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Objectives: Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genetic intra-tumor heterogeneity (ITH), which may hinder precision medicine strategies that depend on results from single tumor-biopsy specimens. Treatment response assessment relies on radiologic imaging, which cannot detect minimal residual disease (MRD). We assessed the relevance of circulating tumor DNA (ctDNA) as a biomarker for ITH and MRD in HNSCC., Materials and Methods: We recruited 41 non-metastatic resectable HNSCC patients treated with upfront curative-intent surgery in the prospective biobanking SCANDARE study (NCT03017573). Thirty-one patients (76 %) showed recurrent disease at a median follow-up of 41 months. Targeted next-generation sequencing was performed on resected tumor tissues, as well as on serial blood samples obtained at surgery, within 14 weeks after surgery, at six months and at recurrence., Results: ctDNA was detected in 21/41 patients at surgery (sensitivity: 51 %; 95 % CI, 35-67 %) and 15/22 patients at recurrence (sensitivity: 68 %; 95 % confidence interval [CI], 45-86 %). Among patients with mutations identified in longitudinal plasma samples, additional mutations missed in tumor tissues were reported in 3/21 patients (14 %), while emerging mutations were reported in 9/21 patients (43 %). In the postoperative surveillance setting, ctDNA-based MRD detection anticipated clinical recurrence with a median lead-time of 9.9 months (interquartile range, 8.0-14.5 months) in 17/27 patients (63 %). When detected within 14 weeks after surgery, MRD correlated with disease recurrence after adjusting for classical prognostic variables (HR = 3.0; 95 % CI, 1.1-7.9; p = 0.03)., Conclusions: ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C. Le Tourneau: Roche, Seattle Genetics, Rakuten, Nanobiotix, MSD, BMS, Merck Serono, AstraZeneca, GlaxoSmithKline, Novartis, Celgene, Exscientia, ALX Oncology, Seattle Genetics. M. Kamal: Roche, AstraZeneca. The other authors have no disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Oral cavity is the most prevalent site of head and neck squamous cell carcinomas (HNSCCs). Most often diagnosed at a locally advanced stage, treatment is multimodal with surgery as the cornerstone. The aim of this study was to explore the molecular landscape of a homogenous cohort of oral cavity squamous cell carcinomas (OCSCCs), and to assess the prognostic value of tumor mutational burden (TMB), along with classical molecular and clinical parameters., Patients and Methods: One hundred and fifty-one consecutive patients with OCSCC treated with upfront surgery at the Institut Curie were analyzed. Sequencing of tumor DNA from frozen specimens was carried out using an in-house targeted next-generation sequencing panel (571 genes). The impact of molecular alterations and TMB on disease-free survival (DFS) and overall survival (OS) was evaluated in univariate and multivariate analyses., Results: Pathological tumor stage, extranodal spread, vascular emboli, and perineural invasion were associated with both DFS and OS. TP53 was the most mutated gene (71%). Other frequent molecular alterations included the TERT promoter (50%), CDKN2A (25%), FAT1 (17%), PIK3CA (14%), and NOTCH1 (15%) genes. Transforming growth factor-β pathway alterations (4%) were associated with poor OS (P = 0.01) and DFS (P = 0.02) in univariate and multivariate analyses. High TMB was associated with prolonged OS (P = 0.01 and P = 0.02, in the highest 10% and 20% TMB values, respectively), but not with DFS. Correlation of TMB with OS remained significant in multivariate analysis (P = 0.01 and P = 0.005 in the highest 10% and 20% TMB values, respectively). Pathological tumor stage combined with high TMB was associated with good prognosis., Conclusion: Our results suggest that a high TMB is associated with a favorable prognosis in patients with OCSCC treated with upfront surgery., Competing Interests: Disclosure CLT participated in advisory boards from MSD, BMS, Merck Serono, AstraZeneca, Nanobiotix, Celgene, GSK, Roche, Rakuten, and Seattle Genetics. All other authors have declared no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations., Competing Interests: Disclosure GC: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, Nanostring, Samsung, Celltrion, Ellipsis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Mylan. CLT: Roche, Seattle Genetics, Rakuten, Nanobiotix, MSD, BMS, Merck Serono, AstraZeneca, GlaxoSmithKline, Novartis, Celgene. XF: Roche, Janssen, BMS, Leo Pharma, Amgen Research. LC: Leo Pharma, Amgen. JG: Roche, Leo Pharma. IP: employee and equity holder in Oncompass Medicine Ltd. RD, PF, and AD are employees of Oncompass Medicine Ltd. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Precision medicine in oncology is becoming reality thanks to the next-generation sequencing of tumours and the development of targeted inhibitors enabling tailored therapies. Many clinical trials base their strategy on the identification of mutations to deliver the targeted inhibitor that counteract supposedly the effect of a mutated gene. Recent results have shown that this gene-centered strategy can be successful, but can also fall short in stopping progression. This is due to the many compensation mechanisms, cross-talks and feedback loops that enable the tumoral cell to escape treatment. Taking into account the regulatory network is necessary to establish which inhibitor or combination of inhibitors would achieve the best therapeutic results. Mathematical modelling of biological networks, together with high-quality pathway databases collecting our knowledge of the molecular circuitry of normal and tumoral cells, hold the hopes of an enhanced future for precision medicine in oncology.

This study was designed to identify predictive signatures of pathological complete response (pCR) in breast cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data (Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial (n = 153,training set) and the publicly available M.D. Anderson data set (n = 133, validation set) were used. A re-sampling method was applied. All predictive models were defined using logistic regression and their classification performances were tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes) differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1, MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered into the model, only CA12 and PIGH, remained informative (p = 0.05 and p = 0.005) showing that a combination of a few genes provided robust and reliable prediction of pCR., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

T helper 17 (Th17) cells produce IL-17 but can also make tumor necrosis factor, interleukin (IL)-6, IL-10, IL-21, and IL-22. These cytokines collectively contribute to the functional outcome of the Th response. IL-22 plays a critical role in some Th17-associated diseases, such as psoriasis, but its relationship to IL-17 remains controversial. Here, we used a systematic multiparametric analysis of Th-17-associated cytokines, which revealed the unexpected finding that the regulation pattern of IL-22 was most closely related to interferon-gamma, the prototypical Th1 cytokine, and not to IL-17. To explain this observation, we systematically tested the role of Th1- and Th17-inducing cytokines. We could show that IL-12 and IL-23 induced high levels of IL-22 but no IL-17. Conversely, transforming growth factor-beta inhibited IL-22 production but promoted IL-17. Thus, IL-17 and IL-22 are differentially regulated during cytokine-induced Th cell differentiation. This has important implications for the understanding and pharmacologic manipulation of Th17-associated pathologies.

In the past 15 years, anomalies of male sexual differentiation have greatly increased in both wildlife and humans in different parts of the world. Environmental endocrine disruptors have been implicated in the dramatic rise in neonatal ambiguous genitalia with variable rates of severity, such as micropenis, cryptorchidism, and isolated or associated hypospadias. Because most environmental pollutants, such as organochlorine pesticides, polychlorinated biphenyls, dioxins and furans, alkylphenol polyetholyethoxylates, and phytoestrogens and phtalates, have estrogenic and antiandrogenic activity, they are able to interfere with normal fetal male sexual differentiation. In a neonatal screening program of ambiguous genitalia, we had the opportunity to evaluate three newborns with male pseudohermaphroditism (MPH) whose mothers were exposed to endocrine disruptors during pregnancy. All had normal testosterone production after human chorionic gonadotrophin stimulation testing, suggesting androgen resistance or so-called idiopathic MPH. Sequences of the 5alpha reductase and androgen receptor genes were normal. Since environmental pollutants are known for their estrogenic activity and can be released progressively from the adipose tissue where they accumulate, we detected their presence by measuring the estrogenic bioactivity of the newborns' serum with a recently developed ultrasensitive bioassay. We found higher estrogenic bioactivity in these newborns than in controls. In conclusion, the maternal exposure to environmental pollutants during pregnancy and high estrogenic bioactivity in the newborns' serum highly suggest that ambiguous genitalia are related to fetal exposure to endocrine disruptors.

Reporter gene technology is widely used to measure activity of hormone analogs, and bioluminescent in vitro assays have allowed rapid screening of numerous chemicals either to identify new agonists or antagonists of hormones or to detect the presence of endocrine disrupters in the environment. Stable bioluminescent cell lines have been established and they provide reproducible dose-response curves and accurate determination of in vitro efficiencies of various chemicals. In vivo, however, these molecules can be metabolized, bound by proteins, or stored in fats and thus could display efficiencies different from those observed in vitro. In vivo assays, such as the uterotrophic bioassay, require numerous sacrificed animals, and responses not only are dependent on an estrogenic action but also imply other factors. For a faster assay and to avoid the use of numerous animals, we developed an in vivo biosensor constituted of stable bioluminescent cells implanted in nude mice. MCF-7 bioluminescent cell lines were chosen since their proliferation is low in the absence of estrogen and the xenograft size can thus be stable for several weeks. Luciferase gene expression was monitored noninvasively with a cooled charge-coupled device camera. Quantitative analysis allowed us to compare in vitro and in vivo actions of different estrogenic compounds (estradiol, estrone) and endocrine disruptors (ethynylestradiol, genistein, octylphenol, and 2,4'-dichlorodiphenyldichloroethylene) in the same cell lines and to follow hormone action on a living animal as a function of time. Different administration protocols have been used and good correlation was observed for most products. However, we found that ethynylestradiol was the most efficient chemical when orally administered.