Recent Advancements,Limitations,and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

Abstract

Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems.

Keywords

colon cancer personalized treatment precision medicine targeted therapy immunotherapy

Introduction

Colon cancer is one of the most common malignancies alongside prostate, lung, and breast cancer. Small growths, called polyps, start to form in the colon and then translate into cancerous tumors, which can metastasize to other body parts. The advancement of colon cancer can be described in four developing stages. Initially, at stages 0 and 1, the tumor grows in the inner layers of the colon, called the “polyp.” During stage 2, cancer moves beyond the walls of the colon and starts to develop in the outer layers but does not advance to the lymph nodes when it is recognized as “adenomas.” The tumor reaches the lymph nodes in stage 3 and forms “carcinoma”; finally, stage 4 has metastasized in the body.¹

The standard treatments available for colon cancer are surgery, chemotherapy, and radiotherapy. Surgery is the best option possible when the tumor is localized. Preoperative chemotherapy and radiotherapy can sometimes aid surgery.² Post-operative adjuvant chemotherapy is given universally for stage 3 colon cancer patients, while for stage 2 patients, the treatment remains debatable.³ Even with the availability of these treatments, the number of deaths and new cases has been on the rise. The cost of the treatment could be an essential factor, but the main reason is the ineffectiveness of the therapeutic in dealing with all the cases.^4,5

Colon cancer is a heterogeneous disease attributed to the accumulation of molecular changes within cells. These genetic and epigenetic mutations vary in patients. This can explain the difference in efficacy of the same treatments in different individuals. Therefore, there is a great need to venture into personalized medicine and harness its potential to respond to the increasing burden of this chronic disease.^6,7

The concept of personalized healthcare is focused on therapeutic or preventive measures taken concurrently with the type of cancer currently known. Colon cancer has distinct genetic and epigenetic components, and biomarkers that can be employed for its early diagnosis are well established. Colonoscopy screening has also effectively identified colon cancer in its earliest stages when polyps form. Microsatellite instability (MSI), correlation of mutations, and hypermethylation in tumors from specific patients help separate the subgroups likely and unlikely to respond to a particular therapy regimen. These aid in treating colon cancer in its early stages, when many patients live for at least 5 years following diagnosis, and the malignancies are considered cured if any recurrence is not seen within the next 5 years.⁸

Personalized treatment involves therapies in a very coordinated and integrated way. It helps start treatments in the preliminary phases as personalized medicine can utilize the molecular understanding of a specific disease. The main objective of advancing these individualized therapies is to provide the best available treatment suited to an individual patient.^9–11

The ability to precisely diagnose patients who can benefit from targeted therapy is essential for the success of customized medications. Targeted therapy, the foundation of personalized medicine, focuses on the current information about the altered route and the components contributing to cancer. For instance, medical professionals now often use the overexpression of human epidermal growth factor receptor type 2 (HER2) as a diagnostic tool to identify breast cancers.^12–14

This review looks at the present targeted drugs in personalized medicine for colon cancer, followed by the discussion of many approaches being investigated to create novel treatments. The review's objective is to evaluate the possibilities of personalized medicine in treating colon cancer. In addition, it includes the most updated trends and strategies currently involved with targeted colon cancer therapy. This information will be helpful for understanding and optimizing personalized colon cancer treatment regimes.

Pathophysiology

Around 60-65% of colon cancer are sporadic and caused due to the accumulation of genetic changes brought along by various environmental factors.¹⁵ The most significant risk factor for colon cancer is age; those over 50 have a higher risk.¹⁶ Other factors include smoking, alcohol consumption, poor dietary patterns, lack of physical activity, and obesity. About 25% of colon cancer cases are related to family without any identified hereditary syndrome. Approximately 5% of the cases are related to inherited syndromes such as familial adenomatous polyposis (<1%) or hereditary nonpolyposis colorectal cancer (CRC), also called Lynch syndrome (2%-4%).¹⁷ The remaining cases are related to lower-level penetration variations in genes (<1%) and unknown hereditary genomic alterations.^18–20

Carcinogenesis: Mechanism of Colon Cancer

Colon cancer is developed by transforming normal colonic mucosa into a precancerous lesion called adenomatous polyps and, ultimately, invasive cancer. The development of the polyps into invasive carcinoma requires neoplastic changes in a timeframe of approximately 10-15 years.²¹ This period can be utilized to diagnose and remove the polyps. Colon cancer is linked to three main molecular mechanisms, the pathway of chromosomal instability, the microsatellite instability pathway, and the aberrant hypermethylated pathway, as described below.

The Chromosomal Instability Pathway

It results from a remarkable surge in adding or removing the whole or major part of the chromosomes. Chromosomal instability (CIN) is observed in 80-85% of all colon cancer cases; hence, it is also regarded as the primary pathway associated with it.²² In the process, oncogenes such as B-rapidly accelerated fibrosarcoma (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS) are activated, tumor suppressor genes (TSGs) such as tumor protein 53 (TP53) and adenomatous polyposis coli (APC) get inactivated, and finally chromosome 18's long arm loses its heterozygosity (18q LOH).^23,24 Vogelstein and Fearon devised a multistep model²⁵ in which the APC gene gets silenced initially, mutations in the KRAS oncogenes occur next, followed by 18q chromosome being deleted, and finally, TP53 getting inactivated. Transforming growth factor β receptor (TGF-βR) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) genes are also affected.^26,27

APC mutation takes place in the early stages of the CIN pathway. It is a crucial alteration seen in about 80% of sporadic cases of colon cancer and the inherited familial adenomatous polyposis (FAP) syndrome.^28,29 The APC gene plays a pivotal role in β-catenin regulation and indirectly controls the expression of β-catenin oncogene targets. Mutation in the APC gene leads to the expression of abnormal truncated APC proteins, which cannot control β-catenin levels.³⁰ As a result, overexpression of β-catenin takes place; it accumulates in the nucleus and activates transcription of genes such as cyclin D1 and c-Myc even in “Wnt off” condition, which facilitates tumor formation.³¹

APC alterations are followed by mutations that help the tumor change from a benign to a malignant phase. The KRAS gene mutation is the initial step in developing from adenoma to cancer. KRAS gene expresses the K-Ras protein, which interacts with GTPase and sends signals for cell growth, proliferation, and differentiation. This step is controlled in normal functioning. During mutation of the KRAS gene, the K-Ras proteins remain overly activated, and cell growth and proliferation of tumor cells take place in an uncontrolled way. KRAS mutation is seen in about 40% of sporadic colon cancer cases.³²

An allelic loss at chromosome 18q follows KRAS mutation, often called loss of heterozygosity (LOH) of chromosome 18q. It is seen in around 70% of colorectal cases, especially in the advanced stages.³³ Deleted in colorectal carcinoma (DCC) and suppressor of mothers against decapentaplegic −4 and −2 (SMAD4 and SMAD2) are some of the tumor suppressor genes located in chromosome 18, which help in growth, apoptosis, and cell differentiation. Allelic loss of the 18q chromosome leads to mutation in these genes and aids in tumor growth.³⁴

TP53 mutation is the final step in the CIN pathway. It is seen in 50%-75% of colorectal cancer cases. TP53 gene abnormalities occur either through mutation or an allelic loss (LOH) of the 17p chromosome where it is located. When TP53 is usually functional, it expresses the p53 protein, which is essential for suppressing tumor growth. TP53 gene mutation results in the expression of an aberrant stable protein that cannot perform its intended role of aiding in DNA repair. The change from adenoma to adenocarcinoma occurs relatively late.³⁵

The Microsatellite Instability Pathway

It is a hypermutable pathway in which the loss of mechanisms of DNA repair takes place.³⁶ Small tandem repeats (STR) of DNA sequences called microsatellites cause errors during replication because of continuous structural repeats, which are generally repaired by the mismatch repair (MMR) system.³⁷ In this pathway, the ability to repair such microsatellites decreases, and mutations occur in those areas. They affect both the coding and non-coding regions, so the working of tumor suppressor genes is affected. MLH1, PMS1, PMS2, MSH2, and MSH6 are examples of MMR genes.³⁸ Microsatellite instability is seen in around 15% of sporadic colon cancer cases and in almost all hereditary nonpolyposis colorectal cancer (HNPCC) cases, also called Lynch syndrome, where germline mutations occur in DNA mismatch repair genes^39,40 . The CIN and MSI pathways are depicted in Figure 1.

Figure 1.

Role of CIN and MSI pathways in colon cancer progression.

CpG Island Methylator Phenotype Pathway

It is an epigenetic instability pathway first identified by Toyota M. et al.⁴¹ Profuse groups of cytosine/guanine (CpG) dinucleotides called CpG islands are abundantly present in gene promoter sites.⁴² In normal cells, these regions are protected from methylation and keep genes active, whereas hypermethylation of CpG island regions inactivates the transcription of several tumor suppressor genes.^42,43 As a result, gene silencing occurs, and a tumor is eventually formed.⁴⁴ These occur in about 20% of colorectal cancer cases.^45,46 It is correlated with BRAF, microsatellite instability, and KRAS mutations. MINT1, MINT31, MINT2, p16, and MLN1 are common CpG island mythelator phenotype (CIMP) markers.^47,48 The involvement of CIMP in colon cancer is depicted in Figure 2.

Figure 2.

Depiction of chromosomal instability due to hypermethylation of CpG island in CRC.

Important Factors Influencing Tumor Growth

Many environmental- and individual-specific factors contribute to the development of CRC. The age distribution of CRC patients in underdeveloped nation provides more evidence of the significant contribution of environmental factors. Young adults now have a higher chance of developing CRC as a result of lifestyle changes such as alterations related to dietary practices, specifically increasing consumption of fat and meat.⁴⁹ Studies reported strong evidences linking several dietary and lifestyle choices to the emergence of colorectal cancer. One of the main risk factors for the development of CRC is alcohol consumption, a prevalent and growing habit in modern society. Many genetic, epigenetic, cell signaling, and immunological processes can be triggered by its oxidative and non-oxidative metabolism and the metabolites and ROS that are produced as by-products of alcohol consumption.⁵⁰

A complex population of microorganisms, particularly in the colon, are found in the gastrointestinal system and are crucial for preserving homeostasis. However, numerous studies in recent years have linked microbiome modifications to the emergence of colorectal cancer. The colon is thought to contain 10¹⁴ microorganisms, the majority of which are bacteria. The two phyla that predominate in the large intestine are Bacteroidetes and Firmicutes, followed by Actinobacteria and Verrucomicrobia. There are also members of the phylum Proteobacteria; however they are less numerous. Initially, specific pathogenic organisms like Escherichia coli, Streptococcus gallolyticus, or Helicobacter pylori were linked to colon cancer. Inflammation, dysplasia, and cancer may begin to develop in the colon because of changes in the colon's microbiota's composition, distribution, and metabolism. According to studies, people who have a diverse gut microbiota respond to immunotherapy better than those who have a homogeneous microbiome.⁴⁹ It has been suggested that intestinal microbiota can produce commensal-specific memory T lymphocytes that cross-react with antigens related to tumors. Indeed, CD4 + and CD8 + T cells specific for Enterococcus hirae, Bacteroides fragilis, and Akkermansia muciniphila memory responses are associated with favorable clinical outcome in cancer patients, indicating that microbe-specific T lymphocytes may contribute to anti-tumor immune responses.⁵¹

Molecular Pathologic Epidemiology of Colorectal Cancer

The idea of molecular pathological epidemiology (MPE) as an integrative field resulted from the fusion of molecular pathology and epidemiology. Because epidemiology is specifically a subject of data science, MPE is a mix of pathology and data science. MPE can therefore satisfy the requirement to convert pathological findings into data science. The MPE approach can be merged with pharmacoepidemiology potentially to uncover new indications for and to repurpose common drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and statins.⁵² A high level of MSI is associated with proximal colorectal carcinoma, whereas the distal carcinoma has an inversely proportional relation with the level of MSI. The “colorectal continuum model” proposed in MPE is a useful tool to distinguish between proximal and distal colorectal carcinoma.⁵² MPE is being used to correlate the interrelationship between genetic, epigenetic, tumoral molecular signatures and tumor progression in colorectal cancer. MPE targets to discuss whether particular exposure factors like diet, lifestyle modifications, smoking, and obesity are associated with a specific molecular change in colorectal cancer pathogenesis which might affect with clinical outcome. Taking into consideration the heterogeneity of colorectal cancer, traditional epidemiology and MPE will continue to provide profound insights on carcinogenic process and help us optimize prevention and treatment strategies.⁵³

Conventional Therapeutic Strategies Against Colon Cancer

The most practiced approaches to deal with colon cancer are surgery, chemotherapy, and radiotherapy. Though these are associated with several risks, to date, these are the most fruitful tools used in cancer treatment. Depending on the location or stage of cancer, these interventions are used alone or in combination.

Surgery

For colon cancer, surgery is the most widely used treatment. The total mesorectal excision (TME) technique is commonly used in rectal cancer. The entire rectum is removed along with the engulfing mesorectum utilizing this method, and the dissection is done around the visceral fascia plane.⁵⁴ It has been the standard effective procedure for rectal cancer for the past two decades.⁵⁵ For colon cancer, a technique having similar principles as TME has been used and is called “complete mesocolic excision (CME).” In CME, the afflicted colon and mesocolon are removed within a dissected peritoneal envelope, supplying arteries are centrally ligated, and extended lymphadenectomy is carried out.⁵⁶ In a study, patients who had surgery using CME increased their disease-free survival by 4years compared to those who had surgery using traditional procedures. In this technique, a high number of lymph nodes are yielded, which improves survival.⁵⁷ However, it remains problematic compared to traditional colectomies, and parts involved in the procedure have a high risk of creating fatal complications for the patient.

Endoscopic full-thickness resection (EFTR) is a modern surgical procedure to remove the tumor through the gastrointestinal tract (GIT) using an endoscope. It is a minimally invasive surgical therapy that helps treat deep-layer lesions in the GIT. In addition, it can treat small local tumors up to 2-2.5 cm in diameter.⁵⁸ The procedure, however, is associated with perforation risk that can lead to its spread in the peritoneum.⁵⁹

If the metastasis is resectable, removal of both the primary and the metastatic tumors is carried out. According to studies, resection of both tumors gave over a 50% chance of 5-year survival.^60–62

Chemotherapy

Surgery for colon cancer is usually accompanied by chemotherapy. Fluoropyrimidines incite disturbance in DNA duplication and transcription, which leads to cellular death. Fluoropyrimidines such as 5-fluorouracil (5-FU) and capecitabine have been used as a single treatment post-surgery or in conjugation with folic acid analogs such as leucovorin, a noncytotoxic compound that enhances the therapeutic efficacy of 5-FU.^63,64 Oxaliplatin is a platinum-containing compound classified as an alkylating agent as it forms cross-linking in DNA. These linkages are identified as defects by the repair pathways, such as base excision repair (BER); consequently, cell cycle arrest and apoptosis are initiated.⁶⁵ Currently, oxaliplatin and fluoropyrimidine are used to treat metastatic colon cancer and in adjuvant therapy. The death risk decreases by 10%-15% for stage 3 colon cancer using only fluoropyrimidine, while a combination with oxaliplatin further reduces it by 4%-6%.⁶⁶ In stage 2 colon cancer, single treatment 5-FU has a 2%-5% survival benefit. Irinotecan interferes with DNA duplication by inhibiting the topoisomerase I enzyme, which causes cell death. Combined with fluoropyrimidines, it produces remarkable results in overall survival.⁶⁷ Chemotherapeutic combinations commonly used are FOLFOX, a combination of 5-FU, leucovorin, and oxaliplatin; FOLFOXIRI, a combination of 5-FU, leucovorin, irinotecan, and oxaliplatin; and FOLFIRI, a combination of 5-FU, leucovorin, and irinotecan.^68–70

Radiotherapy

Radiotherapy is a therapeutic procedure that utilizes high-intensity x-rays to destroy tumor cells. It is generally used along with chemotherapy and only used under certain conditions. It can be used to aid surgical procedures along with chemotherapy to help shrink a tumor before surgery. In addition, radiotherapy can kill cancer cells if there is any evidence of a tumor left after the primary surgery in the surrounding regions. It is used more commonly in rectal than colon cancer.^71–74

Different Genetic Determinants of Colon Cancer

RAS Mutations

RAS are proteins that are expressed in all mammalian cells. They act as switches controlling cell proliferation, migration, differentiation, and survival pathways. These proteins are often mutated in human cancer. Three forms of RAS proteins are expressed: Harvey Ras (H-Ras), Kirsten Ras (K-Ras), and neuroblastoma Ras (N-Ras).⁷⁵

KRAS is the gene that expresses the K-Ras protein. It is the most mutated gene in the RAS family. About 40% of sporadic CRC cases have mutations in KRAS, which are mainly seen in codons 12 (70%-80%), and 13 (15%-20%) of exon 2.⁷⁶ Codon 12 mutations are related to colorectal cancer of mucin, while codon 13 mutations are a more aggressive form with great potential of metastasis. Comparatively a less frequent mutations can be seen in codons 61 and 63. Few mutations are also seen in exons 3 and 4. Some of the exon 2 KRAS mutations are G12D (32.4%), G13D (14.1%), G12V (11.3%), G12S (9.9%), G12C (8.5%), and G12A (2.8%).⁷⁶

NRAS gene expresses the N-Ras protein. It is found in 3%-5% of metastatic colon cancer patients. It is mainly found on the left side of the colon. Women are primarily affected by this mutation. The gene is mutated in codons 2, 3, and 4.⁷⁷

BRAF Mutations

The BRAF gene found in chromosome 7q34 expresses the B-Raf protein, a serine-threonine protein kinase and a RAS downstream target.⁷⁸ In addition, the protein plays an essential role in the mitogen-activated protein kinase (MAPK) signaling pathway which takes part in cell growth, survival, and proliferation.⁷⁹

About 10% of total metastatic colorectal cancer cases contain BRAF mutations, mostly present along with RAS mutations.⁸⁰ Categorically, BRAS mutations occur as V600E (valine (V) is substituted by glutamic acid (E) at amino acid 600) and non-V600E mutations. V600E mutations are often related to female patients, colon cancer on the right side, and metastases at lymph nodes and peritoneum. Non-V600E mutations are associated with males and show fewer peritoneal metastases as compared to V600E.⁸¹

PIK3CA Mutations

The expression of the PIK3CA gene takes place in all cells. It is responsible for encoding phosphoinositide 3-kinase (PI3K), a class of lipid kinases involved in phosphorylating the 3-hydroxyl group of phosphoinositides. They are a part of the PI3K/AKT/mTOR pathway which regulates various cellular processes including cell growth, survival, proliferation, metabolism, and angiogenesis. They also interact with the Ras/MAPK pathway.⁸²

Somatic activating mutations in PIK3CA are seen in 10%-20% of colon cancer cases.⁸³ These mutations result in the PI3K pathway being overly activated, causing Akt serine/threonine kinase family (AKT) activation, irregular cell developments, and the angiogenic factors being downregulated.

TP53 Mutations

TP53 gene is present in chromosome 17 at the p (short) arm. It expresses the tumor protein p53 (p53). The function of p53 is to control cell division by keeping in check cells from growing and proliferating in an uncontrolled manner. When DNA is damaged, p53 plays a pivotal role in deciding whether the DNA can be repaired or the cell will undergo apoptosis. In the case of DNA repair, other genes are activated by p53 to help repair the damage. When the DNA cannot be repaired, p53 inhibits cell division and sends signals for apoptosis or senescence. When the cell is mutated, p53 aids in preventing the development of tumors by inhibiting cell division. The p-arm of chromosome 17 gets deleted in over 70% of colorectal carcinomas.⁸⁴ In the TP53 gene, most alterations occur in exons 5-8. In the case of the p53 protein, the mutations take place in L2, L3, and loop-sheet-helix structural domains.⁸⁵ The mutations result in the formation of a very stable protein that loses the ability to bind to DNA and cannot activate target genes to repair DNA damage.⁸⁶

APC Mutations

The APC gene is in the long arm (q) of chromosome 5. It is a tumor suppressor gene. It expresses the APC protein. The protein's function is to regulate cell growth, ie, it keeps the cells in control and does not allow growth and proliferation in an uncontrolled way. It regulates the number of cell divisions and how it attaches to other cells. The APC protein also helps ensure the number of chromosomes in a cell after cell division is correct. It associates with other proteins, mainly those involved in cell adhesion and signaling, to accomplish these functions. β-Catenin is a protein that associates with APC. Through its association with β-catenin, APC indirectly controls the transcription of some critical cell proliferation genes.^87,88 The interaction of APC and β-catenin results in the breakdown of β-catenin as a signal that is no longer required. The loss of APC function in case of mutation leads to the accumulation of β-catenin in the nucleus and an increase in transcription of oncogenes such as cellular myelocytomatosis (c-Myc), cyclin D, caspases, and ephrins.^89,90

APC is mutated in inherited FAP (familial adenomatous polyposis) and about 80% of sporadic colon cancer cases. When the mutation occurs in the APC gene, mostly the APC protein produced is small. This abnormal protein cannot control the overgrowth in cells resulting in polyps’ formation due to abnormal growth, which can potentially become cancerous. The deletion of five nucleotide blocks in the APC gene is the most common mutation seen in FAP, and this subsequently changes the sequence of amino acids in the corresponding APC protein.⁹¹

β-Catenin Mutations

β-Catenin is primarily present at the junction of many cells and tissues, helping in cell adhesion and communication between cells. β-Catenin plays a significant role in the Wnt signaling pathway. The Wnt signaling pathway involves cell division, proliferation, and differentiation. In this pathway, β-catenin binds to specific proteins, which allows β-catenin to move inside the cell nucleus. β-Catenin associates with other proteins to express various target genes, including cell proliferation, survival, differentiation, migration, and angiogenesis. In normal cell functioning, the level of β-catenin is regulated. When it is not needed, APC interacts with it and breaks it down. In case of aberrations in the function of APC, there is an unregulated accumulation of β-catenin in the nucleus and uncontrolled expression of target oncogenes such as cellular myelocytomatosis (c-Myc), cyclin D, telomerase reverse transcriptase (TRET), caspases, and ephrins. Mutation in β-catenin is seen in about 10% of sporadic colorectal cancer.^92,93

SMAD4 Mutations

SMAD4 is a gene present at the 18q chromosome. It is also called the DPC4 gene. SMAD4 gene expresses the SMAD4 protein which helps transmit signals from the cell's surface to the nucleus. It is involved in a signaling pathway called the TGF-β (transforming growth factor-beta), which controls various cellular processes. Initially, TGF-β binds to receptor proteins on the cell surface and activates some SMAD proteins. These proteins bind specifically to SMAD4 protein and move to the nucleus. The complex formed binds to specific areas of DNA inside the nucleus and regulates the function of certain genes. In this way, it controls the development of cells and characterization.⁹⁴ Allelic loss of 18q and other factors may contribute to SMAD4 mutation which can lead to uncontrolled cell proliferation and ultimately tumor growth.⁹⁵

Significance and Progression of Personalized Medicine

According to GLOBOCAN 2020 estimates, 1.15 million new instances of colon cancer worldwide were reported in 2020, which is expected to rise to 1.92 million by 2040. Despite existing treatment procedures such as surgery, chemotherapy, and radiation therapy, more than 0.5 million deaths were recorded worldwide in 2020 due to colon cancer.⁹⁶ A statistic like this emphasizes that the generalized treatment regime may not be effective and precise enough to handle all colon cancer cases. Thus, a great need is to understand the disease in individual patients.

In the past, factors such as the progression of cancer in the body, the patient's age, and gender were thought to be enough to decide the treatment regime of an individual.⁹⁷ However, it is seen that genes, their composition, expression, and response vary from individual to individual. This plays an essential role in variable responses across generic chemotherapy and radiotherapy treatments.

To understand the complex biology, molecular landscape, and tumor heterogeneity of colon cancer, the application of omics-based strategies has witnessed a tremendous increase due to the demand for personalized medicine. Worth mentioning, an integrative multi-omics approach revealed the role of a RUNX2 transcription factor as a prognostic biomarker of advanced metastatic colon cancer at the epigenetic level through the regulation of epithelial-mesenchymal transition (EMT) process and drug resistance in a panel of colon cancer cell lines with varying Wnt/β-catenin signaling activity.⁹⁸ The advancements in high-throughput technology, specifically at single-cell resolution, have allowed for the identification of colorectal cancer subtypes based on the intrinsic epithelial cell type and fibrosis using single-cell RNA sequencing (scRNA-seq), which led to the modification of previous consensus molecular subtype (CMS) grouping established from the bulk transcriptome profiles. This precise molecular classification can aid in the administration of immunotherapy and chemotherapeutics.⁹⁹To address the need for therapeutic intervention, combining drug sensitivity testing in advanced colorectal cancer patients-derived organoids with proteotranscriptomic analysis facilitated the measurement of overexpressed peroxiredoxin 6 (PRDX6), aldehyde dehydrogenase 9 A1 (ALDH9A1) proteins, and functional enrichment of the t-RNA aminoacylation process associated with oxaliplatin resistance.¹⁰⁰ The apparent potential of incorporating comprehensive omics analysis with colorectal cancer organoid models provided insights into the metastatic role of SMAD4 loss via the upregulated expression of epithelial-mesenchymal transition (EMT) promoting tumor growth, activation of Wnt, and TGF-β signaling pathways.¹⁰¹ In the era of big data, which is being driven by artificial intelligence and machine learning data analytics, knowledge extracted from the incorporation of patient demographics with omics data, clinicopathological features, and tissue scan images are capable of better-stratifying patients which can refine prognosis prediction, biomarker identification, and individualized treatment. Much recently, an AI-based pre-screening tool for the prediction of MSI/mismatch repair deficiency (dMMR) status using routine histopathology slides was able to distinguish between the colorectal cancer patient cohorts which did not require molecular MSI testing, thereby improving early diagnostics.¹⁰²

Interestingly, machine learning models based on different omics highlighted the prediction performance of metagenomics data in the 3-year survival rate of colorectal cancer patients with an area under the curve (AUC) of 0.755.¹⁰³ The gut microbial signature as a candidate functional biomarker for dysbiosis could discriminate colorectal cancer patients from controls across cohorts. Reportedly, Fusobacterium, Peptostreptococcus species, and Porphyromonas asaccharolytica are enriched in the stool samples, and also their abundance is correlated positively in the advanced metastasizing stages of cancer.¹⁰⁴ It should be mentioned that researchers have identified the diagnostic potential of circulating microbial DNA that can drive systemic immune activation in colorectal cancer patients in whom the epithelial barrier function is disrupted resulting in gut microbiota translocation to the bloodstream.¹⁰⁵ The potential of modulating intestinal microbiota with prebiotics and/or probiotics is currently being explored as adjuvant cancer therapy, for example, a clinical trial NCT04021589 was conducted for monitoring treatment efficacy in colorectal cancer patients undergoing chemotherapy.¹⁰⁶

Personalized medicine aims to understand the underlying mechanisms and characterized genetic changes and responses to environmental factors specific to a disease. This can lead to identifying key biological molecules or processes known as biomarkers that play a specific role throughout the course. These biomarkers can be targeted, and specific therapies can be devised.^107–110

Translating a developed therapy into personalized medicine according to patient's condition is a challenging process. Initially, specific gene and mutation data are studied and understood precisely before considering a drug for clinical research. These data are obtained using various techniques such as genome sequencing technologies and transcriptomic, proteomic, and metabolomic studies. Then, patients are categorized into groups for clinical trials based on their data on genes and mutations, and therapy suited to specific individuals is identified.¹¹¹ The term “personalized” is often misleading as the therapy does not involve devising unique treatments for every individual patient. Instead, it is the selection of the best-suited therapy/therapies from the existing therapeutic regime based on the patient's genetic mutations and other related molecular biological data while also considering the patient's age, gender, overall health, cancer progression, and lifestyle factors.

Companion diagnostics are typically used to gather the patient's molecular data (CDx). They are tests that assess the presence of specific genes, proteins, or mutations and can assist in pinpointing the best course of action for treating a patient's disease.¹¹² Real-time PCR analysis and next-generation sequencing-based tests are specific techniques for detecting KRAS mutations.^113,114 For detecting biomarkers such as KRAS, NRAS, and BRAF, several commercially available kits have been developed to help make identifying key biological factors easier.¹¹⁵

The main issue with such general therapy is that not all patients respond to the treatment in the same way. Some medications may work great on certain patients, while they may be less effective or not effective at all for some patients. Even the side effects and their extent can vary from individual to individual. Finding the exact therapy that can work well for an individual can be very challenging.

Personalized medicine is a step taken in the direction of finding the best-fit therapy for a particular patient. In addition to the patient information taken in conventional treatments, an individual's genetic and molecular profile is studied, while the environmental factors and lifestyle are also considered. Accordingly, the most suited treatment is prescribed. Personalized medicine is also, therefore, called precision therapy. Pembrolizumab is an example of targeted therapy in colon cancer where it is specifically used to treat high microsatellite instability or deficient mismatch repair metastatic colorectal cancer.

For conventional medicine, drugs are developed to treat colon cancer or its symptoms directly. Therefore, a large group of colon cancer patients is involved in testing drugs for clinical trials. The Food and Drug Administration (FDA) approval comes when a drug shows a promising activity in most patients. However, this cannot guarantee success for all patients. On the other hand, personalized medicine is much more precise.

In colon cancer, KRAS mutations are seen in many colon cancer patients. Specific micromolecules, adagrasib, and sotorasib (AMG 510) target and inhibit KRASGI2C. Another example is the identification of encorafenib in colon cancer therapy. BRAF mutations are seen in a few metastatic colorectal cases. Encorafenib inhibits BRAFV600E and can be explicitly used in treatments related to BRAF mutations.^116,117

FDA Accepted Personalized Medicine Therapy in Colon Cancer

Bevacizumab

It is a monoclonal immunoglobulin G1 (IgG1) antibody specific to the VEGF-A protein.¹¹⁸ It specifically binds to the circulating VEGF-A protein and inhibits its binding to the VEGFR1 and VEGFR2 receptors on the cell surface. As a result, the microvascular growth of the tumor's blood vessels is reduced, and blood supply to these tumor tissues is reduced.^119,120 Bevacizumab does not have a direct anti-tumor effect, but it helps improve the efficacy of the accompanying chemotherapy.¹²¹ After the administration of bevacizumab, the blood vessels associated with the tumor morphologically normalize and become organized. The pressure of oxygen and interstitial fluid supply is decreased. The delivery of the chemotherapeutic agents is improved; thus, their efficacy in acting on the tumor increases.¹²² It is generally used with FOLFOXIRI.¹²³

Cetuximab

It is a chimeric monoclonal IgG1 antibody of the epidermal growth factor receptor (EGFR).¹²⁴ It selectively binds to the extracellular region of the EGFR and blocks the domain from binding to epidermal growth factor (EGF) and other ligands.¹²⁵ This blockage results in cell growth inhibition, increased apoptosis of tumor cells, reduced angiogenesis, and metastasis.¹²⁶ It is a first-line colon cancer drug used along with chemotherapy. Monotherapy with cetuximab is an option for metastatic colorectal cancer patients with EGFR-expressing, K-Ras wild-type tumors who resist chemotherapy.^127,128

Panitumumab

It is an IgG2 kappa monoclonal antibody (mAb) of EGFR.¹²⁹ It has a mechanism of action similar to cetuximab. It binds specifically to EGFR and does not allow other ligands to bind to it. This causes cell growth inhibition, tumor cell apoptosis induction, decreased angiogenesis, and metastasis.¹³⁰ It was approved in 2006 for treating metastatic colon cancer by the FDA. It is used as a single treatment of metastatic colorectal cancer having EGFR expression or along with chemotherapy.

Ziv-Aflibercept

It is a recombinant protein formed by the fusion of the constant region (Fc) of human IgG1, the second immunoglobulin (Ig) region of human VEGFR-1, and the third Ig region of VEGFR-2.¹³¹ It acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PIGF) 1 and 2 and inhibits their interactions with VEGFR-1 and VEGFR-2. This inhibition leads to a decrease in angiogenesis, tumor growth, and metastasis.¹³² It was approved by the FDA in 2012 for the treatment of metastatic colorectal cancer. It is used in combination with FOLFIRI.¹³³

Regorafenib

Regorafenib is a small monohydrate molecule multi-kinase inhibitor that inhibits abnormally activated or mutated kinases in tumor cells or those helping in oncogenesis such as VEGFRs, BRAF, platelet-derived growth factor receptor (PDGFR), c-Kit, and Tie-2.¹³⁴ As a result, there is inhibition of angiogenesis, cell proliferation, and tumor apoptosis.¹³⁵ In 2012, it was approved by the FDA for the treatment of metastatic colorectal cancer. It is used as a single treatment in anti-VEGF therapy, anti-EGFR therapy in KRAS wild-type tumors, and in metastatic colon cancer patients who have previously undergone chemotherapy.¹³⁶

Ramucirumab

It is a recombinant immunoglobulin G1 (IgG1) monoclonal antibody of VEGFR-2.¹³⁷ It specifically identifies and binds to the domain of VEGFR-2 and blocks the binding of all ligands associated with VEGFR-2, including VEGF-A, VEGF-C, and VEGF-D.¹²⁰ This inhibits tumor cell proliferation, migration, and angiogenesis. Ramucirumab completely blocks the signaling related to VEGFR-2, and hence it has the potential to overcome resistance associated with bevacizumab.¹³⁸ The FDA first approved ramucirumab in 2014 for gastric cancer; in 2015, it was approved for metastatic colon cancer.

Pembrolizumab

It is a monoclonal immunoglobulin G4 (IgG4) antibody of programmed cell death protein 1 (PD-1).¹³⁹ It binds to the PD-1 receptor and blocks the interaction of programmed death ligands 1 (PD-L1) and 2 (PD-L2) with the PD-1 receptor. PD-L1 can aid in cell proliferation and survival in cancer cells, while PD-L2 supports tumor metastasis. The binding of PD-L1 and PD-L2 to the cytotoxic tumor T cells can thus act as a mechanism for cancer cells to evade immunity.¹⁴⁰ Blocking of the PD-1 receptor can therefore inhibit T-cell cytotoxicity response. Pembrolizumab was first approved for microsatellite instability-high cancer in 2017, and in 2020, it was approved for metastatic colon cancer patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) as first-line treatment..¹⁴¹

Nivolumab

It is a monoclonal IgG4 antibody of the PD-1 receptor.¹⁴² The mechanism of action of nivolumab is like that of pembrolizumab. It specifically binds to PD-1 and inhibits PD-L1 and PD-L2 from binding to PD-1 receptor. Nivolumab was approved for the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer in 2017. It is used either as a single drug therapy or in association with ipilimumab after metastatic colorectal cancer with MSI-H or dMMR has progressed following the use of fluoropyrimidine, irinotecan, and oxaliplatin treatment regime.¹⁴³

Ipilimumab

Ipilimumab is a monoclonal IgG1 antibody of CTLA-4 (cytotoxic T-lymphocyte antigen 4).¹⁴⁴ Ipilimumab binds explicitly to CTLA-4 and inhibits the interaction of ligands such as CD80 and CD86 to CTLA-4. This blocking mechanism leads to aiding the activation and proliferation of T cells and T-effector cells. This ultimately contributes to increased T-cell responsiveness, including immune response for battling tumor activity. It was approved in 2018 by the FDA for combinational therapy with nivolumab for the treatment of metastatic colorectal cancer with MSI-H or dMMR. It is used in combination with nivolumab after metastatic colorectal cancer with MSI-H or dMMR has progressed following the use of fluoropyrimidine, irinotecan, and oxaliplatin treatment regime for adult and pediatric patients above 12 years old.¹⁴⁵

Encorafenib

Encorafenib was initially approved for the targeted therapy of melanoma in a multicenter trial (COLUMBUS; NCT01909453), mediated by its inhibitory action against the MAPK signal transduction pathway as it binds to the BRAF protein resulting in cell cycle arrest and senescence. Much recently, the clinical use of encorafenib and cetuximab received FDA approval specifically targeting the BRAF V600E-mutant with the improved response rate in the BEACON trial (NCT01909453) with adult metastatic colorectal cancer patients post-systemic therapy (Table 1).^117,146

Table 1.

FDA-Approved Personalized Targeted Drugs for Colon Cancer Therapy

Chemical name	Year of approval for colon cancer treatment	Type of molecules	Targeted biomarkers
Bevacizumab	2004	Monoclonal antibody	VEGF-A
Cetuximab	2004	Monoclonal antibody	EGFR
Panitumumab	2006	Monoclonal antibody	EGFR
Ziv-aflibercept	2012	Recombinant protein	VEGF-A, VEGF-B, PlGF
Regorafenib	2012	Small monohydrate molecule	VEGFR, EGFR, PDGFR, BRAF, BRAF^V600E mutation
Ramucirumab	2015	Monoclonal antibody	VEGFR-2
Pembrolizumab	2017	Monoclonal antibody	PD-1
Nivolumab	2017	Monoclonal antibody	PD-1
Ipilimumab	2018	Monoclonal antibody	CLTA-4
Encorafenib	2018	Kinase inhibitor	BRAF^V600E

Recent Update on Personalized Therapeutics in Perspective of Various Targeted Strategies

Different types of mutation, responsible for colon cancer progression and targeted therapy, explicitly evolved for it is described in the following subsections, and a pictorial representation is depicted in Figure 3.

Figure 3.

Molecular pathways in normal and colon cancer cells and potential targeted therapies.

RAS Mutation Targeted Therapy

Chemotherapy with bevacizumab is the preferred treatment for KRAS mutation; however, currently, minimal data is available.¹⁴⁷ Targeted therapy with micromolecules, adagrasib, and sotorasib has shown a promising activity recently. They target KRASG12C and inhibit it irreversibly.⁷⁶ Adagrasib monotherapy, in combination with cetuximab, was found to be potent. Currently, a combination of adagrasib and cetuximab and another one of sotorasib and panitumumab are being evaluated for phase III trials.¹⁴⁸ A combination of MEK inhibitors with an anti-PD-L1 has synergized tumor regression.¹⁴⁹ A combination of atezolizumab and cobimetinib (MEK inhibitor) is being studied in phase Ib trials (NCT03785249).¹⁵⁰ In a phase II study, the addition of atezolizumab to FOLFOXIRI, bevacizumab, and fluorouracil regime showed significant results.¹⁵¹ Immunotherapy has also been tried in RAS-mutated patients. Tumor-infiltrating lymphocyte (TIL) therapy showed good activity in KRASG12D mutation.¹²⁹

BRAF Mutation Targeted Therapy

For the initial management of BRAFV600E mutations, FOLFOXIRI has been used with bevacizumab.^152,153 Antiangiogenic agents such as ramucirumab and aflibercept, combined with FOLFIRI, showed a potent activity in second-line BRAFV600E mutation studies.^154,155 BRAFV600E inhibitors have been recently used in the treatment process. They show less activity when used alone, as seen in a study involving vemurafenib, a BRAFV600E inhibitor.¹⁵⁶ The inhibitors are now combined with other agents such as anti-EGFR and MEK inhibitors.^157–160 There is a lot of interest in the FDA-approved BRAFV600E inhibitor encorafenib. A study showed that encorafenib with anti-EGFR inhibitor, cetuximab, and MEK inhibitor binimetinib (triplet therapy) and another combination of encorafenib and cetuximab (doublet therapy) showed greater effects than the standard therapy of FOLFIRI.^161,162 Non-BRAFV600E mutations have shown to respond to anti-EGFR treatments.^162–166

Microsatellite Instability Targeted Therapy and Immunotherapy

About 16% of stage 2 and 3 colon cancer cases have MSI. Fluoropyrimidines have been used in MSI colon cancers. However, it does not show satisfactory results in MSI stage 2 cases; a study even found it detrimental to overall survival.^167–169 So, it is not currently used for MSI stage 2 patients. When compared to stable microsatellite tumors, fluoropyrimidines and oxaliplatin show excellent results for disease-free survival (DFS) and overall survival (OS) in stage 3 patients (MSS).¹⁷⁰ Some studies found irinotecan to be sensitive to MSI cancer.¹⁷¹ However, there seem to be other studies with conflicting results.¹⁷² Bevacizumab has been studied recently in combination with traditional treatments.

Immunotherapy is recently gaining interest, especially in studies related to high levels of microsatellite instability (MSI-H)/deficient mismatch repair (dMMR). Immune checkpoint inhibitor (ICI) class of molecules like anti-PD-1, anti-PD-L1, and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) are used in immunotherapy.¹⁷³ Anti-PD-L1 agent, atezolizumab, is currently being studied with FOLFOX in stage 3 MSI colon cancer.¹⁷⁴ Another anti-PD-L1 agent, avelumab, has also been assessed in another study on stage 3 cancer.¹⁷⁵ Nivolumab, an anti-PD-1 immunoglobulin G4 (IgG4) antibody, in combination with ipilimumab, an anti-CTLA-4 IgG1 monoclonal antibody, showed a promising activity in a phase II study.¹⁷⁶ In a phase III study, pembrolizumab, another anti-PD-1 IgG4 antibody, showed longer progressive-free survival (PFS) than chemotherapy in first-line treatment.¹⁴¹

NTRK Gene Fusion Targeted Therapy

The neurotrophic tyrosine receptor kinase (NTRK) genes are cancer driver genes encoding dysfunctional tropomyosin receptor kinase (TRK) proteins in NTRK fusion tumor types more prevalent in microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) and metastatic patients with RAS/BRAF wild-type in frequencies from 5% to 15%, respectively. A subset of adult and pediatric patients with various gastrointestinal cancers having targetable TRK mutations were administered larotrectinib (Vitrakvi) in the NAVIGATE basket trial (NCT02576431). Currently, the FDA-approved larotrectinib and entrectinib are recommended treatment options for NTRK fusions. At the same time, the assessed long-term comparative efficacy favored larotrectinib with substantial life expectancy for colorectal cancer patients.¹⁷⁷

Phytochemical-Based Targeted Therapy

Phytochemicals have always provided significant resources for cancer therapy. Vinca alkaloids inhibiting microtubules and camptothecin inhibiting the DNA topoisomerase I are well-established natural plant products showing therapeutic potential.¹⁷⁸ A survey conducted in the USA through the National Cancer Institute found that approximately 69% of the drugs used in cancer between 1980 and 2002 were derived from natural products or devised accordingly based on natural products.¹⁷⁹

Curcumin has been widely studied for different cancer treatments. Curcumin was found to inhibit cell growth in HCT-116 and HT29 colon cancer cell lines.^180,181 It interacts with many targets and thus influences key signaling pathways related to colon cancer, such as receptor tyrosine kinase (RTK) signaling, Wnt signaling pathway, Notch signaling, and p53 pathway. Resveratrol, a natural phenol derived from grapes, raspberries, and mulberries, is another phytochemical with anti-colon cancer potential. It has shown a significant activity against breast cancer.¹⁸² It has demonstrated inhibiting and antigenotoxic effects in SW480 and HL60 colorectal cell lines, respectively.^183,184 It functions similarly to curcumin and influences several signaling pathways, including the RTK, notch, and Wnt signaling. Luteolin, a flavone produced from Reseda luteola L., may be utilized in targeted therapy to prevent colon cancer.¹⁸⁵ It aids in the anti-angiogenesis of tumor cells by preventing VEGF from attaching to its receptor. It also inhibits GSK-3B and thus influences the Wnt signaling pathway. Quercetin is another phytochemical that affects the Wnt signaling pathways and T-cell signaling receptor pathways and is a potential targeted therapy drug. Gallic acid and apigenin are EGFR inhibitors and HER2 inhibitors, respectively. Gallic acid also modulates the T-cell signaling receptor pathway. Integration of phytochemicals in targeted therapy could potentially overcome the problems of drug resistance. Various phytochemicals and their interaction with the pathways in colon cancer are depicted in Figure 4.

Figure 4.

Phytochemical-based targeted therapy in colon cancer.

Personalized Medicine in Global Healthcare Systems

Personalized medicine has the potential to revolutionize colon cancer therapy. While personalized medicine has great promise to improve the standard of healthcare systems and the treatment of diseases, its effect on a global level must be considered. Personalized medicine is very active in the healthcare systems in the UK, US, and European countries. Contrary to it, the scenario is very different in middle and low-income countries of Africa and South Asia. Even though many of these countries have started to adopt the use of personalized medicine, they face monumental difficulties in their development, and transition into healthcare systems.

One of the major challenges with the implementation of personalized medicine is the high cost of the treatments. New cancer drugs are costly. For example, the average price of colon cancer drugs such as nivolumab and ipilimumab in the US exceeds 0.1 million USD per patient yearly.¹⁸⁶ The personalized treatment regime's expenses are even comparatively higher than that of conventional treatments. For instance, a three-week chemotherapy cycle for the treatment of metastatic colon cancer costs about 5.6K USD when bevacizumab alone is used.¹⁸⁷ In developed countries, where the per capita income is considerably higher, the cost of treatments from the personalized treatment of colon cancer is feasible. However, patients in middle and low-income nations struggle mightily to cover the costs of personalized medicine, and the majority are left with little choice but to rely on traditional treatments. A possible solution can be to identify and develop similar drugs with identical therapeutic efficacy at a substantially cheaper cost.

The development of personalized medicine requires technologies such as sophisticated imaging modalities, high genome sequencing, proteome, transcriptome, and others which are very expensive. For example, a positron emission tomography (PET) scan, which can help reveal bodily biochemical functions, for a single patient can cost around a thousand USD.¹⁸⁸ Even the companion diagnostic kits available currently for identifying specific biomarkers are comparatively costlier than tests in other treatment regimes. The development of good network models of health insurance and government-based finances available to patients can significantly encourage the use of personalized medicine.

A fundamental aspect of the development of personalized medicine is the support from the government. The UK's National Health Service (NHS) is well supported and endorsed by the government for adopting personalized medication.¹⁸⁹ In the UK, a budget of around 0.2 million euros is allocated annually for developing policies on genomics in healthcare.¹⁹⁰ Substantial funding is provided by the governments in the UK, the USA, and Canada for research in personalized medicine.^190–192 Similarly in Australia, the governance at the state and national levels has a good framework for promoting the integration and implementation of genomics in the healthcare system.¹⁹³ In low- and middle-income countries, the research on personalized medicine is mainly based at the institutional level, with funding from the government, the university, or foreign collaborators. Currently, insufficient funding is a significant issue in developing and sustaining personalized medicine. Only a handful source of large-scale funded research projects and initiatives remain, such as the Agency for Science, Technology and Research (A*STAR) in Singapore and TCELS, a Thai Ministry of Science and Technology organization in Thailand.¹⁹⁴ Low- and middle-income countries need to adopt models for healthcare systems like that of the developed nations. Along with granting adequate funding for research in personalized medicine, specific committees need to be assigned from the grass root level to the highest national levels to implement and monitor the development of personalized medicine in the respective countries. In the healthcare systems, professionals must be trained well to meet the demands of personalized medicine. There is a great need to create awareness in public and patients regarding the benefits and uses of personalized medicine through campaigns and digital media. Though the development of personalized medicine is comparatively slower in low- and middle-income countries, great efforts could see the gap between them, and the developed countries decrease in the coming years.

Advantages and Limitations of Personalized Medicine

One main advantage of personalized medicine is it can help decide which drug can have the best effect on a particular individual. Conventional therapies are prescribed for a large group of patients. So, the treatment may not be very effective for all patients. Depending upon the genetic makeup of a particular individual, personalized medicines are prescribed. So, the chances of the drug being effective are very high compared to traditional medicine.

Cancer drugs tend to be toxic and cause side effects. In personalized therapy, tailored medications are prescribed depending upon the genetic constituents. Since specific mutations are identified, only a few specific drugs are administered. So, unnecessary drugs with potential side effects can be avoided. Also, the cost of the treatment can be less to a certain extent as only particular drugs are required.

Personalized medicine can be used in combination with traditional therapies. It can help improve the choices in treatments and help implement optimized strategies in healthcare systems, including behavior, lifestyle, and surgical changes.

The development of genetic mapping has allowed us to finally comprehend the impact that genes have on a person's health, which further expands our understanding of how to treat chronic illnesses like cancer or diabetes. But the key idea behind this approach is that patients should receive care tailored to their individual needs and the common understanding of their symptoms and conditions. The effectiveness of personalized medicine for the prevention of chronic diseases may necessitate a population-based strategy, notwithstanding the inherent tension between individual health measures that benefit the population and personalized medicine for the benefit of the public.¹⁹⁵

Decisions in personalized medicine are based on the patient's unique circumstances, which may impact their health. Today, patients are responsible for making treatment decisions because doctors do not always know the results of a particular treatment or how it will affect a specific person. With the accuracy of personalized medicine, healthcare professionals can provide each patient with a unique treatment plan, increasing the likelihood that they will recover.

Genetic mapping-based targeted treatment can help save healthcare costs by enabling more intelligent treatment choices that are more likely to succeed. In addition, with a focus on preventive care rather than the treatment of disease, the cost is predicted to be potentially lower.

Finding the general causes of diseases and developing effective treatments can benefit from studying the genetic patterns of a population both as a whole and in portions. Predicting the risk of diseases and their early identification will be much easier with the help of genetic research on certain populations.

The benefits listed above make it appear like an appealing investment to use personalized medication. These areas have already been recognized and are planned to be covered by other concepts and programs. Still, the impact that personalized medicine could have on healthcare is significant and far-reaching.

For personalized medicine to function at its highest level, a sizable and diversified set of genomic data must be gathered. Legal ownership of the data is allegedly ambiguous when such a vast volume of data is compiled. The FDA has prohibited people from obtaining their own genetic information from businesses, and the government does not assume responsibility for the data. Additionally, privacy concerns may arise from the storing and collecting of such massive volumes of data. Therefore, there would be a lot of opposition to the implementation of such a proposal.

Personalized medicine has the potential to have a significant influence on healthcare, but it will take time to implement and will require substantial infrastructure investments. Fundamental modifications are required in the infrastructure and methods of data collecting, exchange, and storage to achieve customized treatment. It is unknown who will be responsible for paying the remaining balance of the budget, such as the state or federal government, patients, or providers. The federal cash set aside for the development of customized medicine will not be sufficient to satisfy the demand.

In general, precision medicine can reduce the flow of money from the healthcare system by removing frequent errors and readmissions and helping to take certain preventive steps against the disease. However, it necessitates a large infrastructure investment for the gathering, archiving, and distribution of this data. Investments in security infrastructure are necessary to safeguard the data and other costs that are becoming burdensome.

Personalized treatment is continuously changing the way we think about medicine. It offers numerous opportunities to improve prevention, prediction, and post-care benefitting the patients. With evidence-based action, sound scientific knowledge, and appropriate priority-setting in basic education, it will be possible to take as many opportunities as possible while avoiding unwelcome developments.

Future Perspectives and Conclusion

In the past few years, there has been a significant change in how colon cancer is treated. The disease's variability has caused the treatment to change to a more individualized strategy. Identifying the simple status of KRAS, BRAF, and other mutations and their specific biomarker therapies have massively improved the overall survival of patients. The development of cetuximab and bevacizumab in 2004 made colon cancer-targeted therapy possible. Targeted therapies’ precision has produced positive outcomes and reduced treatment costs by preventing the necessity for some operations. A different class of drugs depending on specific genetic variations is being investigated. Immunotherapy is one such branch that is being explored which has an excellent potential. Treatment with drugs such as ipilimumab, pembrolizumab, and nivolumab has produced good results in colon cancer therapy.

There are currently very few practical instances of individualized therapy. To successfully adopt personalized medications, infrastructure, and technology to molecular assay analytes and collaboration between all stakeholders is needed. To improve the genotype-phenotype relationship and advance personalized treatment, it is critical to discover essential proteins, gene variations, and various expression patterns linked to the disease or disease propensity. The development of personalized medicine is expected to have positive effects on the therapeutic and diagnostic sectors. Personalized pharmaceuticals are expected to have a positive impact on many consumer-focused sectors in addition to the services and core products. Personalized medicine has a lot to offer for enhancing and advancing cancer treatment for today and tomorrow as the field slowly but steadily develops.

Accessing patient samples, creating trustworthy testing models, and the inherent genetic and non-genetic diversity present in ever-evolving cancer provide many difficulties for developing precision medicine solutions for cancer.

Though there is a sound level of optimism, the reality is there are very few studies available as evidence. Despite the advantages of personalized medicine, the options for oncologists and doctors for individualized therapies are minimal. Extensive research in biomarker discovery is ongoing, yet their translation to therapeutics has not been excellent. The existing identified biomarkers need to be exploited well. New molecular methods need to be devised for biomarker discovery, and the existing ones need to be reviewed and optimized. In terms of technology, a lot of technical improvement needs to be made to upgrade the accuracy and precision of data obtained from the human tissues. Developing more specific assays and incorporating them in clinical trials for validation is also a great challenge for personalized medicine. However, there is a greater hope that these studies can be translated into life-saving therapies in the near future.

Footnotes

Abbreviation

Acknowledgments

The authors are thankful to the Chettinad Academy of Research and Education (CARE) for providing the infrastructural and to DST-SERB for providing financial support to complete this piece of work. The authors declare that they have no conflict of interest.

Author Contributions

Conceptualization: S.P., A.B., H.Z., and X.F.S. Writing—original draft preparation: AM, A.D., A.B., A.S.H., and S.P. Writing—review and editing: S.P., A.B., A.S.H., H.Z., and X.F.S. Supervision: S.P., X.F.S., A.B., and H.Z. All authors have read and agreed to the published version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Science and Engineering Research Board (grant number EMR/2017/001877).

ORCID iD

Antara Banerjee

References

Hossain

Karuniawati

Jairoun

, et al. Colorectal cancer: a review of carcinogenesis, global epidemiology, current challenges, risk factors, preventive and treatment strategies. Cancers (Basel). 2022;14(7). doi:10.3390/cancers14071732

Qari

Alzahrani

Saleh

Almasabi

Bawazir

. Bilateral Wilms’ tumor with different responses to preoperative chemotherapy. Cureus. 2022;14(10):e30593. doi:10.7759/cureus.30593

Taieb

Gallois

. Adjuvant chemotherapy for stage III colon cancer. Cancers (Basel). 2020;12(9). doi:10.3390/cancers12092679

Girigoswami

. A review on the role of nanosensors in detecting cellular miRNA expression in colorectal cancer. Endocrine, Metabolic & Immune Disorders Drug Targets. 2021;21(1):12-26. doi:10.2174/1871530320666200515115723

Ros

Saoudi

Salvà

, et al. Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies. Expert Opin Investig Drugs. 2022;31(3):235-247. doi:10.1080/13543784.2022.2040016

Narayan

. Challenges and Future Opportunities of Nanomedicine in Cancer Therapy. Nanomedicine for Cancer Diagnosis and Therapy. Springer; 2018.

Wang

Sun

Lei

Zhang

H-T

. RNA-binding proteins and cancer metastasis. Semin Cancer Biol. 2022;86(Pt 2):748-768. doi:10.1016/j.semcancer.2022.03.018

Verma

. Personalized medicine and cancer. J Pers Med. 2012;2(1):1-14. doi:10.3390/jpm2010001

Das

Adhikari

Deka

, et al. An updated review on the role of nanoformulated phytochemicals in colorectal cancer. Medicina (B Aires). 2023;59(4):685. doi:10.3390/medicina59040685

10.

Huyghe

Benidovskaya

Stevens

Van den Eynde

. Biomarkers of response and resistance to immunotherapy in microsatellite stable colorectal cancer: toward a new personalized medicine. Cancers (Basel). 2022;14(9). doi:10.3390/cancers14092241

11.

CWK

Reid

Leedham

Lui

. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol. 2022;37(8):1411-1425. doi:10.1111/jgh.15937

12.

Strickler

Yoshino

Graham

Siena

Bekaii-Saab

. Diagnosis and treatment of ERBB2-positive metastatic colorectal cancer: A review. JAMA Oncol. 2022;8(5):760-769. doi:10.1001/jamaoncol.2021.8196

13.

Moutafi

Robbins

Yaghoobi

, et al. Quantitative measurement of HER2 expression to subclassify ERBB2 unamplified breast cancer. Lab Investig. 2022;102(10):1101-1108. doi:10.1038/s41374-022-00804-9

14.

Tarighati

Keivan

Mahani

. A review of prognostic and predictive biomarkers in breast cancer. Clin Exp Med. 2022;23(1):1-16. doi:10.1007/s10238-021-00781-1

15.

Carethers

Jung

. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology. 2015;149(5):1177-1190.e3. doi:10.1053/j.gastro.2015.06.047

16.

Jin

Han

Lee

, et al. Association between metabolic syndrome and the risk of colorectal cancer diagnosed before age 50 years according to tumor location. Gastroenterology. 2022;163(3):637-648.e2. https://doi.org/10.1053/j.gastro.2022.05.032

17.

Kudchadkar

Ahmed

Mukherjee

Sagar

. Current guidelines in the surgical management of hereditary colorectal cancers. World J Gastrointest Oncol. 2022;14(4):833-841. doi:10.4251/wjgo.v14.i4.833

18.

Garcia FA de

de Andrade

de Campos Reis Galvão

, et al. New insights on familial colorectal cancer type X syndrome. Sci Rep. 2022;12(1):1-11. doi:10.1038/s41598-022-06782-8

19.

Turati

Concina

Rossi

, et al. Association of prebiotic fiber intake with colorectal cancer risk: The PrebiotiCa study. Eur J Nutr. 2022;62(1):455-464. doi:10.1007/s00394-022-02984-y

20.

Jasperson

Tuohy

Neklason

Burt

. Hereditary and familial colon cancer. Gastroenterology. 2010;138(6):2044-2058. doi:10.1053/J.GASTRO.2010.01.054

21.

Helsingen

Kalager

. Colorectal cancer screening — approach, evidence, and future directions. NEJM Evid. 2022;1(1):1-13. doi:10.1056/evidra2100035

22.

Ahmed

. Colon cancer: A clinician’s perspective in 2019. Gastroenterol Res. 2020;13(1):1-10. doi:10.14740/gr1239

23.

Markowitz

Bertagnolli

. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2449-2460. doi:10.1056/NEJMra0804588

24.

Grady

Carethers

. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135(4):1079-1099. doi:10.1053/j.gastro.2008.07.076

25.

Fearon

Vogelstein

. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767. doi:10.1016/0092-8674(90)90186-i

26.

Samuels

Wang

Bardelli

, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554. doi:10.1126/science.1096502

27.

Markowitz

Wang

Myeroff

, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268(5215):1336-1338. doi:10.1126/science.7761852

28.

Patil

Jahagirdar

Khot

Sengupta

. Studying the role of chromosomal instability (CIN) in GI cancers using patient-derived organoids. J Mol Biol. 2022;434(3):167256. doi:https://doi.org/10.1016/j.jmb.2021.167256

29.

Cho

Kim

Che

, et al. Role of the WNT/β-catenin/ZKSCAN3 pathway in regulating chromosomal instability in colon cancer cell lines and tissues. Int J Mol Sci. 2022;23(16). doi:10.3390/ijms23169302

30.

Hankey

Frankel

Groden

. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: Implications for therapeutic targeting. Cancer Metastasis Rev. 2018;37(1):159-172. doi:10.1007/S10555-017-9725-6

31.

Xie

Itzkowitz

. Cancer in inflammatory bowel disease. World J Gastroenterol. 2008;14(3):378-389. doi:10.3748/wjg.14.378

32.

Mármol

Sánchez-de-Diego

Pradilla Dieste

Cerrada

Rodriguez Yoldi

. Colorectal carcinoma: A general overview and future perspectives in colorectal cancer. Int J Mol Sci. 2017;18(1). doi:10.3390/ijms18010197

33.

Nguyen

Duong

. The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy (review). Oncol Lett. 2018;16(1):9-18. doi:10.3892/ol.2018.8679

34.

Braumüller

Mauerer

Andris

Berlin

Wieder

Kesselring

. The cytokine network in colorectal cancer: Implications for new treatment strategies. Cells. 2023;12(1):138. doi:10.3390/cells12010138

35.

Nagao

Koshino

Sugimura-Nagata

, et al. The complete loss of p53 expression uniquely predicts worse prognosis in colorectal cancer. Int J Mol Sci. 2022;23(6):1-12. doi:10.3390/ijms23063252

36.

De’ Angelis

Bottarelli

Azzoni

, et al. Microsatellite instability in colorectal cancer. Acta Biomed. 2018;89(9-S):97-101. doi:10.23750/abm.v89i9-S.7960

37.

Oneda

Zaniboni

. Adjuvant treatment of colon cancer with microsatellite instability – the state of the art. Crit Rev Oncol Hematol. 2022;169(1):103537. doi:10.1016/j.critrevonc.2021.103537

38.

André

Cohen

Salem

. Immune checkpoint blockade therapy in patients with colorectal cancer harboring microsatellite instability/mismatch repair deficiency in 2022. Am Soc Clin Oncol Educ B. 2022;42(1):233-241. doi:10.1200/edbk_349557

39.

Lee

Song

Jang

. Feasibility of deep learning-based fully automated classification of microsatellite instability in tissue slides of colorectal cancer. Int J Cancer. 2021;149(3):728-740. doi:10.1002/ijc.33599

40.

Yanus

Akhapkina

Iyevleva

, et al. The spectrum of Lynch syndrome-associated germ-line mutations in Russia. Eur J Med Genet. 2020;63(3):103753. doi:https://doi.org/10.1016/j.ejmg.2019.103753

41.

Toyota

Ahuja

Ohe-Toyota

Herman

Baylin

Issa

. Cpg island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999;96(15):8681-8686. doi:10.1073/pnas.96.15.8681

42.

Skvortsova

Stirzaker

Taberlay

. The DNA methylation landscape in cancer. Essays Biochem. 2019;63(6):797-811. doi:10.1042/EBC20190037

43.

Gul

. Highlight DNA methylation biomarkers in different cancer types for drug designing. Journal of Epigenetics. 2022;3(1):35-42. doi:10.22111/jep.2022.40064.1033

44.

Nguyen

Goel

Chung

. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158(2):291-302. doi:10.1053/j.gastro.2019.08.059

45.

Lee

Dho

Lee

, et al. Hypermethylation of PDX1, EN2, and MSX1 predicts the prognosis of colorectal cancer. Exp Mol Med. 2022;54(2):156-168. doi:10.1038/s12276-022-00731-1

46.

Suzuki

Yamamoto

Maruyama

Niinuma

Kai

. Biological significance of the CpG island methylator phenotype. Biochem Biophys Res Commun. 2014;455(1-2):35-42. doi:10.1016/j.bbrc.2014.07.007

47.

Yamamoto

Oshima

Wang

, et al. Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer. J Pathol. 2022;257(1):39-52. doi:10.1002/path.5868

48.

Kundu

Das

Laskar

Choudhury

Ghosh

. Cancer genomics and diagnostics: Northeast Indian scenario. In: Basu

Panda

Goswami

eds. Cancer diagnostics and therapeutics: current trends, challenges, and future perspectives. Springer; 2022:509-529. doi:10.1007/978-981-16-4752-9_24

49.

Nistal

Fernández-Fernández

Vivas

Olcoz

. Factors determining colorectal cancer: The role of the intestinal microbiota. Front Oncol. 2015;5(1). doi:10.3389/fonc.2015.00220

50.

Rossi

Jahanzaib Anwar

Usman

Keshavarzian

Bishehsari

. Colorectal cancer and alcohol consumption-populations to molecules. Cancers (Basel). 2018;10(2). doi:10.3390/cancers10020038

51.

Hou

Zheng

Wei

Zhao

. Effects of gut microbiota on immune responses and immunotherapy in colorectal cancer. Front Immunol. 2022;13(1). doi:10.3389/fimmu.2022.1030745

52.

Ogino

Nowak

Hamada

Milner

Nishihara

. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology. Annu Rev Pathol Mech Dis. 2019;14(1):83-103. doi:10.1146/annurev-pathmechdis-012418-012818

53.

Ogino

Chan

Fuchs

Giovannucci

. Molecular pathological epidemiology of colorectal neoplasia: An emerging transdisciplinary and interdisciplinary field. Gut. 2011;60(3):397-411. doi:10.1136/gut.2010.217182

54.

Vannijvel Albert

MMW

. Limitations and concerns with transanal total mesorectal excision for rectal cancer. Clin Colon Rectal Surg. 2022;35(02):141-145. doi:10.1055/s-0041-1742115

55.

Delibegovic

. Introduction to total mesorectal excision. Med Arch (Sarajevo, Bosnia Herzegovina). 2017;71(6):434-438. doi:10.5455/medarh.2017.71.434-438

56.

Bertelsen

Neuenschwander

Jansen

, et al. Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: A retrospective, population-based study. Lancet Oncol. 2015;16(2):161-168. doi:10.1016/S1470-2045(14)71168-4

57.

Koh

Tan

K-K

. Complete mesocolic excision for colon cancer: Is it worth it? J Gastrointest Oncol. 2019;10(6):1215-1221. doi:10.21037/jgo.2019.05.01

58.

Zwager

Bastiaansen

BAJ

Van Der Spek

, et al. Endoscopic full-thickness resection of T1 colorectal cancers: A retrospective analysis from a multicenter Dutch eFTR registry. Endoscopy. 2022;54(5):475-485. doi:10.1055/a-1637-9051

59.

Picasso

Parodi

Fisher

Blanchi

Conio

. Full thickness endoscopic resection of a colonic cancer: A case report. Clin Res Hepatol Gastroenterol. 2013;37(4):e99-101. doi:10.1016/j.clinre.2012.10.005

60.

Pericleous

Bhogal

Mavroeidis

. The role of circulating biomarkers in the early detection of recurrent colorectal cancer following resection of liver metastases. Front Biosci - Landmark. 2022;27(6). doi:10.31083/j.fbl2706189

61.

Barkhatov

Aghayan

Scuderi

, et al. Long-term oncological outcomes after laparoscopic parenchyma-sparing redo liver resections for patients with metastatic colorectal cancer: A European multi-center study. Surg Endosc. 2022;36(5):3374-3381. doi:10.1007/s00464-021-08655-z

62.

Khan

Wilkerson

Vassos

, et al. Oncologic outcomes of surgically managed primary pelvic soft tissue sarcoma; tumour biology or surgical constraints of the true pelvis? Eur J Surg Oncol. 2022;49(5):941-949. Published online 2022. doi:10.1016/j.ejso.2022.12.005

63.

Glimelius

Stintzing

Marshall

Yoshino

de Gramont

. Metastatic colorectal cancer: Advances in the folate-fluoropyrimidine chemotherapy backbone. Cancer Treat Rev. 2021;98(1):102218. doi:10.1016/j.ctrv.2021.102218

64.

Sara

Kaur

Khodadadi

, et al. 5-fluorouracil And cardiotoxicity: A review. Ther Adv Med Oncol. 2018;10(1):1-18. doi:10.1177/1758835918780140

65.

Alcindor

Beauger

. Oxaliplatin: A review in the era of molecularly targeted therapy. Curr Oncol. 2011;18(1):18-25. doi:10.3747/co.v18i1.708

66.

Auclin

Zaanan

Vernerey

, et al. Subgroups and prognostication in stage III colon cancer: Future perspectives for adjuvant therapy. Ann Oncol. 2017;28(5):958-968. doi:https://doi.org/10.1093/annonc/mdx030

67.

Wulaningsih

Wardhana

Watkins

Yoshuantari

Repana

Van Hemelrijck

. Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer. Cochrane Database Syst Rev. 2016;2(2):CD008593. doi:10.1002/14651858.CD008593.pub3

68.

Scarabel

Polesel

De Mattia

, et al. Association of HLA-G 3′UTR polymorphisms with response to first-line FOLFIRI treatment in metastatic colorectal cancer. Pharmaceutics. 2022;14(12):1-17. doi:10.3390/pharmaceutics14122737

69.

van den Berg

Schaap

Voogt

ELK

, et al. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk (“ugly”) locally advanced rectal cancer: Study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT). BMC Cancer. 2022;22(1):1-11. doi:10.1186/s12885-022-09947-w

70.

Yamai

Ikezawa

Kawamoto

, et al. 5-Fluorouracil/L-Leucovorin Plus oxaliplatin (FOLFOX) regimen as salvage chemotherapy for patients with unresectable pancreatic cancer receiving gemcitabine and nab-paclitaxel and 5-fluorouracil/L-leucovorin plus nanoliposomal irinotecan: Preliminary resu. Curr Oncol. 2022;29(4):2644-2649. doi:10.3390/curroncol29040216

71.

Pathak

Banerjee

Meng

Nandy

Gopinath

Sun

. Significant expression of tafazzin (TAZ) protein in colon cancer cells and its downregulation by radiation. Int J Radiat Biol. 2018;94(1):79-87. doi:10.1080/09553002.2018.1400191

72.

Wen

Zhao

Holmqvist

, et al. Predictive role of biopsy based biomarkers for radiotherapy treatment in rectal cancer. J Pers Med. 2020;10(4). doi:10.3390/jpm10040168

73.

Pathak

Meng

W-J

Nandy

, et al. Radiation and SN38 treatments modulate the expression of microRNAs, cytokines and chemokines in colon cancer cells in a p53-directed manner. Oncotarget. 2015;6(42):44758-44780. doi:10.18632/oncotarget.5815

74.

Wang

C-J

Chao

C-R

Liu

H-M

, et al. Prognostic value of nuclear FBI-1 in patients with rectal cancer with or without preoperative radiotherapy. Oncol Lett. 2019;18(5):5301-5309. doi:10.3892/ol.2019.10890

75.

Prior

Lewis

Mattos

. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012;72(10):2457-2467. doi:10.1158/0008-5472.CAN-11-2612

76.

Rosati

Aprile

Colombo

, et al. Colorectal cancer heterogeneity and the impact on precision medicine and therapy efficacy. Biomedicines. 2022;10(5). doi:10.3390/biomedicines10051035

77.

Gong

Cho

Salgia

Fakih

. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: A single-institution experience. Oncotarget. 2017;8(26):42198-42213. doi:10.18632/oncotarget.15030

78.

Lebrun

Turpin

Zerbib

. Therapeutic implications of B-RAF mutations in colorectal cancer. J Visc Surg. 2021;158(6):487-496. doi:10.1016/j.jviscsurg.2021.04.002

79.

Shahi Thakuri

Luker

Tavana

. Cyclical treatment of colorectal tumor spheroids induces resistance to MEK inhibitors. Transl Oncol. 2019;12(3):404-416. doi:https://doi.org/10.1016/j.tranon.2018.11.009

80.

Loupakis

Moretto

Aprile

, et al. Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer. Br J Cancer. 2016;114(1):30-36. doi:10.1038/bjc.2015.399

81.

Jones

Renfro

Al-Shamsi

, et al. (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(23):2624-2630. doi:10.1200/JCO.2016.71.4394

82.

Canaud

Hammill

Adams

Vikkula

Keppler-Noreuil

. A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations. Orphanet J Rare Dis. 2021;16(1):306. doi:10.1186/s13023-021-01929-8

83.

Cathomas

. PIK3CA In colorectal cancer. Front Oncol. 2014;4(March):16-19. doi:10.3389/fonc.2014.00035

84.

Baker

Fearon

Nigro

, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244(4901):217-221. doi:10.1126/science.2649981

85.

Osterburg

Dötsch

. Structural diversity of p63 and p73 isoforms. Cell Death Differ. 2022;29(5):921-937. doi:10.1038/s41418-022-00975-4

86.

Vaddavalli

Schumacher

. The p53 network: Cellular and systemic DNA damage responses in cancer and aging. Trends Genet. 2022;38(6):598-612. https://doi.org/10.1016/j.tig.2022.02.010

87.

Novellasdemunt

Kucharska

Baulies

, et al. USP7 Inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development. Stem Cell Rep. 2023;18(2):570-584. https://doi.org/10.1016/j.stemcr.2022.12.013

88.

Lin

Y-M

C-H

Chu

P-H

Ouyang

. Cell cycle expression of FLJ25439, a cytokinesis-associated protein, is mediated by D-box recognition and APC/C-Cdc20 regulated degradation. Biochem Biophys Res Commun. 2022;630(1):151-157. https://doi.org/10.1016/j.bbrc.2022.09.046

89.

Lee

, et al. Synthetic essentiality of tryptophan 2, 3-dioxygenase 2 in APC-mutated colorectal cancer. Cancer Discov. 2022;12(7):1702-1717. doi:https://doi.org/10.1158/2159-8290.CD-21-0680

90.

Daisy Precilla

Biswas

Kuduvalli

Anitha

. Crosstalk between PI3 K/AKT/mTOR and WNT/β-Catenin signaling in GBM - Could combination therapy checkmate the collusion? Cell Signal. 2022;95(1). doi:10.1016/j.cellsig.2022.110350

91.

Nguyen

Thi

Nguyen

Trung

. The mutation Spectrum and two novel point mutations in the APC gene in Vietnamese patients with familial adenomatous polyposis. Asian Pac J Cancer Prev. 2022;23(5):1517-1522. doi:10.31557/APJCP.2022.23.5.1517

92.

Mishra

. STRAP: A Bridge Between Mutant APC and Wnt/ß-Catenin Signaling in Intestinal Cancer. Gastroenterology. 2022;162(1):44-46. doi:10.1053/j.gastro.2021.09.074

93.

Amerizadeh

Rahmani

Maftooh

, et al. Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer. Tissue Cell. 2022;77(1). doi:10.1016/j.tice.2022.101853

94.

Fang

Liang

Wang

, et al. Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: A systematic review and meta-analysis. BMC Gastroenterol. 2021;21(1):297. doi:10.1186/s12876-021-01864-9

95.

Parmar

Easwaran

. Genetic and epigenetic dependencies in colorectal cancer development. Gastroenterol Rep. 2022;10(1). doi:10.1093/gastro/goac035

96.

Sung

Ferlay

Siegel

, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660

97.

Malki

ElRuz

Gupta

Allouch

Vranic

Al Moustafa

A-E

. Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements. Int J Mol Sci. 2020;22(1). doi:10.3390/ijms22010130

98.

Long

, et al. Integrative multi-omics analysis of a colon cancer cell line with heterogeneous Wnt activity revealed RUNX2 as an epigenetic regulator of EMT. Oncogene. 2020;39(28):5152-5164. doi:10.1038/s41388-020-1351-z

99.

Banias

Jung

Chiciudean

Gurzu

. From dukes-MAC staging system to molecular classification: evolving concepts in colorectal cancer. Int J Mol Sci. 2022;23(16). doi:10.3390/ijms23169455

100.

Papaccio

García-Mico

Gimeno-Valiente

, et al.

Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction.

J Exp & Clin Cancer Res CR. 2023;42(1):8. doi:10.1186/s13046-022-02591-z

101.

Dijkstra

Neikes

Rezaeifard

, et al. Multiomics of colorectal cancer organoids reveals putative mediators of cancer progression resulting from SMAD4 inactivation. J Proteome Res. 2023;22(1):138-151. doi:10.1021/acs.jproteome.2c00551

102.

Echle

Ghaffari Laleh

Quirke

, et al. Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application. ESMO open. 2022;7(2):100400. doi:10.1016/j.esmoop.2022.100400

103.

Yang

, et al. A multi-omics machine learning framework in predicting the survival of colorectal cancer patients. Comput Biol Med. 2022;146(1). doi:10.1016/j.compbiomed.2022.105516

104.

Zeller

Tap

Voigt

, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 2014;10(11):766. doi:10.15252/msb.20145645

105.

Mutignani

Penagini

Gargari

, et al. Blood bacterial DNA load and profiling differ in colorectal cancer patients compared to tumor-free controls. Cancers (Basel). 2021;13(24):6363. doi:10.3390/cancers13246363

106.

You

Zhou

Xin

, et al. Novel directions of precision oncology: Circulating microbial DNA emerging in cancer-microbiome areas. Precis Clin Med. 2022;5(1):pbac005. doi:10.1093/pcmedi/pbac005

107.

Zhang

Sun

X-F

Shen

Zhang

. Potential applications of DNA, RNA and protein biomarkers in diagnosis, therapy and prognosis for colorectal cancer: a study from databases to AI-assisted verification. Cancers (Basel). 2019;11(2). doi:10.3390/cancers11020172

108.

Zhang

Shen

Sun

X-F

. Chromogranin-A expression as a novel biomarker for early diagnosis of colon cancer patients. Int J Mol Sci. 2019;20(12):2919. doi:10.3390/ijms20122919

109.

Jiang

Wang

, et al. ITGB4 As a novel serum diagnosis biomarker and potential therapeutic target for colorectal cancer. Cancer Med. 2021;10(19):6823-6834. doi:10.1002/cam4.4216

110.

Zhang

Fan

Hildesjö

Shen

Sun

X-F

. Loss of CHGA protein as a potential biomarker for colon cancer diagnosis: A study on biomarker discovery by machine learning and confirmation by immunohistochemistry in colorectal cancer tissue microarrays. Cancers (Basel). 2022;14(11):2664. doi:10.3390/cancers14112664

111.

Hartl

de Luca

Kostikova

, et al. Translational precision medicine: An industry perspective. J Transl Med. 2021;19(1):245. doi:10.1186/s12967-021-02910-6

112.

Milbury

Creeden

Yip

, et al. Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors. PLOS ONE. 2022;17(3). doi:10.1371/journal.pone.0264138

113.

Sekita-Hatakeyama

Fujii

Nishikawa

, et al. Evaluation and diagnostic value of next-generation sequencing analysis of residual liquid-based cytology specimens of pancreatic masses. Cancer Cytopathol. 2022;130(3):202-214. doi:10.1002/cncy.22525

114.

Matsunaga

Kaneta

Miwa

, et al. A comparison of four methods for detecting KRAS mutations in formalin-fixed specimens from metastatic colorectal cancer patients. Oncol Lett. 2016;12(1):150-156. doi:10.3892/ol.2016.4576

115.

Buckley

Kakar

. Comparison of the Dako EGFR pharmDx kit and Zymed EGFR antibody for assessment of EGFR status in colorectal adenocarcinoma. Appl Immunohistochem Mol Morphol AIMM. 2007;15(3):305-309. doi:10.1097/01.pai.0000213141.47277.bf

116.

Wang

Fakih

. Targeting KRAS (G12C)-mutated advanced colorectal cancer: Research and clinical developments. Onco Targets Ther. 2022;15(1):747-756. doi:10.2147/OTT.S340392

117.

Al-Salama

. Encorafenib: A review in metastatic colorectal cancer with a BRAF V600E mutation. Drugs. 2021;81(7):849-856. doi:10.1007/s40265-021-01501-5

118.

Gürel

Çapkın

Parlar

, et al. Optimized methods for analytical and functional comparison of biosimilar mAb drugs: A case study for Avastin, Mvasi, and Zirabev. Sci Pharm. 2022;90(2). doi:10.3390/scipharm90020036

119.

Mao

Seow

Chen

. The utilization of bevacizumab in patients with advanced ovarian cancer: A systematic review of the mechanisms and effects. Int J Mol Sci. 2022;23(13):1-13. doi:10.3390/ijms23136911

120.

Gao

Yang

. Anti-VEGF/VEGFR2 monoclonal antibodies and their combinations with PD-1/PD-L1 inhibitors in clinic. Curr Cancer Drug Targets. 2020;20(1):3-18. doi:10.2174/1568009619666191114110359

121.

Huang

Liu

Kang

, et al. Effects of microbiota on anticancer drugs: Current knowledge and potential applications. eBioMedicine. 2022;83(1). https://doi.org/10.1016/j.ebiom.2022.104197

122.

Ottaiano

Caraglia

. Bevacizumab-Induced tumor vasculature normalization and sequential chemotherapy in colorectal cancer: An interesting and still open question. Front Oncol. 2021;11(September):10-12. doi:10.3389/fonc.2021.751986

123.

Kazama

Shiozawa

Numata

, et al. Comparison of safety and efficacy of fluorouracil + oxaliplatin + irinotecan (FOLFOXIRI) and modified FOLFOXIRI with bevacizumab for metastatic colorectal cancer: Data from clinical practice. Int J Colorectal Dis. 2022;37(2):337-348. doi:10.1007/s00384-021-04064-9

124.

Goulet

Chatterjee

Lee

Waight

Zhu

Mak

ANS

. Engineering an enhanced EGFR engager: Humanization of cetuximab for improved developability. Antibodies. 2022;11(1):1-14. doi:10.3390/antib11010006

125.

Di Liddo

Verona

Vaccarin

, et al. Preliminary discovery of small molecule inhibitors of epidermal growth factor receptor (EGFR) that bind to the extracellular domain. Cancers (Basel). 2022;14(15). doi:10.3390/cancers14153647

126.

Harding

Burtness

. Cetuximab: An epidermal growth factor receptor chemeric human-murine monoclonal antibody. Drugs Today (Barc). 2005;41(2):107-127. doi:10.1358/dot.2005.41.2.882662

127.

Fornasier

Francescon

Baldo

. An update of efficacy and safety of cetuximab in metastatic colorectal cancer: A narrative review. Adv Ther. 2018;35(10):1497-1509. doi:10.1007/s12325-018-0791-0

128.

Dean

Kane

Cetuximab therapy and RAS and BRAF genotype. In: Pratt

Scott

Pirmohamed

Esquivel

Kattman

Malheiro

eds. National Center for Biotechnology Information (US); 2012:151-164.

129.

Kang

Kil

, et al. EGFR Pathway targeting drugs in head and neck cancer in the era of immunotherapy. Biochim Biophys Acta - Rev Cancer. 2023;1878(1):188827. doi:https://doi.org/10.1016/j.bbcan.2022.188827

130.

Taha

Aboulwafa

Zedan

Helmy

. Ramucirumab combination with sorafenib enhances the inhibitory effect of sorafenib on HepG2 cancer cells. Sci Rep. 2022;12(1):1-16. doi:10.1038/s41598-022-21582-w

131.

Rodriguez

. Ziv-aflibercept use in metastatic colorectal cancer. J Adv Pract Oncol. 2013;4(5):348-352. doi:10.6004/jadpro.2013.4.5.6

132.

Patel

Sun

. Ziv-aflibercept in metastatic colorectal cancer. Biologics. 2014;8(1):13-25. doi:10.2147/BTT.S39360

133.

El-Deiry

Winer

Slifker

, et al. Disease control with FOLFIRI plus Ziv-aflibercept (zFOLFIRI) beyond FOLFIRI plus bevacizumab: Case series in metastatic colorectal cancer (mCRC). Front Oncol. 2019;9(MAR):1-13. doi:10.3389/fonc.2019.00142

134.

Takigawa

Kitadai

Shinagawa

, et al. Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma. Cancer Sci. 2016;107(5):601-608. doi:10.1111/cas.12907

135.

Chen

Wei

Zhang

. Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clin Cancer Res an Off J Am Assoc Cancer Res. 2014;20(13):3472-3484. doi:10.1158/1078-0432.CCR-13-2944

136.

C-J

Huang

C-W

Chang

T-K

, et al. Oncologic outcomes in metastatic colorectal cancer with regorafenib with FOLFIRI as a third- or fourth-line setting. Transl Oncol. 2019;12(3):502-512. doi:https://doi.org/10.1016/j.tranon.2018.12.003

137.

De Luca

Marino

Maio

Ramucirumab

. A second-line option for patients with hepatocellular carcinoma: A review of the evidence. Cancer Manag Res. 2020;12(1):3721-3729. doi:10.2147/CMAR.S216220

138.

Clarke

Hurwitz

. Targeted inhibition of VEGF receptor 2: An update on ramucirumab. Expert Opin Biol Ther. 2013;13(8):1187-1196. doi:10.1517/14712598.2013.810717

139.

Bhattacharyya

Chehal

Migliorati

. Severe oral erosive lichenoid reaction to pembrolizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020;130(5):e301-e307. doi:https://doi.org/10.1016/j.oooo.2020.06.014

140.

Zhang

, et al. A tumor-specific super-enhancer drives immune evasion by guiding synchronous expression of PD-L1 and PD-L2. Cell Rep. 2019;29(11):3435-3447.e4. https://doi.org/10.1016/j.celrep.2019.10.093

141.

André

Shiu

K-K

Kim

, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/nejmoa2017699

142.

Torrente-López

Hermosilla

Salmerón-García

Cabeza

Navas

. Comprehensive analysis of nivolumab, a therapeutic anti-Pd-1 monoclonal antibody: impact of handling and stress. Pharmaceutics. 2022;14(4). doi:10.3390/pharmaceutics14040692

143.

Rajan

Kim

Heery

Guha

Gulley

. Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers. Hum Vaccin Immunother. 2016;12(9):2219-2231. doi:10.1080/21645515.2016.1175694

144.

Lisi

Lacal

Martire

Navarra

Graziani

. Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment. Pharmacol Res. 2022;175(1). doi:10.1016/j.phrs.2021.105997

145.

Korman

Garrett-Thomson

Lonberg

. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov. 2022;21(7):509-528. doi:10.1038/s41573-021-00345-8

146.

Ascierto

Dummer

Gogas

, et al. Update on tolerability and overall survival in COLUMBUS: Landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600–mutant melanoma. Eur J Cancer. 2020;126(1):33-44. doi:10.1016/j.ejca.2019.11.016

147.

Lakatos

Köhne

C-H

Bodoky

. Current therapy of advanced colorectal cancer according to RAS/RAF mutational status. Cancer Metastasis Rev. 2020;39(4):1143-1157. doi:10.1007/s10555-020-09913-7

148.

Pathak

Sushmitha

Banerjee

, et al. Review on comparative efficacy of bevacizumab, panitumumab and cetuximab antibody therapy with combination of FOLFOX-4 in KRAS-mutated colorectal cancer patients. Oncotarget. 2018;9(7):7739-7748. doi:10.18632/oncotarget.22471

149.

Hong

Fakih

Strickler

, et al. KRAS(G12c) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. doi:10.1056/NEJMoa1917239

150.

Weiss

Yaeger

Johnson

, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32(Supplement 5). doi:10.1016/j.annonc.2021.08.2093

151.

Ebert

PJR

Cheung

Yang

, et al. MAP Kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity. 2016;44(3):609-621. doi:10.1016/j.immuni.2016.01.024

152.

Tran

Robbins

Y-C

, et al. T-Cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med. 2016;375(23):2255-2262. doi:10.1056/NEJMoa1609279

153.

Antoniotti

Rossini

Pietrantonio

, et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): A multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022;23(7):876-887. doi:10.1016/S1470-2045(22)00274-1

154.

Yoshino

Arnold

Taniguchi

, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: A JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(1):44-70. doi:10.1093/annonc/mdx738

155.

Van Cutsem

Cervantes

Adam

, et al. ESMO Consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235

156.

Croce

Coperchini

Magri

Chiovato

Rotondi

. The multifaceted anti-cancer effects of BRAF-inhibitors. Oncotarget. 2019;10(61):6623-6640. doi:10.18632/oncotarget.27304

157.

van Geel

RMJM

Tabernero

Elez

, et al. A phase ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discov. 2017;7(6):610-619. doi:10.1158/2159-8290.CD-16-0795

158.

Kopetz

Desai

Chan

, et al. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(34):4032-4038. doi:10.1200/JCO.2015.63.2497

159.

Yoshino

Portnoy

Obermannová

, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol Off J Eur Soc Med Oncol. 2019;30(1):124-131. doi:10.1093/annonc/mdy461

160.

Gelsomino

Casadei-Gardini

Rossini

, et al. The role of anti-angiogenics in pre-treated metastatic BRAF-mutant colorectal cancer: A pooled analysis. Cancers (Basel). 2020;12(4). doi:10.3390/cancers12041022

161.

Yaeger

Cercek

Reilly

, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res an Off J Am Assoc Cancer Res. 2015;21(6):1313-1320. doi:10.1158/1078-0432.CCR-14-2779

162.

Kopetz

Grothey

Yaeger

, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075

163.

Yaeger

Kotani

Mondaca

, et al. Response to anti-EGFR therapy in patients with BRAF non-V600-mutant metastatic colorectal cancer. Clin Cancer Res an Off J Am Assoc Cancer Res. 2019;25(23):7089-7097. doi:10.1158/1078-0432.CCR-19-2004

164.

Tabernero

Grothey

Van Cutsem

, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON study. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088

165.

Huijberts

SCFA

Boelens

Bernards

Opdam

. Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/- binimetinib or alpelisib. Br J Cancer. 2021;124(1):176-182. doi:10.1038/s41416-020-01147-2

166.

Corcoran

Atreya

Falchook

, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(34):4023-4031. doi:10.1200/JCO.2015.63.2471

167.

Hutchins

Southward

Handley

, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(10):1261-1270. doi:10.1200/JCO.2010.30.1366

168.

Sinicrope

Mahoney

Smyrk

, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(29):3664-3672. doi:10.1200/JCO.2013.48.9591

169.

Ribic

Sargent

Moore

, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247-257. doi:10.1056/NEJMoa022289

170.

Cohen

Taieb

Fiskum

, et al. Microsatellite instability in patients with stage III colon cancer receiving fluoropyrimidine with or without oxaliplatin: An ACCENT pooled analysis of 12 adjuvant trials. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(6):642-651. doi:10.1200/JCO.20.01600

171.

Vilar

Tabernero

. Molecular dissection of microsatellite instable colorectal cancer. Cancer Discov. 2013;3(5):502-511. doi:10.1158/2159-8290.CD-12-0471

172.

Klingbiel

Saridaki

Roth

Bosman

Delorenzi

Tejpar

. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: Results of the PETACC-3 trial. Ann Oncol Off J Eur Soc Med Oncol. 2015;26(1):126-132. doi:10.1093/annonc/mdu499

173.

Huang

Yang

. Molecular network of colorectal cancer and current therapeutic options. Front Oncol. 2022;12(1). doi:10.3389/fonc.2022.852927

174.

Sinicrope

F-S

Shi

, et al. Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502). Published online 2017.

175.

Lau

Kalaitzaki

Church

, et al. Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. ESMO open. 2020;5(1). doi:10.1136/esmoopen-2019-000638

176.

Overman

Lonardi

Wong

KYM

, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(8):773-779. doi:10.1200/JCO.2017.76.9901

177.

Kopetz

. The emergence of targetable pathways in colorectal cancer. Clin Adv Hematol Oncol. 2021;19(12):774-783.

178.

Efferth

Saeed

MEM

Mirghani

, et al. Integration of phytochemicals and phytotherapy into cancer precision medicine. Oncotarget. 2017;8(30):50284-50304. doi:10.18632/oncotarget.17466

179.

Safarzadeh

Sandoghchian Shotorbani

Baradaran

. Herbal medicine as inducers of apoptosis in cancer treatment. Adv Pharm Bull. 2014;4(Suppl 1):421-427. doi:10.5681/apb.2014.062

180.

Razali

NSC

Lam

Rajab

Jamal

ARA

Kamaluddin

Chan

. Curcumin piperidone derivatives induce anti-proliferative and anti-migratory effects in LN-18 human glioblastoma cells. Sci Rep. 2022;12(1):13131. doi:10.1038/s41598-022-16274-4

181.

Rahman

Ali

Rahamathulla

Salam

Mittal

Harwansh

. Fabrication of sustained release curcumin-loaded solid lipid nanoparticles (cur-SLNs) as a potential drug delivery system for the treatment of lung cancer : Optimization of formulation and in vitro biological evaluation. Polymers (Basel). 2023;15(3):542.

182.

Vargas

Puga

Lenz

Trindade

Filippi-Chiela

. Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro-in silico model. Oxid Med Cell Longev. 2020;2020(Special Issue). doi:10.1155/2020/5432651

183.

Mazué

Delmas

Murillo

Saleiro

Limagne

Latruffe

. Differential protective effects of red wine polyphenol extracts (RWEs) on colon carcinogenesis. Food Funct. 2014;5(4):663-670. doi:10.1039/C3FO60417A

184.

Abraham

Khandelwal

Hintzsche

Stopper

. Antigenotoxic effects of resveratrol: Assessment of in vitro and in vivo response. Mutagenesis. 2016;31(1):27-33. doi:10.1093/mutage/gev048

185.

Zuo

Xiao

, et al. The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J Cell Biochem. 2018;119(11):9573-9582. doi:10.1002/jcb.27275

186.

Adeniji

Dulal

Martin

. Personalized medicine in oncology in the developing world: Barriers and concepts to improve Status quo. World J Oncol. 2021;12(2-3):50-60. doi:10.14740/wjon1345

187.

Sherman

Lange

Dahdaleh

, et al. Cost-effectiveness of maintenance capecitabine and bevacizumab for metastatic colorectal cancer. JAMA Oncol. 2019;5(2):236-242. doi:10.1001/jamaoncol.2018.5070

188.

Rehman

Awais

Baloch

NU-A

. Precision medicine and low- to middle-income countries. JAMA Oncol. 2016;2(3):293-294. doi:10.1001/jamaoncol.2015.5511

189.

Pokorska-Bocci

Kroese

Sagoo

Hall

Burton

. Personalised medicine in the UK: Challenges of implementation and impact on healthcare system. Genome Med. 2014;6(4):28. doi:10.1186/gm545

190.

Traversi

Pulliero

Izzotti

, et al. Precision medicine and public health: new challenges for effective and sustainable health. J Pers Med. 2021;11(2). doi:10.3390/jpm11020135

191.

Human Genome

Strategy Group

. 2012. Building on our inheritance genomic technology in healthcare. Hum Genomics. (January):1-92.

192.

Canadian Institutes

of Health Research

. 2016.Strategic plan 2015-19: Health system transformation through research innovation. CIHR Inst Heal Serv Policy Res. 2016:1-27. http://www.cihr-irsc.gc.ca/e/49711.html.

193.

Australia. Department of Health

National Health Genomics Policy Framework 2018-2021. 2017:1-20.

194.

Kloypan

Koomdee

Satapornpong

Tempark

Biswas

Sukasem

. A comprehensive review of HLA and severe cutaneous adverse drug reactions: implication for clinical pharmacogenomics and precision medicine. Pharmaceuticals (Basel). 2021;14(11). doi:10.3390/ph14111077

195.

Ciardiello

Arnold

Casali

, et al. Delivering precision medicine in oncology today and in future-the promise and challenges of personalised cancer medicine: A position paper by the European Society for Medical Oncology (ESMO). Ann Oncol Off J Eur Soc Med Oncol. 2014;25(9):1673-1678. doi:10.1093/annonc/mdu217