Elsevier

Drug Discovery Today

Volume 22, Issue 1, January 2017, Pages 111-119
Drug Discovery Today

Review
Gene-to-screen
Chasing the personalized medicine dream through biomarker validation in colorectal cancer

https://doi.org/10.1016/j.drudis.2016.09.022Get rights and content

Highlights

  • mCRC patients’ survival outcomes pose major treatment challenge for oncologists.

  • Personalized medicine is an evolving approach for cancer management including mCRC.

  • New therapeutic concepts have diversified unresectable mCRC treatment strategies.

  • The interdisciplinary MPE is enabling identification of novel predictive biomarkers.

  • Validation of newly identified biomarkers is important for their clinical utility.

Colorectal cancer (CRC) is a major health burden worldwide. The optimal approach to the diagnosis, management, and treatment of CRC involves multidisciplinary and integrated management practices. The field is rapidly changing because of recent advancements in delineating the molecular basis of tumorigenesis, introduction of targeted therapy, varied patient response to mainstay chemotherapeutics, biological drugs, and the effective combination regimes being used for treatment. Recent meta-analysis studies, which tend to establish few clinically useful predictor biomarkers, identify inconsistent results and limitations of the trials. Therefore, molecular pathological epidemiology discipline initiatives are promising. Here, we provide an overview of the potential of biomarker validation for personalized medicine by focusing largely on metastatic (m)CRC. We also highlight new candidate predictive and prognostic biomarkers.

Introduction

CRC is one of the leading causes of cancer related deaths worldwide. It is the most common of all gastrointestinal malignancies and, anatomically, its prevalence is higher in the left side of the bowel (Fig. 1a). CRC ranks as the third most common cancer in males and the second in females, with 60% of cases occurring in developed nations [1]. As outlined in Fig. 1b, invasive colorectal adenocarcinoma develops from a benign adenoma as a result of the stepwise progression through several molecular and genetic alterations [2]. Unfortunately, most CRC tumors grow slowly, remaining silent or symptomless until they reach to a large size. CRC usually develops over a period of 10–15 years. The past decade has uncovered various new molecular and genetic pathways in the development of CRC; however, because of specific CRC phenotypes with their unique molecular and genetic alterations, [2] an integrated view of the implications of several molecular, genetic, and epigenetic changes on colorectal tumorigenesis is yet to be established.

CRC is highly treatable by surgical removal if diagnosed in the early stages; however, its recurrence after surgery and adjuvant therapy because of nonresponsive metastatic tumors with a median patient overall survival (OS) of ∼24 months pose major challenge for oncologists [3]. Nevertheless, an improvement in patient survival and response rate has been observed with the introduction of new cytotoxic and targeted drugs. Fig. 2 schematically shows the evolution in CRC treatment strategies. However, because of tumor heterogeneity, patient response rates to CRC treatment vary widely for mCRC management. Importantly, to treat patients with an optimally effective therapeutic with reduced toxicity, oncologists require predictive biomarkers. Thus, the future strategy to improve survival outcomes and clinical management of mCRC lies in personalized therapy, which is an evolving approach with a focus on identifying highly specific and sensitive predictive biomarkers. In this review, we focus on recent updates in the field with regard to prognostic and predictive biomarker development for mCRC and the management of patient response to therapy.

Section snippets

Biomarkers for chemotherapy

Owing to the limitations of surgery for most metastatic cases, the systemic therapy directed at metastatic colonies becomes the only option to prolong patient survival [4]. As shown in Fig. 2, chemotherapy drugs currently in use to treat mCRC include: 5-fluorouracil (5-FU), capecitabine (Xeloda®), oxaliplatin (Eloxatin®), and irinotecan (Camptosar®), with 5-FU having been the mainstay of treatment for several years. The introduction of combination regimens of oxaliplatin or irinotecan with

MSI and 18qLOH as prognostic factors for 5-FU-based chemotherapy

Over the past decade, epigenetic changes in CRC tumors have been studied extensively for their clinical significance as potential biomarkers for therapy. Microsatellite instability (MSI) is present in approximately 10–15% of CRC cases of diverse CRC tumor phenotypes and genotypes, because they do not have the same response to treatment strategies as tumors without MSI. Good prognosis has been observed in patients with MSI-H colon cancer; however, patients with MSI-H stage II CRC do not benefit

Targeted therapy

The selection of a targeted therapeutic for mCRC depends on the underlying gene mutations as well as on previous treatment. As detailed below, the FDA-approved targeted mCRC drugs include vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor (HER-1/EGFR)-targeting biological drugs. Targeted therapy for mCRC ranges from monoclonal antibodies (mAbs) to fusion proteins and small-molecule inhibitors (Fig. 2). The combination of chemotherapy with targeted drugs has

KRAS: a validated predictive biomarker

V-ki-ras2 Kristen rat sarcoma viral oncogene homolog (KRAS) is a signal transducer regulated by the EGFR signaling pathway. It is the most frequently mutated gene in CRC (20–40%) [45]. It has been well established that patients with wild-type (WT) KRAS have better outcomes with anti-EGFR treatment, whereas these mAbs have no effect in patients with mutated KRAS. Data analysis from the CRYSTAL and OPUS trials showed that cetuximab significantly reduced the risk of disease progression by 34% in

Concluding remarks and future perspectives

Research into the diagnosis and treatment of CRC has seen substantial advancement over the past few decades. Over the past 5–6 years, research dynamics have shifted, in particular to the identification of more useful predictive biomarkers to support the complex decision-making process for determining outcomes for treating patients with mCRC. As reviewed here, there are only a few predictive biomarkers currently available to select patients who would respond best to specific tumor treatments.

Acknowledgments

The authors acknowledge the financial support of the Deakin India Research Initiative (DIRI) program initiated between the Reliance Institute of Life Sciences, India and Deakin University, Australia. The authors also gratefully acknowledge Reliance Life Sciences Pvt. Ltd., Mumbai, for financial support for the project.

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