Evaluating polygenic risk score prediction model for melanoma prognosis

abstracts

Annals of Oncology 1365P

Final results from phase II of combination with canerpaturev (formerly HF10), an oncolytic viral immunotherapy, and ipilimumab in unresectable or metastatic melanoma in second-or later line treatment

Background: Canerpaturev (C–REV) is an oncolytic, spontaneous mutant of HSV-1, and is one of immunotherapies that can not only kill tumor cells but also modulate immune responses. We report the efficacy of Phase II multicenter trial of combination therapy using C-REV and ipilimumab (ipi) in melanoma patients (pts) who were refractory or intolerant to prior therapies. Methods: Key entry criteria: age  20 yrs, ECOG PS 0-2, AJCC 7th Stage IIIB-IV unresectable melanoma, who received prior therapies and had measurable non-visceral lesion(s) suitable for C-REV injections. C-REV was injected into each tumor (1 x 107 TCID50/mL/dose, up to 5 mL); 4 injections q1wk; then up to 15 injections q3wks. Ipi (3 mg/kg) was administered 4 times, q3wks. Primary endpoint was Best Overall Response Rate (BORR) by immune-related response criteria (irRC). Results: 28 pts were enrolled. Disease stage: 7.1% IIIB, 28.6% IIIC and 64.3% IV, and disease type: 39.3% acral lentiginous and 21.4% mucosal melanoma. Anti-PD-1 antibody was previously used in 89.3%. Severe adverse events (AEs, G3) related to the study treatment was 35.7 %. Of 27 efficacy evaluable pts, BORR and disease control rate by irRC 11.1% and 55.6%, respectively. Pts with irPR and durable irSD longer than 24 wks were confirmed in 22.2 % (6 pts) and had no deaths (follow-up period: 298 - 446 days). The median OS was 318.0 days (95% C.I. 211.00 – not reached). Conclusions: In melanoma, various immunotherapies and molecular targeted drugs have been approved for treatment options, but there are still unmet medical needs in particular in pts who failed in the 1st line therapy. In this trial, C-REV did not show the exacerbation in ipi toxicity and patients with irPR and durable irSD contributed to prolonging OS. Thus, C-REV plus ipi has potential to become a new treatment option for melanoma in  2nd-line setting. Clinical trial identification: NCT03153085. Legal entity responsible for the study: Takara Bio Inc. Funding: Takara Bio Inc. Disclosure: K. Yokota: Research grant / Funding (institution): Takara Bio Inc. T. Isei: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb K.K.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ono Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis Pharma K.K.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD K.K.; Honoraria (self): Mochida Pharmaceutical Co., Ltd.; Honoraria (self): Pfizer Japan Inc.; Honoraria (self), Travel / Accommodation / Expenses: Kaken Pharmaceutical Co.,Ltd.; Honoraria (self): Daiichi Sankyo Company, Limited.; Honoraria (self), Travel / Accommodation / Expenses: Maruho Co.,Ltd. ; Honoraria (self), Travel / Accommodation / Expenses: Kyowa Hakko Kirin Co., Ltd.; Honoraria (self): POLA-Pharma; Advisory / Consultancy: Merck Biopharma Co., Ltd; Research grant / Funding (institution): Takara Bio Inc.; Research grant / Funding (institution): Array BioPharma, Inc.; Research grant / Funding (institution): Amgen Inc. H. Uhara: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono Pharmaceutical Co., LTD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD K.K.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Maruho Co.,Ltd. ; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): POLA-Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Kyowa Hakko Kirin Co., Ltd.; Speaker Bureau / Expert testimony: Janssen Pharmaceutical K.K.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Mitsubishi Tanabe Pharma Corporation; Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Eisai Co., Ltd. ; Research grant / Funding (institution): AbbVie GK.; Research grant / Funding (institution): Maruho Co.,Ltd. ; Research grant / Funding (institution): Daiichi Sankyo Company, Limited. ; Research grant / Funding (institution): Tsumura & Co.; Research grant / Funding (institution): Mochida Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Nippon Kayaku Co.,Ltd.; Research grant / Funding (institution): Torii Pharmaceutical Co.,Ltd; Research grant / Funding (institution): Kaken Pharmaceutical Co.,Ltd. Y. Fujisawa: Advisory / Consultancy: Eli Lilly Japan K.K. ; Advisory / Consultancy: Novartis Pharma K.K.; Research grant / Funding (institution): Ono Pharmaceutical Co., LTD; Research grant / Funding (institution): Bristol-Myers Squibb K.K.; Research grant / Funding (institution): Eisai Co., Ltd. ; Research grant / Funding (institution): Takara Bio Inc. T. Takenouchi: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Novartis Pharma K.K.; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Research grant / Funding (institution): Takara Bio Inc. Y. Kiyohara: Honoraria (self), Research

Volume 30 | Supplement 5 | October 2019

1366P

Evaluating polygenic risk score prediction model for melanoma prognosis

M. Potrony1, N. Calbet-llopart2, M. Combalia2, G. Tell-Martı1, J.A. Puig-Butille3, A. Barreiro2, S. Podlipnik2, C. Carrera1, J. Malvehy1, S. Puig1 1 Dermatology Department, Melanoma Unit, Hospital Clınic of Barcelona, Institut D’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), CIBERER, Barcelona, Spain, 2 Dermatology Department, Melanoma Unit, Hospital Clınic of Barcelona, Institut D’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 3 Molecular Biology Core, Biochemistry and Molecular Genetics Department, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain Background: Melanoma is the most aggressive of common skin cancers. We aimed to create a polygenic risk score (PRS) and evaluate its capability to predict melanoma prognosis better than staging. Methods: The cohort included 1126 melanoma patients (567 males, 559 females); 57%, 24% and 19% patients stage I, II and III at diagnosis, respectively. The mean age at diagnosis was 54 yo (range 12-97). We genotyped 252 candidate SNPs by OpenArray. After quality control, we selected SNP associated with disease-free survival (DFS) and melanoma-specific survival (MSS) (log Rank P < 0.05), in the whole cohort and independently by sex. We performed cross-validation using 2/3 for training and 1/3 for validation. If the model was consistent in the three comparisons (concordance rate > 0.75), we created a PRS based on the weight of each SNP in MSS or DFS modulation. We compared the score including PRS and clinical data (age, sex, staging), with the clinical score alone or the staging score alone. ROC curves were calculated for each score to assess the capability to predict DFS and MSS. Results: We identified 29 SNPs associated with DFS survival in the whole cohort. The score with PRS had a higher prediction capability (AUC 0.844), compared to clinical score (AUC 0.770) or staging alone (AUC 0.741). Male-specific analyses revealed 8 male-specific SNPs. The male-PRS improved also the prediction capability (AUC 0.831), compared to clinical (AUC 0.760) or staging alone score (AUC 0.735). Femalespecific analyses revealed 21 female-specific SNPs. The female-PRS improved also the prediction capability (AUC 0.868), compared to clinical (AUC 0.767) or staging alone score (AUC 0.742). Using an optimal PRS þ clinical score cut-off, we improved the classification of patients into low and high-risk groups within each stage and comparison (Table). Similar results were obtained regarding MSS.

Table: 1366P 5-year DFS rate (%) Sex

Stage

ALL

Low-risk group

High-risk group

ALL

I II III I II III I II III

92.5 69.7 59.3 91.4 68.0 56.3 93.5 72.2 62.6

94.9 87.7 90.2 92.0 87.4 86.3 96.1 94.1 94.1

62.7 50.6 50.3 80.0 49.6 48.1 69.8 47.9 42.7

MALE

FEMALE

doi:10.1093/annonc/mdz255 | v557

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz255.054/5576347 by guest on 26 October 2019

K. Yokota1, T. Isei2, H. Uhara3, Y. Fujisawa4, T. Takenouchi5, Y. Kiyohara6, H. Uchi7, H. Saruta8, H. Ihn9, T. Inozume10, D. Watanabe11, A. Takahashi12, S. Fukushima9, M. Tanaka13, N. Yamazaki12 1 Department of Dermatology, Nagoya University school of medicine, Aichi, Japan, 2 Tumor Dermatology, Osaka International Cancer Institute, Osaka, Japan, 3Department of Dermatology, Sapporo Medical University Hospital, Hokkaido, Japan, 4Department of Dermatology, University of Tsukuba Hospital, Ibaraki, Japan, 5Department of Darmatology, Niigata Cancer Center Hospital, Niigata, Japan, 6Division of Dermatology, Shizuoka Cancer Center, Shizuoka, Shizuoka, Japan, 7Dermatology, Kyushu University Hospital, Fukuoka, Japan, 8Department of Dermatology, Kurume University Hospital, Fukuoka, Japan, 9Dermatology, Kumamoto Universtiy Hospital, Kumamoto, Japan, 10Dermatology, University of Yamanashi Hospital, Yamanashi, Japan, 11Dermatology, Aichi Medical University, Aichi, Japan, 12Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan, 13Gene Medicine Business Unit, Takara Bio Inc., Kusatsu, Japan

grant / Funding (institution), Travel / Accommodation / Expenses: Ono Pharmaceutical Co., Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb K.K.; Honoraria (self): Novartis Pharma K.K.; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Toray Industries, Inc.; Honoraria (self), Research grant / Funding (institution): Merck Biopharma Co., Ltd; Honoraria (self): Boehringer Ingelheim Japan, Inc.; Research grant / Funding (institution): Takara Bio Inc.; Honoraria (self), Research grant / Funding (institution): Amgen Inc. H. Uchi: Research grant / Funding (institution): Takara Bio Inc. H. Saruta: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., Ltd.; Speaker Bureau / Expert testimony: Kyowa Hakko Kirin Co., Ltd.; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Minophagen Pharmaceutical Co., LTD.; Research grant / Funding (institution): MSD K.K.; Research grant / Funding (institution): Takara Bio Inc. H. Ihn: Research grant / Funding (institution): Takara Bio Inc. T. Inozume: Research grant / Funding (institution): Takara Bio Inc. D. Watanabe: Advisory / Consultancy: Japan vaccine; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Maruho Co.,Ltd. ; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): Nippon Zoki Pharmaceutical Co., Ltd. ; Research grant / Funding (institution): Daiichi Sankyo Company, Limited.; Research grant / Funding (institution): Takara Bio Inc. A. Takahashi: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb K.K.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Research grant / Funding (institution): Takara Bio Inc. S. Fukushima: Research grant / Funding (institution): Takara Bio Inc. M. Tanaka: Full / Part-time employment: Takara Bio Inc. N. Yamazaki: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb K.K.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD K.K.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma K.K.; Research grant / Funding (institution): Takara Bio Inc.

abstracts

Annals of Oncology

Conclusions: We have identified a potential PRS that improves classification of melanoma patients within prognostic groups. Legal entity responsible for the study: The authors. Funding: Instituto de Salud Carlos III. Disclosure: All authors have declared no conflicts of interest.

1367P

Impact of sarcopenia in patients with metastatic melanoma treated with immunotherapy

Background: High BMI is associated with better survival in metastatic melanoma patients (MM pts), while sarcopenia is linked to poorer outcome in pts with stage III. The aim of this study was to examine the prognostic impact of body-mass index (BMI), baseline sarcopenia, loss of skeletal muscle mass (LSMM) on overall survival (OS) in MM pts who received immunotherapy (IT). Methods: The retrospective series included 42 consecutive MM pts (Jan 2011-Dec 2018) treated with IT in a single referral center. Sarcopenia was defined according to Prado’s criteria. Skeletal muscle index (SMI) was calculated as cross-sectional-area of muscle (cm2), using CT-scan, at the L3 level divided by the square of the height (m2). Early LSMM, during IT, was defined as a decrease in SMI > ¼10% from baseline at first evaluation. BMI was calculated as weight (kg) divided by the square of height (m2) and categorized according to standard WHO definitions. Weight loss was analyzed as continuous variable. Results: At baseline, 27 pts (64,3%) were male, 26 pts (61.9%) were < 70 years and 31 pts (73.8%) had ECOG PS ¼ 0. Overall, 26 patient (61.9%) had LDH ¼25. Out of 42 pts, 30 (71.4%) had a CT-scan at first evaluation, and 30% of them had an early LSMM. Median OS was 11.38 months. Both in univariate and multivariate analysis, ECOG PS > ¼1, and early LSMM > ¼10% were significantly associated worse OS. Conversely, pts with weight loss had better OS (Table).

1367P OS univariate analysis Factors

HR

p

OS multivariate analysis

95% Confidence HR Interval

PS ECOG31 3.02 0.01 (1.29-7.08) Weight loss 0.88 0.03 (0.78-0.98) Early LSMM 4.24 0.006 (1.50-11.97) > ¼10%

p

95% Confidence Interval

Table:

3.99 0.043 (1.04-15.31) 0.85 0.02 (0.74-0.97) 3.09 0.04 (1.04-9.22)

Conclusions: Early LSMM > ¼10% and ECOG PS > ¼1 may negatively influence the outcome of MM pts treated with IT. Further prospective studies are needed to confirm these data. Legal entity responsible for the study: Maria Grazia Vitale. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

v558 | Melanoma and other skin tumours

Ancillary evaluation of systemic immune antitumour response (SIAR) and tumour growth rate (TGR) of patients (pts) with metastatic melanoma (MM) treated with radiotherapy (RT) combined with ipilimumab (ipi) in the phase I study Mel-Ipi-Rx

C. Boutros1, N. Chaput2, E. Lanoy3, A. Larive3, C. Mateus4, E. Routier4, S. Roy4, R. Sun5, A. Lancia5, Y. Tao5, N. Ibrahim6, R.M. Khoury-Abboud6, C. Massard7, R. Bahleda7, D. Schwob3, C. Caramella8, L. Cassard9, J-C. Soria10, C. Robert11, E. Deutsch12 1 Dermatology Unit, Outpatient clinic, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France, 2Laboratory of Immunomonitoring in Oncology, University Paris-Saclay, Faculty of Pharmacy, Gustave Roussy Cancer Campus, Villejuif, France, 3 Biostatistic and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France, 4 Dermatology Unit, Gustave Roussy Cancer Campus, Villejuif, France, 5Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France, 6Outpatient clinic, Department of Medicine, Gustave Roussy Cancer Campus, Villejuif, France, 7 DITEP, Gustave Roussy - Cancer Campus, Villejuif, France, 8Department of radiology, Gustave Roussy Cancer Campus, Villejuif, France, 9Laboratory of Immunomonitoring in Oncology, Gustave Roussy Cancer Campus, Villejuif, France, 10MedImmune, MedImmune, Gaithersburg, MD, USA, 11Dermatology Unit, University Paris-Saclay, Faculty of Medicine, INSERM Unit U981, Gustave Roussy Cancer Campus, Villejuif, France, 12Department of Radiation Oncology, Radiomics Team, Molecular Radiotherapy INSERM U1030, University Paris-Saclay, Faculty of Medicine, Gustave Roussy Cancer Campus, Villejuif, France Background: Ipi 10 mg/kg (every 3 weeks for 4 doses) combined with a 3 þ 3 dose-escalation design of RT at week 4 (W4) seemed to have antitumor activity in the 19 pts treated in the phase I study Mel-Ipi-Rx from August 2011 to July 2015 (ESMO 2016, 1117P). This ancillary study assesses the impact of ipi þ RT on SIAR and TGR variation (DTGR) of irradiated (TGRirr) and non-irradiated (TGRnon-irr) lesions. Methods: Blood samples were collected at baseline (W0), W4 (before 2nd ipi injection) and W6 (after ipi þ RT) to phenotype T cells. TGR, defined as an increase in tumor volume during 1 month, was computed for TGRirr, and TGRnon-irr in 2 periods: (i) Reference-TGR (REF-TGR) on W0, and (ii) Experimental-TGR (EXP-TGR) between W0 and 1st evaluation. The DTGR between REF-TGR and EXP-TGR was used to assess the treatment (TRT) effect. A negative value reflected a slowdown of disease progression (DP). Results: Ipi alone was associated with increased effector T cells (TEM), Treg and ICOSþ CD4þ T cells at W4. At W6, only TEM and ICOSþ CD4þ T cells significantly increased, suggesting that RT þ ipi could increase activated memory CD4þ T cells rather than Treg cells. CD8þ T cells did not increase at W4 while central memory T cells (TCM) and terminally differentiated (TEMRA) increased between W4 and W6, suggesting that RT þ ipi could boost these CD8þ T populations. Increased CD8 from W0 to W4 was significantly correlated to progession-free survival (PFS) (p ¼ 0.0163). Increased CD8 tended to be positively correlated to overall survival (OS) from W0 to W6 (p ¼ 0.0786). Interestingly, a higher effect of RT þ ipi seemed to be associated with a deeper DTGRnon-irr than DTGRirr, although insignificant. The EXP-TGRnon-irr was significantly associated with DP. Conclusions: RT þ ipi was associated with increased CD4þ and CD8þ ICOSþ T cells. Increased CD8þ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. The DTGRnon-irr lesions could be more important than DTGRirr lesions in responding pts and may be related to an abscopal effect. Updated PFS and OS will be presented. Clinical trial identification: EUDRACT 2010-020317-93 NCT01557114. Legal entity responsible for the study: Eric Deutsch and Caroline Robert are both corresponding authors and contributed equally to the work. Funding: Has not received any funding. Disclosure: C. Boutros: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Speaker Bureau / Expert testimony: Merck. N. Chaput: Research grant / Funding (self): Cytune Pharma; Research grant / Funding (self): BMS; Research grant / Funding (self): Sanofi; Research grant / Funding (institution): GSK; Honoraria (self), Advisory / Consultancy: AstraZeneca. C. Mateus: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck. E. Routier: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pierre Fabre. C. Massard: Honoraria (self), Advisory / Consultancy: AMGEN; Honoraria (self), Advisory / Consultancy: ASTELLAS; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BeiGene; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Merck; Non-remunerated activity/ies: AstraZeneca; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: BMS; Non-remunerated activity/ies: Johnson and Johnson; Non-remunerated activity/ ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: Merck. C. Caramella: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: MSK; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Amgen. J. Soria: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Astex; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: GammaMabs; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Roche/genentech; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Takeda; Full / Part-time employment, Full time employee since 2017: MedImmune; Shareholder / Stockholder / Stock options: AstraZeneca; Shareholder / Stockholder / Stock options: Gristso. C. Robert: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck

Volume 30 | Supplement 5 | October 2019

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz255.054/5576347 by guest on 26 October 2019

M.G. Vitale1, D. Basile2, E. Bertoli1, M. Giavarra1, G. Pelizzari2, L. Palmero1, D. Zara1, G. Targato1, G. Pascoletti3, M. Cinausero3, E. Poletto3, D. Iacono3, F. Puglisi2, G. Fasola3, A.M. Minisini3 1 Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine; Department of Medicine (DAME), University of Udine, Udine, Italy, 2Department of Medicine (DAME), University of Udine; Department of Medical Oncology and cancer prevention, IRCCS CRO National Cancer Institute, Aviano, Italy, 3Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy

1368P