-authored by Dr Josep Tabernero, director of the Vall d’Hebron Oncology Institute (VHIO) and head of the Vall d’Hebron University Hospital’s Medical Oncology, reviews the advances achieved in the treatment of metastatic colorectal cancer (mCRC) and how precision medicine can help to improve existing therapies for patients who develop this illness.
“Metastatic colorectal cancer is highly heterogeneous and it has a complex molecular biology that affects the patient’s response to therapies and conditions their survival. The tumour’s heterogeneity can already be found in the initial stages of the illness and this is determined by genetic and epigenetic regulations that influence the tumour’s various molecular profiles. In this regard, advances in our knowledge of the molecular bases of the tumours is essential for dealing with them appropriately”, affirms Dr Josep Tabernero. In the case of colorectal cancer, three main types of carcinogenesis have been identified (chromosome suppression or instability event, mutation or microsatellite instability event and methylation or CpG island methylator phenotype event) which make it possible to identify various phenotypes within this type of cancer and determine channels from a prognosis standpoint, or response to specific therapies, with the aim of continually advancing towards an individualised treatment of these patients. But in the case of mCRC, after more than 20 years of traditional clinical research on the epidermal growth factor receptor family (EGFR) and their cellular signalling events, this continues to be the cornerstone for obtaining treatments aimed at this illness.
The high EGFR levels, a tyrosine kinase from the family of human receptors for epidermal growth factor, which also includes HER2/c-neu (ERBB2), HER3 (ERBB3) and HER4 (ERBB4), have been identified as a common component of multiple types of cancer and seem to promote the growth of solid tumours. In the case of metastatic colorectal cancer, a number of specific ligands have been discovered which trigger a complex mechanism of intracellular signalling in events that regulate the proliferation of cancer cells, the survival or propagation of the metastasis.
Great efforts have also been expended on biologically identifying homogeneous subtypes of CRC, for a better prognosis and for the development of new therapies. Currently, thanks to the study carried out by an international consortium analysing the transcriptome of tumour cell gene expression, as well as the tumour infiltrating stroma and the tumour microenvironment, four molecular subgroups were defined.
The challenges of precision medicine in the treatment of metastatic colorectal cancer
The first successful step towards personalised cancer medicine is the definition of various options for treatment and sequences, which is based on the molecular characterisation of the tumour. Research into alterations of the RAS and BRAF genes, and also recently HER2, along with the evaluating the state of microsatellites, are currently the gold standard for the molecular characterisation of mCRC, which is necessary for selecting the most appropriate treatments. In addition to molecular characterisation, there are various factors that influence the selection of the most appropriate treatment for each patient, such as their characteristics (comorbidities, age, etc.) and the characteristics of the tumour (tumour burden, location of the metastasis, etc.). Currently, the first line of treatment is mainly based on chemotherapy, which includes doublets such as FOLFIRI or FOLFOX, or, according to the state of the tumour, triplets such as FOLFOXIRI (folinic acid, 5-FU, oxaliplatin and irinotecan) in certain patients.
In order to implement effective treatment strategies based on precision medicine, it would be necessary to integrate all possible information on the tumour and its behaviour, from exhaustive knowledge of the gene alterations of the tumours to the gene and protein expression of the tumour microenvironment, and their dynamic changes over the course of the illness in each patient. In this regard, the molecular stratification on which current mCRC treatment is carried out does not completely represent the heterogeneity of the complex genotypes and phenotypes of this illness. Furthermore, there is another factor that adds complexity to characterising this illness: the gut microbiota. Recent studies have shown that there are bacteria linked to the development and progression of colorectal cancer, as well as to the response to treatments, and this is a field of research in which various international groups and consortiums are working.
Fortunato Ciardiello, Davide Ciardiello, Giulia Martini, Stefania Napolitano, Josep Tabernero, Andrés Cervantes. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:000-000.