Colorectal Cancer: An Outlook on the Disease and Treatments
By Pavel Ryzhov, Ph.D.
As one of the common types of cancer, affecting 1-2 million people globally every year, colorectal cancer (CRC) has been the subject of progressively more intense investigation over the last hundred years . Since then, we have had a better understanding of the molecular complexity of pathogenic progression from polyps or benign adenomas to malignant carcinomas.
This has helped us piece together the interplay between the sequence of mutations in various oncogenes, the protective and destructive role of gut microbiota and diet, and the patterns of inheritance that confer susceptibility to CRC development in certain groups of patients. Besides, entry of new chemotherapy drugs, continuous development of less invasive surgical interventions, and advances in screening methods have all steadily improved the clinical outcomes over the past decades.
Classification & Risk Factors
It is now widely accepted that the appearance of colorectal polyps (clumps of cells on the lining) may lead to the eventual carcinogenesis over time . Over the course of the last few decades, it was elucidated that 70% of all CRC cases are sporadic, and the specific sequence of point mutations of different genes typically translates into the changes of tissue morphology.
The second class of CRCs is of inherited nature and accounts for 5% of all cases. Among those, researchers have delineated between familial adenomatous polyposis (FAP) (with multiple likely-to-be malignant polyps), and DNA repair damage-associated hereditary non-polyposis colorectal cancer (HNPCC) . The latter type is caused by Lynch syndrome, characterized by specific mutated alleles, coding for various repair proteins . The other 25% of CRC cases are familial, or, in other words, associated with inherited mutations, shared environmental and social risk factors.
Age is a typical risk factor that exacerbates the clinical outcomes for CRC patients, with patients after 50 years exhibiting a significantly higher predisposition for the development of cancer . Other factors include inflammatory bowel diseases like ulcerative colitis and Crohn’s disease and family history. Furthermore, environmental factors, such as sedentary lifestyle, coincidental obesity and diet, and species composition of gut microbiota, have been linked to increased chances of higher CRC risk and are now subject to close investigation .
Molecular Insights into CRC Pathology
To lay the groundwork for the development of treatment options, the cellular and molecular nature of the aforementioned carcinogenesis had to be understood. While other types of cancers may display specific genetic mutations in oncogenes in key cellular pathways of cell proliferation, DNA repair, or cell cycle, CRC is characterized by broader genetic instability [1,2]. This can be due to chromosomal instability (CIN), microsatellite instability (MSI), and CpG island (DNA stretch with higher GC content) methylator phenotype (CIMP) .
Each of these underlying genetic instabilities is responsible for a range of cellular alterations. CIN may manifest in chromosomal alterations, like aneuploidy of the tumor, and affect cell function via KRAS, APC, PI3K, and TP53-related pathways. MSI-associated effects on DNA repair mechanisms can lead to frameshift mutations of oncogenes, while epigenetic instability in CIMP is characterized by hypermethylation of oncogenic promoters and the resulting loss of protein expression.
The number of various alterations that originate from these instabilities is leveraged for the development of novel biomarkers for CRC. However, currently, only DNA-based methods evaluating MSI, and mutations in KRAS and BRAF have been clinically validated and are routinely used to estimate disease prognosis. In the case of KRAS and BRAF, they are also used to predict whether a tumor will respond to anti-EGFR (epidermal growth factor receptor) therapy . Other types of biomarkers (such as RNA or protein) are at various stages of testing and are complicated by reproducibility and reliability of results . Conventionally, more invasive methods of disease evaluation are used: colonoscopy, sigmoidoscopy, and fecal blood tests, among others .
Treatment Options for CRC
Classification of CRC stages is broadly similar to other types of cancer, with localization of the primary tumor, level of penetration of the epithelial lining, and metastatic spread to proximal and distal tissues being the key indicators of the severity of the disease . Coincidently, treatment options would vary accordingly and are chosen based on these factors.
Broadly, surgical interventions are employed across most of the CRC stages and have found to be primarily effective in earlier stages of disease progression . Benign polyps, as well as more advanced adenomas that undergo their carcinogenic changes, can typically be detected during colonoscopy procedures and simultaneously resected.
More invasive options are typically reserved for advanced CRC stages and include open surgery or laparoscopic resections of tumors and/or nearby lymph nodes and tissues, particularly liver, with novel approaches to surgical interventions being currently developed . The analysis of the excised tissue for specific biomarkers using genotypic screening and histopathological examination would then guide the additional treatment options if required, such as adjuvant chemotherapy (post-surgery), radiation treatment, or neoadjuvant chemotherapy (pre-surgery).
Chemotherapy options (such as treatment duration, neoadjuvant or adjuvant choice, and the specific combination would largely depend on the individual genetic makeup and subsequent response. Among first-line agents, 5-fluorouracil (5-U) was introduced in 1958 and later modified into an oral prodrug form, capecitabine. Typically, 5-U is given with leucovorin (LV) to reduce toxicity.
Other first-line agents include combination therapies such as FOLFOX and CAPOX, which leverages 5-U and capecitabine respectively together with LV and oxaliplatin (derivative of cisplatin), one of the first metal-containing chemotherapeutic agents that bind DNA, inducing apoptosis. In addition, FOLFIRI, which contains 5-U, LV, and a broad-spectrum antitumor drug, irinotecan, is also used for that purpose. Second-line treatments are based on the clinical outcomes of the first round of chemotherapy and the response to individual drugs or combination therapies.
Monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF) are also typically used in combination with chemotherapy. Some examples include bevacizumab and recombinant protein Aflibercept, targeting VEGF-A and VEGF-B, and ramucirumab, targeting the VEGF receptor. Furthermore, mAbs targeting EGFR such as cetuximab and panitumumab, are also commonly used. However, they can only be administered if there are no mutations in KRAS, NRAS, or BRAF genes .
Currently, Amgen is testing sotorasib as monotherapy, an inhibitor of mutated KRAS in the ongoing clinical trial, and reported preliminary positive results at last year’s ASCO conference . A kinase inhibitor drug, regorafenib, has been approved for patients if the CRC does not respond to other types of treatments. Programmed death-1 receptor inhibitor nivolumab has been authorized under accelerated FDA approval and is currently further evaluated in further clinical trials in combination with ipilimumab.
|Drug name||Brand Name||Drug Target||Company||Initial year of FDA Approval|
|Ramucirumab||Cyramza®||VEGF receptor 2||Eli Lilly||2014|
|Nivolumab||Opdivo®||PD-1||Bristol Myers Squibb||2014|
Table: List of approved biologics for a range of CRC indications
Other Treatment Options
CRC is known to induce chronic inflammation, via different mechanisms, including cyclooxygenase-dependent mechanism and production of arachidonic acid derivatives . To address that, non-steroid anti-inflammatory drugs (NSAIDs), like aspirin, are currently evaluated for their efficacy in reducing CRC risk . Additionally, selective COX-2 inhibitor celecoxib, which has fewer side effects, has been approved for FAP as a supplemental care regimen. It is also worth mentioning that probiotics and functional foods are being evaluated in different research settings for their potential to reduce the production and effect of reactive oxygen species, detrimental to various cell structures .
Overall, the advances in the characterization of molecular pathways affected in CRC, less invasive, and more timely surgical interventions and development of more accurate biomarkers have advanced the life expectancy of patients in the last few decades. More light on the influence of gut microbiota, dieting, and familial factors, will provide a better foundation towards more personalized treatment options going forward.
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