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PD-L1 inhibitor; Anal cancer; Retifanlimab Inhibidor de PD-L1; Cáncer anal; Retifanlimab Inhibidor de PD-L1; Càncer anal; Retifanlimab Background Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. Patients and methods Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. Conclusions Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy. This work was supported by Incyte Corporation (Wilmington, DE, USA) (no grant number).

Cemiplimab; Càncer de coll uterí metastàtic; Càncer de coll uterí recurrent Cemiplimab; Cáncer de cuello uterino metastásico; Cáncer de cuello uterino recurrente Cemiplimab; Metastatic cervical cancer; Recurrent cervical cancer Objectives To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens ( N = 155), PD-L1 protein expression in tumor and immune cells was negative (

Simple Summary Drug resistance is the principal limiting factor to achieving good survival rates in patients with cancer. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving head and neck squamous cell carcinoma (HNSCC) patient outcomes. In this sense, the sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. We conducted a proteomic study involving cisplatin-resistance and CSCs with the aim to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. Syntenin-1 (SDCBP) was identified as an important protein involved in the chemoresistance and stemness of HNSCC tumors. Abstract To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.

Simple Summary Oral potentially malignant disorders (OPMDs) include a group of oral mucosal diseases with different morphological characteristics that are able to progress to oral squamous cell carcinoma (OSCC). Given OSCC’s poor prognosis and high mortality, early diagnosis is a priority step in OSCC. Extrinsic and intrinsic risk factors and etiologies are involved in developing and malignant transformation of oral lesions, and different molecular alterations have been described in early lesions associated with a potential malignant behavior. This review summarizes the information about clinical, morphological and molecular features of OPMDs, with an emphasis on the early detection techniques and an overview of the surgical and systemic therapies’ effectiveness. Abstract Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs’ development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments.

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial&ndash, mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.

Carcinoma anal de cèl·lules escamoses; Biologia molecular; Proteòmica Anal squamous cell carcinoma; Molecular biology; Proteomics Carcinoma anal de células escamosas; Biología molecular; Proteómica Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy. This study was supported by the Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry, Spain and co-sponsored by the FEDER program, “Una forma de hacer Europa” (PI15/01310), a Roche Farma grant, Cátedra UAM-Amgen and a grant of Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD1403). LT-F is supported by the Spanish Economy and Competitiveness Ministry (DI-15–07614). GP-V is supported by the Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (IND2017/BMD7783); AZ-M is supported by Jesús Antolín Garciarena fellowship from IdiPAZ. The authors have declared a conflict of interest. JAFV and AG-P are shareholders in Biomedica Molecular Medicine SL. LT-F and GP-V are employees of Biomedica Molecular Medicine SL. JC has received honoraria for scientific consulting (as speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi and Merck Serono and research support from Eisai, Novartis, Ipsen, Astrazeneca, Pfizer and Advanced Accelerator Applications. IG has received honoraria and/or travel expenses from Roche, Sanofi, Merck, Servier, Amgen and Sirtflex, and for advisory role from Merck and Sanofi. JF has received consulting and advisory honoraria from Amgen, Ipsen, Eissai, Merck, Roche and Novartis; research funding from Merck, and travel and accommodation expenses from Amgen and Servier. The other authors declare no conflicts of interest.

Aim VITAL, a phase II single‐arm study, aimed to evaluate efficacy and safety of panitumumab addition to 5‐fluorouracil (5‐FU), mitomycin‐C (MMC) and radiotherapy (RT) in patients with localized squamous cell carcinoma of the anal canal (SCCAC). Methods Adult, treatment‐naïve SCCAC patients (Stage T2‐T4, any N, M0) and ECOG‐PS ≤2, received panitumumab (6 mg/kg, day 1 and Q2W; 8 weeks), 5‐FU (1000 mg/m2/d, days 1‐4 and 29‐32), MMC (10 mg/m2, days 1 and 29) and RT 45 Gy (1.8 Gy/fraction) to the primary tumor and mesorectal, iliac and inguinal lymph nodes, plus 10‐15 Gy boost dose to the primary tumor and affected lymph nodes. The primary objective was disease free survival rate (DFS) at 3‐years (expected 3‐year DFS rate: 73.7 ± 12%). Results Fifty‐eight patients (31 women; median age: 59 years; ECOG‐PS 0‐1:98%; TNM II [29%] (T2 or T3/N0/M0)/IIIA (T1‐T3/N1/M0 or T4/N0/M0) [21%]/IIIB (T4/N1/M0 or any T/N2 or N3/M0) [47%]/nonevaluable [4%]) were included. The median follow‐up was 45 months. The 3‐year DFS rate was 61.1% (95% CI: 47.1, 72.4). The 3‐year overall survival rate was 78.4% (95% CI: 65.1, 87.1). Eighteen patients (31.0%) required a colostomy within 2 years posttreatment. Grade 3‐4 toxicities were experienced by 53 (91%) patients. Most common grade 3‐4 treatment‐related events were radiation skin injury (40%) and neutropenia (24%). No toxic deaths occurred. Improved efficacy in colostomy‐free survival and complete response rate was observed in human papilloma virus positive patients. Conclusions Panitumumab addition to MMC‐5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes. RT plus MMC‐5FU remains the standard of care for localized SCCAC patients., VITAL, a phase II single‐arm study, was aimed to evaluate efficacy and safety of panitumumab addition to 5‐fluorouracil (5‐FU), mitomycin‐C (MMC) and radiotherapy in patients with localized squamous cell carcinoma of the anal canal (SCCAC). The study concluded that panitumumab addition to MMC‐5FU regimen in SCCAC patients increases toxicity and does not improve patients’ outcomes.

Carcinoma de mama metaplàsic; Alteracions moleculars; Pronòstic Carcinoma de mama metaplásico; Alteraciones moleculares; Pronóstico Metaplastic breast carcinoma; Molecular alterations; Prognosis Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent invasive carcinomas that display differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-type elements. Most MBC have a triple negative phenotype and poor prognosis. Thus, MBC have worse survival rates than other invasive breast carcinomas, including other triple negative breast carcinomas (TNBC). In this study, we reviewed the molecular features of MBC, pointing out the differences among subtypes. The most frequently mutated genes in MBC were TP53 and PIK3CA. Additionally, mutations in the other genes of the PI3K/AKT pathway indicated its importance in the pathogenesis of MBC. Regarding copy number variations (CNVs), MYC was the most frequently amplified gene, and the most frequent gene loss affected the CDKN2A/CDKN2B locus. Furthermore, the pattern of mutations and CNVs of MBC differed from those reported in other TNBC. However, the molecular profile of MBC was not homogeneous among histological subtypes, being the alterations in the PI3K pathway most frequent in spindle cell carcinomas. Transcriptomic studies have demonstrated an epithelial to mesenchymal program activation and the enrichment of stemness genes in most MBC. In addition, current studies are attempting to define the immune microenvironment of these tumors. In conclusion, due to specific molecular features, MBC have a different clinical behavior from other types of TNBC, being more resistant to standard chemotherapy. For this reason, new therapeutic approaches based on tumor molecular characteristics are needed to treat MBC. This review was funded by grants from the Instituto de Salud Carlos III (ISCIII) (PI19/01331) and CIBERONC (CB16/12/00316 and CB16/12/00449), co-financed by the European Development Regional Fund. ‘A way to achieve Europe’ (FEDER), and by the Spanish Association Against Cancer Scientific Foundation (Grupos Coordinados Traslacionales aecc 2018).

Metastasis; Fibrosis; Cutaneous squamous cell carcinoma Metástasis; Fibrosis; Carcinoma cutáneo de células escamosas Metàstasi; Fibrosi; Carcinoma cutani de cèl·lules escamoses Although desmoplasia has been associated with poor prognoses in cutaneous squamous cell carcinoma, little attention has been paid to the patterns of fibrosis. This study aimed to examine the different stromal fibrotic patterns as markers of metastatic risk. We performed a multicenter retrospective study that included 102 cutaneous squamous cell carcinomas (52 non-metastatic and 50 metastatic carcinomas). Clinical and histopa-thological data were registered. The fibrotic reaction pattern was classified as mature, intermediate or immature depending on the presence of keloid-like collagen and myxoid stroma. The immature pattern (areas characterized by myxoid changes with no inflammation) was observed in 18 samples and its presence was significantly associated with immuno-suppression, budding, desmoplasia, perineural invasion, anatomic level, tumoural depth and metastatic risk in the multivariate analysis. Our findings suggest that the presence of an immature myxoid fibrotic pattern, which can be easily identified by routine hematoxylin-eosin staining, is strongly associated with metastatic risk. This work has been supported by grant PI15/00236 from Fondo de Investigación Sanitaria (FIS), Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III, Ministerio de Sanidad, and the ‘‘Xarxa de Bancs de Tumours”.