INTRODUCTION:Although basal cell carcinomas (BCC) are the most common skin cancer and usually considered as 'easy-to-treat,' locally advanced BCC (laBCC) and metastatic BCC (mBCC) are rather exceptional and often more 'difficult-to-treat.' They load a high burden on the quality of life (QoL) of the patients, often elderly and frail individuals. Several management options are possible, varying from supportive therapy without any therapeutic intervention until anti-programmed cell death protein-1 (PD-1) immunotherapy, such as cemiplimab, either administered intravenously or intralesional. In between this spectrum, oral hedgehog inhibitors including vismodegib and sonidegib, electrochemotherapy, different types of radiotherapy, and surgery can be considered. CAR-T cell therapy, anti-LAG therapy, and multiple combination therapies are currently under investigation for laBCC and mBCC. AREAS COVERED:Current and future treatment options for the management of laBCC and mBCC, limitations of different approaches as well as some practical and financial aspects are presented. EXPERT OPINION:The management of laBCC and mBCC patients is determined by a multidisciplinary dermato-oncology board, including dermatologists, medical oncologists, radiotherapists, pathologists, and surgeons, as well as the patient's GP. Today, experts recommend keeping as long as possible laBCC and mBCC patients under sequential courses of HHIs, if surgery and/or radiotherapy are not amenable.

Metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer often develops resistance to first-line treatment, typically combining cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with hormone therapy (HT) [1, 2]. After an initial response, most patients become resistant, and compensatory mechanisms are not fully uncovered [3]. To address this, we analyzed HR+ resistant CAMA1 and 747D cells using whole-exome and RNA sequencing, supplemented by proteomics and target validation with human samples. Additionally, we conducted combination therapy trials using xenografts and patient-derived xenografts (PDXs). Detailed study designs and methods are provided in the Supplementary file. In a cohort of 27 patients with metastatic breast cancer, we observed reduced progression-free survival in second- and third-line therapies following progression post palbociclib-HT treatment (Supplementary Figure S1A and Supplementary Table S1). Resistant tumors showed reduced estrogen receptor alpha (ERα) and progesterone receptor (PR) and increased proliferation rates (Supplementary Figure S1B-D). CAMA1 and T47D cells, treated with palbociclib and fulvestrant (PF) for 2 years, developed resistance (CAMA1-PFR and T47D-PFR) confirmed by proliferation assays and elevated half-maximal inhibitory concentrations. Resistant cells exhibited reduced levels of ERα and retinoblastoma protein (Supplementary Figure S2). Exome analysis revealed no drug resistance-related mutations (Supplementary Tables S2-S3), suggesting non-genetic factors. RNA sequencing of T47D cells treated with DMSO or PF for 20 days and T47D-PFR cells revealed 1,172 upregulated genes and 824 downregulated genes in the resistant cells (Supplementary Figure S3A). Gene set enrichment analysis indicated increased fatty acid localization (Supplementary Figure S3B), with a heatmap showing elevated fatty acid uptake and metabolism-related genes, such as fatty acid binding protein-6 (FABP6), FABP7, cluster of differentiation-36 (CD36), and proteasome proliferator-activated receptor-gamma (PPARγ) in T47D-PFR cells (Figure 1A). Lipid droplets accumulated in PF-treated parental and PF-resistant T47D and CAMA1 cells (Figure 1B and Supplementary Figure S3C). FABP6 levels were elevated in PF-treated parental and PF-resistant cells, with CD36 overexpression unique to T47D-PFR cells at both protein and mRNA levels (Figure 1C and Supplementary Figure S3D-E), suggesting that lipid uptake might be an adaptive response to oxidative stress [4, 5]. This was supported by elevated reactive oxygen species (ROS) levels in PF-treated parental cells (Figure 1D). Furthermore, proteomic analysis in human biopsies revealed a functional network of 11 oxidative stress-triggered proteasomes (Supplementary Figure S4A and Supplementary Tables S4-S5) as indicators of oxidative stress [6]. Immunohistochemistry validated increased proteasome subunit alpha type-7 (PSMA7) in resistant biopsies (Supplementary Figure S4B). Ferroptosis inducers overcome resistance of HR+HER2− breast cancer cells to palbociclib-hormone therapy. (A) Heatmap of upregulated genes (red) or downregulated genes (blue) during the treatment of T47D cells with PF combination for 20 days, and in PF-resistant cells (T47D-PFR) after continuous PF treatment for 2 years, compared to parental T47D cells treated with vehicle (DMSO). All represented genes had a P value < 0.05. (B) Lipid droplet detection by BODIPY 493/503 staining in parental CAMA1 and T47D cells after treatment with the PF combination for 20 days, and in CAMA1-PFR and T47D-PFR cells after continuous PF treatment for 2 years. DAPI staining was used to visualize the nuclei. (C) Western blot analysis of FABP6 and CD36 in parental CAMA1 and T47D cells after treatment with the PF combination for 20 days, and in CAMA1-PFR and T47D-PFR cells after continuous PF treatment for 2 years. (D) Measurement of ROS levels by DCFDA ROS assay in parental CAMA1 and T47D cells and in CAMA1-PFR and T47D-PFR cells treated for 5 days with DMSO or PF. Continuous PF treatment for resistant cells was discontinued 3 days prior to the assay. (E) Western blot analysis of GPX4 in parental CAMA1, T47D and ZR75.1 cells after treatment with PF combination for 20 days and in CAMA1-PFR, T47D-PFR and ZR75.1-PFR cells after continuous PF treatment for 2 years. (F) Immunohistochemistry analysis (images) and quantification (bar chart) of GPX4-positive cells in biopsies of patients taken before treatment with palbociclib-HT or after resistance (*P < 0.05). (G) Assessment of cell proliferation according to the fold change in confluence in parental and PF-resistant CAMA1 and T47D cells treated with DMSO, the ferroptosis inducer RSL3 (1 µmol/L), the ferroptosis inhibitor Trolox (10 µmol/L), or a combination of both for 7 days. Continuous PF treatment for resistant cells was discontinued 3 days prior to the assay. (H) Assessment of cell proliferation according to the fold change in confluence in parental and PF-resistant CAMA1 and T47D cells treated with different combinations of DMSO, palbociclib (P) (0.3 µmol/L), fulvestrant (F) (30 nmol/L), or eprenetapopt (Ep) (25 µmol/L) for 7 days. Continuous PF treatment for resistant cells was discontinued 3 days prior to the assay. (I, J) Tumor growth curves of parental CAMA1 (6 mice per group) (I) and CAMA1-PFR (8 mice per group) (J) xenografts treated with different combinations of palbociclib (P) 75 mg/kg daily, fulvestrant (F) 50 mg/kg once a week, and eprenetapopt (Ep) 150 mg/kg, 2 times/day or RSL3 100 mg/kg by intratumoral injection every two days for two weeks (***P < 0.001). (K) Growth curves of palbociclib-HT-naïve HBCx-124 PDXs (5 mice per group) treated with different combinations of palbociclib (P) 75 mg/kg daily, fulvestrant (F) 50 mg/kg once a week, and eprenetapopt (Ep) 150 mg/kg, 2 times/day (***P < 0.001). (L) Growth curves of palbociclib-HT-resistant HBCx-180 PDXs (8 mice per group) treated with different combinations of palbociclib (P) 75 mg/kg daily, fulvestrant (F) 50 mg/kg once a week, and eprenetapopt (Ep) 150 mg/kg, 2 times/day. The difference between the measured tumor volumes was significant between the "vehicle" group and the eprenetapopt + fulvestrant + palbociclib (FPE) group from Day 25 until the end of the experiment (P < 0.05). Tumor evolution formula is (Vf − V0 / V0) × 100%, where V0 is the initial volume and Vf is the final volume measured at each time point. Abbreviations: CD36, cluster of differentiation 36; DAPI, 4′,6-diamidino-2-phenylindole; DCFDA, 2′,7′-Dichlorofluorescin Diacetate; DMSO, dimethyl sulfoxide; Ep, eprenetapopt; FABP6, fatty acid binding protein 6; GPX4, Glutathione peroxidase 4; HR+HER2−, hormone receptor positive and human epidermal growth factor receptor-2 negative; HT, hormone therapy; PDX, patient-derived xenograft; PF, palbociclib-fulvestrant; PF RSL3, palbociclib-fulvestrant-RSL3; PFE, palbociclib-fulvestrant-eprenetapopt; ROS, reactive oxygen species, RSL3, ras-selective lethal small molecule 3; Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. We investigated whether cell survival is affected by ferroptosis—a type of non-apoptotic cell death linked to lipid peroxidation. GPX4 protein, the main protector against ferroptosis, was overexpressed in parental cells after PF treatment and in PF-resistant cells, even after drug wash-out, with no changes in mRNA levels (Figure 1E and Supplementary Figure S5A-C). Silencing GPX4 expression reduced cell proliferation in parental and PF-resistant cells (Supplementary Figure S5D-F), indicating their reliance on GPX4. GPX4 overexpression was also observed in resistant human tumors (Figure 1F). Cells were treated with the GPX4 inhibitor RAS-selective lethal 3 (RSL3) and the antioxidant Trolox for 6 days. CAMA1 and T47D cells were insensitive to RSL3, whereas CAMA1-PFR and T47D-PFR cells showed high sensitivity to RSL3 (Figure 1G). Trolox reversed RSL3's effect in both cell lines (Figure 1G), highlighting the role of GPX4 in PF-resistant cell proliferation. Due to unverified safety of RLS3, we used eprenetapopt (Ep), a p53 activator and GSH depletory [7] proven safe in hematological cancer patients [8]. In vitro, CAMA1 and CAMA1-PFR cells were sensitive to Ep, while T47D cells were insensitive; T47D-PFR showed higher sensitivity (Figure 1H). To investigate the effect of pharmacologically induced ferroptosis on the palbociclib-fulvestrant response in vivo, we used nude mice implanted with estrogen pellets. Due to its low pharmacokinetics in mouse plasma [9], RSL3 was administered via intratumoral injection. Mice were treated with vehicle, PF, Ep, RSL3, a combination of palbociclib-fulvestrant and eprenetapopt (PFEp), or a combination of palbociclib-fulvestrant and RSL3 (PF-RSL3). PF effectively inhibited the growth of the CAMA1 xenografts, while CAMA1-PFR tumors were insensitive (Figure 1I and J). RSL3 alone did not affect CAMA1-PFR tumor growth, whereas PF-RSL3 demonstrated a strong antitumor effect (Figure 1J), suggesting that RSL3 sensitizes CAMA1-PFR cells to PF, or vice versa. Similarly, Ep alone did not inhibit CAMA1-PFR tumor growth, but its combination with PF completely abolished tumor growth (Figure 1J). To evaluate treatment effects on proliferation and cell death, we assessed Ki67, caspase-3 and hydroxynonenal (HNE) in tumors by immunohistochemistry. Parental CAMA1 tumors treated with PF showed a significant decrease in Ki67, with no effect on caspase-3, while CAMA1-PFR tumors exhibited no significant changes in either marker after treatment with PF, PFEp, or PF-RSL3 (Supplementary Figure S6A-D). HNE labeling revealed no difference between PF- and vehicle-treated CAMA1 tumors (Supplementary Figure S6E), but HNE increased moderately in CAMA1-PFR tumors treated with RSL3 and significantly with PFEp or PF-RSL3 (Supplementary Figure S6F), indicating potential cell death by ferroptosis. No treatments affected CD36 expression in either tumor type, although CAMA1-PFR xenografts showed significantly increased basal expression compared to human biopsies (Supplementary Figure S6G-J). To strengthen the translational impact of our findings, we used patient-derived xenografts (PDXs) from HR+HER2− breast cancer patients without p53 mutations (Supplementary Figure S7A) [10]. Consistent with human samples, GPX4 protein was upregulated in the palbociclib-HT-resistant PDX model (HBCx-180) compared to the palbociclib-HT-naïve PDX model (HBCx-124) (Supplementary Figure S7B). While GPX4 mRNA levels were unaffected in resistant cells, its expression was significantly higher in HBCx-180 (Supplementary Figure S7C), suggesting specific transcriptional/translational regulation differing between in vitro and in vivo contexts. In the HBCx-124 model, all the tumors (n = 5) responded well to PF, with no added benefit from Ep (PFEp), although a partial response to Ep monotherapy was observed (Figure 1K). Conversely, the HBCx-180 model showed no significant response to PF or Ep, with significant differences in tumor volumes between PFEp and vehicle and Ep groups from Day 25 onward (P < 0.05) (Figure 1L). These results confirm that adding Ep to PF in PF-resistant tumors produces a strong antitumor effect. Ki67 labeling decreased with PF in the HBCx-124 PDX but not in the HBCx-180 PDX (Supplementary Figure S8A-B). Aside from reduction in caspase-3 labeling in the HBCx-124 treated with PF, no significant changes were observed with Ep or PFEp, and none of the treatment conditions affected HBCx-180 (Supplementary Figure S8C-D), indicating that proliferation and apoptosis are not affected in HBCx-180. HNE labeling suggested that PF promoted ferroptosis in HBCx-124, while only tumors treated with PFEp in HBCx-180 exhibited significant HNE increase compared to vehicle (Supplementary Figure S8E-F). PF slightly increased HNE in HBCx-124 without significance but the only vulnerability of HBCx-180 is attributed to ferroptosis induced with PFEp. The p53-dependent antitumor effect of eprenetapopt was excluded, as p53 expression was similar in parental and PF-resistant cells and in PDXs, while slightly elevated in resistant human tumors (Supplementary Figure S9). Finally, the addition of Ep or RSL3 to PF did not induce significant renal, hepatic, or hematological toxicity in mice (Supplementary Figure S10). In conclusion, HR+HER2− tumors resistant to palbociclib-HT are vulnerable to ferroptosis inducers, highlighting the potential of collateral drug sensitivity and the promise of developing pro-ferroptosis agents for treating drug-resistant metastatic breast cancer (Supplementary Figure S11). Conception and design: CP and NES. Development of methodology: CP, LMR, NES. Acquisition of data: CP, LMR, RT, CW, RJ, AR, JC, CJ, SG, SB, AD, PD, LM and EM. Analysis and interpretation of data (e.g., statistical analysis, biostatistics): CP, LMR, DB, GM, RT, CJ and NES. Writing, review, and/or revision of the manuscript: CP, GJ, AN and NES. Study supervision: GJ and NES. The authors thank the Cell Imaging Core Facility of the GIGA institute for Incucyte and fluorescence microscopy experiments; Isabelle Dasoul, Emilie Feyereisen, Erika Konradowski and Nathalie Lefin for their technical support; Maud Piron for enrolling the cohort of patients; and Hélène Schroeder for correcting the file sent to the human ethics committee and the Biobank of Liège University for providing human samples. The authors also thank Latifa Karim and Manon Deckers from the GIGA Sequencing Platform (ULiège, Belgium) for their help and advice; Erik Maquoi for image acquisition with Nanolive and Louis Baudin (Animascience, Liège, Belgium) for the graphical abstract. The authors declare no competing interest except for Dr. Guy Jerusalem, who declares receiving grant support, paid to his institution, advisory board fees, lecture fees, travel support, and writing assistance from Novartis, Roche, and Pfizer. Disclosure is provided with the full text of this article. No other potential conflicts of interest relevant to this article were reported. This work was supported by grants from the National Fund for Scientific Research (NFSR-FNRS) Belgium (NES: PDR T.023020; CDR J.0178.22); the credit sectorial of the University of Liege (NES: FSR-S-SS-22/61; FSR-S-SS-22/64); and the Foundation Contre le Cancer, Belgium (NES and AN: FCC-2022-181). RNA sequencing data were deposited in the GEO-NCBI depository with the accession number: GSE270021 Exome sequencing data were registered in the BioProject database with the identification number: PRJNA1027140 Proteomic data were deposited in PRIDE with accession number: PXD053296. The data that support the findings of this study are available from the corresponding author upon reasonable request. A protocol was approved by the institutional Ethics Committee of the University Hospital of Liege (Liege, Belgium; file#2018/312) for the use of human samples in this study, and the ethical guidelines of the Declaration of Helsinki were followed. The ethical committee has authorized on May 15, 2019, to retrospectively use biopsies stored in the biobank of the University of Liège and anonymized clinical data associated with these biopsies. The committee noted that this non-interventional use has no impact on patients and is not within the scope of the law of May 7, 2004, on experiments on human beings and thus did not require informed consents. For the animal study, all procedures were performed according to the Federation of European Laboratory Animal Sciences Associations (FELASA) within the accredited GIGA animal facility (University of Liege, Liege, Belgium) (project authorization no. 2078). PDX experiments were performed at the Institute of Curie, in accordance with institutional guidelines and the rules of the French Ethics Committee (project authorization no. 02163.02). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380.

1105 Background: Approximately 2-5% of breast cancers harbor HER2 mutations, often occurring in hormone receptor-positive (HR+) disease. There are currently no approved treatment options for patients (pts) with HER2-mutated metastatic breast cancer (HER2-mut MBC). Tucatinib (TUC) is a tyrosine kinase inhibitor highly selective for HER2 and is approved for previously treated HER2+ MBC with or without brain metastases in combination with trastuzumab (Tras) and capecitabine. Here, we report the efficacy and safety results of TUC combined with Tras in pts with previously treated HER2-mut MBC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with metastatic HER2-altered solid tumors. Pts in the HER2-mut MBC cohort must have HER2 mutations determined locally by tissue- or blood-based next-generation sequencing, not be HER2+ per local testing, been previously treated with ≥1 systemic therapy in the locally advanced, unresectable, or metastatic setting, and if HR+, have received a CDK4/6 inhibitor. Pts were treated in 21-day cycles with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Pts with HR+ disease also received fulvestrant (F; 500 mg IM once every 4 wks starting from cycle 1 day 1, and cycle 1 day 15). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is cORR per investigator assessment. Secondary endpoints include OS, DCR, DOR, PFS, and safety. Results: As of Nov 1, 2023, 31 pts were enrolled in the HER2-mut MBC cohort. The median duration of follow-up for OS was 15.0 months. Twenty-seven (87%) pts had HR+ disease and 18 (58%) had lobular histology. The pts received a median of 4 prior lines of systemic therapy in any setting. cORR was 41.9% (90% CI, 26.9-58.2) with 13 responses including 2 complete responses. Median DOR was 12.6 months (90% CI, 4.7, not estimable), DCR was 80.6% (n=25; 90% CI, 65.3-91.2), median PFS was 9.5 months (90% CI, 5.4-13.8), and median OS was 20.1 months (90% CI, 15.9 to not estimable). The most common treatment-emergent adverse events (TEAEs) reported were diarrhea (64.5%) and nausea (35.5%). The most common grade ≥3 TEAEs reported were diarrhea (13%), alanine aminotransferase increase (10%), and hypertension (10%). Two (6.5%) pts discontinued TUC due to TEAEs, but these pts continued Tras. No deaths were due to TEAEs. Additional biomarker analyses will be included in the presentation. Conclusions: The investigational combination of TUC and Tras, plus F in pts with HR+ disease, was well tolerated and had clinical activity in pts with previously treated HER2-mut MBC. The results support further evaluation of the combination of TUC and Tras as a potential treatment option for this pt population. Clinical trial information: NCT04579380 .

Adjuvant NIVO is approved for pts with melanoma with lymph node involvement/metastatic disease who have undergone complete resection. PRESERV MEL is an observational study aiming to describe effectiveness, safety, and quality of life in pts treated with adjuvant NIVO in the RW. Updated results are shown. Pts were enrolled prospectively/retrospectively over a 2-y period and are being followed for 5 y. Index date was first NIVO administration. Pts received NIVO for ≤ 12 mo per label. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS; including baseline stage IV pts), time to discontinuation (TTD), subsequent treatment (tx), and adverse events (AEs)/tx-related AEs (TRAEs) were assessed. In total, 152 pts (125 prospective; 27 retrospective) were enrolled (Jan 2019–Dec 2020) at 15 sites in Belgium and Luxembourg. Median follow-up was 25 mo. Median TTD was 11.1 mo. All pts ended tx due to tx completion (56%), AE (23%), recurrence (15%), pt decision unrelated to AE (1%), or other reason (5%). Median RFS was 47.2 mo, 2-y RFS rate was 62%, median DMFS was not reached, and 2-y DMFS rate was 72% (Table). Sites of first recurrence in pts with distant recurrence (n = 41; 27%) were soft tissue (39%), lungs (34%), multiple organs (37%), skin (27%), liver (22%), lymph nodes (22%), bone (15%), brain (7%), intestines (5%), other visceral organs (17%), and other (2%). Subsequent tx was used in 51 pts (34%), including surgery (9%), radiotherapy (8%), and systemic tx (32% [adjuvant tx, 10%; unresectable/metastatic tx, 22%]). Median time from NIVO discontinuation (D/C) to subsequent tx was 12.6 mo. Grade 3/4 TRAEs occurred in 21 pts (14%). Any AEs led to tx D/C in 35 pts (23%). Late-emergent grade 3/4 TRAEs (100 d–2 y after tx) were reported in 3 pts (2%; 2 of 3 pts had prior TRAE occurrence).Table 108PAdjuvant NIVO (n = 152)Median RFS, mo (95% CI)47.2 (33.2–NR)RFS rate, % (95% CI)1 y75 (67–81)2 y62 (54–70)3 y56 (46–65)Recurrence, n (%)59 (39)Local17 (11)Regional14 (9)Distant26 (17)Died before recurrence, n (%)3 (2)Median DMFS, mo (95% CI)NR (45.7–NR)DMFS rate, % (95% CI)1 y80 (73–86)2 y72 (64–79)3 y66 (57–74)Distant recurrence, n (%)41 (27)Died before distant recurrence, n (%)6 (4)NR, not reached. Open table in a new tab NR, not reached. RW effectiveness and safety of adjuvant NIVO in pts with resected stage III/IV melanoma in PRESERV MEL were consistent with CheckMate 238 results.

In this clinical case, we describe the cardio-oncological history and the complexity of the management of a patient presenting a breast cancer diasgnosed during pregnancy followed by a postpartum cardiomyopathy. A multidisciplinary approach is mandatory.

Introduction Locally advanced basal cell carcinoma (laBCC) represents approximatively 1% of all BCCs. Metastatic BCC (mBCC) is even more rare. Most cases are observed in immunocompromised patients, particularly solid organ transplant recipients (OTRs). When surgery and/or radiation therapy for laBCC or mBCC is not reasonable, oral hedgehog inhibitor (HHI) therapy may be initiated. LaBCC or mBCC patients with primary or secondary resistance, progression or intolerance to HHIs could benefit from programmed cell death protein-1 (PD-1) inhibitors as this has recently been published for cemiplimab, a recombinant IgG4 human monoclonal antibody anti-PD-1 for the intravenous treatment of laBCC and mBCC. Areas covered Principal studies evaluating the efficacy and safety of cemiplimab for laBCC and mBCC are presented and discussed. Expert opinion Cemiplimab is the first FDA (2021) approved anti-PD-1 antagonist for the systemic treatment of laBCC and mBCC which had previously shown disease progression on or intolerance to HHIs. Experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is associated with a risk of organ graft rejection, advantages and disadvantages should be evaluated for every individual OTR patient with laBCC or mBCC, eligible for cemiplimab therapy.

Reprogramming of mRNA translation has a key role in cancer development and drug resistance 1 . However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation 2 , 3 . Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U 34 ) tRNA (U 34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAF V600E -expressing melanoma cells are dependent on U 34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U 34 enzymes. Mechanistically, U 34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U 34 enzymes and HIF1α. Together, these results demonstrate that U 34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.

565 findings may, as in the present case, indicate a combination of traits indicative of psoriasis and toxicoderma [7, 8]. In most of these patients, the lesions can be controlled with topical therapy [4-6, 8]. In the present case, however, the skin condition not only worsened when the anticancer therapy was stopped (perhaps because cessation coincided with the withdrawal of oral corticosteroids) but also prevented the use of alternative therapies to halt tumour progression. Ixekizumab is an anti-IL-17A drug approved for the treatment of moderate-to-severe plaque psoriasis. It is highly effective and produces a rapid clinical response, achieving a 75-90% reduction in PASI score in 70-90% of patients at 12 weeks [9]. A case of prembrolizumab-induced psoriasis treated with secukinumab is documented in the literature [10]. However, there are no previous reports of ixekizumab use for psoriasis triggered by tremelimumab and durvalumab. In the present case, given the urgent need to obtain clinical remission, ixekizumab was administered, achieving complete resolution of the skin condition within a few weeks. Biologic therapy may be a rapid and effective therapeutic option in patients with severe psoriasis triggered by immunotherapy, although more information is needed on long-term outcome and safety in these patients.

The management of melanoma is a typical example of a pluridisciplinary approach, in order to provide the patient with a rapid and adequate treatment plan after the initial diagnosis. Both in the domains of dermatology, pathology and oncology, enormous progress has been made. Recent advances permit a rapid access to diagnostic techniques using teledermoscopy, an improved diagnostic accuracy using dermoscopy, pre-interventional high-frequency ultrasound and optical coherence tomography, a determination of risk factors using immunohistochemistry and genetic analyses on the pathology samples. Furthermore, the development of immunotherapies, in particular the anti-PD1 antibodies, and the directed therapies, therapies permitting an increased number of patients to experience an increased survival with an acceptable tolerance profile in the event of metastatic lesions. This article describes the patient's care pathway, from the initial diagnosis, staging, to an eventual treatment and follow-up.

Abstract Background The spread of the COVID‐19 pandemic has led to a rapid reorganization in all human and hospital activities, with impact on cancer patients. Aim An analysis of cancer patients fears, and awareness of COVID‐19 has been done in this study. Methods and results We analyzed cancer patients' reactions to the pandemic and their perception of oncological care reorganization, through a 12‐item survey, proposed at the peak of pandemic and 3 months later. Overall, 237 patients were included in the study. During the peak of pandemic 34.6% of patients were more worried about COVID‐19 than cancer versus 26.4% in the post‐acute phase (p = .013). Although 49.8% of patients in the acute phase and 42.3% in the post‐acute phase considered their risk of death if infected ≥50%, and more than 70% of patients thought to be at higher risk of complications, the majority of them did not consider the possibility to stop or delay their treatment. Patients were more interested in following news about COVID‐19 than cancer and they complied with all preventive measures in more than 90% of the cases. Conclusions Although cancer patients worried about COVID‐19 and evaluated the risk of complication or death due to COVID‐19 as extremely high, they were still asking for the best oncological treatment.

INTRODUCTION:Locally advanced cutaneous squamous cell carcinoma (lacSCC) is rare. Approximately one-fourth of the cases are observed among immunocompromised patients, in particular in solid organ transplant recipients (OTRs). LacSCC has a very poor prognosis. Surgery with or without radiotherapy remains the golden standard of treatment for cSCC. However, in advanced cases, there is a medical need for alternative treatment options. Classic systemic treatments include chemotherapy and/or EGFR inhibitors. Recently the effectiveness of programmed cell death protein-1 (PD-1) inhibitors has been demonstrated for lacSCC. Cemiplimab is a recombinant IgG4 human monoclonal antibody against the PD-1 protein for the intravenous treatment of lacSCC.AREAS COVERED:The principal studies evaluating the efficacy and safety of cemiplimab for lacSCC are presented.EXPERT OPINION:Cemiplimab is the first anti-PD-1 antibody that was FDA (2018) and EMA (2019) approved as a systemic treatment for lacSCC and/or metastatic cSCC when curative surgery or radiotherapy is no longer amenable. For this situation, experts currently recommend cemiplimab as a first-line systemic alternative. As cemiplimab therapy is potentially associated with a risk of organ graft rejection, pros and cons should be evaluated for every individual OTR patient with lacSCC.

No data concerning systemic oncological treatments' safety during COVID-19 outbreak were available in Belgium. The aim of this study is to analyse patients' perception of both the risk of infection and the need for change in clinical practice in oncology. A 12-items questionnaire using the Likert scale for 11 of these questions concerning the patients' perception of COVID-19 was distributed to patients admitted for systemic therapy of solid tumours in our day-care unit between April 14th and 30th, 2020 (4-6 weeks after lockdown in Belgium). 237 patients were included in our research project after signing an informed consent. Median age was 63 years-old (range 26-90). Most patients suffered from lung (n=59), breast (n=54), gastrointestinal (n=47), gynaecological (n=34) or urological (n=16) cancers or melanoma (n=15). 87 patients received (neo)adjuvant treatments, 150 patients were treated for metastatic disease. Patients received chemotherapy (n=106), immunotherapy (n=60), targeted therapy (n=36) or combinations (n=35). The patients who estimated their risk of dying because of COVID-19 infections as <0.1%, 1%, 10%, 20%, 50% or 100% were respectively 9.7%, 15.2%, 13.5%, 6.3%, 32.4%, 11.4% (no opinion: 10.8%). Most patients agreed (21.5%) or strongly agreed (64.6%) that it is important for them to receive the best cancer treatment available even if this may increase the infection risk. Very few patients agreed (1.3%) or strongly agreed (2.5%) that they were considering stopping the ongoing therapy because of the COVID-19 outbreak. Most patients agreed (33.8%) or strongly agreed (49.4%) that the institution was doing everything possible for risk reduction of contamination while receiving the therapy in the day-care unit. Although patients evaluated the risk of dying due to COVID-19 infection as extremely high, they are still asking for the best oncological care available. The majority recognize the effort of the institution in minimizing infectious risk. Additional analyses will be reported at time of presentation. Questionnaires will be repeated 3 months after the peak of the COVID-19 outbreak.

No specific safety data concerning systemic oncological treatments were available at time of COVID-19 outbreak in Belgium. In our hospital we decided to maintain adjuvant and early line treatments for metastatic disease in patients under 65 and without specific comorbidities and to apply a shared decision approach in other patients while following closely the safety of these treatments. Real time safety monitoring was proposed to all patients treated for solid tumours in our day-care unit starting March 1st, 2020. After signing informed consent patients were asked questions concerning protective measures at home, signs of SARS-CoV-2 infection and hospitalisation. Patients' charts were reviewed for outcome, including death, after suspected or proven SARS-CoV-2 infection. Minimum follow-up was 5 weeks after day care unit attendance. 387 patients were included in our registry between March 1st and March 31st, 2020. Median age was 64 years-old (range 27-90). Most patients suffered from lung (n=96), breast (n=93), gastrointestinal (n=87), gynaecological (n=38) or urological (n=33) cancers. 131 patients received (neo)adjuvant treatments, 256 patients were treated for metastatic disease. Patients received chemotherapy (n=170), immunotherapy (n=103), targeted therapy (n=68) or other combinations (n=46). Although Belgium had one of the highest infection rates in the world, safety data concerning risk of SARS-CoV-2 infection and outcomes were rather reassuring. A total of 11 patients had either suspected (n=5, 1.3%) or proven (n=6, 1.6%) SARS-CoV-2 infection. Only one 74 years old patient died of COVID-19, another 51 years old patient died of progressive disease but presented also suspicion of SARS-CoV-2 infection at the time of death. Analysis of our data for patients treated in March 2020 in the day-care unit are reassuring and suggest higher risk related to under-treatment compared to risk related to continuation of systemic therapy at time of COVID-19 outbreak. Patients' follow-up will be updated and additional analyses and data in particular for April 2020, when the infection rate was still extremely high in Belgium, will be presented.

We report the case of a 47-year-old woman with unexplained inflammatory syndrome and asthenia. Imaging findings show bilateral abnormalities of femurs and tibias, suggesting an Erdheim-Chester disease, which is confirmed by a bone marrow biopsy of the left femur. The BRAF V600E mutation is detected, allowing the administration of targeted therapies such as BRAF and MEK inhibitors that lead to the improvement of symptoms.