What’s driving cancer in your HNSCC patients?

HRAS is an important biomarker that is estimated to drive tumor growth in ~4-8% of patients with advanced head and neck squamous cell carcinoma (HNSCC).1-4 A clinical trial for a novel investigational therapy that targets HRAS activity in advanced HNSCC is underway. 

Uncover more for your patients.

What’s the role of HRAS mutations in advanced HNSCC?

HRAS mutations may drive the growth of head and neck cancer cells.

The MAPK signaling pathway plays a major role in the proliferation, survival, and migration of head and neck cancer cells. Unlike in other tumors, the MAPK mutational profile in HNSCC is characterized primarily by HRAS mutations.1,5,6,7

HRAS is one of three members of the RAS protein family, along with KRAS and NRAS.1 Although HRAS mutations are the least common RAS mutations in cancer overall, they are the most prevalent ones in HNSCC.6

Mutant HRAS Signaling

HRAS undergoes a process called farnesylation, where farnesyltransferase (FT) attaches a farnesyl group to HRAS.8
HRAS acts as a molecular switch. Activated HRAS recruits and activates proteins necessary for the propagation of the HRAS signaling pathway.1
Farnesylation localizes HRAS to the inner cell membrane, allowing it to function in cell signaling pathways.3
Mutations cause HRAS to be permanently turned “on.” This persistent activation of downstream growth and proliferation drives HNSCC tumor cell growth.1

How can you screen for HRAS mutations?

It’s as easy as using the diagnostic tools that are already available to you.

Early next-generation sequencing can help you determine the best course of action for your patients, including those whose cancer may be driven by HRAS mutations. The HRAS biomarker can be found on commercially available genomic panels, such as:

FoundationOne® Liquid
Caris Molecular Intelligence®
Paradigm PCDx™
Tempus xT
CANCERPLEX®
Guardant360®
FoundationOne® CDx
Oncomine Comprehensive Assay
PGDx elio™
Even after the initial screening, patients should be routinely tested following progression. Common chemotherapies are known to alter key mediators of tumor growth, which means that HRAS mutations could emerge in any line of treatment.9,10
HRAS mutations may be driving cancer in ~4-8% of patients with HNSCC3,4

How effective are current treatments for advanced HNSCC?

Unfortunately, many of today’s therapies are suboptimal for most patients.

Today, there is a clear unmet need in advanced HNSCC.11 Each year, there are around 65,000 new cases of HNSCC and 14,500 deaths in the United States alone.12 But even with the availability of immuno-oncology therapies, second-line treatments for HNSCC provide little clinical benefit for many patients.13,14

*Based on patients with recurrent or metastatic HNSCC who progressed on prior therapies in two studies. Outcomes may differ with other treatment regimens such as combination, single-agent, or targeted therapies.

Is HRAS being investigated in advanced HNSCC?

Yes, and your patients with HRAS mutations may be eligible.

There are currently no approved therapies that target HRAS-mutant tumors.3 But advances in the understanding of HRAS have led to further studies, which may provide important insights into the role this oncogene plays in HNSCC.1,2,5  For now, an investigational therapy that targets mutant HRAS activity in HNSCC is being evaluated in a clinical trial. 

Patient enrollment is currently open.

REFERENCES

1. Castellano E, Santos E. Functional specificity of ras isoforms: so similar but so different. Genes Cancer. 2011;2(3):216-231. 2. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129(7):1287-1292. 3.Malone E, Siu LL. Precision Medicine in Head and Neck Cancer: Myth or Reality? Clin Med Insights Oncol. 2018;12:1179554918779581. 4. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582. 5. Rampias T, Giagini A, Siolos S, et al. RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma. Clin Cancer Res. 2014;20(11):2933-2946. 6. Kodaz H, Kostek O, Hacioglu, MB, et al. Frequency of RAS mutations (KRAS, NRAS, HRAS) in human solid cancer. EJMO. 2017;1(1):1-7. 7. Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact. Ann Oncol. 2014;25(10):1889-1900. 8. Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Regulating the Regulator: Post-Translational Modification of Ras. Nat Rev Mol Cell Biol. 2011;13(1):39-51. 9. Braig F, Voigtlaender M, Schieferdecker A, et al. Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma. Oncotarget. 2016;7(28):42988-42995. 10. Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer. 2013;4(1):66-83. 11. Cohen EEW, Bell RB, Bifulco CB, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer. 2019;7(1):184. 12. American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer Society; 2020. 13. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: Results from a single-arm, phase II study. J Clin Oncol. 2017;35(14):1542-1549. 14. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-1867. 

FoundationOne is a registered trademark of Foundation Medicine, Inc. 
CANCERPLEX is a registered trademark of KEW, Inc.
Paradigm Cancer Diagnostics (PCDx) is a trademark of Paradigm Diagnostics, Inc.
Guardant360 is a registered trademark of Guardant Health, Inc.
Caris Molecular Intelligence is a registered trademark of Caris Life Sciences.
Oncomine Comprehensive Assay is a trademark of Thermo Fisher Scientific, Inc.
PGDx elio is a registered trademark of Personal Genome Diagnostics Inc.