In the phase III CheckMate 238 trial, NIVO showed improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs IPI in pts with high-risk, resected stage IIIB–C or IV melanoma, sustained for 5 y; no significant difference was observed in OS. Updated 7-y results are presented. Pts aged > 15 y (stratified by disease stage and PD-L1 status) were randomized 1:1 to NIVO 3 mg/kg Q2W (n = 453) or IPI 10 mg/kg Q3W for 4 doses then Q12W (n = 453), for up to 1 y or until disease recurrence/unacceptable toxicity. Endpoints included RFS, OS, DMFS in stage III pts, and safety. Progression-free survival through next-line therapy (PFS2) and melanoma-specific survival (MSS) are post hoc analyses presented here for the first time. At 7-y, RFS remained superior with NIVO vs IPI (HR 0.74; 95% CI 0.62–0.88) with DMFS and PFS2 also favoring NIVO (Table). New recurrence events since 5 y included 12 new events (2 regional, 7 distant, 2 new primary, 1 death) for NIVO and 7 new events (1 local, 2 distant, 4 deaths) for IPI; 6% and 5% of at-risk pts relapsed after yr 5. For NIVO vs IPI respectively, there were a total of 13 and 12 new deaths overall (8 and 10 due to melanoma). Subsequent systemic therapy was less frequent with NIVO than IPI (36% vs 44%), including subsequent immunotherapy in 26% vs 36% of pts. No new voluntarily reported late-emergent treatment-related adverse events were reported since the 4-y database lock, and overall rates remain low. At 7-y follow-up, the longest follow-up of any anti–PD-1 therapy in this setting, NIVO showed superior long-term RFS vs IPI in pts with stage IIIB–C or IV resected melanoma. DMFS and PFS2 also favored NIVO, and OS and MSS rates were high in both arms, with no significant difference between arms. The additional recurrences at 7-y vs 5-y follow-up may indicate a clinical consideration for imaging and follow-up visits beyond 5 y.Table: 1089PNIVO (n = 453)IPI (n = 453)7-y rates, % (95% CI) HRa (95% CI)RFS45 (40–50)38 (33–42)0.74 (0.62–0.88)OS71 (66–75)69 (64–73)0.89 (0.70–1.14)MSS75 (70–79)72 (68–76)0.89 (0.68–1.16)DMFSb54 (48–60)50 (44–55)0.82 (0.66–1.01)PFS259 (54–64)52 (48–57)0.76 (0.62–0.93)aNIVO vs IPI (Stratified Cox proportional hazards model). bIn stage III patients (NIVO = 307; IPI = 366). Open table in a new tab

Dans l'essai clinique de phase 3 CheckMate 238, NIVO a démontré une amélioration de la survie sans récidive (SSR) et de la survie sans métastases à distance (SSMD) versus IPI, maintenues pendant 5 ans, chez les patients à haut risque de récidive atteints d'un mélanome opéré, de stade IIIB-C ou IV. Aucune différence significative n'a été observée pour la survie globale (SG). Les résultats actualisés à 7 ans sont présentés. Des patients âgés de plus de 15 ans (stratifiés selon le stade de la maladie et le statut PD-L1) ont été randomisés 1 :1 dans le bras NIVO 3 mg/kg toutes les 2 semaines (n = 453) ou dans le bras IPI 10 mg/kg toutes les 3 semaines pour 4 doses puis toutes les 12 semaines (n = 453), jusqu'à 1 an ou jusqu'à récidive de la maladie ou toxicité non acceptable. Les critères d'évaluation comprenaient la SSR, la SG, la SSMD chez les patients de stade III et la tolérance. La survie sans progression jusqu'à la prochaine ligne de traitement (SSP2) et la survie spécifique au mélanome (SSM) sont des analyses post hoc présentées ici pour la première fois. À 7 ans, la SSR est restée supérieure avec NIVO par rapport à IPI (HR 0,74 ; IC à 95 % 0,62–0,88), la SSMD et la SSP2 étant également en faveur de NIVO. Les nouveaux cas de récidive survenus depuis l'analyse à 5 ans comprenaient 12 nouveaux événements (2 régionaux, 7 distants, 2 nouveaux mélanomes primaires, 1 décès) pour NIVO et 7 nouveaux événements (1 local, 2 distants, 4 décès) pour IPI ; 6 % et 5 % des patients à risque ont rechuté après la 5ème année. Pour NIVO vs IPI respectivement, il y a eu un total de 13 et 12 nouveaux décès (8 et 10 dus au mélanome). Les traitements systémiques ultérieurs ont été moins fréquents avec NIVO qu'avec IPI (36 % contre 44%), y compris les traitements par immunothérapie chez 26 % vs 36 % des patients à récidive. Aucun nouvel événement indésirable (EI) tardif lié au traitement n'a été signalé depuis le gel de la base de données à 4 ans, et globalement les taux de survenus des EI restent faibles. Après un suivi de 7 ans, le plus long suivi de toute les thérapies anti-PD-1 dans ce contexte, NIVO a montré une SSR à long terme supérieure à celle de l'IPI chez les patients atteints de mélanome réséqué de stade IIIB-C ou IV. La SSMD et la SSP2 étaient également en faveur de NIVO, et les taux de SG et de SSM étaient élevés dans les deux bras, sans différence significative entre les bras. Les récidives survenant entre 5 et 7 ans peuvent justifier d'adaptation du suivi clinique et/ou radiologique. Précédemment présenté au Congrès de l'ESMO 2023, FPN : 5427, Paolo Ascierto et al. – Réutilisé avec permission.

Background: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date. Materials and methods: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors. Results: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together. Conclusions: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

BACKGROUND:In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT).PATIENTS AND METHODS:The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included.RESULTS:Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS [hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001] and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS [adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028] was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS [aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513] and OS [aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548].CONCLUSIONS:ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.

Background: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. Methods: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. Results: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. Conclusions: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.

The European SARS-CoV-2 pandemic had its first epicentre in Italy, particularly in the area of Bergamo. In spite of a significant mortality rate, in the majority of cases the spectrum of COVID-19 ranges from asymptomatic to mildly symptomatic infection. No information is available on the prevalence and clinical impact of asymptomatic or mildly symptomatic SARS-CoV-2 infection among actively treated cancer patients during pandemic. From April 1st, 2020 to the end of the month, 560 consecutive and unselected patients, scheduled for anticancer treatment at our facility and without clinical suspicious of COVID-19, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including a rapid serological immunoassay for anti-SARS-CoV-2 IgG/IgM and a pharyngeal swab RT-PCR assay in case of IgM seropositivity. In 560 patients, 172 (31%) resulted positive for SARS-CoV-2 IgM/IgG antibodies, regardless of type of cancer, stage and treatment. All IgM-seropositives were then tested with RT-PCR pharyngeal swabs and 55/146 (38%) proved to be SARS-CoV-2 carriers, with slightly difference b/w mildly symptomatic vs. asymptomatic patients (38 vs. 17). Therefore, the two-step procedure allowed the identification of 55 (10%) silent carriers in the whole study population and magnified the number needed to test (NNT) with the pharyngeal swab RT-PCR assay to detect a silent virus carrier (NNT: 2.6 vs. 10, with or without serological selection). At a very early follow up (8 wks), in 114 SARS-CoV-2-seropostive/RT-PCR-negative patients, who continued their anticancer therapies, none but one developed a symptomatic COVID-19 illness. Among cancer patients, the two-step diagnostics strategy with serology followed by pharyngeal swab for asymptomatic or mildly symptomatic SARS-CoV-2 infection is feasible and effective and can help selecting cancer patients on treatment who might be silent carriers of the virus. The early safety outcome of patients previously exposed to SARS-CoV-2 supports the recommendation to continue active treatment, at least in the case of negative RT-PCR test.

BACKGROUND:The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). OBJECTIVES:To investigate whether the extent of ulceration (EoU) predicts relapse-free survival (RFS) and overall survival (OS) in PCM. MATERIALS AND METHODS:We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. RESULTS:A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1-mm increase) 1·26, 95% confidence interval (CI) 1·08-1·48, P = 0·0047] and OS [HR (1-mm increase) 1·25, 95% CI 1·05-1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour-infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01-4 mm and > 4 mm BT. CONCLUSIONS:This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports.

Backgroud Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile. Method We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms. Results We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents. Conclusion This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.

Background We have previously shown that a possible complementary target to PD1-based immune-checkpoint blockade (ICB) is the adhesion molecule CD155, which promotes tumor growth and metastasis in mouse models. To date, it is unclear to what extent tumor CD155 expression impacts the immune infiltrate contexture or if expression of CD155 by human tumors affects sensitivity to ICB. Methods We assessed pretreatment tumor FFPE specimens from 146 metastatic melanomas patients treated with immune checkpoint blockade (ICB) and 41 patients that have received 1st line BRAF/MEK targeted therapy and no ICB. CD155 expression was defined by immunohistochemistry (IHC) H-score. The immune infiltrate was separately analysed in stroma and parenchymal (intratumor) regions using multiplex immunohistofluorescence (IHF) for CD8, PD1 and SOX10. Associations were made between IHC analyses, bulk tumor RNA-seq results, and immunotherapeutic response (RECIST, PFS, and disease specific OS). Key findings were functionally validated in a relevant mouse melanoma model. Results Melanoma patients with high levels of tumor CD155 (score 3+) frequently had progressive disease or shorter PFS through promotion of dysfunctional PD1+CD8+ T cells. Further, the intratumor ratio of PD1+CD8+ to total CD8+ T cells (PD1tR) is a strong predictor of ICB refractory patients. Importantly, outcome correlations appeared specific to ICB therapy and were not present in melanoma patients treated with BRAF/MEK targeted therapy. In humans, CD155 high tumors show reduced Interferon-gamma and cytotoxic gene signatures. In PD1 resistant mouse tumor models, deletion of CD155 prevented accumulation of intratumor PD1hiCD8+ T cells. Additionally, therapeutic blockade of the CD155 cognate receptors TIGIT and CD96 restored IFNγ production and improved anti-PD1 tumor control. Conclusion Our findings are the first to demonstrate that tumor CD155 underpins the accumulation of dysfunctional PD1hiCD8+ T cells in human tumors and propose pretreatment PD1tR as a potential biomarker of response to ICB. Legal entity responsible for the study The Council of the Queensland Institute of Medical Research. Funding Bristol-Myers Squibb. Disclosure P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (self): Array; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore. G. V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. R. A. Scolyer: Advisory / Consultancy: Merck Sharp Dohme; Advisory / Consultancy: Novartis; Advisory / Consultancy: Myriad; Advisory / Consultancy: NeraCare. W. C. Dougall: Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Omeros Corporation ; Advisory / Consultancy: Cascadia Drug Development Group. M. W. L. Teng: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. M. Smyth: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Aduro Biotech; Research grant / Funding (self): Tizona Pharmaceuticals. All other authors have declared no conflicts of interest.

Introduction: Stratification of cancer outpatients for VTE risk before anti-tumor therapies is an area of intense investigation. Besides tumor-related and patients-related risk factors, different hemostatic biomarkers may possibly play a role in the prediction of VTE development in these patients. The use of risk assessment models (RAM) involving both clinical and biological (i.e. circulating thrombotic markers) parameters appears to be a very important and promising approach to identify patients at high VTE risk.

Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutateci in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L 1 or PD-L2. Furthermore, the presence of oncogenic BRAF leads to an immune suppressive phenotype characterized by the presence of inhibitory immune cells such as regulatory T cells, myeloid-derived suppressor cells, or tumor-associated macrophages, which can in turn inhibit the function of tumor-infiltrating T cells. Growing evidence suggests that, in addition to their established molecular mechanism of action, the therapeutic efficacy of BRAF inhibitors and MEK inhibitors relies on additional factors that affect the tumor-host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Focus of the present review is to summarize the off target mechanisms of response to BRAF inhibitors and MEK inhibitors and the synergy between targeted therapy and immunotherapy as the biologica! source to open a window of strategie opportunities for the design of new exciting clinica! trials.

Background: Identification of cancer outpatients who might benefit from primary thromboprophylaxis is still actually a major challenge for cancer patient management. A promising approach is the stratification of patients according to their risk of thrombosis, applying risk assessment models that include clinical parameters and biomarkers. Aim of this study is to assess whether in a cohort of newly diagnosed metastatic non-small cell-lung, gastric, colorectal and breast cancer patients, enrolled in the ongoing HYPERCAN study (Thromb.Res. 2014), the measurement thrombin generation assay (TG), fibrinogen, and D-dimer, may be predictive of VTE and may help physician in the better treatment of cancer patients. Methods: As of September 2016, overall 739 patients with metastatic cancer have been enrolled. Blood samples of patients are collected at enrollment (before starting chemotherapy treatment), after 3 and 6 chemotherapy cycles, and at end of treatment, or earlier if VTE occurrence or cancer disease progression. We measured TG, fibrinogen, and D-dimer levels at enrollment from the first 433 patients (NSCL= 50.1%, gastric= 11.5%, colorectal= 20.6%, breast= 17.8%). TG was measured by the Calibrated automated thrombogram (CAT assay, STAGO, France) at 1pM TF and results expressed as Peak of thrombin; fibrinogen and D-dimer were measured by commercial assays (Q.F.A. Thrombin; D-dimer HS; Werfen, Italy). Results: In our group of patients, VTE incidence is 25%. At enrollment, patients have Peak, fibrinogen and D-Dimer levels significantly greater than those of healthy subjects (p < 0.01). Pre-chemotherapy levels of D-dimer ≥493 ng/ml or Peak ≥407 nM are associated with increased VTE rates (p < 0.05). Differently, fibrinogen levels are not associated with an increased VTE risk. Khorana score fails to identify HYPERCAN patients at higher risk of VTE. We tried to modify the Khorana score adding D-dimer and Peak, assigning 1 point to each biomarker over the cut-off value. Integration of the Khorana score with these biomarkers allowed us to identify those patients at higher VTE risk. Conclusions: This study supports the hypothesis that measurement of plasma coagulation markers can improve the identification of cancer subjects at high VTE risk. These subjects may probably be best candidate for primary thromboprophylaxis. Project funded by AIRC "5xMILLE" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)".

Background: Screening for breast cancer has greatly increased early diagnoses, leading to anticipated cancer treatments by surgery and systemic adjuvant chemotherapy (SAC) and reducing the risk of disease recurrence (DR). However, local relapses and distant metastasis may occur in 2-7% and 20% of resected patients, respectively, in the 10 years following surgery. In this setting, the identification of high-risk patients who might most benefit from more aggressive therapy is fundamental. Aim of this study is to evaluate whether some hemostatic biomarkers may be prognostic of early (first two years) disease recurrence (EDR) in a group of breast cancer patients undergoing post-surgical SAC. Methods: Plasma samples from 690 limited-resected breast cancer patients (10M/680F), enrolled in the Italian, prospective, multicenter HYPERCAN study, were obtained at enrollment before starting SAC and after 1, and 2 years follow-up. Samples were tested for fibrinogen, D-dimer, and thrombin generation (TG). Clinical data and information regarding surgery, cancer subtype, and treatment were recorded. DR was routinely monitored by imaging during post-treatment surveillance. Results: At enrollment, fibrinogen levels were in the normal range (316±87 mg/dl), while D-dimer and endogenous thrombin potential (ETP) were increased (respectively 257±353 ng/ml and 1680±377 nM*min) compared to a control group of healthy subjects. During follow-up, D-dimer significantly diminished over time, while no modifications occurred in the other biomarkers. After 2 years follow-up, 5.7% of patients presented with EDR. Kaplan-Meier analysis revealed that an ETP value ≥1670 nM*min at enrollment was an independent risk factor for EDR (HR = 3.65; 95% CI 1.60-8.34; p < 0.01). Differently, EDR was not associated with fibrinogen and D-dimer levels. A risk assessment score for the identification of breast cancer patients at higher risk of EDR has been created using ETP, hemoglobin level and triple-negative subtype variables, that were found to be independent risk factor of EDR in multivariate analysis. Conclusion: We showed, for the first time, the prognostic significance of measuring pre-chemotherapy TG levels on the risk of EDR in resected breast cancer patients. After a proper validation, this biomarker could be a candidate to tailor a risk-adapted adjuvant treatment. Project funded by AIRC "5xMILLE" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)".

BACKGROUNDBRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP.METHODSPD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAF(V600)-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining.RESULTSForty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P < 0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P < 0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival.CONCLUSIONOur results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi.

ABSTRACT Aim: Background Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAFV600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6 months months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (TBP). Methods: In this retrospective study, we analyzed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirtyfive patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. Results: Median overall survival beyond documented progression was found to be 5.2 months versus 1.4 months (95% CI: 3.8-7.4 vs. 0.6-3.4; Log-Rank p = 0.0001) in favour of TBP. In the multivariate survival analysis, stopping treatment at disease progression was independently and significantly associated with shorter survival (Hazard Ratio: 1.92; 95% CI: 1.04-3.55; p = 0.04). Conclusions: Our results clearly suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients. Prospective confirmation, however, is warranted before implementation into daily practice. Disclosure: J.B.A.G. Haanen: Advisory role and research grant form GSK. All other authors have declared no conflicts of interest.

BACKGROUND Programmed cell death ligand 1 (PD-L1) is a cell surface molecule that plays a critical role in suppressing immune responses, mainly through binding of the PD-1 receptor on T lymphocytes. PD-L1 may be expressed by metastatic melanoma (MM). However, its clinical and biological significance remains unclear. Here, we investigated whether expression of PD-L1 in MM identifies a biologically more aggressive form of the disease, carrying prognostic relevance. PATIENTS AND METHODS PD-L1 expression was analyzed by immunohistochemistry using two different antibodies in primary tumors and paired metastases from 81 melanoma patients treated at a single institution. Protein expression levels were correlated with PD-L1 mRNA, BRAF mutational status and clinical outcome. PD-L1(+) and PD-L1(-) subsets of the A375 cell line were stabilized in vitro and compared using gene expression profiling and functional assays. Results were confirmed using xenograft models. RESULTS PD-L1 membrane positivity was detected in 30/81 (37%) of patients. By multivariate analysis, Breslow thickness and PD-L1 membrane positivity were independent risk factors for melanoma-specific death {PD-L1 5% cutoff [hazard ratio (HR) 3.92, confidence interval (CI) 95% 1.61-9.55 P < 0.003], PD-L1 as continuous variable (HR 1.03, 95% CI 1.02-1.04 P < 0.002)}. PD-L1 expression defined a subset of the BRAF-mutated A375 cell line characterized by a highly invasive phenotype and by enhanced ability to grow in xenograft models. CONCLUSIONS PD-L1 is an independent prognostic marker in melanoma. If confirmed, our clinical and experimental data suggest that PD-L1(+) melanomas should be considered a disease subset with distinct genetic and morpho-phenotypic features, leading to enhanced aggressiveness and invasiveness.