Precision Medicine for Colorectal Cancer: What does the future hold?
By Ibrahim Halil Sahin, Associate Professor of Medicine, GI Medical Oncologist. Colorectal Cancer. Precision Medicine and Immunotherapy, University of Michigan Medical School/Rogel Cancer Center
Colorectal Cancer at a Glance
Colorectal cancer refers to the cancer of the large bowel and is the most common gastrointestinal cancer seen in Western Countries. It is also one of the leading causes of cancer-related deaths in the United States. Screening modalities, including colonoscopy and stool-based tests, have significantly reduced the incidence and mortality of colorectal cancer in the screening population. At the same time, there is a worrisome trend with increased incidence and mortality among young adults for whom we do not have established screening guidelines, except those with a family history of colorectal cancer or known germline mutation carriers.
The evolution of molecular testing technology has dramatically changed our understanding of colorectal cancer and shed light on the biological heterogeneity of this disease. The heterogeneity originates from founder alterations, which trigger cancer formation, resulting in distinct biological and clinical characteristics. The molecular technology also revealed that genomic instability seen in cancers results in new mutations during the evolution and progress of cancer clones, which are referred to as “progressor mutations”. Founder and progressor mutations represent the molecular underpinnings of highly varying clinical outcomes we observe in our clinical practice.
All these progresses clearly point out that precision Oncology will continue to revolutionize cancer management for patients with colorectal cancer and will create new avenues for more cures and better outcomes.
Precision Medicine
Precision medicine, which refers to a personalized approach by utilizing patient-specific molecular markers to treat the disease, has revolutionized our management approaches in the field of cancer and created a new era named precision oncology. Targeting patient-specific molecular alterations, which include driver oncogenes such as BRAF and ERBB2 (HER2) or loss of function in tumor suppressor genes such as BRCA and MMR, can offer more meaningful treatment outcomes than unmatched therapies such as chemotherapeutic agents. Several studies revealed that matched therapies can potentially improve overall survival and quality of life for patients living with certain cancers, including colorectal cancer, which underscores that these novel approaches can be life-changing for our patients, and the application of precision oncology to daily practice is highly relevant and essential. Our approach to managing cancer has been fundamentally altered by the development of next-generation sequencing, and newly available tumor DNA-based tumor profiling platforms and assays have opened up new avenues for the prompt delivery of a precision oncology approach, especially for frontline therapies and the comprehension of resistance mechanisms.
Where does Precision Medicine stand for patients with colorectal cancer?
The last ten years have seen a substantial shift in the therapeutic paradigm for colorectal cancer due to advancements in our knowledge of molecular biology and its application to clinical practice. This resulted in rapid drug development in the space of precision medicine by targeted therapeutics. Currently, several actionable molecular alterations in colorectal cancer have been identified, each with matched therapeutic agents. These molecular targets include ERBB2/HER2 amplification, BRAF V600E mutation, NTRK fusions, and, most recently, KRAS G12C mutation. Among those, BRAF directed targeted therapy is now part of frontline therapy, based on findings reported in the BREAKWATER trial, which showed significant improvements in survival outcomes for patients with BRAF 600E-mutated colorectal cancer. Long believed to be untargetable because of its distinct molecular structure, the KRAS oncogene is now seen as actionable. KRAS G12C, a specific KRAS mutant allele, can now be targetable with many therapeutic agents with significant antitumor activity, which resulted in improved survival outcomes for patients whose cancer harbors this mutation, including those with colorectal cancer. This led to the recent FDA approval for some of the KRAS G12 inhibitors (adagrasib and sototarasib). Our learning from allele-specific KRAS targeting will result in drug development for the rest of the KRAS alleles, and some efforts are already in place to target this oncogene more broadly by covering more KRAS alleles and the NRAS oncogene (another member of the RAS subfamily), named as panKRAS and panRAS inhibitors, respectively. While these novel agents are currently being investigated, KRAS G12C inhibitors are being brought to the frontline in combination with chemotherapeutics for patients with colorectal cancer. All these progresses clearly point out that precision oncology will continue to revolutionize cancer management for patients with colorectal cancer and will create new avenues for more cures and better outcomes, which is a significant unmet need, particularly in light of the fact that colorectal cancer is increasingly being seen in the younger population.