Imagine loosening the grip of RAS
Given its pivotal role in PDAC, RAS is an important therapeutic target1
- Oncogenic RAS mutations are among the most common drivers of human cancers2,3
- Even nonmutated wild-type RAS may play a role in oncogenesis4-6
- Nearly all RAS mutations in PDAC occur at KRAS position G12, but RAS mutations in other isoforms and at KRAS positions G13 and Q61 are also observed1
RAS is the key oncogenic driver of PDAC1,7
- RAS proteins regulate cell growth by switching between the RAS(ON) and RAS(OFF) states3,8
- In normal adult cells, RAS is predominantly in the inactive OFF state and is only transiently switched to the active ON state in response to growth signals9,10
- Oncogenic RAS mutations increase the amount of RAS in the ON state, resulting in overactive RAS signaling and uncontrolled cell growth3,9
In PDAC, RAS mutations are thought to play an integral role in:
Initiation
Oncogenic RAS mutation is an initiating genetic event in the development of PDAC7
Progression
The resulting oncogenic RAS(ON) signaling drives tumor proliferation and cell survival4,7,11,12
Resistance
Oncogenic RAS(ON) signaling may promote an immunosuppressive tumor microenvironment that can contribute to resistance to therapy12,13
RAS mutations are highly heterogeneous1
RAS mutations in PDAC1
- ~86% of PDAC has a KRAS mutation at position G121
- The KRAS G12D variant is the most common mutation in PDAC (~40%), followed by G12V (~29%) and G12R (~15%)1
- The KRAS G12C variant is rare in PDAC (<2%)1
National Comprehensive Cancer Network® (NCCN®) recommends determining your patient's mutation status at PDAC diagnosis14
Metastatic PDAC remains one of the most lethal cancers, with a 5-year survival rate of about 3%15
Chemotherapy provides limited clinical benefit
- The median OS in patients receiving 1L chemotherapy for metastatic PDAC ranged from 8.5 months to 11.7 months16-22
- The median OS in patients receiving 2L+ chemotherapy ranged from 6.1 months to 6.7 months23-29
*Includes any NRAS mutation at positions G12, G13, or Q61.1
†Includes any mutation at this KRAS position.1
‡Tumor/somatic molecular profiling, preferably using a next-generation sequencing (NGS) assay, is recommended for all patients who are candidates for anticancer therapy to identify clinically actionable and/or emerging alterations. These alterations include, but are not limited to: fusions (ALK, NRG1, NTRK, ROS1, FGFR2, and RET), mutations (BRAF, BRCA1/2, KRAS, and PALB2), amplifications (HER2), microsatellite instability (MSI), mismatch repair deficiency (dMMR), or tumor mutational burden (TMB) using comprehensive genomic profiling via an FDA-approved and/or validated next-generation sequencing (NGS)–based assay, and HER2 overexpression via IHC ± FISH. In addition to DNA sequencing, RNA sequencing is recommended since it is better at detecting gene fusions. Testing on tumor tissue is preferred; however, circulating tumor DNA (ctDNA) testing can be considered if tumor tissue testing is not feasible.14
1L=first-line; 2L=second-line; ALK=anaplastic lymphoma kinase; BRAF=B-Raf proto-oncogene, serine/threonine kinase; BRCA=breast cancer gene; DNA=deoxyribonucleic acid; FGFR2=fibroblast growth factor receptor 2; FISH=fluorescence in situ hybridization; HER2=human epidermal growth factor receptor 2; HRAS=Harvey rat sarcoma virus; IHC=immunohistochemistry; KRAS=Kirsten rat sarcoma virus; NRAS=neuroblastoma rat sarcoma virus; NRG1=neuregulin 1; NTRK=neurotrophic tyrosine receptor kinase; OS=overall survival; PALB2=partner and localizer of BRCA2; RAS=rat sarcoma virus; RET=ret proto-oncogene protein; RNA=ribonucleic acid; ROS1=ROS proto-oncogene 1, receptor tyrosine kinase.
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