Publications by authors named "William N William"

95 Publications

Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer.

Nat Commun 2021 08 19;12(1):5045. Epub 2021 Aug 19.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Radiographic imaging is the standard approach for evaluating the disease involvement of lymph nodes in patients with operable NSCLC although the impact of neoadjuvant immune checkpoint inhibitors (ICIs) on lymph nodes has not yet been characterized. Herein, we present an ad hoc analysis of the NEOSTAR trial (NCT03158129) where we observed a phenomenon we refer to as "nodal immune flare" (NIF) in which patients treated with neoadjuvant ICIs demonstrate radiologically abnormal nodes post-therapy that upon pathological evaluation are devoid of cancer and demonstrate de novo non-caseating granulomas. Abnormal lymph nodes are analyzed by computed tomography and F-fluorodeoxyglucose positron emission tomography/computer tomography to evaluate the size and the maximum standard uptake value post- and pre-therapy in NEOSTAR and an independent neoadjuvant chemotherapy cohort. NIF occurs in 16% (7/44) of patients treated with ICIs but in 0% (0/28) of patients after neoadjuvant chemotherapy. NIF is associated with an inflamed nodal immune microenvironment and with fecal abundance of genera belonging to the family Coriobacteriaceae of phylum Actinobacteria, but not with tumor responses or treatment-related toxicity. Our findings suggest that this apparent radiological cancer progression in lymph nodes may occur due to an inflammatory response after neoadjuvant immunotherapy, and such cases should be evaluated by pathological examination to distinguish NIF from true nodal progression and to ensure appropriate clinical treatment planning.
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http://dx.doi.org/10.1038/s41467-021-25188-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376947PMC
August 2021

Impact of the COVID-19 Pandemic on Oncology Clinical Research in Latin America (LACOG 0420).

JCO Glob Oncol 2021 04;7:649-658

Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil.

Purpose: COVID-19 has affected cancer care worldwide. Clinical trials are an important alternative for the treatment of oncologic patients, especially in Latin America, where trials can be the only opportunity for some of them to access novel and, sometimes, standard treatments.

Methods: This was a cross-sectional study, in which a 22-question survey regarding the impact of the COVID-19 pandemic on oncology clinical trials was sent to 350 representatives of research programs in selected Latin American institutions, members of the Latin American Cooperative Oncology Group.

Results: There were 90 research centers participating in the survey, with 70 of them from Brazil. The majority were partly private or fully private (n = 77; 85.6%) and had confirmed COVID-19 cases at the institution (n = 57; 63.3%). Accruals were suspended at least for some studies in 80% (n = 72) of the responses, mostly because of sponsors' decision. Clinical trials' routine was affected by medical visits cancelation, reduction of patients' attendance, reduction of other specialties' availability, and/or alterations on follow-up processes. Formal COVID-19 mitigation policies were adopted in 96.7% of the centers, including remote monitoring and remote site initiation visits, telemedicine visits, reduction of research team workdays or home office, special consent procedures, shipment of oral drugs directly to patients' home, and increase in outpatient diagnostic studies. Importantly, some of these changes were suggested to be part of future oncology clinical trials' routine, particularly the ones regarding remote methods, such as telemedicine.

Conclusion: To our knowledge, this was the first survey to evaluate the impact of COVID-19 on Latin American oncology clinical trials. The results are consistent with surveys from other world regions. These findings may endorse improvements in clinical trials' processes and management in the postpandemic period.
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http://dx.doi.org/10.1200/GO.20.00663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162498PMC
April 2021

Immune evasion in HPV head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss.

Proc Natl Acad Sci U S A 2021 May;118(19)

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3 and CD8 T cell microenvironments in precancer (mostly CD3, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and - codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.
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http://dx.doi.org/10.1073/pnas.2022655118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126856PMC
May 2021

Overcoming Resistance to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinomas.

Front Oncol 2021 5;11:596290. Epub 2021 Mar 5.

Centro de Oncologia, Hospital BP, A Beneficência Portuguesa de São Paulo, São Paulo, Brazil.

Preclinical data suggest that head and neck squamous cell carcinomas (HNSCC) may evade immune surveillance and induce immunosuppression. One mechanism of immune evasion involves the expression of programmed death ligand-1 (PD-L1) in tumor and immune cells, which is, to date, the only biomarker routinely used in clinical practice to select patients with advanced HNSCCs more likely to benefit from anti-PD-1 therapy. Nonetheless, PD-L1 expression alone incompletely captures the degree of sensitivity of HNSCCs to PD-1 inhibitors. Most patients exposed to anti-PD-1 antibodies do not respond to therapy, suggesting the existence of mechanisms of resistance to immunotherapy. Furthermore, patients that initially respond to PD-1 inhibitors will eventually develop acquired resistance to immunotherapy through mechanisms that have not yet been completely elucidated. In this article, we will provide an overview of the immune landscape of HNSCCs. We will briefly describe the clinical activity of inhibitors of the PD-1/PD-L1 axis in this disease, as well as biomarkers of benefit from these agents that have been identified so far. We will review pre-clinical and clinical work in cancers in general, and in HNSCCs specifically, that have characterized the mechanisms of and acquired resistance to immunotherapy. Lastly, we will provide insights into novel strategies under investigation to overcome resistance to immune checkpoint inhibitors.
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http://dx.doi.org/10.3389/fonc.2021.596290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973277PMC
March 2021

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Nat Med 2021 03 18;27(3):504-514. Epub 2021 Feb 18.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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http://dx.doi.org/10.1038/s41591-020-01224-2DOI Listing
March 2021

A Phase 1b trial of prexasertib in combination with chemoradiation in patients with locally advanced head and neck squamous cell carcinoma.

Radiother Oncol 2021 04 9;157:203-209. Epub 2021 Feb 9.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.

Background And Purpose: This study explored the feasibility of safely combining prexasertib, with cisplatin-radiotherapy (Part A) or cetuximab-radiotherapy (Part B) in patients with previously untreated, locoregionally advanced head and neck squamous cell carcinoma (HNSCC).

Materials And Methods: Escalating doses of prexasertib were administered in each combination using a modified Time-to-Event Continual Reassessment Method. Pharmacokinetic (PK) analysis was performed using standard non-compartmental methods of analysis. Antitumor activity was evaluated using RECIST version 1.1.

Results: In Part A, 7 patients received 20 mg/m prexasertib and cisplatin-radiotherapy. This dose exceeded the maximum tolerated dose (MTD); no other prexasertib dose was assessed. In Part B, 18 patients received prexasertib (20-40 mg/m) and cetuximab-radiotherapy. The 30 mg/m dose of prexasertib was determined as the MTD. Febrile neutropenia was the dose-limiting toxicity in each arm. Most common treatment-emergent adverse events with both combinations were neutropenia, thrombocytopenia, dysphagia, stomatitis, dry mouth, anemia, radiation skin injury [reported term radiation dermatitis], and nausea. PK of prexasertib was consistent with previously published data following prexasertib monotherapy. Overall response rate in Parts A and B was 71.4% and 83.3%, respectively. The small number of patients and follow-up limits the interpretation of efficacy data.

Conclusion: This study did not establish a safe dose of cisplatin-radiotherapy. However, it demonstrates the proof-of-principle that prexasertib could be safely combined with cetuximab-radiotherapy. These data will provide the basis to leverage the potential radio-sensitization properties of a CHK1 inhibitor in combination with radiation or other targeted agents in a variety of therapeutic settings.
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http://dx.doi.org/10.1016/j.radonc.2021.01.032DOI Listing
April 2021

Impact of the COVID-19 Pandemic on Physicians Working in the Head and Neck Field.

Int Arch Otorhinolaryngol 2021 Jan 1;25(1):e150-e159. Epub 2021 Feb 1.

Department of Head and Neck Surgery, Instituto do Câncer do Estado de São Paulo (Icesp), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

 With the COVID-19 pandemic, the clinical practice of physicians who work in the head and neck field in Brazil dropped dramatically. The sustained impact of the pandemic is not known.  An anonymous online survey was distributed to Brazilian otolaryngologists, head and neck surgeons, medical and radiation oncologists, asking about their clinical practice in the third to fourth months of the pandemic.  The survey was completed by 446 specialists. About 40% reported reduction of more than 75% in outpatient care. A reduction of 90% to 100% in airway endoscopies was reported by 50% of the responders, and the same rate of reduction regarding surgeries (pediatric or nasosinusal) was reported by 80% of them. Family income decreased by 50%, and the psychological burden on physicians was considerable. The availability of personal protective equipment and safety precautions were limited, especially in the public sector.  COVID-19 is still impacting the head and neck field, and safety concerns may hinder the prompt resumption of elective care.
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http://dx.doi.org/10.1055/s-0040-1722254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851365PMC
January 2021

Immune manifestations with checkpoint inhibitors in a single Brazilian center: experience and literature review.

Future Sci OA 2020 Nov 23;7(1):FSO655. Epub 2020 Nov 23.

Oncology Center & Center for Autoimmune Diseases at Hospital A Beneficência Portuguesa, São Paulo, Brazil.

Objectives: The presence of autoimmune events were recorded in patients receiving immune checkpoint inhibitors.

Materials & Methods: Retrospective study in patients receiving immune checkpoint inhibitors (ICIs) during the period of 2012-2019.

Results: A total of 554 patients received ICIs of which 123 developed an immune related adverse event. Twenty one (17%) with toxicity were identified as having a pre-existing autoimmune disease and 88 required treatment with corticosteroids or hormone replacement. Thirty two (26%) out of 123 had to temporarily discontinue ICIs due to autoimmune manifestations. Endocrine and skin manifestations were the most prevalent immune disorders in our cohort. In melanoma better efficacy was seen in patients with immune toxicity.

Conclusion: Autoimmune diseases appear in patients receiving ICIs in this real world experience. Our results differ from other series on the frequency of autoimmunity. Complete discontinuation of ICIs due to autoimmunity was rare.
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http://dx.doi.org/10.2144/fsoa-2020-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787148PMC
November 2020

Targeting of CD40 and PD-L1 Pathways Inhibits Progression of Oral Premalignant Lesions in a Carcinogen-induced Model of Oral Squamous Cell Carcinoma.

Cancer Prev Res (Phila) 2021 Mar 4;14(3):313-324. Epub 2020 Dec 4.

Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1-knockout (PD-L1) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting. PREVENTION RELEVANCE: PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0418DOI Listing
March 2021

F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer.

Cancer Immunol Immunother 2020 Aug 16;69(8):1519-1534. Epub 2020 Apr 16.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX, 77030, USA.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUV, SUV, SUV, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated F-FDG SUV was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other F-FDG PET parameters. Increased SUV was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57 cell density, and increased T cell exhaustion gene signature. Elevated SUV identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that F-FDG SUV has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.
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http://dx.doi.org/10.1007/s00262-020-02560-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997043PMC
August 2020

A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel, and Nintedanib for Resectable Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 07 19;26(14):3525-3536. Epub 2020 Mar 19.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non-small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint.

Patients And Methods: Eligible patients had stage IB (≥4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m), docetaxel (75 mg/m) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%.

Results: Twenty-one patients (stages I/II/III, = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%-32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%-54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related grade 3-4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3 and cytotoxic CD3CD8 T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm, = 0.048; 142.3 vs. 35.6 cells/mm, = 0.018).

Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446232PMC
July 2020

PI3-kinase pathway biomarkers in oral cancer and tumor immune cells.

Head Neck 2019 03 16;41(3):615-622. Epub 2018 Dec 16.

The University of Texas MD Anderson Cancer Center, Department of Thoracic/Head and Neck Medical Oncology.

Background: This study investigated the hypothesis that phosphoinositide 3-kinase (PI3-kinase) pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence outcomes of patients with surgically treated oral tongue squamous cell carcinomas (SCC).

Methods: We constructed tissue microarrays containing 123 oral tongue SCC samples and performed immunohistochemistry using antibodies against 7 PI3-kinase pathway markers: phosphatase and tensin homolog (PTEN), Akt, p-Akt, mammalian target of rapamycin (mTOR), phosphorylated-mammalian target of rapamycin (p-mTOR), survivin, and Ki-67). Expression levels in cancer cells or tumor infiltrating immune cells were correlated with outcomes.

Results: Higher levels of PTEN expression in immune cells were significantly associated with improved recurrence-free survival (heart rate (HR) = 0.45, 95% confidence interval (CI) 0.23-0.90, P = .03), and overall survival (HR = 0.34, 95% CI 0.15-0.76, P = .01) on univariate and multicovariate models.

Conclusions: We identified a novel, negative prognostic role of PI3-kinase activation (as determined by PTEN loss) in oral SCC infiltrating immune cells. These findings could be relevant for clinical development of PI-3 kinase inhibitors for this disease.
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http://dx.doi.org/10.1002/hed.25350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382518PMC
March 2019

Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in -Mutant NSCLC.

Clin Cancer Res 2018 12 18;24(24):6195-6203. Epub 2018 Sep 18.

Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of -mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.

Experimental Design: Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.

Results: In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, = 0.02).

Conclusions: Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295279PMC
December 2018

Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis.

J Cancer Res Clin Oncol 2018 Nov 21;144(11):2245-2261. Epub 2018 Aug 21.

AstraZeneca, One MedImmune Way, Gaithersburg, MD, USA.

Purpose: Classical clinical endpoints [e.g., objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)] may not be appropriate for immune checkpoint blockers (ICBs). We evaluated correlations between these endpoints and overall survival (OS) for surrogacy.

Methods: Randomized controlled trials (RCTs) of solid tumors patients treated with ICBs published between 01/2005 and 03/2017, and congress proceedings (2014-2016) were included. Arm-level analyses measured 6-month PFS rate to predict 18-month OS rate. Comparison-level analyses measured ORR odds ratio (OR), DCR OR, and 6-month PFS hazard ratio (HR) to predict OS HR. A pooled analysis for single-agent ICBs and ICBs plus chemotherapy vs chemotherapy was conducted. Studies of single-agent ICBs vs chemotherapy were separately analyzed.

Results: 27 RCTs involving 61 treatment arms and 10,300 patients were included. Arm-level analysis showed higher 6- or 9-month PFS rates predicted better 18-month OS rates for ICB arms and/or chemotherapy arms. ICB arms had a higher average OS rate vs chemotherapy for all PFS rates. Comparison-level analysis showed a nonsignificant/weak correlation between ORR OR (adjusted R = - 0.069; P = 0.866) or DCR OR (adjusted R = 0.271; P = 0.107) and OS HR. PFS HR correlated weakly with OS HR in the pooled (adjusted R = 0.366; P = 0.005) and single-agent (adjusted R = 0.452; P = 0.005) ICB studies. Six-month PFS HR was highly predictive of OS HR for single-agent ICBs (adjusted R = 0.907; P < 0.001), but weakly predictive in the pooled analysis (adjusted R = 0.333; P = 0.023).

Conclusions: PFS was an imperfect surrogate for OS. Predictive value of 6-month PFS HR for OS HR in the single-agent ICB analysis requires further exploration.
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http://dx.doi.org/10.1007/s00432-018-2738-xDOI Listing
November 2018

Randomized phase II trial of cixutumumab alone or with cetuximab for refractory recurrent/metastatic head and neck squamous cell carcinoma.

Oral Oncol 2018 07 19;82:83-90. Epub 2018 May 19.

University of Texas M. D. Anderson Cancer Center, Houston, TX, United States. Electronic address:

Objectives: Cixutumumab (CIX) and cetuximab (CET) monoclonal antibodies block ligand-binding to insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) respectively. The objective of this study was to assess the efficacy of CIX alone or combined with CET in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients.

Methods: In this open-label phase II trial, 91 R/M HNSCC patients who progressed within 90 days of platinum-based chemotherapy, were randomized to CIX 10 mg/kg alone or with CET 500 mg/m every 2 weeks. Patients were stratified by prior CET use. The primary endpoint was median progression-free survival (PFS). Exploratory biomarker assessments included relevant markers on archival tumor and serial cytokine/angiogenic-factor profiles in blood.

Results: Forty-seven patients were treated with CIX monotherapy and 44 with combination. The median PFS was 1.9 and 2.0 months and clinical benefit rate (complete or partial responses and stable disease) was 5.9% and 15.3%, respectively. There was no exacerbation of CET toxicity by concurrent CIX exposure. Higher tumor expression of IGF-1 was associated with improved PFS in the CIX + CET arm while increased p-EGFR expression correlated with shorter PFS in patients receiving single agent CIX. Higher serum baseline levels of IGF-1 and IGFBP-3 correlated with improved PFS and overall survival (OS) in the CIX arm. Neither regimen resulted in improved PFS or OS compared to historical data with CET alone.

Conclusion: The results of this study do not support the use of cixutumumab alone or with cetuximab in unselected patients with R/M HNSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2018.05.014DOI Listing
July 2018

Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches.

J Immunother Cancer 2018 06 6;6(1):48. Epub 2018 Jun 6.

Department of Translational Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Blvd, Houston, TX, 77030, USA.

Background: The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT).

Methods: We analyzed immune markers in formalin-fixed, paraffin-embedded tumor tissues resected from 112 patients with stage II/III NSCLC, including 61 non-NCT (adenocarcinoma [ADC] = 33; squamous cell carcinoma [SCC] = 28) and 51 NCT (ADC = 31; SCC = 20). We used multiplex immunofluorescence to identify and quantify immune markers grouped into two 6-antibody panels: panel 1 included AE1/AE3, PD-L1, CD3, CD4, CD8, and CD68; panel 2 included AE1/AE3, PD1, granzyme B, FOXP3, CD45RO, and CD57.

Results: PD-L1 expression was higher (> overall median) in NCT cases (median, 19.53%) than in non-NCT cases (median, 1.55%; P = 0.022). Overall, density of TAICs was higher in NCT-NSCLCs than in non-NCT-NSCLCs. Densities of CD3+ cells in the tumor epithelial compartment were higher in NCT-ADCs and NCT-SCCs than in non-NCT-ADCs and non-NCT-SCCs (P = 0.043). Compared with non-NCT-SCCs, NCT-SCCs showed significantly higher densities of CD3 + CD4+ (P = 0.019) and PD-1+ (P < 0.001) cells in the tumor epithelial compartment. Density of CD68+ tumor-associated macrophages (TAMs) was higher in NCT-NSCLCs than in non-NCT-NSCLCs and was significantly higher in NCT-SCCs than in non-NCT-SCCs. In NCT-NSCLCs, higher levels of epithelial T lymphocytes (CD3 + CD4+) and epithelial and stromal TAMs (CD68+) were associated with better outcome in univariate and multivariate analyses.

Conclusions: NCT-NSCLCs exhibited higher levels of PD-L1 expression and T-cell subset regulation than non-NCT-NSCLCs, suggesting that NCT activates specific immune response mechanisms in lung cancer. These results suggest the need for clinical trials and translational studies of combined chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC.
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http://dx.doi.org/10.1186/s40425-018-0368-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989476PMC
June 2018

Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma.

Clin Cancer Res 2018 07 11;24(14):3263-3272. Epub 2018 Apr 11.

Sarah Cannon Research Institute, Nashville, Tennessee.

Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Patients were given prexasertib 105 mg/m as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed. Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress. Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m was confirmed as the recommended phase II dose. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050086PMC
July 2018

Met Receptor Tyrosine Kinase and Chemoprevention of Oral Cancer.

J Natl Cancer Inst 2018 03;110(3)

UC San Diego Moores Cancer Center, San Diego, CA.

Background: We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).

Methods: We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.

Results: The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001).

Conclusion: Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.
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http://dx.doi.org/10.1093/jnci/djx186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946820PMC
March 2018

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial.

Cancer 2018 05 26;124(10):2169-2173. Epub 2018 Mar 26.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Cutaneous squamous cell carcinoma (CSCC) is a very common malignancy in which most patients present with localized disease. Recurrent and metastatic disease is rare, and there is no standard therapy. These tumors frequently overexpress the epidermal growth factor receptor (EGFR). We conducted a phase 2 trial to determine the response rate to therapy with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with locoregionally recurrent or metastatic CSCC that was not amenable to curative treatment (NCT01198028).

Methods: Eligible patients had CSCC not amenable to curative intent therapy. Patients who had previously received anti-EGFR targeted therapy were excluded. All patients received oral therapy with erlotinib 150 mg daily. Response was assessed every 8 weeks, and treatment continued until progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate according to RECIST 1.1 criteria.

Results: A total of 39 patients received treatment during the trial; 29 of these patients were evaluable for response. The overall response rate was 10% (3/29); all responses were partial responses. The disease control rate (partial response + stable disease) was 72% (21/29). The median progression-free survival was 4.7 months (95% confidence interval, 3.5-6.2 months); the median overall survival was 13 months (95% confidence interval, 8.4-20.5 months). No unexpected toxicities were seen.

Conclusion: Erlotinib therapy was feasible for most patients with incurable CSCC and was associated with expected toxicities. However, only a modest response rate of 10% was observed. Further study of EGFR tyrosine kinase inhibitors in this patient population is not warranted. Cancer 2018;124:2169-73. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935588PMC
May 2018

Multiregion gene expression profiling reveals heterogeneity in molecular subtypes and immunotherapy response signatures in lung cancer.

Mod Pathol 2018 06 6;31(6):947-955. Epub 2018 Feb 6.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Intra-tumor heterogeneity may be present at all molecular levels. Genomic intra-tumor heterogeneity at the exome level has been reported in many cancer types, but comprehensive gene expression intra-tumor heterogeneity has not been well studied. Here, we delineated the gene expression intra-tumor heterogeneity by exploring gene expression profiles of 35 tumor regions from 10 non-small cell lung cancer tumors (three or four regions/tumor), including adenocarcinoma, squamous cell carcinoma, large-cell carcinoma, and pleomorphic carcinoma of the lung. Using Affymetrix Gene 1.0 ST arrays, we generated the gene expression data for every sample. Inter-tumor heterogeneity was generally higher than intra-tumor heterogeneity, but some tumors showed a substantial level of intra-tumor heterogeneity. The analysis of various clinically relevant gene expression signatures including molecular subtype, epithelial-to-mesenchymal transition, and anti-PD-1 resistance signatures also revealed heterogeneity between different regions of the same tumor. The gene expression intra-tumor heterogeneity we observed was associated with heterogeneous tumor microenvironments represented by stromal and immune cells infiltrated. Our data suggest that RNA-based prognostic or predictive molecular tests should be carefully conducted in consideration of the gene expression intra-tumor heterogeneity.
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http://dx.doi.org/10.1038/s41379-018-0029-3DOI Listing
June 2018

Single Arm, Phase II Study of Cisplatin, Docetaxel, and Erlotinib in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas.

Oncologist 2018 05 25;23(5):526-e49. Epub 2018 Jan 25.

Levine Cancer Institute, Charlotte, North Carolina, USA.

Lessons Learned: The combination of cisplatin, docetaxel, and erlotinib as frontline treatment for recurrent and/or metastatic head and neck squamous cell carcinomas led to a response rate of 62%.This result exceeded the prespecified target response rate of 50% and represented an improvement compared with historical controls.This regimen warrants further investigation.

Background: The epidermal growth factor receptor (EGFR) plays a key role in the carcinogenesis of head and neck squamous cell carcinomas (HNSCC). We conducted this clinical study to test the hypothesis that the addition of erlotinib to first-line cisplatin and docetaxel for patients with recurrent and/or metastatic HNSCC would yield a response rate of at least 50%, representing an improvement from historical controls.

Methods: Patients with recurrent and/or metastatic HNSCC, with at least one measurable lesion, no prior chemotherapy for recurrent and/or metastatic disease, prior combined modality therapy completed >6 months before enrollment, and performance status ≤2 were treated with cisplatin, docetaxel, and erlotinib for up to six cycles, followed by maintenance erlotinib until disease progression. The primary endpoint was response rate.

Results: Fifty patients were enrolled (42 male, 12 never smokers, 19 with oropharynx cancer). The median number of cycles was five; 31 patients initiated maintenance erlotinib; 14 patients required erlotinib dose reductions. The objective response rate was 62%, and the median progression-free and overall survival were 6.1 and 11.0 months, respectively. Toxicity profiles were consistent with the known side effects of the study drugs.

Conclusion: The study met its primary endpoint and improved response rates compared with historical controls. The findings support further evaluation of the regimen for recurrent and/or metastatic HNSCCs.
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http://dx.doi.org/10.1634/theoncologist.2017-0661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947451PMC
May 2018

Induction Cisplatin Docetaxel Followed by Surgery and Erlotinib in Non-Small Cell Lung Cancer.

Ann Thorac Surg 2018 Feb 6;105(2):418-424. Epub 2017 Dec 6.

Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background: Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib.

Methods: Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m, docetaxel 75 mg/m every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384).

Results: Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival.

Conclusions: Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies.
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http://dx.doi.org/10.1016/j.athoracsur.2017.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783769PMC
February 2018

Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Lung Cancer 2017 10 3;112:90-95. Epub 2017 Aug 3.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX, 77030, USA. Electronic address:

Introduction: Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in overall response rate (ORR) to chemotherapy after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if single-agent chemotherapy (3rd-line or beyond) would yield improved ORR when given after exposure to programmed death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer (NSCLC).

Materials And Methods: We queried the Thoracic GEMINI database of MD Anderson Cancer Center for patients treated between 06/12 and 11/16 who received at least one single-agent chemotherapy as 3rd-line or beyond, following progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS).

Results: Out of 306 anti-PD1-treated patients registered in the database, 28 met eligibility criteria - 54% were male, median age was 66 years, 82% had adenocarcinoma, and 71% were former/current smokers. The anti-PD1 and single-agent chemotherapy most commonly used were nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis was the only factor associated with response to single-agent chemotherapy on univariate analysis (p<0.05).

Conclusion: In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line platinum-based chemotherapy. Further investigation of a possible immunotherapy-induced chemosensitization effect is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2017.07.034DOI Listing
October 2017

Distinct pattern of TP53 mutations in human immunodeficiency virus-related head and neck squamous cell carcinoma.

Cancer 2018 Jan 20;124(1):84-94. Epub 2017 Oct 20.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Human immunodeficiency virus-infected individuals (HIVIIs) have a higher incidence of head and neck squamous cell carcinoma (HNSCC), and clinical and histopathological differences have been observed in their tumors in comparison with those of HNSCC patients without a human immunodeficiency virus (HIV) infection. The reasons for these differences are not clear, and molecular differences between HIV-related HNSCC and non-HIV-related HNSCC may exist. This study compared the mutational patterns of HIV-related HNSCC and non-HIV-related HNSCC.

Methods: The DNA of 20 samples of HIV-related HNSCCs and 32 samples of non-HIV-related HNSCCs was sequenced. DNA libraries covering exons of 18 genes frequently mutated in HNSCC (AJUBA, CASP8, CCND1, CDKN2A, EGFR, FAT1, FBXW7, HLA-A, HRAS, KEAP1, NFE2L2, NOTCH1, NOTCH2, NSD1, PIK3CA, TGFBR2, TP53, and TP63) were prepared and sequenced on an Ion Personal Genome Machine sequencer. DNA sequencing data were analyzed with Ion Reporter software. The human papillomavirus (HPV) status of the tumor samples was assessed with in situ hybridization, the MassARRAY HPV multiplex polymerase chain reaction assay, and p16 immunostaining. Mutation calls were compared among the studied groups.

Results: HIV-related HNSCC revealed a distinct pattern of mutations in comparison with non-HIV-related HNSCC. TP53 mutation frequencies were significantly lower in HIV-related HNSCC. Mutations in HIV+ patients tended to be TpC>T nucleotide changes for all mutated genes but especially for TP53.

Conclusions: HNSCC in HIVIIs presents a distinct pattern of genetic mutations, particularly in the TP53 gene. HIV-related HNSCC may have a distinct biology, and an effect of the HIV virus on the pathogenesis of these tumors should not be ruled out. Cancer 2018;124:84-94. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785080PMC
January 2018

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions.

Cancer Prev Res (Phila) 2017 Dec 10;10(12):684-693. Epub 2017 Oct 10.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti-PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8 and CD4 T cells and the accumulation of CTLA-4 T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFNγ, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti-PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti-PD-1. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716880PMC
December 2017

Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial.

J Am Acad Dermatol 2017 Dec 28;77(6):1110-1113.e2. Epub 2017 Sep 28.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.

Background: Preclinical data demonstrate a key role for the epidermal growth factor receptor (EGFR) in the carcinogenesis of cutaneous squamous cell carcinomas (CSCCs). There are, however, limited data on the efficacy of EGFR inhibitors in incurable, recurrent, and/or metastatic CSCC.

Objective: To determine the response rate to gefitinib in patients with CSCC not amenable to curative therapy including surgery or radiation.

Methods: This was a single-arm phase II study. A total of 40 patients were treated with gefitinib, 250 mg orally daily, until disease progression or intolerable toxicities. The prespecified target response rate of interest was 20%.

Results: The overall response rate was 16% (95% confidence interval, 0.06-0.32; 6 partial responses in 37 evaluable patients). An additional 13 patients (35%) had stable disease at 8 weeks. The median durations of response and progression-free survival were 31.4 months (95% confidence interval, 3.91-not applicable) and 3.8 months (95% confidence interval, 2.2-5.7), respectively. The side effect profile was consistent with the previous experience with gefitinib in other tumor types.

Limitations: This was a single-institution, single-arm study. The prespecified target response rate was not met.

Conclusion: Gefitinib demonstrated modest activity in incurable CSCC, with a favorable adverse event profile.
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http://dx.doi.org/10.1016/j.jaad.2017.07.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685879PMC
December 2017

Prognostic biomarkers in patients with human immunodeficiency virus-positive disease with head and neck squamous cell carcinoma.

Head Neck 2017 12 25;39(12):2433-2443. Epub 2017 Sep 25.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.

Background: We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer).

Methods: Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables.

Results: Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site (P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome (P = .001).

Conclusion: Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies.
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http://dx.doi.org/10.1002/hed.24911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808949PMC
December 2017

Outcomes of oral cavity cancer patients treated with surgery followed by postoperative intensity modulated radiation therapy.

Oral Oncol 2017 09 16;72:90-97. Epub 2017 Jul 16.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Objectives: Although treatment paradigms have not changed significantly, radiotherapy, surgery, and imaging techniques have improved, leading us to investigate oncologic and survival outcomes for oral cavity squamous cell cancer (OCSCC) patients treated with surgery followed by postoperative IMRT.

Material And Methods: Records of patients with pathological diagnosis of OCSCC treated between 2000 and 2012 were retrospectively reviewed. Patients' demographic, disease, and treatment criteria were extracted. Kaplan-Meier method was used to calculate survival curves.

Results: Two hundred eighty-nine patients were analyzed. Median follow-up was 35months. Two hundred sixty-eight had neck dissections (93%), of which 66% had nodal involvement, and 51% of those positive dissections had extracapsular extension. Forty patients received induction chemotherapy and 107 received concurrent chemotherapy. Median dose to high risk clinical target volume was 60Gy/30 fractions. The 5-year locoregional control and overall survival rates were 76% and 57%, respectively. Tumors with >1.5cm depth of invasion had significantly higher risk of local failure compared with ≤1.5cm (p<0.001). In multivariate analysis, positive and no neck dissection (p=0.01), positive lymphovascular invasion (p=0.006) and >1.5cm depth of invasion (p=0.003) were independent predictors of poorer survival.

Conclusions: Disease outcomes were consistent with historical data and did not appear compromised by the use of IMRT.
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http://dx.doi.org/10.1016/j.oraloncology.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796661PMC
September 2017

TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence.

Cancer Discov 2017 10 21;7(10):1088-1097. Epub 2017 Jul 21.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity. The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628137PMC
October 2017

Facilitating anaplastic thyroid cancer specialized treatment: A model for improving access to multidisciplinary care for patients with anaplastic thyroid cancer.

Head Neck 2017 07 28;39(7):1291-1295. Epub 2017 Apr 28.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Several treatment trials are available, but the number of eligible patients to participate is very low because of the rarity and aggressiveness of the disease.

Methods: Facilitating Anaplastic Thyroid Cancer Specialized Treatment (FAST) is a quality improvement project aimed at decreasing time from referral to disposition (scheduling of first appointment) to our institution. After identifying reasons for delays, we created a new process flow specifically for patients with ATC allowing patients to be scheduled immediately.

Results: Historical data revealed a mean referral to disposition time for patients with ATC of 8.7 days before our intervention. After the intervention, the mean referral to disposition time was reduced to 0.5 days. Participation in treatment trials for all patients with ATC was 34%.

Conclusion: Since the implementation of FAST, the access time has decreased and the number of successful referrals for ATC has increased significantly.
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http://dx.doi.org/10.1002/hed.24784DOI Listing
July 2017
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