CUHK researchers discover a mutation prognostic of prolonged survival in SCCHN

Researchers from the Chinese University of Hong Kong (CUHK) have discovered a novel genetic biomarker associated with extended survival in head and neck squamous cell carcinoma (HNSCC), which is found in almost 20 percent of HNSCC tumours.

Using a comprehensive pan-pathway approach, the researchers examined the prognostic impact of mutational events of seven major cancer-related signalling pathways on HNSCC patients’ survival with The Cancer Genome Atlas (TCGA) dataset (n=508). [Sci Rep 2015;5:13546]

MAPK pathway mutations, found in one-fifth of HNSCC tumours, were associated with a doubling of overall survival (OS) with a median of 95.27 months vs 47.93 months for MAPK wild-type (wt) patients (p=0.0201). MAPK-mutant (mut) patients also had a reduced risk of death vs MAPKwt patients (odds ratio [OR], 0.5466; p=0.0156). [Life Science Alliance 2020;3:e201900545]

“This finding may lead to future clinical trials for treatment de-intensification in particular patients based on the presence of MAPK pathway mutations in their tumours,” commented investigator Professor Vivian Lui of the School of Biomedical Sciences, CUHK.

“Most strikingly, MAPK pathway mutations were also prognostic of markedly improved survival even among patients with TP53 mutations, which are usually indicative of aggressive disease and are prognostic of HNSCC progression,” the researchers pointed out. “In fact, MAPK and TP53 double-mutant patients [n=363] had an extremely long median OS of 169.25 months [approximately 14 years], which was 4.77 times longer than that of their MAPKwt/TP53mut counterparts [35.45 months; p=0.0074].” The double-mutant patients also had a 55.26 percent reduction in likelihood of death (OR=0.4474) vs MAPKwt patients (p=0.0063).

Furthermore, the prognostic power of MAPK pathway mutations was found to be independent of human papillomavirus (HPV) infection status. “Importantly, unlike HPV-positive HNSCC, which is associated with favourable outcomes [mainly for oropharynx subsite tumours], MAPK pathway mutations span multiple head and neck anatomic subsites, including oral cavity, larynx, oropharynx, and others,” noted the researchers.

In the study, over 87 percent of MAPK pathway–mutated tumours were HPV-negative. “Upon HPV stratification, MAPK pathway mutations were still found to be prognostic of HPV-negative HNSCC [p=0.0352],” reported the researchers.

“Mechanistically, our findings identified a previously undescribed mechanism of p-ErbB3 regulation by MAPK pathway mutants,” wrote the researchers. ErbB3 activation contributes to HNSCC proliferation and is a key mediator of progression. [Mol Cancer Ther 2014;13:1345-1355] Data from The Cancer Protein Atlas have established tumour overexpression of phospho-ErbB3(Y1289) as the top protein signalling event most significantly associated with decreased HNSCC patient survival among 273 key signalling proteins examined (p=0.0006). [Cancer Res 2017;77:e51-e54] “The negative regulation of p-ErbB3 by ERK activity is uniquely found in MAPKmut, but not in MAPKwt HNSCC,” highlighted the researchers.

The researchers have also found that immunocompetent MAPKmut HNSCC models display active cell death coupled with massive CD8+ T-cell recruitment in situ. “Our findings highlight the potential clinical utility of MAPK pathway mutations in identifying HNSCC patients with CD8+ T-cell–inflamed tumours, independent of tumour mutation burden, who are likely to benefit from PD1/PD-L1 inhibitor treatment,” they wrote.

“Our study uncovers novel clinical, biological, and immunological understanding of MAPK pathway mutations in HNSCC, which may be used as biomarkers for predicting potential immunotherapy benefit or even as de-intensification biomarkers, with broad applicability in terms of HNSCC subsites,” concluded the researchers.