Molecular Targets for the Treatment of Metastatic Colorectal Cancer

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

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Current and emerging biomarkers in metastatic colorectal cancer

Current Oncology ◽

10.3747/co.26.5719 ◽

2019 ◽

Vol 26 (1) ◽

Cited By ~ 1

Author(s):

M.K.C. Lee ◽

J. M. Loree

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Her2 Amplification ◽

Liquid Biopsies ◽

Braf Mutations ◽

Pik3ca Mutations ◽

Improved Outcomes ◽

Therapeutic Choice ◽

Novel Biomarkers ◽

Deficient Mismatch Repair

Background The incorporation of novel biomarkers into therapy selection for patients with metastatic colorectal cancer (mcrc) has significantly improved outcomes. Optimal treatment planning now takes into account diverse characteristics of patients and their tumours to create personalized therapeutic plans.Discussion This review is split into two sections. In the first section, we review the prognostic and predictive significance of expanded RAS mutation testing, BRAF mutations, ERBB2 (her2) amplification, microsatellite instability (msi) and deficient mismatch repair (dmmr) protein, NTRK fusions, PIK3CA mutations, and met amplifications. The therapeutic implication of each of those biomarkers for personalizing therapies for each patient with mcrc is discussed. In the second section, we touch on testing methods and considerations of relevance to clinicians when they interpret companion diagnostics meant to guide therapy selection. The advantages and pitfalls of various methods are evaluated, and we also look at the potential of liquid biopsies and circulating tumour dna (ctdna) to change the landscape of therapeutic choice and biologic understanding of the disease.Summary Routine testing for extended RAS, BRAF, dmmr or high msi, and NTRK fusions is necessary to determine the best sequencing of chemotherapy and biologic agents for patients with mcrc. Although next generation sequencing and ctdna are increasingly being adopted, other techniques such as immunohistochemistry retain their relevance in detection of her2 amplification, NTRK fusions, and dmmr.

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Recent Advances in the Discovery of Biomarkers for Canine Osteosarcoma

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.734965 ◽

2021 ◽

Vol 8 ◽

Author(s):

Anita K. Luu ◽

Geoffrey A. Wood ◽

Alicia M. Viloria-Petit

Keyword(s):

Clinical Practice ◽

Standard Treatment ◽

Predictive Biomarkers ◽

Response To Treatment ◽

Liquid Biopsies ◽

Future Directions ◽

Diagnostic Biomarkers ◽

Canine Osteosarcoma ◽

The Past ◽

Biomarker Research

Canine osteosarcoma (OSA) is an aggressive malignancy that frequently metastasizes to the lung and bone. Not only has there been essentially no improvement in therapeutic outcome over the past 3 decades, but there is also a lack of reliable biomarkers in clinical practice. This makes it difficult to discriminate which patients will most benefit from the standard treatment of amputation and adjuvant chemotherapy. The development of reliable diagnostic biomarkers could aid in the clinical diagnosis of primary OSA and metastasis; while prognostic, and predictive biomarkers could allow clinicians to stratify patients to predict response to treatment and outcome. This review summarizes biomarkers that have been explored in canine OSA to date. The focus is on molecular biomarkers identified in tumor samples as well as emerging biomarkers that have been identified in blood-based (liquid) biopsies, including circulating tumor cells, microRNAs, and extracellular vesicles. Lastly, we propose future directions in biomarker research to ensure they can be incorporated into a clinical setting.

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KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Cells ◽

10.3390/cells9010219 ◽

2020 ◽

Vol 9 (1) ◽

pp. 219 ◽

Cited By ~ 3

Author(s):

Nuria Garcia-Carbonero ◽

Javier Martinez-Useros ◽

Weiyao Li ◽

Alberto Orta ◽

Nuria Perez ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Predictive Biomarkers ◽

Braf V600e ◽

Chemotherapy Response ◽

First Line ◽

Standard Chemotherapy ◽

Braf Mutations ◽

Kras Mutations ◽

Line Standard

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

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Survival outcome in HER2-amplified metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.642 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 642-642

Author(s):

Kentaro Sawada ◽

Wataru Okamoto ◽

Yoshiaki Nakamura ◽

Takeharu Yamanaka ◽

Satoshi Yuki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Primary Tumor ◽

Survival Outcome ◽

Braf V600e ◽

Her2 Status ◽

Her2 Amplification ◽

Braf Mutations ◽

Signal Ratio ◽

Group B

642 Background: HER2 amplifications have been observed in approximately 3% of patients (pts) with metastatic colorectal cancer (mCRC). Early clinical trials with combined HER2-targeted therapies showed promising activities. However, it remains unclear whether HER2 amplification in mCRC is as prognostic as RAS or BRAF V600E mutant (mt). We aimed to evaluate survival outcome for mCRC pts with HER2 amplification compared to those with RAS or BRAF mt. Methods: mCRC pts who received a palliative resection of the primary tumor with metastatic diseases at presentation, or recurred after curative resection of the primary tumor between 2005 and 2015, were analyzed. HER2 immunohistochemistry (IHC) was performed using formalin-fixed and paraffin-embedded (FFPE) sections obtained from the primary tumor, and HER2 amplification was confirmed by fluorescence in situ hybridization (FISH) in case of IHC 2+ or 3+. Criteria for HER2 amplification were a HER2- to CEP17- signal ratio of 2.0 or higher. RAS / BRAF status was centrally assessed by a PCR-based method. The pts were classified into four subgroups based on RAS, BRAF and HER2 status: Group R , RAS mt; Group B, BRAF V600E mt; Group H, HER2 amplification with RAS / BRAF wild-type (wt); and Group W, RAS / BRAF wt. Results: Among 370 pts, 359 pts (97%) were successfully analyzed. A total of 15 pts (4%) had HER2 amplifications, out of which four pts had overlapped RAS mt (subclassified as Group R). RAS or BRAF mutations are mutually exclusive. The number in Group R, B, H and W was 204 (57%), 13 (4%), 11 (3%) and 131 (36%), respectively. There was no remarkable difference in baseline characteristics among groups. With a median follow-up time of 63 months (mos), the median overall survival of the 359 pts was 27 mos (95%CI 24 - 29 mos); Group R, 24 mos; Group B, 14 mos; Group H, 20 mos; and Group W, 39 mos. The HR of R vs. H is 0.83 (95%CI 0.41-1.70, p= 0.618), B vs. H is 1.16 (95%CI 0.47-2.84, p= 0.748), and W vs. H is 0.52 (95%CI 0.25-1.08, p= 0.080), respectively. Conclusions: This study suggests that the prognosis of mCRC pts with HER2 amplification tends to be worse as compared to those with RAS / BRAF wt, similar to those with RAS mt, and better than those with BRAF mt, although these comparisons were not statistical significant.

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Exosomal Non Coding RNA in LIQUID Biopsies as a Promising Biomarker for Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21041398 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1398 ◽

Cited By ~ 5

Author(s):

Amro Baassiri ◽

Farah Nassar ◽

Deborah Mukherji ◽

Ali Shamseddine ◽

Rihab Nasr ◽

...

Keyword(s):

Colorectal Cancer ◽

Sensitivity And Specificity ◽

Liquid Biopsy ◽

Early Stage ◽

Noncoding Rnas ◽

Predictive Biomarkers ◽

Carbohydrate Antigen ◽

Combination Regimen ◽

Liquid Biopsies ◽

Diagnostic Potential

Colorectal cancer (CRC) is one of the most common cancers worldwide, with a high mortality rate, especially in those that are diagnosed in late stages of the disease. The current screening blood-based markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), have low sensitivity and specificity. Meanwhile, other modalities are either expensive or invasive. Therefore, recent research has shifted towards a minimally invasive test, namely, liquid biopsy. Exosomes are favorable molecules sought in blood samples, since they are abundant, stable in circulation, and harbor genetic information and other biomolecules that could serve as biomarkers or even therapeutic targets. Furthermore, exosomal noncoding RNAs, such as miRNAs, lncRNAs, and circRNAs, have demonstrated the diagnostic potential to detect CRC at an early stage with a higher sensitivity and specificity than CEA and CA19-9 alone. Moreover, they have prognostic potential that is TNM stage specific and could serve as predictive biomarkers for the most common chemotherapeutic drug and combination regimen in CRC, which are 5-FU and FOLFOX, respectively. Therefore, in this review, we focus on the role of these exosomal noncoding RNAs as diagnostic, prognostic, and predictive biomarkers. In addition, we discuss the advantages and challenges of exosomes as a liquid biopsy target.

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BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835921992974 ◽

2021 ◽

Vol 13 ◽

pp. 175883592199297

Author(s):

Javier Ros ◽

Iosune Baraibar ◽

Emilia Sardo ◽

Nuria Mulet ◽

Francesc Salvà ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Treatment Strategies ◽

Standard Of Care ◽

Therapeutic Strategies ◽

Braf V600e ◽

Driver Mutations ◽

Braf Mutations ◽

Egfr Inhibition ◽

Braf Inhibition

Introduction: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. Areas covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. Expert opinion: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.

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Therapeutic strategies for synchronous and multiple liver metastases from colorectal cancer

Oncology Reviews ◽

10.4081/oncol.2012.e9 ◽

2012 ◽

Vol 6 (1) ◽

pp. 9 ◽

Cited By ~ 4

Author(s):

Shinji Osada ◽

Hisashi Imai ◽

Yoshiyuki Sasaki ◽

Yoshihiro Tanaka ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Therapeutic Strategies ◽

Optimal Timing ◽

Critical Factors ◽

Synchronous Liver Metastasis ◽

Surgical Strategies ◽

The Past ◽

Synchronous Metastases ◽

Multiple Liver Metastases

Metastasis in the liver is one of the most critical factors in the prognosis of patients with colorectal cancer. The incidence of synchronous liver metastasis has been found to be approximately 20-25%, but the optimal timing of surgical resection remains controversial. Neoadjuvant chemotherapy has also been found to be beneficial not only for initially unresectable but also resectable synchronous metastases and traditional surgical strategies of hepatic resection with past chemotherapeutic regimens have been used less and less over the past several years. This review will discuss treatments in association with the recently developed chemotherapeutic regimens.

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Isolation and Enumeration of Circulating Tumor Cells (CTC) as Prognostic and Predictive Biomarkers in Post-Operative m-CRC

10.52916/otr214006 ◽

2021 ◽

pp. 1-6

Author(s):

Swaroop G

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Metastatic Disease ◽

Treatment Options ◽

Predictive Biomarkers ◽

Liquid Biopsies ◽

Prognostic Information ◽

Clinical Prognosis

Circulating Tumor Cells (CTCs) presents non-invasive, repeatable investigation of patient‘s disease. In metastatic Colorectal Cancer (m-CRC) patients, CTC enumerations have been comprehensively studied in evaluating metastatic disease. CTC analysis has been shifting from enumeration to more sophisticated molecular depiction of tumor cells, which is used for liquid biopsy of the tumor, reflecting cytological and molecular changes in metastatic patients over time. In this study, CTC enumeration in advanced and localized metastatic colorectal cancer, highlights the vital gains as well as the challenges posed by various approaches, and their implications for advancing disease management. Detection of circulating tumor cells (CTC‘s) or circulating free tumor DNA (ctDNA) to conduct chemotherapy and reporting prognosis is extremely important, In view of the detail CTC has the potential to offer multiple samples by way of sequential minimally-invasive liquid biopsies. In fastidious, there is escalating evidence for the efficacy of CTC‘s in the clinical management of metastatic colorectal cancer (CRC). With most studies confirming the association of elevated CTC counts with worse prognosis. CTC‘s were first identified by Ashworth in 1869. CTC research has been vulnerable by the failure to constantly detect these typical cells. While the normal range of WBCs in human blood is 4.5-119/L, there may only be a few CTC‘s. The most widely used CTC enumeration platform, Cell-Search (Veridex LLC, NJ, USA) was approved for clinical use. As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. Investigations were carried out that Circulating Tumor Cells (CTCs) could predict clinical prognosis in patients with mCRC. This pilot study, demonstrates that CTCs can serve as both prognostic and predictive factor for patients with mCRC. The presence of at least three CTCs at baseline and follow-up is a strong independent prognostic factor for inferior PFS and OS. When utilized in combination with imaging studies, CTCs provide additional prognostic information. There are several studies for which CTCs could have efficacy inmetastatic colorectal cancer. The statistics suggests that CTCs may be used as a stratification feature in metastatic disease treatment trials. The current list of validated prognostic factors is short, with only routine status being universally recognized. Further study should prospectively deal with modification of regimens based on unfavorable CTCs early in the course of treatment will result in enhancement in PFS or OS. As treatment has become more effective for metastatic disease, decision making has become more complicated. Five classes of drugs are on hand for treatment. The most common initial chemotherapy is a fluoropyrimidine with oxaliplatin or irinotecan. CTC levels drawn at 3 to 5 weeks and 6 to 12 weeks, before PET imaging, may lead to prospective regimen choices and standby patients from unnecessary drug toxicity by suggesting that an early change in treatment is defensible.

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Molecular and Immunohistochemical Markers with Prognostic and Predictive Significance in Liver Metastases from Colorectal Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms19103014 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3014 ◽

Cited By ~ 3

Author(s):

Gianluca Lopez ◽

Francesca Boggio ◽

Stefano Ferrero ◽

Nicola Fusco ◽

Alessandro Del Gobbo

Keyword(s):

Colorectal Cancer ◽

Targeted Therapy ◽

Colorectal Carcinoma ◽

Liver Metastases ◽

Predictive Biomarkers ◽

Treatment Modalities ◽

Multiple Treatment ◽

The Past ◽

Immunohistochemical Markers ◽

Current State

Despite the significant recent achievements in the diagnosis and treatment of colorectal cancer (CRC), the prognosis of these patients has currently plateaued. During the past few years, the opportunity to consider multiple treatment modalities (including surgery and other locoregional treatments, systemic therapy, and targeted therapy) led to the research of novel prognostic and predictive biomarkers in CRC liver metastases (CRCLM) patients. In this review, we seek to describe the current state of knowledge of CRCLM biomarkers and to outline impending clinical perspectives, in particular focusing on the cutting-edge tools available for their characterization.

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Circulating Tumour DNAs and Non-Coding RNAs as Liquid Biopsies for the Management of Colorectal Cancer Patients

Gastrointestinal Disorders ◽

10.3390/gidisord2030022 ◽

2020 ◽

Vol 2 (3) ◽

pp. 212-235

Author(s):

Andrea Lampis ◽

Michele Ghidini ◽

Margherita Ratti ◽

Milko B. Mirchev ◽

Ali Fuat Okuducu ◽

...

Keyword(s):

Colorectal Cancer ◽

Predictive Biomarkers ◽

Minimal Invasive ◽

Response To Therapy ◽

Precision Oncology ◽

Liquid Biopsies ◽

Tumour Formation ◽

Non Coding Rnas ◽

Metastatic Sites ◽

Colorectal Cancer Patients

Circulating tumour DNAs and non-coding RNAs present in body fluids have been under investigation as tools for cancer diagnosis, disease monitoring, and prognosis for many years. These so-called liquid biopsies offer the opportunity to obtain information about the molecular make-up of a cancer in a minimal invasive way and offer the possibility to implement theranostics for precision oncology. Furthermore, liquid biopsies could overcome the limitations of tissue biopsies in capturing the complexity of tumour heterogeneity within the primary cancer and among different metastatic sites. Liquid biopsies may also be implemented to detect early tumour formation or to monitor cancer relapse of response to therapy with greater sensitivity compared with the currently available protein-based blood biomarkers. Most colorectal cancers are often diagnosed at late stages and have a high mortality rate. Hence, biomolecules as nucleic acids present in liquid biopsies might have prognostic potential and could serve as predictive biomarkers for chemotherapeutic regimens. This review will focus on the role of circulating tumour DNAs and non-coding RNAs as diagnostic, prognostic, and predictive biomarkers in the context of colorectal cancer.

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