Biomarkers in Metastatic Colorectal Cancer: Status Quo and Future Perspective

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Abstract

Colorectal cancer (CRC) is the third most frequent cancer worldwide, and its incidence is steadily increasing. During the last two decades, a tremendous improvement in outcome has been achieved, mainly due to the introduction of novel drugs, targeted treatment, immune checkpoint inhibitors (CPIs) and biomarker-driven patient selection. Moreover, progress in molecular diagnostics but also improvement in surgical techniques and local ablative treatments significantly contributed to this success. However, novel therapeutic approaches are needed to further improve outcome in patients diagnosed with metastatic CRC. Besides the established biomarkers for mCRC, such as microsatellite instability (MSI) or mismatch repair deficiency (dMMR), RAS/BRAF, sidedness and HER2 amplification, new biomarkers have to be identified to better select patients who derive the most benefit from a specific treatment. In this review, we provide an overview about therapeutic relevant and established biomarkers but also shed light on potential promising markers that may help us to better tailor therapy to the individual mCRC patient in the near future.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Dung Le, Jennifer Uram, Hao Wang … (2015)

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.