Identifying and clinically validating biomarkers for immunotherapy in colorectal cancer

ABSTRACT

Introduction

Colorectal cancer (CRC) is a leading cause of death. For three decades, chemotherapy with or without targeted therapy (provided before or after tumor resection surgery) has been the standard treatment for patients with CRC. Biomarkers are key tools for performing early detection, prognostication, and survival and treatment response predictions. Notably, immune checkpoint inhibitors (ICIs) have transformed prognoses for solid tumors (including CRC).

Area covered

Although immunotherapy has developed considerably, it is only effective for a small number of microsatellite instability–high (MSIH) cancer cases; such cases represent only 5% of metastatic CRC (mCRC) cases, which are characterized by an immune-inflamed microenvironment that can be rewired against cancer cells through ICI administration. Immunotherapy research is gradually uncovering the mechanism underlying immune resistance in patients with CRC and discovering new biomarkers. For example, studies have clinically validated the associations of deficient mismatch repair system/microsatellite instability, tumor mutation burden, programmed death ligand 1 expression, and polymerase epsilon with CRC in patients undergoing immunotherapy.

Expert opinions

Clinical trials documenting the effect of immune checkpoints were performed to produce long-lasting effects for patients with mCRC. Consequently, therapeutic decision-making models are further refined by the inclusion of powerful molecular biomarkers in patients with CRC.

KEYWORDS:

• Biomarker
• immunotherapy
• colorectal cancer
• microsatellite instability (MSI)

Article highlights

• Immunotherapy, specifically immune checkpoint inhibition (ICIs), has transformed the prognosis for solid tumors, including advanced and metastatic colorectal cancer (mCRC) tumors.

• Therapeutic decision-making models and numerous biomarkers for advanced colorectal cancer (CRC) and mCRC can be used to identify the patients who can benefit from immunotherapy.

• For patients with mCRC, microsatellite instability status is a predictive biomarker of immunotherapy because of the accumulation of mutation-associated neoantigens that can be recognized by the immune system.

• Among patients with CRC, the correlation between the expressions of programmed cell death-1 and programmed death ligand 1, the prognostic or predictive role of this correlation, and various clinical and pathological features remain unclear.

• Tumor mutation burden can be used as an alternative biomarker for assessing the response of patients with mCRC to immunotherapy.

• Efforts to identify novel biomarkers and new combination methods when ICI resistance occurs must continue.

Declarations of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by grants through funding from the Ministry of Science and Technology (MOST 109-2314-B-037-046-MY3, MOST 111-2314-B-037-070-MY3, MOST 111-2314-B-037-049) and the Ministry of Health and Welfare (12D1-IVMOHW02) and funded by the health and welfare surcharge of on tobacco products, and the Kaohsiung Medical University Hospital (KMUH111-1R31, KMUH111-1R32, KMUH111-1M28, KMUH111-1M29, KMUH111-1M31) and Kaohsiung Medical University. In addition, this study was supported by the Grant of Taiwan Precision Medicine Initiative and Taiwan Biobank, Academia Sinica, Taiwan, R.O.C.