Sage Journals: Discover world-class research

Abstract

Background:

Human papilloma virus (HPV)–negative oropharyngeal squamous cell carcinomas (OPCs) have a poorer prognosis and best management is an unmet need. We studied the prognostic role of epidermal growth factor receptor (EGFR) and PIK3CA amplifications and TP53 functional status.

Methods:

Between 1992 and 2000, 90 consecutive patients with OPCs were treated with surgery, followed by radiotherapy in case of high-risk pathologic features. Of those, 73 cases were HPV-negative and therefore were selected for molecular analysis (PIK3CA and EGFR fluorescent in situ hybridization [FISH] analysis and TP53 mutation analysis).

Results:

FISH analyses of EGFR and PIK3CA were successfully conducted on 69 and 63 of 73 tumor samples, respectively. EGFR alterations were detected in 43% of patients but just 7% showed amplification. Seven cases (11%) carried PIK3CA amplification and 18 (29%) gene gain or high polysomy. TP53 was detected as nonfunctional in 24 of 67 (36%) successfully analyzed cases.

Both univariable and multivariable analysis showed statistically significantly worse disease-free survival (DFS) for patients with PIK3CA disomy compared to those with gene gain or high polysomy. No differences in overall survival or DFS for EGFR and TP53 alteration were evident. The combined evaluation of PIK3CA and TP53 showed that PIK3CA gene copy number gain separated a population with better outcome, defining an overall worse prognosis population (disomy) now clearly further divided according to TP53 functional status.

Conclusion:

PIK3CA gene copy number increase is associated with a favorable clinical outcome in HPV-negative OPCs treated with surgery ± postoperative radiotherapy. In patients without PIK3CA alteration, TP53 nonfunctional mutations are associated with poor prognosis.

Keywords

Oropharyngeal squamous cell carcinomas

Get full access to this article

View all access options for this article.

References

Argiris

Karamouzis

Raben

et al . Head and neck cancer. Lancet 2008; 371: 1695–1709.

Leemans

Braakhuis

Brakenhoff

RH.

The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11: 9–22.

Bhatia

Burtness

Human papillomavirus-associated oropharyngeal cancer: Defining risk groups and clinical trials. J Clin Oncol 2015; 33: 3243–3250.

Fakhry

Psyrri

Chaturvedhi

HPV and head and neck cancers: State-of-the-science. Oral Oncol 2014; 50: 353–355.

Dillon

Harrington

KJ.

Human papillomavirus-negative pharyngeal cancer. J Clin Oncol 2015; 33: 3251–3261.

Poeta

Manola

Goldwasser

et al . TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007; 357: 2552–2561.

Bossi

Resteghini

Paielli

et al . Prognostic and predictive value of EGFR in head and neck squamous cell carcinoma. Oncotarget 2016; 7: 1–44.

Agrawal

Frederick

Pickering

et al . Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011; 333: 1154–1157.

Stransky

Egloff

Tward

et al . The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

10.

Chung

Guthrie

Masica

et al . Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing. Ann Oncol 2015; 26: 1216–1223.

11.

Lawrence

MSMS

Sougnez

Lichtenstein

et al . Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015; 517: 576–582.

12.

Seiwert

Zuo

Keck

et al . Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 2015; 21: 632–641.

13.

Chau

et al . Incorporation of next-generation sequencing into routine clinical care to direct treatment of head and neck squamous cell carcinoma. Clin Cancer Res 2016; 22: 2939–2949.

14.

Pickering

Zhang

Yoo

et al . Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013; 3: 770–781.

15.

Lui

VWY

Hedberg

et al . Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013; 3: 761–769.

16.

Perrone

Suardi

Pastore

et al . Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. Clin Cancer Res 2006; 12: 6643–6651.

17.

Petitjean

Mathe

Kato

et al . Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53 database. Hum Mutat 2007; 28: 622–629.

18.

Broek

Mohan

Eytan

Chen

Van Waes

The PI3K / Akt / mTOR axis in head and neck cancer: functions, aberrations, cross-talk, and therapies. Oral Dis 2015; 53: 815–825.

19.

Perrone

Gloghini

Cortelazzi

et al . Isolating p16-positive/HPV-negative oropharyngeal cancer: an effort worth making. Am J Surg Pathol 2011; 35: 774–777.

20.

Concato

Peduzzi

Holford

et al . Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol 1995; 48: 1495–1501.

21.

The R Project for Statistical Computing [cran.r-project.org/].

22.

Feldman

Gatalica

Knezetic

et al . Molecular profiling of head and neck squamous cell carcinoma. Head Neck 2015; 38 Suppl 1: E1625–E1638.

23.

Pedrero

JMG

Carracedo

Pinto

et al . Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer 2005; 114: 242–248.

24.

Suda

Hama

Kondo

et al . Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma. BMC Cancer 2012; 12: 416.

25.

Brauswetter

Dános

Gurbi

et al . Copy number gain of PIK3CA and MET is associated with poor prognosis in head and neck squamous cell carcinoma. Virchows Arch 2016; 468: 579–587.

26.

Shigaki

Baba

Watanabe

et al . PIK3CA mutation is associated with a favorable prognosis among patients with curatively resected esophageal squamous cell carcinoma. Clin Cancer Res 2013; 19: 2451–2459.

27.

Mayer

Arteaga

CL.

PIK3CA activating mutations: A discordant role in early versus advanced hormone-dependent estrogen receptor-positive breast cancer?

J Clin Oncol 2014; 32: 2932–2934.

28.

Linnerth-Petrik

Santry

Moorehead

et al . Akt isoform specific effects in ovarian cancer progression. Oncotarget 2016; 7: 74820–74833.

29.

Wyszomierski

A knotty turnabout? Akt1 as a metastasis suppressor. Cancer Cell 2005; 8: 437–439.

30.

Oyama

Okawa

Nakagawa

et al . AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. Oncogene 2007; 26: 2353–2364.

31.

Yoeli-Lerner

Yiu

Rabinovitz

et al . Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005; 20: 539–550.

32.

Baba

Nosho

Shima

et al . Phosphorylated AKT expression is associated with PIK3CA mutation, low stage, and favorable outcome in 717 colorectal cancers. Cancer 2011; 117: 1399–1408.

33.

Vasudevan

Barbie

Davies

et al . AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009; 16: 21–32.

34.

Vogt

Gymnopoulos

Hart

JR.

PI 3-kinase and cancer: changing accents. Curr Opin Genet Dev 2009; 19: 12–17.

35.

Fan

Q-W

Cheng

Knight

et al . EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal 2009; 2: ra4.

36.

Lauring

Cosgrove

Fontana

et al . Knock in of the AKT1 E17K mutation in human breast epithelial cells does not recapitulate oncogenic PIK3CA mutations. Oncogene 2010; 29: 2337–2345.

37.

Smeets

Braakhuis

BJM

Abbas

et al . Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 2006; 25: 2558–2564.

38.

Wilting

Smeets

Snijders

PJF

et al . Genomic profiling identifies common HPV-associated chromosomal alterations in squamous cell carcinomas of cervix and head and neck. BMC Med Genomics 2009; 2: 32.

39.

Velculescu

El-Deiry

WS.

Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem 1996; 42: 858–868.

40.

Gasco

Crook

The p53 network in head and neck cancer. Oral Oncol 2003; 39: 222–231.

41.

Olivier

Eeles

Hollstein

et al . The IARC TP53 database: New online mutation analysis and recommendations to users. Hum Mutat 2002; 19: 607–614.

42.

Zhou

Zhiyi

Myers

JN.

TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. J Cell Biochem 2016; 117: 2682–2692.

43.

Soulières

Sandrine Faivre Mesía

et al . Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol 2017; 18: 323–335.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB

Prognostic role of PIK3CA and TP53 in human papillomavirus–negative oropharyngeal cancers