Background
Evidence surrounding the effect of adjuvant treatment in salivary gland cancers is limited. The benefit of adding chemotherapy to adjuvant treatment is also of interest. We investigated ...the association of these treatments with survival and whether this differed by stage or the presence of adverse features.
Methods
A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the National Cancer Data Base (NCDB) was conducted.
Results
Treatment with adjuvant radiotherapy was associated with improved survival for both patients with early‐stage (hazard ratio HR 0.744; P = .004) and late‐stage (HR 0.688; P < .001) disease with adverse features. Further addition of chemotherapy to the adjuvant treatment of patients with late‐stage disease with adverse features was not associated with a survival benefit (HR 1.028; P = .705).
Conclusion
Adjuvant radiotherapy is associated with improved survival for patients with adverse features, regardless of stage. The addition of chemotherapy to the adjuvant treatment of patients with late‐stage disease with adverse features is not associated with improved outcomes.
Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of ...positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities-PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.
The validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck ...dissection.
This prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with (99m)Tc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB.
In the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%.
For T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).
Human papilloma virus (HPV)-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) have different molecular and biologic characteristics and clinical behavior compared with HPV-negative ...(HPV-) OPSCC. PIK3CA mutations are more common in HPV(+) OPSCC. To define molecular differences and tumor subsets, protein expression and phosphorylation were compared between HPV(+) and HPV(-) OPSCC and between tumors with and without PIK3CA mutations.
Expression of 137 total and phosphorylated proteins was evaluated by reverse-phase protein array in 29 HPV(+) and 13 HPV(-) prospectively collected OPSCCs. Forty-seven OPSCCs were tested for hotspot-activating mutations in PIK3CA and AKT. Activation of PIK3CA downstream targets and sensitivity to pathway inhibitors were determined in HPV(+) head and neck cancer cells overexpressing wild-type or mutant PIK3CA.
Analyses revealed 41 differentially expressed proteins between HPV(+) and HPV(-) OPSCC categorized into functional groups: DNA repair, cell cycle, apoptosis, phosphoinositide 3-kinase (PI3K)/AKT/mTOR, and receptor kinase pathways. All queried DNA repair proteins were significantly upregulated in HPV(+) samples. A total of 8 of 33 HPV(+) and 0 of 14 HPV(-) tumors contained activating PIK3CA mutations. Despite all activating PIK3CA mutations occurring in HPV(+) samples, HPV(+) tumors had lower mean levels of activated AKT and downstream AKT target phosphorylation. Ectopic expression of mutant PIK3CA in HPV(+) cells increased mTOR, but not AKT activity. HPV E6/E7 overexpression inhibited AKT phosphorylation in HPV-negative cells. Mutant PIK3CA overexpressing cells were more sensitive to a dual PI3K/mTOR inhibitor compared with an AKT inhibitor.
Protein expression analyses suggest that HPV(+) and HPV(-) OPSCC differentially activate DNA repair, cell cycle, apoptosis, PI3K/AKT/mTOR, and receptor kinase pathways. PIK3CA mutations are more common in HPV(+) OPSCC and are associated with activation of mTOR, but not AKT. These data suggest that inhibitors for mTOR may have activity against HPV(+) PIK3CA mutant oropharyngeal cancers.
Objectives
To compare long‐term oncologic outcomes and adjuvant therapies for patients treated with transoral robotic surgery (TORS), nonrobotic surgery, or transoral laser microsurgery (TLM).
Study ...Design
A retrospective analysis of the National Cancer Database (2010–2014).
Methods
Patients with clinical tumor (T)1 and T2 oropharyngeal squamous cell carcinomas (OPSCC) were classified into those receiving TORS versus nonrobotic surgery versus TLM. Univariate and multivariate survival analyses were conducted with chi‐square tests; Kaplan‐Meier log‐rank test; and Cox multivariate, logistic regression, and multinomial regression modeling.
Results
We identified 2,224 OPSCC TORS patients; 6,697 nonrobotic surgery patients; and 333 TLM patients. The majority of patients were white males with a mean age of approximately 59 years. No significant difference was noted between the cohorts in tumor stage; however, TORS patients were more likely to have nodal (N)1 to N3 disease than nonrobotic surgery and TLM patients, respectively (69.8% vs. 62.0% vs. 59.7%, P < 0.001).
TORS was associated with a lower likelihood of positive margins when compared to nonrobotic surgery, although not TLM (nonrobotic surgery: hazard ratio HR 1.51, P < 0.001, TLM: HR 1.13, P = 0.582). TORS was associated with lower likelihood of postsurgical chemoradiotherapy (TLM: HR 2.07, P < 0.001, nonrobotic surgery: 1.65, P < 0.001) but not adjuvant radiotherapy alone (TLM: HR 1.06, P = 0.569, nonrobotic surgery: 0.96, P = 0.655). On multivariate Cox analysis of overall survival, the use of TORS was not associated with increased survival (TLM: HR 1.31, P = 0.233, nonrobotic surgery: HR 1.12, P < 0.303).
Conclusion
The advantages of TORS for early‐stage OPSCC may be a lower likelihood of postsurgical positive margins and subsequent need for adjuvant chemoradiotherapy.
Level of Evidence
NALaryngoscope, 129:1844–1855, 2019
Objectives
Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present ...a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment‐related outcomes for HPV‐associated and HPV‐negative HNCUP.
Methods
A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan‐Meier analyses were conducted.
Results
Patients with HPV‐associated disease had superior survival, with a 3‐year survival of 94.8% (standard error SE: 1.0), compared with 80.3% (SE: 2.9) among those with HPV‐negative disease. Among HPV‐negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV‐associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival.
Conclusion
Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV‐negative patients, whereas it may be a promising option for further investigation in HPV‐positive patients.
Level of Evidence
4 Laryngoscope, 129:684–691, 2019
Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last ...two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.
Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in
, resulting in treatment resistance. In these patients, direct targeting of ...p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition.
AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using
and
HNSCC models.
Elevated nuclear AURKA correlated with worse survival among patients with p16(-) HNSCC. Alisertib caused spindle defects, G
-M arrest and inhibitory CDK1 phosphorylation, and cytostasis in
mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared with either vehicle or single-agent treatment.
Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in
and
HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for
mutated cancers.
The prognostication of head and neck squamous cell carcinoma (HNSCC) is largely based upon the tumor size and location and the presence of lymph node metastases. Here we show that gene expression ...patterns from 60 HNSCC samples assayed on cDNA microarrays allowed categorization of these tumors into four distinct subtypes. These subtypes showed statistically significant differences in recurrence-free survival and included a subtype with a possible EGFR-pathway signature, a mesenchymal-enriched subtype, a normal epithelium-like subtype, and a subtype with high levels of antioxidant enzymes. Supervised analyses to predict lymph node metastasis status were approximately 80% accurate when tumor subsite and pathological node status were considered simultaneously. This work represents an important step toward the identification of clinically significant biomarkers for HNSCC.
High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR ...pathway may improve the use of EGFR inhibitors in HNSCC.
EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points.
Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors.
High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.
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