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Purpose: We sought to understand clinician-level barriers to providing HPV vaccination to survivors of childhood and young adult cancers (CYACs). Methods: We conducted 30-minute qualitative intervi...

Background Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. Methods In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. Results Forty‐eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty‐five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. Conclusion CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. Level of evidence 1b; individual prospective cohort study., Circulating tumors cells (CTCs) were detected in 6/25 patients with locoregionally advanced disease (24%) and 4/11 with metastatic squamous cell carcinoma of the head and neck (36%). On univariate analysis, smoking was associated with CTCs.

Frontiers in oncology 11, 630953 (2021). doi:10.3389/fonc.2021.630953 special issue: "Advances in Mathematical and Computational Oncology, Volume II", Published by Frontiers Media, Lausanne

Aims The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients. Methods We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts. Results We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy. Conclusion CNAs in the 21–27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

Simple Summary As the leading human papillomavirus (HPV)-related cancer, oropharyngeal cancer places a significant burden on patients, families, and health systems. Techniques to easily and quickly test people for HPV through non-invasive means (saliva or blood tests) could, in principle, help us better understand this disease, prevent it, and treat it. However, there is currently no standardized methodology for testing saliva or blood for HPV, and such testing is not a part of routine clinical practice. In this review, we discuss and compare some of the collection and testing platforms that researchers have studied to date. We also evaluate the potential strengths and limitations of these technologies for addressing unmet needs in specific clinical contexts. Abstract The burden of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has risen, now representing the most common HPV-related malignancy. For years, researchers have explored the utility of measuring HPV-related markers from mouth, throat, and blood samples, often with the aim of gathering more information about an existing HPV-related tumor in a given patient. We review the widely varying methods for collecting and testing saliva and blood samples and offer guidance for standardizing these practices. We then review an array of clinical contexts in which non-invasive testing holds the most promise for potentially addressing unmet needs. In particular, such testing could help clinicians and researchers monitor the effects of vaccination and treatment. Meanwhile, due to the currently incomplete understanding of how carrying HPV relates to infection and subsequent oncogenesis, non-invasive testing methods may not be suitable for the screening setting at this time.

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.

Background Merkel cell carcinoma is a rare cancer for which the standard-of-care is immune checkpoint blockade in the recurrent/metastatic setting. However, immunotherapy is not effective in all patients. A greater understanding of molecular mechanisms and potential predictive biomarkers are unmet needs for clinicians and researchers. Methods We undertook a retrospective analysis of 45 patients treated at our institution from 2013 to 2020 to understand the clinical and genomic correlates of clinical benefit from immunotherapy. We gathered data from the electronic health record, including provider notes and results from our institutional next-generation sequencing panel of actionable genomic alterations. Results Our cohort predominantly included individuals with stage III disease at diagnosis and stage IV disease at the time of diagnosis of recurrent/metastatic disease. Most patients received immunotherapy in the first line. 43% of patients experienced an objective response to immunotherapy (median duration of response 24.2 months, 95% confidence interval 8.8-not reached) and median overall survival was 15.5 months (95% confidence interval 9.0–28.7) (median follow-up 25.2 months). Lower stage at diagnosis of primary disease and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p=0.04 for stage; odds ratio 0.75, p=0.05 for disease-free interval). The most common single-nucleotide variants among the sequenced cohort were those in TP53 (59%) and RB1 (51%). Single-nucleotide variants in the ARID2 and NTRK1 genes were associated with response without Bonferroni correction (p=0.05), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes (figure 1). Conclusions Patients with shorter disease-free interval after definitive treatment may be particularly suitable candidates for immunotherapy. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample. Acknowledgements AJK receives research funding from the American Society of Hematology and from the Pritzker School of Medicine. Ethics Approval The study was approved by the Dana-Farber institutional review board, protocol numbers 11–104 and 17–000. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as first-line treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.

BackgroundInterleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking.MethodsWe conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel.FindingsA total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75·0% vs. 34·2%, p = 0·001) and CRP decline (86·2% vs. 14·3%, p < 0·001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related (p=0·80 and p=0·10, respectively). Within the 28-day follow-up, 5 (15·6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15·6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls.InterpretationLow-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.FundingClinicalTrials.gov number NCT04331795. Study infrastructure was supported by NIH CTSA UL1 TR000430.Research in ContextEvidence before this studyMany patients with novel coronavirus disease 2019 (Covid-19) develop acute lung injury and hypoxic respiratory failure possibly due to a hyperinflammatory state similar to the cytokine release syndrome that occurs as a complication of chimeric antigen receptor T-cell therapy. Interleukin-6 (IL-6) has been implicated in both processes, leading to the hypothesis that patients with Covid-19 may benefit from IL-6 axis-directed therapies such as the IL-6 receptor-blocking monoclonal antibody tocilizumab. No dose-finding studies have been performed for tocilizumab in the setting of Covid-19.Added value of this studyThis prospective phase 2 clinical trial is, to our knowledge, the first to evaluate low-dose tocilizumab in patients with Covid-19 and the first to evaluate the effect of tocilizumab on anti-SARS-CoV-2 antibody response.Implications of all the available evidenceThe COVIDOSE study, together with retrospective and real-world evidence studies demonstrating the efficacy of tocilizumab, suggests that low-dose tocilizumab is a potential treatment for hyperinflammation among patients with Covid-19 and merits randomized, controlled testing in this patient population.

OBJECTIVES To identify molecular characteristics of keratosis of unknown significance and to nominate pathways of molecular progression to oral cancer. Our work could provide a rationale for monitoring and treating these lesions definitively. METHODS Patients with oral leukoplakia were eligible for our prospective observational study. We correlated alterations in cancer-associated genes with clinical and histopathologic variables (keratosis of unknown significance vs. moderate-to-severe dysplasia) and compared these alterations to a previously molecularly characterized oral cancer population. RESULTS Of 20 enrolled patients, 13 (65%) had evidence of keratosis of unknown significance, while seven (35%) had dysplasia. Nine patients (45%) developed oral cancer (4/13 with keratosis of unknown significance, 5/7 with dysplasia). At a median follow-up of 67 (range 22-144) months, median overall survival was significantly shorter for patients with dysplasia (hazard ratio 0.11, p = .02). KMT2C and TP53 alterations were most frequent (75% and 35%, respectively). There were molecular similarities between keratosis of unknown significance and dysplasia patients, with no significant differences in mutational frequency among genes with ≥15% rate of alteration. CONCLUSIONS Among patients with leukoplakia, both patients with keratosis of unknown significance and patients with dysplasia developed oral cancer. Molecular alterations between these two groups were similar at this sample size.

e18828 Background: Trastuzumab-related costs of human epidermal growth factor receptor 2 (HER2) positive breast cancer treatment are significant, approaching $70,000 per patient in the adjuvant setting alone. Recently developed population pharmacokinetic models demonstrate that therapeutic levels of trastuzumab are maintained despite decreased maintenance dose or dose frequency, potentially improving trastuzumab’s value proposition. In this observational study, we evaluate the potential patient- and health system-level financial implications of low-dose trastuzumab. Methods: We identified 196 individuals who received treatment for HER2-positive breast cancer with trastuzumab or its biosimilars at a single urban comprehensive cancer center between January 1, 2017 and October 31, 2019. We estimate, using publicly available information, patient-experienced out-of-pocket costs using deterministic modeling under different conditions corresponding to changes in dosing practices, geographic site of trastuzumab administration, patient employment status, intent of treatment, and billing procedures, as well as Medicare cost-savings estimates. Results: Both reducing the maintenance dose of trastuzumab from the FDA-labeled dose of 6 mg/kg to 4 mg/kg Q3W and reducing maintenance dose frequency of trastuzumab from 6 mg/kg Q3W to Q4W were each associated with significant patient savings on drug- and administration-related out-of-pocket costs. Depending on billing practice and clinical scenario, patient savings as a percentage of total costs were 9-20% (neoadjuvant), 17-22% (adjuvant), and 14-19% (metastatic) with 6 mg/kg Q4W dosing. Similarly, 4 mg/kg Q3W dosing had savings of 15-25% (neoadjuvant), 19-28% (adjuvant), and 13-28% (metastatic). Utilization of off-label dosing regimens could result in $2.69 billion USD in annual Medicare spending on trastuzumab, an estimated savings of $670-810 million USD. Conclusions: Meaningful patient-level and system-level financial savings in the treatment of HER2-positive breast cancer can be achieved using pharmacokinetically near-equivalent low-dose or reduced frequency maintenance trastuzumab dosing. Given the significant potential savings, further prospective studies aimed at reducing dose or frequency of monoclonal antibodies in the treatment of cancer are warranted.

Given that immune checkpoint inhibitors (ICIs) are now preferred agents in first-line treatment of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), we retrospectively studied outcomes on post-ICI therapies.We collected data from the medical records of 60 patients with R/M SCCHN who received ICIs followed by at least one further line of cytotoxic or biologic therapy at our institution from 2014 to 2019. We also compared outcomes with those of historical trials in the ICI-naïve, second-line or greater setting.Patients who received platinum-based regimens as their post-ICI therapies experienced improved overall response (ORR) (50% versus 10%, p 0.01) and improved overall survival (OS) (15.1 months versus 7.3 months, HR 0.46, p = 0.04) compared to the rest of the cohort. Patients receiving platinum re-challenge were more likely to respond than all other patients in the cohort (OR 8.37, p = 0.01). The ORR for patients on 5-fluorouracil (5-FU)-containing regimens (63%) was also higher than other patients in the cohort (p = 0.03). Immunotherapy-based regimens compared favorably to historical data of first exposure to ICIs (disease control rate 54% versus 36%). Singlet regimens were associated with shorter OS than other regimens (HR = 2.38, p = 0.01).Platinum- and 5-FU-based doublet or triplet regimens may be superior options in the post-ICI setting. Immunotherapy re-challenge following ICI therapy may also be a reasonable option.

6513 Background: Treatment options for aggressive TC are limited. Pre-clinical data suggests efficacy of CTLA-4 plus PD-1 blockade in aggressive RAIR TC. Methods: This investigator initiated phase II study tested N (3mg/kg every 2 weeks) plus I (1mg/kg every 6 weeks) until disease progression or completion of 24 mo of treatment in RAIR differentiated TC including poorly differentiated TC (PDTC) with exploratory cohorts in anaplastic (ATC) and medullary TC (MTC). Radiographic response rate by RECIST v1.1 (CR+PR) was primary endpoint. At least 6 pts with disease response among n=32 DTC provided 84% power to distinguish between a 10% and a 25% RR (one-sided 9% binomial test). Results: Accrual is complete with n=32 patients with DTC, 10 with ATC and 7 with MTC enrolled between October 2017 and May 2019. Thirty-two DTC included: n=17 papillary, n=7 Hurthle, n=4 follicular TC, n=4 PDTC. Among n=49, median (range) age was 65 (30-88), 51% (25/49) were female. To date, in DTC, 3/32 achieved a PR (n=2 Hurthle and n=1 PDTC), 9.4% RR (.95CI:2%-25%). One near complete response has been observed. Among pts w ATC, 3/ 10 profound PR by RECIST occurred (30% RR, .95CI: 7%-65%). Among them, two remain without clear evidence of disease at 26 and 13 mo after treatment start. No PR's were observed in MTC. Most frequent grade 3-4 TRAEs were as expected and included increased lipase (n=8), increased serum amylase (n=4). There was an unexpected number of treatment related adrenal insufficiency (AI) (n=4) which was associated with long PFS (range 10.1—16.4+mo). Conclusions: N+I appears to have considerable activity in ATC. In unselected RAIR DTC, activity was low but responses were seen in PDTC and Hurthle cell TC. Exceptional responses with prolonged remissions were observed. Clinical trial information: NCT03246958 .

While it has been recognized that human papillomavirus-associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.

e18230 Background: Medical insurance coverage is known to correlate with improved long-term (LT) outcomes in head and neck cancers (HNC) patients. However, associations with dental insurance coverage (DI) are not established. Methods: In 2012, we sent surveys to determine DI and LT symptom (Sx) burden (EORTC QLQ-30, National Health and Nutrition Examination Survey Oral Health, and Vanderbilt Head and Neck Sx Survey) to patients who had completed definitive chemoradiotherapy (sequential or concurrent) for locally advanced (LA) HNC at the Dana-Farber Cancer Institute from 2002-2011 (2013 ASCO annual meeting, abstract 9530). In 2019, we retrospectively collected demographic and clinical information from patient charts and publicly available records and correlated these data with 2012 survey data. We used Fisher’s exact tests for association of categorical variables and Student’s t-tests for continuous variables. We used univariate and multivariate Cox proportional hazard modeling for hazard ratios (HRs). Results: Of the 103 survey responders, 84% were male. Most had oropharyngeal (90, 88%) or unknown primary (9, 9%) and 52 (50%) tested positive for human papilloma virus-associated disease (40% not tested). 71 (69%) had DI, while 100 (98%) had medical health insurance. Subjects with DI were diagnosed (Dxed) at a younger age (53 vs. 59, p < 0.01). Stage at Dx did not vary by DI status (p = 0.27). At median follow-up of 10.4 years from Dx (range 2.0 -16.6), recurrence was not associated with DI status (6 (8%) for DI vs. 4 (13%) for no DI, p = 0.27, HR 0.55, 95% CI 0.15-1.93, p = 0.35). We identified 9 subjects (9%) who had died of any cause. Subjects with DI experienced lower mortality from all causes than those without (3% vs. 19%, p = 0.01) and longer median overall survival (OS) (range 4.3 - 16.6 years, HR 0.19, 95% CI 0.05-0.76, p = 0.02) on univariate analysis. The longer OS was not significant when controlling for age and stage at Dx (p = 0.12). DI was also associated with less frequent need for liquid supplements to maintain weight (p = 0.01). Conclusions: In our cohort, DI was associated with Dx at a younger age and longer OS, although future work should consider possible confounding factors such as differences in socioeconomic status. Our data highlight the need for further research to investigate the importance of DI in improving LT outcomes in HNC patients.

6071Background: Prognosis in smokers with LASCCHN remains poor. Activating mutations of PI3K are linked to poor outcome and PI3K activation in response to RT is implicated in resistance to CRT. Met...