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Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.See related commentary by Chau and Hammerman, p. 3710

Fig S2. Technical validation using NuGEN's Ovation System. The scatter plot shows the fold change consistency of genes differentially expressed using WG-DASL and NuGEN methods. Only 6 out of the 509 DE genes were found discordant, confirming the WG-DASL patterns. Data are plotted as log2 fold change (FC) expression long/short PFS; positive log2(FC) values stand for genes up-regulated in long-PFS cases, while negative values stand for up-regulation in short-PFS cases. Statistical significance was tested through Monte Carlo test (1000 interactions) yielding p-value

Fig S1. Volcano plot for the 17,378 genes detected by microarray analysis. The x-axis is the fold-change, and the y-axis is log10 p value. A total of 509 probes (blue dots) were differentially expressed in long-PFS patients (14) compared with short-PFS patients (26), imposing a FDR < 15%. Probability of finding by chance 509 significant DE genes between the classes: p = 0.016.

FigS3: Biasogram representing the influence of tissue origin on outcome. Y axes indicate the outcome vector (long- versus short- PFS), while B indicates the nuisance variable (tissue origin; primary versus recurrence/metastatic). The colorgram represents a bivariate histogram of all the 17,378 detected genes; the green circles indicate the genes present in our signature.

Fig S4. Ability of existing gene signatures to predict outcome following cetuximab treatment. Five available prognostic gene-expression based signatures were taken into account: i) the hypoxia metagene (Winter, 2007); ii) the 13-gene OSCC signature (Lohavanichbutr, 2013); iii) the RSI-index (Eschrich, 2009); iv) the 42-gene Chung's high risk signature (Chung, 2006); v) the 172-gene signature (De Cecco, 2014). A score was assessed for each sample entering into our study following the model developed by the authors and compared among long- and short PFS cases. The boxplots depicts the data in the two groups. Green: long-PFS; Red: short-PFS.

Supplementary Table S2 Gene sets associated to long- and short-PFS patients

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response. Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project. Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR. See related commentary by Chau and Hammerman, p. 3710

Introduction: During the last months coronavirus disease 2019 (COVID-19) has spread abruptly to nearly every country, taking on pandemic proportions. The Italian government ordered a nationwide lockdown to hinder the spread of the contagion with unavoidable social isolation and substantial changes in lifestyle habits. Therefore, COVID-19 affected not only physical but also psychological health and well-being. Health care professionals fighting the epidemic represent the most involved category, resulting in more physical and emotional involvement. The aim of this study is to assess the social stress level of health care workers in Italy. Materials and Methods: In this online, totally anonymous survey, 24 multiple-choice questions were broadcast to medical staffs employed in the Italian health care system during COVID-19 pandemic. Data collection was performed from 30th March to 24th April 2020. Descriptive statistics have been applied to describe and summarize our findings and the correlation analyses between categorical variables were performed using Pearson’s Chi-Square. Results: A total of 600 health care professionals completed the questionnaire with a prevalence of young (32.3% between 36 and 45 years old), female (74.0%) oncologists (58.8%). Participants mainly belong to Lombardy (31.3%) and Marche (30.3%), two of the most affected regions, but almost all the Italian regions contributed to the survey. The majority of respondents expressed the fear of being at higher risk of contagion than the general population (83.3%) and the weighty concern of infecting their own families (72.5%). An insufficient supply of personal protective equipment (p = 0.0003) and inadequate training about procedures to follow (p = 0.0092) significantly correlated with these worries. Furthermore, more than two thirds declared a change in family organization and daily life, showing a significant correlation with worry about infecting their own relatives (p < 0.0001). Discussion: This is the first Italian survey on social distress among health care professionals during the COVID-19 pandemic. The unavailability of personal protective equipment, periodic screening procedures, adequate training, and the correct spread of information strongly conditioned health care professionals’ emotional status, family organization, and daily life. With this survey we underlined the social impact that this health emergency has on health care workers, especially on women, who deal with “caring” in the hospital as well as at home, juggling to fulfill multiples roles of professionals, mothers, wives, and caregivers for elderly parents. We wish that institutions could involve themselves concretely to guarantee that health care professionals safely perform their work in a context appropriate to proper professional skills and with the adequate social and psychological support. Reducing workers’ fear of contagion and psychological distress will certainly bring significant positive repercussions for the national health system. Citation Format: Rossana Berardi, Mariangela Torniai, Maria Silvia Cona, Fabiana Cecere, Rita Chiari, Valentina Guarneri, Nicla La Verde, Laura Locati, Domenica Lorusso, Erika Martinelli, Marina Garassino. COVID-19 pandemic in Italy: Social distress and gender imbalance among health care professionals [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-087.