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Purpose: To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. Patients and Methods: BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician’s choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results: After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n ¼ 141) versus 3.1 months in the PC arm [n ¼ 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P ¼ 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm. Conclusions: Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib’s activity in this patient population., SCOPUS: ar.j, info:eu-repo/semantics/published

Secondary amyloidosis is a rare complex complication related to chronic inflammatory disease. This complication is sparsely associated to malignant neoplasms. Renal cell carcinoma (RCC) is the most common solid organ malignancy related with this paraneoplastic syndrome. Some case reports have described stabilisation or even remission of amyloidosis with cytoreductive nephrectomy. Majority of those reports were based on locally advanced RCC. We report the first case of early aggressive systemic secondary amyloidosis in high-volume metastatic RCC. The subject was diagnosed with metastatic RCC within 6 months of secondary amyloidosis; on month 5 of initiation of targeted therapy (pazopanib) developed nephrotic syndrome with a heavy proteinuria (>18 g/day), severe hypoalbuminaemia (1.53 g/dL), intense and progressive oedema, severe pancolitis and mild dyspnoea with hypotension. A colon biopsy and the immunohistochemistry confirmed the histological diagnosis of a secondary amyloidosis. The multidisciplinary tumour board decided to perform cytoreductive nephrectomy in order to reduce the pro-inflammatory status. Pathology report showed a complete resection of clear cell RCC plus renal amyloid deposits. The patient died within 4 days of surgery due to multiorgan failure.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

Aim Cabazitaxel (CBZ), a novel tubulin-binding taxane, improves overall survival in metastatic castration-resistant prostate cancer (mCRPC) that progresses during or after docetaxel treatment. We have designed a phase II study to evaluate the efficacy and safety of CBZ as a weekly schedule for ‘unfit’ mCRPC patients after docetaxel failure. Methods In this single arm phase II study. CBZ was weekly administered in 1-hour infusion on days 1, 8, 15 and 22, every 5 weeks at 10 mg/m2 to eligible ‘unfit’ patients; oral prednisone (5 mg) was administered twice a day. Circulating tumour cells (CTCs) were also collected. New treatment scheme was considered effective if at least 65% of patients met a clinical benefit criteria based on prostate-specific antigen (PSA)-progression-free survival (PFS) values at week 12. Results Seventy patients (median age: 73.9 years) were enrolled; overall, 71.4% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2; and 84%, 16% and 11% had bone, liver and lung metastases, respectively. Objective partial response or stable disease was achieved in 61% of patients, while PSA responses of ≥50% and ≥80% were observed in 34.8% and 10.6%, respectively. The median PSA-PFS was 4.8 months; and 68.6% of patients had no progression at week 12. The most frequent grade 3/4 toxicities were neutropenia (2.8%), leukopenia (5.7%) and thrombocytopaenia (9%); no cases of febrile neutropenia were reported. Early CTC response was significantly correlated with PSA-PFS. Conclusions CBZ/prednisone administered weekly to ‘unfit’ mCRPC patients appears to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance. Early CTC response appears to be valuable as an early end-point of therapeutic efficacy.

95 Background: Abiraterone acetate (AA) improves OS and rPFS in first line mCRPC patients (pts). After AA progression D is commonly used as standard second line therapy. However, the value of maintaining AA in combination with D despite progression has not been tested beyond small exploratory studies (Tagawa ST, Eur Urol 2016) ABIDO is a randomized-phase II trial that evaluates efficacy and safety of D + AA vs D after first-line AA progression in mCRPC. Methods: Asymptomatic or minimally symptomatic mCRPC pts with no visceral metastases, ECOG PS 0-1, and adequate organ functions were included. The study has two stages: In stage I pts receive AA (1000 mg/d + prednisone (P) 10 mg qd) until radiological or unequivocal clinical progression. In stage II pts were randomized to D 75 mg/m2 q3wk in combination with AA 1000 mg/d (arm A) or without AA (arm B) The primary endpoint was rPFS and the secondary endpoints radiological response (RR), OS, PSA-response, PSA-PFS and safety. Results: 88 pts were randomized, (46 arm A, 42 Arm B). Median age was 69 y/o, 43% had ECOG 0 and 91%/11%/5% had bone, liver and lung metastases. Median rPFS was 11.4 months (m) in arm A vs 10.5 m in ARM B; 12-m rPFS was 43% vs 45%; Median PSA PFS was 6.2 vs 5.5 m and median OS was 17.3 vs 16.9 m. Twenty four pts (52%) in arm A and 19 (46%) in arm B achieve ≥50% PSA response. RR was achieved in 15% vs 7% of pts and disease control rate in 74% in both arms. No statistically significant differences were found in efficacy parameters. Half of pts received 10 cycles of D (median 7 and 8). D median dose intensity was 86% and 90% for each arm and 91% for AA. Eleven pts discontinued treatment due to non-hematological toxicity, 5 in arm A and 6 in arm B. Most frequent G3-4 toxicities per arm (A/B) were: neutropenia (57%/29%; P=0.027), febrile neutropenia (17%/10%), diarrhea (9%/7%), and asthenia (11%/10%). Conclusions: ABIDO trial was unable to demonstrate the significant clinical benefit of maintenance AA approach + D after AA first-line therapy. No differences were observed in RR, PSA PFS, rPFS and OS. In AA + D cohort, more frequent and severe hematological toxicity (neutropenia and febrile neutropenia) were reported. Clinical trial information: NCT02036060.

The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.

ObjectivePatients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. MethodsOne hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1week, 3 months, and 12months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. ResultsA pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value=.87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value

176 Background: Cabazitaxel (CBZ) improves overall survival in mCRPC that progresses during or after docetaxel treatment. CABASEM is a phase II study to evaluate the efficacy and safety of a weekly schedule of CBZ for 'unfit' (ECOG2, previous neutropenic fever with docetaxel, or radiotherapy to

198 Background: Different treatments efficacy for mCRPC when progression after docetaxel x 6 cycles + ADT (as CHAARTED scheme) are unknown as all pivotal trials where performed in patients who progressed to mCPRC after ADT. Methods: A retrospective analysis of 175 mCRPC patients of 10 spanish hospitals who were treated with docetaxel + ADT as first line treatment was performed. Patients characteristics at diagnosis (age, gleason) and at progression to mCRPC were analyzed (PSA, presence of visceral mets, type of progression). As efficacy endpoints, clinical and objective response, and survival from progression to mCRPC were analyzed. Results: Median age at diagnosis 65.2 years old (range 44-84). Metastatic at diagnosis 173. Bone metastasis 155 (88,5%), visceral 31 (17.7%), gleason >7 130 (74,3%), number docetaxel cycles: 6 (80%), 5 (5,7%)

This study aims to identify signatures of miR associated with hereditary, BRCA1 or BRCA2 mutation positive breast cancer (BC), and non-hereditary BC, either sporadic (SBC) or non-informative (BRCAX). Moreover, we search for signatures associated with tumor stage, immunohistochemistry and tumor molecular profile. Twenty formalin fixed paraffin embedded (FFPE) BCs, BRCA1, BRCA2, BRCAX and SBC, five per group were studied. Affymetrix platform miRNA v.3.0 was used to perform miR expression analysis. ER, PR, HER2 and Ki67 protein expression was analyzed by immunohistochemistry. BRCA1, BRCA2 and RASSF1 methylation analysis, AURKA copy number variations, and BRCA1 and BRCA2 deletions, were studied by MLPA. We validated eight of the miR selected by the arrays in 77 BCs by qRT-PCR. The miR profiles associated with tumor features were studied applying the Sparse Partial Least Squares Discriminant Analysis. MiR discrimination capability to distinguish hereditary and non-hereditary BC was analyzed by the discriminant function. With 15 out of 1,733 hsa-miRs, it was possible to differentiate the four groups. BRCA1, BRCA2 and SBC were associated with clusters of hyper-expressed miRs, and BRCAX with hypo-expressed miRs. Hsa-miR-4417 and hsa-miR-423-3p expressions (included among the eight validated miRs) differentiated 70.1 % of hereditary and non-hereditary BCs. We found miR profiles associated with tumor features like node involvement, histological grade, ER, PR and HER2 expression. Regarding molecular parameters, we only found a weak association of miRs in BC harboring losses in AURKA. We conclude that array miR expression profiles can differentiate the four study groups using FFPE BC. However, miRs expression estimated by qRT-PCR differentiates only hereditary and non-inherited BCs. The miR expression array is a simple and rapid approach that could be useful to facilitate the identification of those SBC carrying genetic or epigenetic changes in BRCA genes responsible of BRCA-like phenotype. These patients could benefit from the treatment with PARP inhibitors.

BACKGROUND: Olaparib is a well-tolerated oral PARP inhibitor. Olaparib has shown promising monotherapy activity in patients with germline mutations in BRCA genes and cancers that exhibited a failure in DNA repair mechanism. The aim of this trial is to evaluate the efficacy of olaparib as single agent in non-BRCA MBC patients whose tumors exhibit an homologous recombination deficiency (HRD) signature. TRIAL DESIGN: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive oral olaparib 300 mg twice a day during 28 days cycles until progression or unacceptable toxicity. HRD signature will be evaluated with one tumor tissue-based test: FMI Lynparza HRR. The stage I principal selection criteria are: (1) Confirmed non-BRCA triple negative locally advance (LA) or MBC; (2) HRD signature; (3) one to three previous lines for the MBC and prior taxanes exposure; (4) RECIST v1.1 evaluable disease. In stage II the study will be extended to patients with luminal subtype and confirmed non-BRCA LA or MBC with HRD signature. The primary goal is to evaluate the efficacy of olaparib monotherapy. Primary endpoint are the clinical benefit rate (CBR), defined as the percentage of patients who experienced overall response (as best response) or stable disease ≥24 weeks in accordance with RECISTv1.1. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CBR ≤5% while targeting an improvement of the CBR to ≥20% would be an optimal approach to evaluation of the study strategy. At first stage, ≥1 patient with clinical benefit among 17 patients will be necessary to continue. At the study end, ≥5 subjects with clinical benefit out of 35 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 39 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. We anticipate a 40% of screened TNBC and 25% of luminal (RH-positive HER2-negative) non-BRCA patients will exhibit HRD signature. Therefore, we expect to screen 48 patients in the 1st stage and 80 patients in the 2nd stages to accomplish with the accrual goal (a total of 128 patients screened). Secondary objectives include (1) efficacy measures: objective response rate (ORR), progression-free survival (PFS) and overall survival; (2) the assessment of HRD signatures agreement and validity to predict clinical benefit and overall response; and (3) safety-related outcomes. Citation Format: Elena Aguirre, Kepa Amillano, Alfonso Cortés, María José Juan, Antonia Márquez, Manuel Ruiz, Sonia Servitja, Ander Urrutikoetxea, Antonio Llombart, José Perez, Javier Cortes. A two-stage Simon Design phase II study for NOn-BRCA metastatic BReast cancer (MBC)patients with homologous recombination deficiency treated with OLAparib single agent.(NOBROLA study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT165.

1527Background: Conservative surgery (CS) and radiotherapy (RT) has a 3-5% local recurrence rate in patients with sporadic breast cancer (BC), but offers equivalent survival to mastectomy. For BRCA...

Background The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). Methods Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. Results Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p

Background Context Spinal instability is an acknowledged complication of spinal metastases; in spite of recent suggested criteria, it is not clearly defined in the literature. Purpose This study aimed to assess intra and interobserver agreement when using the Spine Instability Neoplastic Score (SINS) by all physicians involved in its management. Study Design Independent multicenter reliability study for the recently created SINS, undertaken with a panel of medical oncologists, neurosurgeons, radiologists, orthopedic surgeons, and radiation oncologists, was carried out. Patient Sample Ninety patients with biopsy-proven spinal metastases and magnetic resonance imaging, reviewed at the multidisciplinary tumor board of our institution, were included. Outcome Measures Intraclass correlation coefficient (ICC) was used for SINS score agreement. Fleiss kappa statistic was used to assess agreement on the location of the most affected vertebral level; agreement on the SINS category ("stable," "potentially stable," or "unstable"); and overall agreement with the classification established by tumor board. Methods Clinical data and imaging were provided to 83 specialists in 44 hospitals across 14 Spanish regions. No assessment criteria were pre-established. Each clinician assessed the SINS score twice, with a minimum 6-week interval. Clinicians were blinded to assessments made by other specialists and to their own previous assessment. Subgroup analyses were performed by clinicians' specialty, experience (≤7, 8–13, ≥14 years), and hospital category (four levels according to size and complexity). This study was supported by Kovacs Foundation. Results Intra and interobserver agreement on the location of the most affected levels was "almost perfect" (κ>0.94). Intra-observer agreement on the SINS score was "excellent" (ICC=0.77), whereas interobserver agreement was "moderate" (ICC=0.55). Intra-observer agreement in SINS category was "substantial" (k=0.61), whereas interobserver agreement was "moderate" (k=0.42). Overall agreement with the tumor board classification was "substantial" (κ=0.61). Results were similar across specialties, years of experience, and hospital category. Conclusions Agreement on the assessment of metastatic spine instability is moderate. The SINS can help improve communication among clinicians in oncology care.

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 (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

PURPOSE: To assess variability in the use of Tomita and modified Bauer scores in spine metastases. MATERIALS AND METHODS: Clinical data and imaging from 90 patients with biopsy-proven spinal metastases, were provided to 83 specialists from 44 hospitals. Spinal levels involved and the Tomita and modified Bauer scores for each case were determined twice by each clinician, with a minimum of 6-week interval. Clinicians were blinded to every evaluation. Kappa statistic was used to assess intra and inter-observer agreement. Subgroup analyses were performed according to clinicians' specialty (medical oncology, neurosurgery, radiology, orthopedic surgery and radiation oncology), years of experience (⩽7, 8-13, ⩾14), and type of hospital (four levels). RESULTS: For metastases identification, intra-observer agreement was "substantial" (0.600.80) at the other levels. Inter-observer agreement was "almost perfect" at lumbar spine, and "substantial" at the other levels. Intra-observer agreement for the Tomita and Bauer scores was almost perfect. Inter-observer agreement was almost perfect for the Tomita score and substantial for the Bauer one. Results were similar across specialties, years of experience and type of hospital. CONCLUSION: Agreement in the assessment of metastatic spine disease is high. These scoring systems can improve communication among clinicians involved in oncology care., This study was funded by the Kovacs Foundation, a not-for-profit Spanish institution specializing in neck and back pain research, and with no links to the health industry.

et al., Male breast cancer (MBC) is a rare disease that represents, This study has been supported, in part, by grants from the Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; Mutua Madrileña Foundation (FMMA); Spanish Association against Cancer (AECC08); FMM Foundation given to AV and the following projects: ISCIIIRETIC; RD06/0020/1051; RD12/0036/008; PI10/01422; PI10/00748; PI13/00285; 2009SGR290; RTICC 06/0020/1060; FISPI12/00070 and 10PXIB 9101297PR.

5052 Background: Circulating tumor cells (CTCs) enumeration using CellSearch correlates with clinical outcome in prostate cancer, but is limited for gene expression analysis. AdnaTest ProstateCancer is a commercially available CTC immune-enrichment and PCR-related detection method that allows gene expression studies (Antonarakis E, NEJM 2014). It has demonstrated incremental detection of CTCs in patients with no CTCs identified by CellSearch (Samoila A, ASCO 2013) but needs to be clinically qualified. There is a strong need for studies to assess the association with the clinical outcome in CRPC. Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC pts were recruited in 16 institutions. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma AR (Grande E, ASC0 2017 #) and CTC characterization (Grande E, ESMO 2016). Outcome measures included PSA-PFS (sPFS), radiographic PFS (rPFS) and OS. Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-eight patients had CTC blood samples available. CTCs were detected at baseline, 12 weeks and progression in 36% (35/98), 27% (26/95) and 78% (32/41), respectively. The CTC conversion rate (positive to negative after 12 w) was 43% (15/35). All CTC conversions had ≥50% decline in PSA (15/15) whereas only 35% (7/20) of pts with persistent CTCs. At first interim analysis, with a median follow-up of 10.6 months, detection of CTCs at baseline was associated with worse sPFS (median, 7.59 m versus NR, HR, 3.67; 95% CI 1.90-7.10; P < 0.001), rPFS (median, 12.9 m versus NR; HR, 7.61; 95% CI, 2.80-20.64; P < 0.001) and OS (medians NR, HR, 9.51; 95% CI, 1.11-81.52; P = 0.0398). CTC positive pts were less likely to have a ≥90% decline in PSA (OR, 2.88; 95% CI, 1.13-7.72; P = 0.02). Conclusions: CTC detection using AdnaTest is associated with an adverse outcome in chemotherapy-naïve asymptomatic or oligo-symptomatic mCRPC pts. Clinical trial information: NCT02288936.

Background: We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain). Methods: Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex. Results: We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%. Conclusions: The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype. This work was supported by the Institute for Health and Biomedical Research of Alicante (ISABIAL, UGP‐16‐146). RFA is recipient of a Fellowship from the Consellería Educación of the Valencian Community. ACA is funded by the Acción Juvenil from the Spanish Ministry of Economy and Competitiveness. VDO is recipient of a Fellowship from the Spanish Association Against Cancer (AECC). AC and MIC are funded by Health and Biomedical Research Foundation from the Valencian Region (FISABIO). EHI is recipient of a fellowship from the Fondo Investigación Sanitaria ISCIII (FI12/00233).

Germline mutations in DNA polymerase E > (POLE) and delta (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C > G (p.Leu424Val) or POLD1 c.1433G > A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T > C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.

Background and aims: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients. (C) 2014 Elsevier Ltd. All rights reserved.

El cancer es un dels problemes sanitaris mes importants dels paisos occidentals, donada l’alta incidencia i elevada mortalitat que te. Constitueix la segona causa de mort despres de les malalties cardiovasculars, i la primera causa en la poblacio menor de setanta anys. En aquest article ens ocuparem dels factors externs capacos d’induir el desenvolupament d’un cancer: agents quimics, fisics i biologics.

e16080Background: Normal and pathological angiogenesis is under the control of various developmental genetic programs, including Notch and Hedgehog pathways. More recently, miRNAs have emerged as k...

5058Background: Abiraterone acetate (AA) improves OS and rPFS in asymptomatic/minimally symptomatic mCRPC patients (pts) who are chemotherapy (CT) naive through CYP17 inhibition. Upon progression t...

El trabajo y la composición de los actualmente denominados Centros de Desarrollo Infantil y Atención Temprana han cambiado en las últimas décadas, pasando de los equipos multiprofesionales a los equipos interdisciplinares. También se ha pasado de una intervención centrada exclusivamente en el niño a una intervención que tiene en cuenta a la familia y a los contextos naturales de desarrollo de los niños. En este trabajo se pretenden revisar estos cambios y comentar la situación a la que se enfrentan en la actualidad los profesionales de la atención temprana, tales como las necesidades de formación y de coordinación de todos los componentes del equipo The kind of work and the organization of the currently called Childhood Development and Early Intervention Centres have changed in the last decades; this change has meant a shift from multi-professional to interdisciplinary teams. The kind of intervention in those centres has also been modified, from an intervention focused solely on the child to an intervention which takes into account the children’s families as well as their natural developmental contexts. The current work reviews these changes and discusses the situation that early intervention professionals are currently facing up, which points towards a need to update the training and coordination of all the components of the team.

e15597 Background: The IMRCC prognostic model for mRCC treated with VEGF-targeted agents (Heng, JCO '09) has been externally validated (Heng, Lancet Oncol '13), however, pt treated with Pz were not...

4525 Background: Treatment of mTCC progressing to cisplatin is an unmet need. Prognostic factors (PF) for worse overall survival (OS) are ECOG >0, Hb

1525 Background: Mammographic density (MD) is one of the strongest determinants of breast cancer (BC). In this case-control study, we compared MD in BRCA1/2 mutation carriers and non-carriers from ...

4578 Background: Deregulation of stem cell signaling pathways, such as Notch and Sonic Hedgehog (SHH) seems necessary for tumor initiation, maintenance and progression. Preclinical evidence support...

e16034 Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with mCRPC. Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival imp...

e12513 Background: Family history (FH) of breast cancer (BC), ovarian cancer (OC), and individual features (IF), like early age of onset, bilateral BC, coexistence of BC and OC, and triple negative BC (TNBC) younger than 50 years, are suspicion criteria of hereditary BC. Although it is assumed in the literature that 15-30% of BC cases can be familial BC (FBC), only 5-10% of BC are hereditary, explained by a germline mutation in BRCA1 or 2. Moreover, there is no international consensus to define FBC (e.g. number of relatives affected, age of onset), in contrast with, e.g. Lynch syndrome and Amsterdam/Bethesda criteria, in order to offer genetic counseling. In Spain, there are not population-based studies analyzing the real percentage of BC with familial and/or individual high risk features. Methods: A retrospective study based on 10,641 Spanish BC patients diagnosed from 1998-2001, collected in the “El Álamo III project”, was conducted. Specific data regarding FBC were analyzed: IF (age of onset, bilateral breast cancer, ovarian cancer and TNBC; and FH features (first and second degree relatives with BC and /or OC). Results: The Table summarizes the results. Conclusions: 21% of BC patients in Spain diagnosed from 1998 to 2001 have at least one relative with BC and/or OC. In addition, 2.8 % of patients with no FH of BC/OC fulfill high risk criteria. However, several study characteristics, such as 18% patients with no FH recorded, and lack of data regarding age of affected relatives, limit the interpretation of these results, being necessary to improve the family data collection in further “El Álamo” project studies. [Table: see text]