Update on Emerging Therapies for Advanced Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.

KRAS Mutation Status in Bulgarian Patients with Advanced and Metastatic Colorectal Cancer

“…A lower frequency of KRAS mutations is found in left-sided colon tumors compared to right-sided colon tumors [ 12 , 13 , 14 , 15 ]. Tumor localization has gained importance with the finding that anti-EGFR therapy combined with chemotherapy is more effective in wild-type KRAS , NRAS , and BRAF patients with left-sided primary CRC tumors [ 16 ]. It is already known that right-sided tumors derive limited benefits from first-line anti-EGFR treatment, even with wild-type RAS status [ 17 ].…”

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

“…Furthermore, biomarker research in CRC is rapidly evolving with the aim of identifying molecular signatures crucial for diagnosis, prognosis, and treatment decisions. Biomarkers, such as mutations in genes such as KRAS and BRAF, not only influence tumor behavior, but also affect responses to targeted therapies, notably anti-EGFR antibodies[ 24 ]. Additionally, MSI status serves not only as a guide for immunotherapy but also as a valuable prognostic indicator as well.…”

“…Liquid biopsies offer a noninvasive method to analyze circulating tumor DNA and to monitor disease progression and treatment responses[ 189 ]. Epigenetic alterations, such as DNA methylation patterns and microRNA expression profiles, are promising diagnostic and prognostic markers[ 24 , 195 ]. Traditional biomarkers, such as carcinoembryonic antigen, provide insights into tumor burden and treatment response, while gene expression signatures, such as Oncotype DX and ColoPrint, offer predictive value for treatment outcomes and recurrence risk assessment[ 196 ].…”

“…To this end, immunotherapy targeting immune checkpoints such as PD-1/PD-L1 axis and CTLA-4 shows promise in treating advanced CRC, particularly in CRC tumors with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR)[ 22 ]. Combination therapies, involving immunotherapy with chemotherapy, targeted therapies, and other immunomodulators, further offer the potential of synergistic effects and enhanced treatment efficacy[ 23 , 24 ]. Ongoing research efforts on predictive biomarkers, such as tumor mutational burden (TMB) and immune cell infiltration patterns, aim to identify patients most likely to benefit from immunotherapy[ 25 , 26 ].…”

Classification of patients with metastatic colorectal cancer into consensus molecular subtypes into real-world: A pilot study

“…At the time of diagnosis, approximately 25% of patients already present with metastatic disease, while 50% of those initially diagnosed with localized stages later develop disseminated disease[ 1 ]. Recent years have seen significant advancements in systemic therapies for metastatic colorectal cancer (mCRC) patients, including diverse combination chemotherapy regimens, targeted therapy, immunotherapy, and multi-kinase inhibitors[ 2 ]. Despite these improvements, patients’ responses remain variable and unpredictable due to the molecular heterogeneity of this disease.…”