Blog | Jan. 11, 2023
Importance of PI3K-AKT pathway-based biomarkers in breast cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is any cancer that affects the colon and/or rectum.1 The American Cancer Society (ACS) estimates that there will be 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer in the U.S. in 2022.2 CRC is the third leading cause of cancer-related deaths in men and in women, and the second most common cause of cancer deaths when numbers for men and women are combined. It’s expected to cause about 52,580 deaths during 2022.2 Overall, the lifetime risk of developing CRC is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women.1
From 2013 to 2017, incidence of CRC dropped by about 1% each year, primarily in older adults, due to increased screening and lifestyle changes.1 However, from 2012 through 2016, the rate increased by 2% each year in people younger than 50 and 1% in 50-64 year-olds.1 The overall five-year survival rate for people with CRC is 65% but is stage-dependent (localized 91%,regional 72%, and distant 15%).1
Choice of first-line treatment for CRC is influenced by the stage of the disease, drug tolerability, patient’s comorbidities and age. Standard of care is chemotherapy using a combination of 5-fluorouracil/leucovorin with either oxaliplatin or irinotecan with a monoclonal antibody against either vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR).3
CRC is widely considered a heterogeneous disease, with multiple gene alterations which lead to diverse prognoses and resistance to treatment.4 Kirsten rat sarcoma (KRAS) oncogene is mutated in approximately 40% of all CRC cases and is associated with dismal prognosis.5 The mutations result in constitutive KRAS expression to persistently stimulate downstream MAPK and PI3K signaling cascade pathways causing tumorigenesis.6 Lacking an ideal small molecular binding pocket and having a high affinity for the abundant guanosine triphosphate (GTP), KRAS was deemed undruggable until the development of KRAS G12C allele-specific inhibitors, e.g., Bevacizumab against VEGF and cetuximab and panitumumab against EGFR.3
In CRC, 85% of KRAS mutations occur in one of three major hotspots (codons 12, 13 and 61).7 Among them, codon 12 mutation is dominant, accounting for approximately 65% of all KRAS alleles. Moreover, G12D (glycine 12 to aspartic acid) and G12V (glycine 12 to valine) are the two most common subtypes in CRC.7
Due to the diversity of KRAS alleles in CRC, patients harboring different KRAS mutations may have a distinct prognosis. KRAS codon 12 mutations rather than codon 13 mutations have been associated with dismal prognosis compared with KRAS wild-type cases, an inferior response to chemotherapy, and a high risk of recurrence.8,9 Targeting EGFR has been one of the most effective colorectal cancer strategies. Monoclonal antibodies (mAbs) targeting EGFR have been proven to benefit CRC patients who were refractory to other therapies.10 However, patients whose tumors harbor KRAS mutations in exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146) cannot derive benefit from treatment with anti-EGFR therapy, which means that these KRAS mutations are negative biomarkers for this therapy.11 Multiple therapeutic strategies have been investigated to overcome resistance to anti-EGFR mAbs, including EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, and microsatellite instability etc.12
Given that oncogenic point mutation of KRAS is a common event during CRC and plays a critical role in prognostic evaluation and therapeutic decisions, KRAS mutations should routinely be determined in the diagnosis of CRC. KRASG12C allele-specific inhibitors inhibit mutant’s signaling and the cancer cell growth by reducing the level of GTP-bound KRAS by more than 95%.13 It has led to the development of more promising KRAS-targeted approaches and provide the possibility for conquering KRAS mutations in CRC.
Therapeutic approaches targeting KRAS mutations:6
Due to KRAS-mutant heterogeneity in CRC, combination therapies may be required to target multiple steps in the pathway to provide more efficacious and personalized treatment for patients.
When ultra-sensitive detection of low-level genomic mutations matters, using an expertly designed technology to preserve all input molecules for analysis is crucial. Sysmex Inostics’ RAS-RAF-SEQ liquid biopsy assay uses Plasma-Safe-SeqS technology. RAS-RAF-SEQ is a rapid and minimally invasive test which identifies KRAS mutations and provides a comprehensive genetic signature which:
RAS-RAF-SEQ is a CLIA-validated clinical-grade test for the identification of actionable gene mutations in exons within KRAS, NRAS, BRAF, as well as PIK3CA and AKT1, to inform therapy selection by detecting established and emerging predictive markers. By identifying mutant molecules at low levels, RAS-RAF-SEQ increases clinical trial efficiency by facilitating the identification of eligible patients for novel therapies across multiple cancer types, including CRC. This would save money, expedite discovery of clinically-relevant targets, and streamline the participant selection process.