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Second- or third-line treatment options for metastatic renal cell carcinoma (mRCC) have dramatically changed in the last few years. There are no criteria for the choice between nivolumab and cabozantinib, which both demonstrated overall survival (OS) gain in pivotal trials.We conducted an analysis of oncological outcomes in patients treated in the Veneto Region (Italy), studying different sequences of TKI-nivolumab-cabozantinib or TKI-cabozantinib-nivolumab in a publicly funded healthcare system.We conducted a retrospective, real-world analysis of all consecutive patients with mRCC treated with nivolumab or cabozantinib in 2017-2018 at 19 Oncology Units in the Veneto Region.We identified 170 patients, 73 % males, median age 68.4 years. All patients started second-line treatment, 59 % received a third-line therapy. Patients with NLR3 had a shorter OS (p0.0001). In the second-line treatment, nivolumab was administered to 108 patients (63 %), cabozantinib to 29 (17 %); in the third-line treatment nivolumab was administered to 42 patients (25 %), cabozantinib to 49 (29 %). Median OS and PFS in second line treatment were 28.4 and 6.6 months for nivolumab, 16.8 and 6.6 months for cabozantinib. Median OS and PFS in third-line treatment were 27 and 5.2 months for nivolumab, 16.6 and 7.5 months for cabozantinib. Median OS for nivolumabcabozantinib sequence versus cabozantinibnivolumab was 28.8 versus 19.9 months (p = 0.2); median PFS for both the sequences were similar at 5.7 months. A cost effectiveness per month of survival of the two sequences analysis was performed: the cost per month for the nivolumabcabozantinib sequence was 1738.60whereas the cost for the other one was €1624.80.In our real-world cohort, most patients received nivolumab as second-line treatment. Outcomes of single drugs are superimposable with those in the published literature. Both the sequences of nivolumab and cabozantinib appear to be viable, effective strategies from an OS and cost-effective perspective.

In previous studies, steady‐state Z‐endoxifen plasma concentrations (ENDOss) correlated with relapse‐free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen‐adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N‐desmethyl‐tamoxifen (ND‐TAM), Z‐4OH‐tamoxifen (4OH‐TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log‐transformed ENDOss (log‐ENDOss). Genotype‐derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log‐ENDOss. Genotype‐phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients’ age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log‐ENDOss = 0.162 ‐ log(DM/DX) × 0.170 + age × 0.0063 ‐ weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R 2 = 0.51). In conclusion, log(DM/DX) seems superior to genotype‐derived CYP2D6 phenotype in predicting ENDOss.

Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63&ndash, 75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status (p = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03&ndash, 2.27, p = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05&ndash, 2.60, p = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients.

290 Background: Second (2L) or third-line (3L) treatment options for mRCC have dramatically changed in the last years. The standard of care as per Italian Regulatory Agencies approvals is N or C. To date, there are no criteria for the choice between N and C, which both demonstrated OS gain in the pivotal trials. Methods: We planned a retrospective, real world analysis of the use of N and C as 2L and 3L treatment in 17 Oncology Units of Veneto Region. All consecutive patients (pts) with mRCC treated in advanced setting in 2017-2018 were included. Results: We identified 170 pts, 73% males, median age 68.4 years. All pts started a 2L treatment while only 59% received a 3L treatment. In our cohort, patients with NLR > 3 at treatment start had a shorter OS (43 vs 90 months (mos), p < 0.0001); IMDC classification maintained its prognostic role. In 2L, N was administrated in 108 pts (63%), C in 29 pts (17%); in 3L N was administrated in 42 pts (25%), C in 49 pts (29%). Reported oncologists’ reasons for 2L choice were: change of mechanism of action compared to first line (28%), response to previous TKI (21.2%), intolerance to TKI (17.6%), previous toxicity (12.9%), tumor burden (11.2%), age of the patient (4.1%). Median OS and PFS in 2L were 28.4 and 6.6 mos for N, 16.8 and 6.6 mos for 2L C. Median OS and PFS in 3L were 27 and 5.2 mos for N, 16.6 and 7.5 mos for C. 46 pts received the sequence of drugs N > C, 12 the opposite sequence C > N. Median OS for N > C vs C > N were 96.6 vs 36 mos (p > 0.0001); median PFS for both the sequences were similar at 5.7 mos (p = ns). The cost per patient of the sequence N > C is 51.606 € while for the sequence C > N is 31.480,00 €. Between the two sequences a cost effectiveness per month of survival analysis was performed: the cost per month of OS for the sequence N > C was 534,18 € while for the sequence C > N was 874,46 €, heavily higher. Conclusions: In our real-world setting cohort, most of the pts received N as 2L treatment and a minority received C. Outcome of single drug are superimposable to published literature. With the limits of the retrospective nature of the study, with a cost per month of OS lower a much longer OS, the sequence N > C appear to be a better treatment strategy.

Background Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer, but limited studies have been performed to investigate the association between ADT and immune alterations, such as autoimmune diseases and risk of second tumours, considering that androgens may also play a role in the immune modulation. Methods We retrospectively evaluated patients (pts) treated with abiraterone (abi) and enzalutamide (enza) in 12 Italian Institutes between July 2011 and December 2018. In particular, we assessed the risk of systemic or single-organ autoimmune diseases [according to the International Classification of Diseases 10th Revision (ICD-10)] and second tumors, by performing a logistic regression analysis. Results We included 844 pts receiving abi/enza, whose 36 (4.3%) had diagnosis of autoimmune diseases at baseline [13 (1.5%) arthritis (rheumatoid or psoriatic), 12 (1.4%) autoimmune thyroiditis, 4 (0.5%) gastrointestinal autoimmune disease, 4 (0.5%) psoriasis, and 3 (0.4%) vasculitis] and 58 (6.9%) had second tumors (45 solid and 13 hematological). Median age was 70 years [interquartile range (IQR) 63-75]. Median duration of hormone sensitive of prostate cancer was 29 months (IQR 14-59), while median CRPC duration was 22 months (IQR 13-39). Most pts (N = 764, 90.5%) did ≤ 2 therapeutic lines, whose 477 (56.5%) and 367 (43.5%) were treated with abi and enza, respectively, and 359 (42.5%) were chemotherapy naive. We observed a significant increase in the risk of autoimmune diseases and a trend for higher incidence of second tumors in pts showing a shorter time to CRPC [odd ratio (OR) 0.98 (95% CI 0.96-0.99) p = 0.01, and OR 0.99 (95% CI 0.98-1.01) p = 0.09, respectively], whereas no association was reported between CRPC duration and the incidence of immune disorders. Clinical outcome associated with abi/enza in CRPC was independent from pre-treatment presence of immune diseases, but a worse overall survival was observed from diagnosis of prostate cancer in pts developing autoimmune diseases (HR 1.69, 95% CI 1.10-2.61, p = 0.016) . Conclusions Time to CRPC may represent a risk factor of developing immune alterations with a negative prognostic role in the overall survival of prostate cancer pts. Further larger prospective studies are warranted. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Conteduca: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Janssen-Cilag; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas. O. Caffo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen-Cilag; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. E. Zanardi: Advisory / Consultancy: Janssen. G. Procopio: Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: BMS. U.F.F. De Giorgi: Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS. All other authors have declared no conflicts of interest.

The aims of the present study were to verify whether an innovative therapeutic strategy for the treatment of mild-moderate chronic cancer pain, passing directly from step I to step III of the WHO analgesic ladder, is more effective than the traditional three-step strategy and to evaluate the tolerability and therapeutic index in both strategies.Patients aged 18 years or older with multiple viscera or bone metastases or with locally advanced disease were randomized. Pain intensity was assessed using a 0-10 numerical rating scale based on four questions selected from the validated Italian version of the Brief Pain Inventory. Treatment-specific variables and other symptoms were recorded at baseline up to a maximum follow-up of 90 days per patient.Fifty-four patients were randomized onto the study, and pain intensity was assessed over a period of 2,649 days. The innovative treatment presented a statistically significant advantage over the traditional strategy in terms of the percentage of days with worst painor =5 (22.8 vs 28.6%, p0.001) andor =7 (8.6 vs 11.2%, p = 0.023). Grades 3 and 4 anorexia and constipation were more frequently reported in the innovative strategy arm, although prophylactic laxative therapy was used less in this setting.Our preliminary data would seem to suggest that a direct move to the third step of the WHO analgesic ladder is feasible and could reduce some pain scores but also requires careful management of side effects.

The aim of the present study was to evaluate the impact of palliative care on patients' symptoms, using the Edmonton Symptom Assessment System (ESAS) to measure symptom intensity at the time of admission and variations registered during the first 7 days' hospitalization. Three hundred fourteen patients were admitted to the unit during its first year of activity. Of these, 162 patients (51.6%) completed, 62 (19.7%) partially completed, and 90 (28.7%) did not complete the ESAS. The mean (+/-SD) value of the Symptom Distress Score (SDS) (sum of the values of the different symptoms) for the 162 evaluable patients on Day 1 was 33.93 (+/-16.24). On Day 7 the mean was 28.14 (+/-15.11) (ANOVA for repeated measurements, P < 0.0001). ESAS values for patients with moderate-severe symptom intensity (average values Day 1-Day 7 and P value, ANOVA for repeated measurements) were as follows: pain (7.12-4.23, P < 0.0001), fatigue (7.46-5.68, P < 0.0001), nausea (7.12-1.96, P < 0.0001), depression (7.26-5.28, P < 0.0001), anxiety (7.13-5.14, P < 0.0001), drowsiness (7.42-6.40, P = 0.002), anorexia (7.33-4.33, P < 0.0001), well-being (6.83-3.85, P < 0.0001), and dyspnea (7.08-3.86, P < 0.0001). These data seem to indicate that the patients who benefit most from inpatient palliative care are those with the most complex symptomatology.

The problem of post-surgical clinical follow-up for breast cancer patients is still open. A lot of comparative studies between intensive and minimal follow-up showed no advantage of the former vs. the latter modality. The above data have been confirmed also from sistematic revisions and from pharmaco-economic studies. The ASCO guidelines confirm the importance of clinical surveillance, together with annual mammography and pelvic examination, while no blood tests or other instrumental examinations are indicated in absence of specific symptoms. The follow-up program needs to be realized under the supervision of a specialist with specific experience in the oncologic evaluation. Concerning the patients with high risk of recurrence, there is no agreement, even if no advantage seems to exist with an intensive follow-up program in terms of quality or quantity of life. The Authors suggest that the standard follow-up program should include a thoracic X-ray picture and an abdominal USG, in order to detect early a small number (or = 2 sites) of visceral metastases, amenable of a treatment. The above program should be realized from a multidisciplinary team (surgeon, medical oncologist, radiotherapist) gaining in terms of quality and sparing time and resources.

line (ln) treatment (tx) was: sunitinib (su) 74%, sorafenib (so) 15.5%, temsirolimus (tem) 5%, others (5.5%). mOS was 26.7 for su, 21 for so (p= NS) and 4 for tem. Median 1 st ln PFS was 9.8 mo: su 12.3, so 7.2 (su vs so: p= 0.02), tem 1.9 (so vs tem: p > 0.001). Disease control rate was 64% (293 pts). Toxicities for su/so (% of all grades) were as follows: mucosites (42/31), hypertension (41/25), haematological (54/4), diarrhea (14/25), fatigue (50/53), rash (10.5/24), HFS (17/39). Main G3 toxicities were hypertension (11%) and fatigue (8%); G4 were 6 mo were statistically related to execution of 2 nd line tx at logistic regression. At Cox multivariate analysis, CC histology, nephrectomy, good PS, response, duration of 1 st ln tx >6 mo, execution of 2 nd

e13514 Background: Endoxifen (EN), the main active metabolite of tamoxifen (T), reaches steady state (SS) plasma levels after about 4 months of administration. It derives principally by cytochrome CYP2D6 activity, which is highly variable among patients. In order to predict individual SS EN exposure, three different approaches were investigated. Methods: Before starting T administration, 73 breast cancer patients (median age: 59 yrs, range: 30-89) were characterized by means of: 1) a phenotyping test of CYP2D6 activity, based on the urinary metabolic ratio of dextromethorphan/dextrorphan (log transformed, LMR). 2) CYP2D6 genotyping (alleles *1, *3, *4, *5, *6, *9, *10, *41), to classify patients in 3 functional groups: Extensive (EM), Intermediate (IM) and Poor (PM) Metabolizers. After starting T treatment (20mg/day), EN plasma levels were measured after 1 month (1M EN, pre- steady state) and 4 months of therapy (SS EN). ANOVA, paired and unpaired T test and linear regressions were performed to analyze associations between LMR, CYP2D6 genotype, 1M EN and SS EN. Multivariate linear regression was used to create a predictive equation; its mean prediction and absolute errors (MPE% and MAE%) and the positive and negative predictive values (PPV% and NPV%, according to median SS EN) were calculated. Results: SS EN plasma levels varied between 2.4 and 39.2 (median: 8.7) ng/ml. LMR (median: -1.6; range: -3.1- +1.2) showed a significant linear correlation with SS EN (r=-0.59; p

e13019 Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.