Gender Difference in sidE eFfects of ImmuNotherapy: a possible clue to optimize cancEr tReatment (G-DEFINER): study protocol of an observational prospective multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Translational Insights in the Landscape of Salivary Gland Cancers: Ready for a New Era?

Salivary gland carcinomas (SGCs) are rare neoplasms, representing less than 10% of all head and neck tumors, but they are extremely heterogeneous from the histological point of view, their clinical behavior, and their genetics. The guidelines regarding their treatment include surgery in most cases, which can also play an important role in oligometastatic disease. Where surgery cannot be used, systemic therapy comes into play. Systemic therapy for many years has been represented by polychemotherapy, but recently, with the affirmation of translational research, it can also count on targeted therapy, at least in some subtypes of SGCs. Interestingly, in some SGC histotypes, predominant mutations have been identified, which in some cases behave as "driver mutations", namely mutations capable of governing the carcinogenesis process. Targeting these driver mutations may be an effective therapeutic strategy. Nonetheless, it is not always possible to have drugs suitable for targeting driver mutations-and targeting driver mutations is not always accompanied by a clinical benefit. In this review, we will analyze the main mutations predominant in the various histotypes of SGCs.

Tumor molecular landscape of Epstein-Barr virus (EBV) related nasopharyngeal carcinoma in EBV-endemic and non-endemic areas: Implications for improving treatment modalities.

Epstein-Barr virus (EBV) related- nasopharyngeal carcinoma (NPC) is a squamous carcinoma of the nasopharyngeal mucosal lining. Endemic areas (EA) are east and Southeast Asia, were NPC was recorded with higher incidence and longer estimated survival than in non-endemic area (NEA) such as Europe, We analyzed the gene expression and microenvironment properties of NPC in both areas to identify molecular subtypes and assess biological and clinical correlates that might explain the differences in incidence and outcome between EA- and NEA-NPCs. Six EA-NPC transcriptomic datasets, including tumor and normal samples, were integrated in a meta-analysis to identify molecular subtypes using a ConsensusClusterPlus bioinformatic approach. Based on the biological/functional characterization of four identified clusters were identified: Cl1, Immune-active; Cl2, defense-response; Cl3, proliferation; Cl4, perineural-interaction/EBV-exhaustion. Kaplan-Meier survival analysis, applied to the single dataset with available disease-free survival indicated Cl3 as the cluster with the worst prognosis (P = 0.0476), confirmed when applying four previously published prognostic signatures. A Cl3 classifier signature was generated and its prognostic performance was confirmed (P = 0.0368) on a validation dataset. Prediction of treatment response suggested better responses to: radiotherapy and immune checkpoint inhibitors immune-active and defense-response clusters; chemotherapy proliferation cluster; cisplatin perineural-interaction/EBV-exhaustion cluster. RNA sequencing for gene expression profiling was performed on 50 NEA-NPC Italian samples. In the NEA cohort, Cl1, Cl2 and Cl3 were represented, while perineural-interaction/EBV-exhaustion was almost absent. The immune/biological characterization and treatment-response prediction analyses of NEA-NPC partially replicated the EA-NPC results. Well characterized EA- and NEA-NPC retrospective and prospective cohorts are needed to validate the obtained results and can help designing future clinical studies.

HER2-targeted therapies for salivary gland cancers.

Salivary gland cancers (SGCs) are a heterogeneous group of rare tumors including various histological subtypes with different molecular profiling. Human epidermal growth factor receptor 2 (HER2) is one of the most intriguing and studied molecular alterations with prognostic and predictive roles. Indeed, HER2 overexpression is commonly correlated with aggressive histological subtypes and poorer prognosis. However, HER2 may represent the target of personalized treatment. We performed a literature review of use of anti-HER2 targeted agents for treatment of recurrent or metastatic SGCs. The efficacy and safety of anti-HER2 were firstly evaluated in patients affected with other solid tumors, mostly breast and gastric cancers. For SGCs the literature is mainly comprised of case reports or case series and small clinical trials. The most common used drug is trastuzumab in combination with chemotherapy (i.e. taxanes, capecitabine, carboplatin, eribulin) or with another anti-HER2 targeted agent (i.e. pertuzumab). The use of anti-HER2 therapies induces improvement in clinical responses, which are mostly durable. Besides, new anti-HER2 drugs such as antibody-drug conjugates (ADC) (i.e. trastuzumab emtansine, trastuzumab deruxtecan) have been introduced in this setting inducing further therapeutic advances. Anti-HER2 treatment strategy is emerging as potentially effective in selected HER2 overexpressing SGCs. However, prospective and multicentric clinical trials are needed to evaluate the efficacy of these therapeutic regimens within larger cohorts and to assess the most appropriate treatment sequence strategy.

Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Multidisciplinary management of pregnancy-associated and early post-partum head and neck cancer patients.

Background: Pregnancy-associated cancer (PAC) occurs during pregnancy or within 12 months after the delivery. Head and neck cancer (HNC) during pregnancy is infrequent, therefore diagnosis and personalized therapy are intricate. Methods: We investigated outcomes of 15 PAC patients (5 salivary, 4 nasopharyngeal, 3 thyroid, 2 oral cavity, one HPV-related carcinoma) diagnosed in the period 2005-2019. A literature review on PAC is provided. Results: Median gestational age at PAC diagnosis was 28 weeks (range: 16-40 weeks) in ten cases, at 5 months after delivery (range: 1 week-6 months) in the remaining five. Treatments included surgery (3 during pregnancy, 5 after childbirth), chemoradiation (8), and 3 patients with upfront metastatic disease received chemotherapy. Median survival was 6.6 years (eight women remain with no evidence of disease six years after diagnosis). Conclusion: All patients received state-of-the-art therapy, with encouraging long-term results, highlighting treatment safety in women with HNC during pregnancy.

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience.

OBJECTIVES: Cisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. MATERIAL AND METHODS: We retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6-20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. RESULTS: Of the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. CONCLUSIONS: Identifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes.

Muscle quality and not quantity as a predictor of survival in head and neck squamous cell carcinoma.

BACKGROUND: Sarcopenia is frequent in head and neck squamous cell carcinoma (HNSCC), as a consequence of malnutrition related to risk factors or tumoral mass. Treatment is associated with toxicities that lead to reduced calories intake and muscle mass wasting. Sarcopenia has been negatively associated with tumor control and survival outcomes. PURPOSE: Our aim is to evaluate the prognostic impact of sarcopenia on overall survival (OS) and progression free survival (PFS) in HNSCC patients undergoing chemoradiation therapy within a prospective clinical trial of chemoradiation vs induction chemotherapy followed by radiation and cetuximab (INTERCEPTOR). MATERIALS AND METHODS: On baseline CT or MRI, we investigated the association between OS and PFS with radiological markers of sarcopenia, measured at the third cervical vertebra level. We studied paravertebral skeletal muscles area (cm2), muscle density (HU), muscle index (cm2/m2), and intermuscular adipose tissue (IMAT) area (cm2). RESULTS: Imaging of 128 patients was evaluable. We found out that higher body mass index (BMI) was associated with better OS (p = 0.02), and PFS (p = 0.04). Skeletal muscle area (p = 0.02), and IMAT (p = 0.02) were negatively associated with PFS. IMAT was positively correlated with muscle area (Correlation coefficient 0.6, CI95% 0.47-0.7), and negatively associated with muscle density (Correlation coefficient -0.37, CI95% -0.53 - -0.18). CONCLUSIONS: IMAT can be used as predictor of PFS in HNC patients undergoing chemoradiation therapy. The amount of intermuscular fat deposits induces alterations of muscle quality, without alterations of muscle quantity, influencing patients' prognosis.

A systematic review and meta-analysis on the optimal treatment duration of checkpoint inhibitoRS in solid tumors: The OTHERS study.

No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). We performed a systematic review and meta-analysis of randomized controlled trials reporting the duration of ICIs (alone or in combination with standard of care (SoC)) across various solid tumors. Overall, we identified 28,417 records through database searching. Based on the eligibility criteria, 57 studies were identified for the quantitative synthesis, including 22,977 patients receiving ICIs (with or without SoC). Prolonged ICI correlated with better overall survival (OS) than 2yICI in patients with melanoma (HR:1.55; 95%CI: 1.22,1.98), while 2yICI-SoC led to better OS than prolonged ICI-SoC in patients with NSCLC (HR: 0.84; 95%CI: 0.68,0.89). Prospective randomized trials are needed to assess the most appropriate duration of ICIs. OBJECTIVE: No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). Here, we assessed the optimal treatment duration for ICIs in solid tumors. CONCLUSIONS: Prolonged ICIs administration does not seem to improve the outcomes of patients with NSCLC an RCC.

The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer.

Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.

The Interplay between Age and Viral Status in EBV-Related Nasopharyngeal and HPV-Related Oropharyngeal Carcinoma Patients.

Background. The aim of this work was to analyze the interplay between age and viral status on the outcomes in loco-regionally advanced oropharyngeal and nasopharyngeal cancer patients treated with radiotherapy and different chemotherapy combinations. Methods. A retrospective (2006−2017) analysis was performed on non-metastatic loco-regionally advanced oropharyngeal (both HPV+ and HPV−) and EBV+ nasopharyngeal cancer patients (young: <65 years vs. elderly: ≥65 years) treated with radiotherapy with or without chemotherapy. The impact of age and viral status on overall (OS) and disease-free survival (DFS) were studied with multivariable models, which were adjusted for smoking, stage, comorbidities, chemotherapy dose intensity and treatment strategy. Results. We analyzed 324 patients (146 HPV+ oropharynx, 63 HPV−, 115 nasopharynx). Elderly patients had more comorbidities, and received less intensive treatments when compared to younger subjects. Although OS and DFS were shorter in older patients, after adjustment for stage, smoking, comorbidities, treatment strategy and dose intensity, no significant differences in terms of survival were observed according to age (65 vs. 50 years of age: HR 1.89, 95% CI 0.45−7.84 for HPV+ OPC; HR 0.91, 95% CI 0.29−2.89 for HPV− OPC; HR 1.99, 95% CI 0.9−4.39 for NPC; p = 0.395). Conclusions. Several potential age-related (comorbidities, treatment intensity) and disease-related (stage) confounding factors play a prognostic role with differential impacts on both virus and non-virus-related tumors. In HPV+ oropharyngeal cancer and in EBV+ nasopharyngeal cancer patients, age should be considered as the expression of an array of host- and tumor-related features rather than an independent prognostic factor.

Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown. METHODS: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model. RESULTS: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED. CONCLUSIONS: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.

Comparing BamHI-W and CE-marked assays to detect circulating Epstein-Barr Virus (EBV) DNA of nasopharyngeal cancer patients in a non-endemic area.

OBJECTIVES: Plasma Epstein-Barr Virus (EBV)-DNA is a well-established prognostic biomarker in nasopharyngeal carcinoma (NPC). Different methods for assessment include single-copy gene targeted, European Conformity (CE)-marked assays, which are mostly employed in non-endemic settings, vs multiple-copy gene targeted, in-house BamHI-W based assays, which currently represent the most widely used method for EBV-DNA quantification. To date, evidence concerning the commutability of these different assays is still limited. MATERIALS AND METHODS: From August 2016 to March 2018, 124 plasma and 124 whole blood (WB) samples from 93 NPC patients were collected at different time-points for each patient. EBV-DNA viral load was quantified in pre- (n = 12) and post-treatment (n = 9), follow-up (n = 53), and recurrent/metastatic (R/M) (n = 50) phase. For each sample, one in-house BamHI-W vs three different CE-marked plasma assays were compared; the performance of plasma vs WB matrix was also assessed. Quantitative agreement of EBV-DNA values was evaluated by linear correlation and Bland-Altman analysis. RESULTS: A statistically significant (p = 0.0001) agreement between all CE-marked and the BamHI-W assays was found using plasma matrix, regardless of clinical phase. The results obtained in copies/ml were comparable to those expressed in IU/ml. When using WB matrix, the number of positive detections increased in the post-treatment phase. CONCLUSIONS: Our retrospective comparison supported an agreement between Plasma BamHI-W and CE-marked assays in measuring EBV-DNA for non-endemic NPC patients. There were no significant interferences from different measurement units (IU/ml vs copies/ml). Further evaluations are needed to better clarify the role of WB.

Tissue and circulating PD-L2: moving from health and immune-mediated diseases to head and neck oncology.

Amongst the chief targets of immune-checkpoint inhibitors (ICIs), namely the Programmed cell death protein 1 (PD-1)/PD-Ligands (Ls) axis, most research has focused on PD-L1, while to date PD-L2 is still under-investigated. However, emerging data support PD-L2 relevant expression in malignancies of the head and neck area, mostly in head and neck squamous cell carcinoma (HNSCC) and salivary gland cancers (SGCs). In this context, ICIs have achieved highly heterogeneous outcomes, emphasizing an urgent need for the identification of predictive biomarkers. With the present review, we aimed at describing PD-L2 biological significance by focusing on its tissue expression, its binding to PD-1 and RGMb receptors, and its impact on physiological and anti-cancer immune response. Specifically, we reported PD-L2 expression rates and significant clinical correlates among different head and neck cancer histotypes. Finally, we described the biology of soluble PD-L2 form and its potential application as a prognostic and/or predictive circulating biomarker.

Monitoring patients with head and neck cancer for flu-like symptoms during the COVID-19 pandemic.

OBJECTIVE: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic. METHODS: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2. RESULTS: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications (p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 (p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m2, p = 0.0066). CONCLUSIONS: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

Prognostic factors in salvage surgery for recurrent head and neck cancer: A systematic review and meta-analysis.

INTRODUCTION: Although salvage surgery (SS) is considered the best curative choice in recurrent head and neck cancer, the identification of patients who can benefit the most from this treatment is challenging. METHODS: We systematically reviewed the prognostic role of pre- and post-surgery factors in patients undergoing SS for recurrent head and neck cancer (oral cavity, oropharynx, hypopharynx, and larynx). RESULTS: Twenty-five studies met the inclusion criteria out of 1280 screened citations. Pre-surgery factors significantly associated with worse overall survival were age>60 years, advanced initial stage, early recurrence, and regional recurrence; no heterogeneity between study emerged. Among post- surgery factors, worse survival emerged for positive surgical margins, extracapsular extension and perineural invasion. CONCLUSION: The identification of pre-surgery factors associated with poor outcomes may help the selection of the best candidate to SS; alternative treatments should be considered for high-risk patients. Post-surgery predictors of worse prognosis may guide clinicians in tailoring patients' surveillance.

HER2 status in recurrent/metastatic androgen receptor overexpressing salivary gland carcinoma patients.

Background: Overexpression of human epidermal growth factor receptor type 2 (HER2) occurs in almost 25-30% of androgen receptor (AR)-positive salivary gland carcinomas (SGCs), notably salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified (NOS). In the last years, several studies have reported the clinical benefit of HER2 directed therapies in this setting. This work aims at describing the natural history of AR-positive recurrent/metastatic (R/M) SGC patients, based on HER2 amplification status. Methods: Consecutive R/M AR-positive SGC patients accessing our Institution from 2010 to 2021 were analyzed. Descriptive statistics and survival analyses were performed to present the clinical characteristics of the selected patients and the outcomes, based on HER2 status. A specific focus was dedicated to patients developing metastases to the central nervous system (CNS). Results: Seventy-four R/M AR-positive SGC patients (72 men) were analyzed. Median follow-up was 36.18 months (95% CI 30.19-42.66). HER2 status was available in 62 cases (84%) and in 42% the protein was overexpressed (HER2+). Compared with patients with HER2- SGCs, in patients with HER2+ disease, HR for disease recurrence was 2.97 (95% CI 1.44-6.1, p=0.003), and HR for death from R/M disease was 3.22 (95% CI 1.39-7.49, p=0.007). Moreover, the HER2+ group showed a non-significant trend towards a higher prevalence of CNS metastases (40% vs. 24%, p=0.263). Patients developing CNS metastases had shorter survival than those who did not; at bivariate analysis (covariates: CNS disease and HER2 status), HER2 status demonstrated its independent prognostic significance. Discussion: In our patient population, HER2 amplification was a negative prognostic factor, and it was associated with a non-statistically significant higher risk of developing CNS metastasis. Further studies are needed to explore the potential clinical benefit of tackling the two biological pathways (AR and HER2) in patients affected by this rare and aggressive malignancy.

Abiraterone Acetate in Patients With Castration-Resistant, Androgen Receptor-Expressing Salivary Gland Cancer: A Phase II Trial.

PURPOSE: The activity of androgen-deprivation therapy (ADT) in androgen receptor-positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS: This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS: From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non-drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION: Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.

Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. METHODS: This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. RESULTS: 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3-4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status ≥1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. CONCLUSIONS: Our real-world study showed safety and effectiveness results comparable to those obtained in clinical trials. We identified some clinical and biochemical factors potentially associated with response to cemiplimab.