Abstract
Simple SummaryMetastatic colorectal cancer (mCRC) represents a significant burden in cancer-related morbidity and mortality. The study of mCRC-related genetic alterations and the molecular landscape of the disease has been ongoing and continues to improve the efficacy of the available treatment options. Here, we review various molecular pathways that are involved in colorectal carcinogenesis with driving mutations that could be targeted for precision approaches in the treatment of mCRC. We summarize groundbreaking clinical trials that are shaping the evolving role of precision approaches in the practice guidelines and discuss the latest advancements in emerging new modalities, novel technologies, and future directions toward individualizing the managemet approaches to the treatment of colorectal cancer.The genetic and molecular underpinnings of metastatic colorectal cancer have been studied for decades, and the applicability of these findings in clinical decision making continues to evolve. Advancements in translating molecular studies have provided a basis for tailoring chemotherapeutic regimens in metastatic colorectal cancer (mCRC) treatment, which have informed multiple practice guidelines. Various genetic and molecular pathways have been identified as clinically significant in the pathogenesis of metastatic colorectal cancer. These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications. RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively. Furthermore, there are several emerging pathways and therapeutic modalities that have not entered mainstream use in mCRC treatment and are ripe for further investigation. The well-established data in the arena of targeted therapies provide evidence-based support for the use or avoidance of various therapeutic regimens in mCRC treatment, while the emerging pathways and platforms offer a glimpse into the future of transforming a precision approach into a personalized treatment.
Highlights
Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer-related death worldwide [1]
Clinical applications of these findings include the CRYSTAL trial, a phase III study, which showed improved response rate (RR) (RR of 65.2% with the addition of cetuximab compared to 38.6%), progression-free survival (PFS) and median overall survival (OS) with the first-line treatment of metastatic colorectal cancer (mCRC) in patients with rat sarcoma (RAS) wt tumors [24]
III EPIC trial showed that the combination of irinotecan and cetuximab in comparison to irinotecan alone improved quality of life, increased PFS and RR (RR 16.4% with the addition of cetuximab, compared to RR of 4.2%), but no difference in OS (10.7 months with cetuximab compared to 10.0 months) in patients who previously failed first-line systemic treatment of mCRC [25]
Summary
Colorectal cancer (CRC) is the third most common malignancy and the fourth leading cause of cancer-related death worldwide [1]. These social and epidemiological changes, coupled with improvements in preventive care, sanitation, and communicable disease prevention, have led to an increased age expectancy and an older population with a higher risk of developing CRC. CRC secondary to hereditary syndromes such as familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC), which have associations primarily with CRC in addition to other malignancies as well [1,11] These hereditary CRC syndromes are associated with specific genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), APC, and mutY DNA glycosylase (MUTYH) [1]. Advancements in translating molecular studies have led to a growing role for personalized treatment for individual patients based on their specific disease process rather than a “one-size-fits-all”.
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