Colorectal Cancer: Open Access

Introduction

Almost all patients with advanced cancer who receive palliative systemic therapy develop therapeutic resistance. Resistance to cancer-directed therapy is generally categorized as either primary or secondary (acquired). Primary resistance is defined as a lack of clinical or radiographic response to therapy. Secondary resistance is defined as therapeutic resistance that develops after a period of disease stability or response. 4 Although these terms will be used throughout this review, it is important to note that this simple distinction becomes less clear as the precision of surveillance imaging and/or blood-based tests improves. For example, biochemical or molecular assessment of response may differ from imaging studies, which may be due to disease natural history, imaging frequency, or—in the case of cancer treatments.

Cancer categorized based on resistance as single mutation

Historically, the objective response rate (ORR) was recognised as a proxy for clinical benefit, even when the OS benefit was unknown. Therapies that are designed to target a single aberrant growth signal, on the other hand, these are susceptible to rapid outgrowth of resistant subclones, limiting the durability of response.

When resistant subclones drive signalling through alternate pathways, the promise of targeted therapy—targeting only the gene or protein that is driving cellular proliferation—may become a liability. The rapid evolution of treatment resistance is a recurring challenge for drug development in mCRC. Targeting a single mutation is either ineffective (primary resistance) or leads to relatively rapid disease progression after a period of response in the vast majority of colon cancers (secondary resistance). Clinical trials for mCRC will need to evolve in the future.

KRAS and NRAS disease

In CRC, EGFR is frequently overexpressed. This understanding led to the initial development and, eventually, approval of the monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) for the therapies of mCRC. 9,10 Despite these approvals, a large proportion of patients did not benefit significantly from cetuximab or panitumumab treatment. KRAS genetic variants were later identified as the primary cause of EGFR blockade resistance in multiple studies. 11-13 While initial studies only looked at KRAS exon 2 mutations, it was later discovered that KRAS exon 3 and 4 mutations, as well as NRAS exon 2, 3, and 4 mutations, had a similar negative predictive value. 14,15 These discoveries eventually led to amended drug approvals, limiting treatment to patients with KRAS and NRAS (RAS) wild-type disease. RAS mutations continue to exist.

Tolerance to BRAF V600E Inhibitors, Both Primary and Secondary

BRAFV600E mutations are found in about 7% of patients with mCRC and are associated with a significantly worse response to chemotherapy and a poor prognosis. 36,37 Several studies have been conducted in an attempt to target BRAF V600E–mutated mCRC.

however, these improvements are typically fleeting due to the relatively rapid development of secondary resistance. Patients in the phase 3 BEACON trial were given a combination of the BRAF inhibitor encorafenib (Braftovi) and cetuximab with or without the Binimetinib a MEK inhibitor, was compared to a control arm of irinotecan-based chemotherapy. The targeted inhibitor combinations improved ORRs median PFS and median OS 42 Despite a numerically higher response rate with the addition of MEK inhibition, there was no clinically significant difference in outcomes between patients who received triplet (BRAF, MEK, EGFR) vs doublet (BRAF, EGFR) inhibition.

Acknowledgements

The author is thankful to the people who supported and participated in this research. as well as the research and development team for their invaluable support during the study.

Conflict of Interest

There is no conflict disclosed in this article.