Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we ...evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.
Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical ...behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In a patient with lung cancer, severe pruritus in response to antibodies that block programmed death 1 protein was promptly relieved by adding intravenous naloxone to the treatment regimen.
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor ...neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.
Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance.
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Genetic alterations of
(
), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have ...revealed somatic
alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma),
alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function
alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of
somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor
alterations are also discussed. IMPLICATIONS: Alterations in
gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.
Low absolute lymphocyte count (ALC) has previously been established as a marker of poor prognosis in multiple cancer types. There is growing evidence that ALC may also be associated with response to ...immunotherapy. This study explores whether response to PD1 inhibitors in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is associated with pretreatment ALC.
Thirty-four R/M HNSCC patients who received either nivolumab or pembrolizumab between January 2014 and May 2018 at Johns Hopkins were identified retrospectively. Pretreatment blood counts in patients with and without clinical benefit from PD1 inhibitors were compared. Time-to-progression analyses were performed by dichotomizing the study cohort with the threshold of ALC 600 cells/μl, which is approximately 1.5 standard deviations away from treatment-naïve baseline mean.
Patients with lower ALC appeared to have significantly less clinical benefit from anti-PD1 therapy. Those patients with pretreatment ALC < 600 cells/μl also had shorter PFS than patients with pretreatment ALC ≥ 600 cells/μl (median PFS 60 days vs. 141 days, p < 0.05). These results were consistent with multivariate proportional hazards analyses demonstrating significant association with progression. These observations were further supported by an expansion cohort analysis incorporating additional fourteen R/M HNSCC patients who received other checkpoint immunotherapy regimens at our institution.
This study for the first time demonstrates that pretreatment ALC is significantly associated with response to PD1 inhibitors in R/M HNSCC patients.
We previously demonstrated an association between decreased
expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate ...the clinical relevance of SMAD4 loss in HNSCC.
SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high
mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines
and
Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in
-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that
depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model
We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss.
Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.
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High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity ...and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked ...condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity.
We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except
and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation.
Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity.
Validated high-fidelity identification of different variant types-especially for diseases with complicated molecular genetics-maximizes at-risk couple detection.
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