BACKGROUND:Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. METHODS:This phase 3, open-label, superiority trial included patients aged 18 years or older with treatment-naive or previously treated unresectable or metastatic (or both) grade 1-2 GEP NETs. Patients were enrolled from 49 specialist neuroendocrine tumour treatment centres across 14 countries in Africa, Europe, North America, and Oceania and randomised (2:1) to intravenous [177Lu]Lu-edotreotide (7·5 ± 0·7 GBq every 3 months, maximum four cycles) or oral everolimus (10 mg/day) for up to 30 months. Random assignment was via a central, web-based randomisation system (block size of 6) and stratified by primary tumour origin and previous therapy. The primary endpoint was progression-free survival, assessed via blinded independent central review in all randomly assigned patients at 30 months. Harms were assessed in all enrolled patients who received at least one dose of a study drug. This study was registered with ClinicalTrials.gov (NCT03049189) and is no longer recruiting. FINDINGS:Between April 13, 2017, and June 20, 2022, 324 patients were enrolled and 309 patients (including 168 [54%] male patients and 141 [46%] female patients) were randomly assigned to treatment: 207 to the [177Lu]Lu-edotreotide group and 102 to the everolimus group. The median follow-up for progression-free survival was 27·5 months (IQR 19·6-30·4) for the [177Lu]Lu-edotreotide group and 21·2 months (8·9-29·4) for the everolimus group. Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23·9 months [95% CI 18·7-30·0] vs 14·1 months [9·2-20·9]; stratified hazard ratio 0·67 [95% CI 0·48-0·95]; p=0·022). Treatment-related adverse events occurred in 178 (82%) of 217 patients in the [177Lu]Lu-edotreotide group and 96 (97%) of 99 patients in the everolimus group. 40 (18%) patients in the [177Lu]Lu-edotreotide group and 40 (40%) in the everolimus group had at least one treatment-related grade 3-4 adverse event. The most common treatment-related adverse events in the [177Lu]Lu-edotreotide group were diarrhoea and nausea (both 79 [36%] patients) and asthenia (66 [33%] patients), whereas those in the everolimus group were diarrhoea (45 [45%] patients), asthenia (36 [36%] patients), and anaemia (27 [27%] patients). No treatment-related deaths occurred in either study group. INTERPRETATION:[177Lu]Lu-edotreotide led to statistically significant and clinically meaningful improvements in progression-free survival. Efficacy and harms results support the use of [177Lu]Lu-edotreotide in early lines of therapy in patients with advanced, progressive GEP NETs. FUNDING:ITM Solucin.

OBJECTIVE:Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways.DESIGN AND METHODS:Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA).RESULTS:Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs.CONCLUSIONS:We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.

Background Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH (NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. Results Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61–0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH _c.1118A > G variant is a Spanish founder mutation that originated 12–26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. Conclusions In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.

Background More accurate predictive biomarkers in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are needed. This study aims to investigate radiomics-based tumour phenotypes as a surrogate biomarker of the tumour vasculature and response prediction to antiangiogenic targeted agents in patients with GEP-NETs. Methods In this retrospective study, a radiomics signature was developed in patients with GEP-NETs and liver metastases receiving lenvatinib. Patients were selected from the multicentre phase II TALENT trial (NCT02678780) (development cohort). Radiomics variables were extracted from liver metastases in the pre-treatment CT-scans and selected using LASSO regression and minimum redundancy maximum relevance (mRMR). Logistic regression and Cox proportional-hazards models for radiomics and combined radiomics with clinical data were explored. The performance of the models was tested in an external cohort of patients treated with sunitinib (test cohort). Associations between the radiomics score and vascularisation factors in plasma were studied using hierarchical clustering and Mann–Whitney U test. Results A total of 89 patients were included in the study, 408 liver metastases were analysed. The CT-based radiomics signature was associated with clinical benefit in the development (training and validation sets) and test cohorts (AUC 0.75 [0.66–0.90], 0.67 [0.49–0.92] and 0.67 [0.43–0.91], respectively). The combined radiomics-clinical signature (including the radiomics score, Ki-67 index and primary tumour site) improved on radiomics-only signature performance (AUC 0.79 [95% CI 0.64–0.93]; p < 0.001). A higher radiomics score indicated longer progression-free survival (hazard ration of 0.11 [0.03–0.45]; p = 0.002) and was associated with vascularisation factors ( p = 0.01). Conclusions Radiomics-based phenotypes can provide valuable information about tumour characteristics, including the vasculature, that are associated with response to antiangiogenics. Clinical trial registration This is a study of the Lenvatinib Efficacy in Metastatic Neuroendocrine Tumours (TALENT) phase II clinical trial (NCT02678780).

PURPOSEApproved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs.PATIENTS AND METHODSThis was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780 ) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety.RESULTSBetween September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions.CONCLUSIONWe report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Background: Whether risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 carriers reduces the breast cancer (BC) risk is conflicting, potentially due to methodological issues of prior analysis. We analysed the association between premenopausal RRSO and BC risk in BRCA1/2 carriers after adjusting for potential biases. Methods: We analysed data from 444 BRCA1 and 409 BRCA2 carriers under age 51 with no cancer prior to genetic testing or during first 6 months of surveillance (to avoid cancer-induced testing bias and prevalent-cancer bias). Observation started 6 months after genetic testing (to avoid event-free time bias), until BC diagnosis, risk-reducing mastectomy (RRM) or death. A multistate model with four states (non-RRSO, RRSO, RRM and BC) and five transitions was fitted to characterise outcomes and to calculate the BC risk reduction after premenopausal RRSO (before age 51). A systematic review was performed to assess the association between premenopausal RRSO and BC. Results: During a mean follow-up of 4.3 years, 96 women (11.3%) developed BC (54 BRCA1, 42 BRCA2). The risk of BC after premenopausal RRSO decreased significantly in BRCA1 carriers (hazard ratio (HR) = 0.45 [95% confidence interval (CI):0.22-0.92]), but was not conclusive in BRCA2 carriers (HR = 0.77 [95%CI:0.35-1.67]). The systematic review suggested that premenopausal RRSO is associated with a decrease of BC risk in both BRCA1 and BRCA2 carriers. Conclusions: Premenopausal RRSO was associated with BC risk reduction in BRCA1 carriers, which can help guide cancer risk-reducing strategies in this population. Longer follow-up and larger sample size may be needed to estimate the potential benefit in BRCA2 carriers. (C) 2020 Elsevier Ltd. All rights reserved.

TPS4146 Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. Clinical trial information: 2016-002858-20.

332 Background: Pts with advanced G1/G2 NETs have limited treatment options with overall response rates (ORR) with targeted agents (TA) < 10%. Benefit on PFS after TA therapy has not been demonstrated. The mechanism of action of lenvatinib (VEGFR1-3 & FGFR1-4 inhibitor) may increase efficacy and revert primary and acquired resistance to TA. We report the updated results on PFS, safety and subgroups. Methods: This prospective phase II study had two cohorts: G1/G2 panNETs and giNETs. All pts had baseline documented disease progression (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT), and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was ORR by central radiology review. PFS was calculated by investigator assessment. Biochemical responses were defined as reduction from baseline > 50%. With 55 pts per arm our study was powered to identify an ORR ≥ 25% (90% power, 5% α-error). Results: We recruited 111 pts (55 panNETs/56 giNETs). Prior therapies were CHT 32%, SSAs 87%, everolimus (E) 70% and sunitinib (S) 30% for panNETs. ORR was 29%, 40% for panNETs and 18.5% for giNETs. With a median follow-up of 17 months (m), PFS for panNETs was 15.8 m (95% CI 11.4-NR) and 15.4 m (95% CI 11.5-19.5) for giNETs. Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. In the subgroups analyses, all pts obtained the same benefit in PFS and ORR, including grade and prior therapy with S (PFS: 16.4 m, ORR: 43.7%) or E (PFS: 15 m, ORR: 37.1%) (p = ns). A significant correlation of chromogranin A decrease and prolonged PFS in giNETs (17.6 m vs NR, p = 0.032) was observed. The most frequent G3-4 adverse events were hypertension (20.7%), asthenia (13.5%), diarrhea (7.2%) and abdominal pain (5.4%). Conclusions: Lenvatinib showed the highest reported ORR with a TA by central radiology assessment in panNETs and giNETs with promising PFS in a pretreated population. The benefit was observed across subgroups analyses, including pretreated pts with TA. Clinical trial information: NCT02678780.

BACKGROUND:Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials.MATERIALS AND METHODS:This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression).RESULTS:Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS.CONCLUSION:The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting.IMPLICATIONS FOR PRACTICE:The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.

e22049 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. It is mostly diagnosed in elderly people, with a median age at diagnostic of 70 years. The aim of this study is to explore whether oncogeriatric screening (OS) may be helpful in decision-making about treatment. Methods: From October 2015 to June 2017, we prospectively screened 137 ≥75-years-old patients diagnosed with CRC who were referred for chemotherapy. Our OS combines 4 scales, with a positive result in ≥85-years-old patients or 75-85-years-old patients with 2 of the following criteria: G8 scale < 14, Pfeiffer > 2, Barthel index < 90 and positive TIRS scale. In addition, age, comorbidity and ECOG functional status were taken into account for final treatment decision. Results: The median age was 80.44 years (75’1 – 88’9). The most frequent diagnosis was colon cancer (71´8%) versus rectal cancer (28´2%). 47´4% of patients had metastatic disease. Whilst the OS was positive in 32´1% of cases, vulnerability ( < 14 score in G8 scale) was detected in 62% of patients. Chemotherapy was more frequently dismissed in that vulnerable patients (45´9% of G8 < 14 patients vs 28´6% of G8≥14 patients). Finally, 67 patients received chemotherapy (capecitabine 70´1%, FOLFOX 19´4%, FOLFIRI 1´5%, clinical trial 9%). Interestingly, for those patients who initiated treatment at full-dose intensity, a dose reduction was needed in 76% of G8 < 14 patients vs 28.6% of G8≥14 patients. A dose-intensity of 100% could be maintained during the whole treatment (initial and subsequent cycles) in 13% vs 33% respectively. Tolerance of the treatment also differed, with grade 3 / 4 toxicity seen in 58´69% vs 26´66% and interruption of treatment due to toxicity in 15´2% vs 6´7%, respectively. There were no toxic deaths. Conclusions: In our cohort, patients who finally did not receive chemotherapy obtained a < 14 score in G8 scale in a higher proportion. This scale identifies patients who need dose-reduction or present relevant toxicity with a greater probability. For this reason, the G8 scale is considered a helpful screening tool for decision-making in treatment for CRC in elderly patients.

e22046 Background: The human aging is an ongoing process, expressing a functional worsening, subjective or objective. Before to consider colorectal surgery in the elderly we have to assess the need of surgery, the ethical guidelines, the risk/benefit and the expected survival.The aim of the study is to assess if age, Charlson Comorbidity (CC) and ASA determine the odds ratio (OR) of global, surgical and medical complications, anastomotic leakages and reoperations in colorectal elective surgery. Methods: A clinical series reviewing the period 2004-2013 in which we performed 643elective colectomies. We selected groups and subgroups according to age: Group 1: < 75 years (Subgroup 1.1: < 65 ; Subgroup 1.2: 65-75 ); Group 2: > 75 (Subgroup 2.1: 75-85 ; Subgroup 2.2: > 85 ). Age, CC and ASA were included as predictor variables in the multivariate analysis. Results: The OR of global complications in patients between 75 and 85 compared with under 75 is 1.89. However in patients over 85 compared with under75 is 1.143 . This OR increases 1.317 times per each increased grade of ASA .The OR of surgical complications in patients between 75 and 85 compared with under 75 is 2. However in patients over 85 compared with patients under 75 is 1.494. This OR increases 1.315 times per each increased grade of ASA.The OR of medical complications increases 1.736 times per each increased grade of ASA. The OR of anastomotic leakages increases 1.596 times per each increased grade of ASA.The OR of reoperations in patients between 75 and 85 compared with under 75 is 2.367. However in patients over 85 compared with under 75 is 1.385. Conclusions: The risk of global and surgical complications is determined by age and ASA . The risk of medical complications and anastomotic leakages is just determined by ASA .The risk of reoperations is just determined by the age . Thus, in patients over 85 , those who have achieved a successful aging and with a right selection of surgery candidates, we didn´t show a major percentage of global and surgical complications, neither reoperations compared with patients under 75 . Despite that patients over 75 have a higher CCI, we didn´t demonstrate any statistical significant relationship between postoperative complications and this scale.

Throughout the Genetic Counselling process a great emphasis is done on the need to communicate the familial risk information and the genetic study to the relatives. In addition, the clinical reports specify the relatives at risk situation. However, the familial communication pattern of genetic results after the counselling remains unknown. Objective: To conduct a descriptive study about the communication pattern of results of the diagnostic genetic test in hereditary predisposition to cancer at the ICO Genetic Counselling Unit. Methods: A descriptive study has been performed by telephone interview on a sample of index individuals attended at the Genetic Counselling Unit. Patients were asked whether if they had communicated their genetic study results and to whom. Similarly, demographic, personal and genetic result itself variables have been collected to explore whether any of them could modify the communication pattern. Results: Most patients report the results of the genetic studies to their relatives. However, this communication is not complete, so it is possible to design intervention strategies which may improve the communication pattern of the patients who receive diagnostic genetic tests in the context of the hereditary predisposition to cancer.

BACKGROUND This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

e17071 Background: Since the approval of the PARP inhibitor olaparib, the TFGT indications for OC have dramatically increased. Furthermore, several guidelines include genetic testing for all non-mucinous OC patients irrespectively of age and family history. Methods: The ICO network comprises 4 Medical Oncology Departments, 3 Cancer Genetic Counselling Units (CGCU) and 2 Cancer Family Units (CFU) being all of them referral centres for a total of 25 hospitals that cover a population of 3.5 m inhabitants. In December 2014, the Gyne Oncologists Team in collaboration with the CGCU members and the Molecular Diagnosis Laboratory (MDL) of the ICO network established a consensus protocol on indications for risk assessment (RA) and TFGT. All new pts diagnosed with epithelial non-mucinous OC or platinum sensitive relapse were referred to CGCU. An express track for RA at CGCU (0-10 days) and test results delivery ( < 35 days) was defined for OC patients whose germline BRCA1/2 test results were needed to tailor their treatment. Results: Between January 1st and November 30th, 115 new OC patients were refered to the CGCU. 27 (23 %) followed the express track. Median time from the referral date to test results for standard GC was 77 days (36-98) and 27 days (18-65) for express GC. Median age was 59 (23-80) and 63% had not family history of cancer. Serous carcinoma was the most frequent histology (96 %). BRCA1/2 results were available for 100 patients. Deleterious mutations were identified in 22% of patients (15% in the group without family history of cancer). Variants of uncertain significance were found in 9% of cases. Conclusions: After an initial 11 months experience review, our protocol warrants adequate RA for all patients tested for BRCA1/2 mutations as well as quick results when needed to establish a therapeutic strategy. Time to first appointment for RA and test results was optimal for patients with olaparib indication. The relatively high frequency of germline BRCA1/2 mutations could be explained by the bias selection of patients with platinum sensitive relapse. We continue to implement the protocol to end up testing all patients at diagnosis after having the results for all prevalent cases.

TPS479 Background: Pancreatic-NETs are highly vascular tumors. The anti-angiogenetic sunitinib was approved in advanced pNETs based on prolongation of progression-free survival. Upregulation of several proangiogenic factors that reflects intratumor hypoxia conditions might drive resistance to sunitinib in pNETs. Evofosfamide is a prodrug that under hypoxic conditions preferentially releases a brominated version of isophosphoramide mustard and has shown activity in cell lines from neural crest derived tumors such as melanoma and glioblastoma/astrocytoma. We hypothesize that evofosfamide may have activity in the pathologic hypoxic conditions present in the tumor environment of neuroendocrine tumors inducing responses that may be consolidated and prolonged with sunitinib in patients with advanced pNETs that are naïve for systemic treatment. Methods: This is a prospective, non randomized, open-label, phase II study that is being conducted in 10 university sites belonging to the Spanish Task Force Group for NETs (GETNE) in Spain. Patients with histologically proven diagnosis of progressive unresectable or metastatic pNET with Ki67 < 20% and grade 1 or 2 will receive sunitinib orally at 37.5 mg PO daily on days 1 to 28 of a 28-day cycle (4 weeks) plus evofosfamide administered at 340 mg/m2 by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a 28-day cycle (4 weeks). Hypoxia-related tumor markers, single nucleotide polymorphisms related to activity and metabolism of antiangiogenic agents (VEGFR2, VEGFR3, PDGFR-α, VEGF-A, IL8, CYP3A4, CYP3A5, ABCB1-2) will be correlated with clinical outcome. In this study it is planned to include 43 patientsbased on a two-stage Simon’s phase II design (α = 0.05, β = 80%). If the trial shows 8 responses or more among 43 patients, the treatment will be considered for further investigation. EudraCT number: 2014-004072-30 Clinical trial information: NCT02402062.

INTRODUCTION:Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS:The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS:We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS:Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare and complex neoplasms that present many clinical challenges. Most GEP-NETs are sporadic, but they can be multiple and a component of a familial syndrome. Assessment of the location and extent of GEP-NETs is crucial for management and a number of novel imaging modalities are under evaluation with the principal goal of increasing sensitivity for the detection of micro-metastases while retaining specificity. The appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Management strategies include surgery, radiological intervention, cytotoxic chemotherapies, somatostatin analogs and novel biological agents such as sunitinib and everolimus. Other biological agents, new chemoteraphy regimens and somatostatin-tagged radionuclide therapies are also under investigation. In spite of this, comparison between therapeutic modalities is currently difficult. Further studies are warranted to individualize and optimize the diagnosis and treatment of these tumors.

BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.

While traditional cytotoxic drugs have shown limited efficacy in neuroendocrine tumors (NETs), their biological features have been characterized and can be exploited therapeutically. Their most prominent trait is an extraordinary vascularization in low-grade NETs and an hypoxia-dependent angiogenesis in high-grade NETs, which is associated to a significant expression of many proangiogenic molecules. Therefore, several antiangiogenic compounds have been tested in these malignancies, and among these, sunitinib has demonstrated activity in pancreatic NET patients by dually targeting the VEGFR and PDGFR pathways. In spite of these efficacious clinical results, apparent resistance to antiangiogenic therapies has been described in NET animal models and in clinical trials. Therefore, overcoming antiangiogenic resistance is a crucial step in the subsequent development of antiangiogenic therapies. Several strategies have been postulated to fight resistance, but preclinical studies and clinical trials will investigate and address these therapeutic approaches in the coming years in order to overcome resistance to antiangiogenic therapies in NETs.