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Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy.

ABSTRACT: About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.

SUBMITTER: Vossen DM

PROVIDER: S-EPMC6521057 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy.

Vossen David M DM Verhagen Caroline V M CVM van der Heijden Martijn M Essers Paul B M PBM Bartelink Harry H Verheij Marcel M Wessels Lodewyk F A LFA van den Brekel Michiel W M MWM Vens Conchita C

Cancers 20190329 4

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were assoc ...[more]

PMID: 30934880

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Project description:IntroductionMuscle wasting conditions such as sarcopenia may be highly prevalent in advanced head and neck cancer (HNC) patients (16-71%), with these prevalence rates substantially greater in those who have received chemo-radiotherapy (CRT). According to the updated European Working Group on Sarcopenia in Older People consensus statement, sarcopenia is defined as the age-related loss of muscle strength, muscle mass and physical performance. The high prevalence of sarcopenia in HNC patients is concerning as it has been associated with substantially increased risk of CRT toxicity, respiratory complications and early mortality. With the high prevalence of HNC and sarcopenia in India and the strong link between sarcopenia and poor HNC patient outcomes, it is important to screen for the presence of sarcopenia in Indian patients receiving CRT for HNC.MethodsThis longitudinal pilot study aimed to routinely monitor 19 men receiving CRT for their HNC for a variety of sarcopenic-related outcomes over three time points during their 7 weeks of CRT. Participants were required to be male, with a minimum age of 30 years, with a Stage III, IVa or IVb diagnosis of HNC and be currently undergoing a 7 weeks course of CRT in an oncology department. Outcomes included probable sarcopenic diagnosis were estimated by the SARC-F, handgrip strength, skeletal muscle mass was estimated by bioelectrical impedance and physical performance was assessed by the Timed Up and Go. Repeated measures ANOVA and Bonferroni post-hoc tests were used to identify significant differences at the three time points with a p < 0.05.ResultsThe 19 participants in this trial at a mean age of 56.5 ± 10.2 years (range = 39-75 years), with most (n = 13, 68.4%) employed in laboring occupations. At baseline, 31.5% (n = 6) of the participants already had probable sarcopenia based on their total SARC-F score, with this increasing to 89.4% (n = 17) at the end of 7 weeks CRT. In addition, significant decreases in strength, skeletal muscle mass and Timed Up and Go performance were observed, with these declines significantly greater at 7 weeks than 3 weeks after commencing CRT.ConclusionsPatients with HNC undergoing 7 weeks of CRT showed clinically significant increases in the incidence of probable sarcopenia based on their total SARC-F score as well as clinically significant declines in handgrip strength, skeletal muscle mass and Timed Up and Go performance. Due to the relationship between sarcopenia and a host of adverse events related to CRT in HNC patients, these results suggest that oncologists and their allied health teams should routinely monitor these patients during CRT and provide the relevant exercise therapy and nutritional support to those patients in need.

Dataset Information

Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy.

Publications

Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy.

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