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Colorectal cancer; Driver gene; Mutant allele fraction Càncer colorectal; Gen conductor; Fracció d'al·lel mutant Cáncer colorrectal; Gen conductor; Fracción de alelo mutante Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.

3509Background: The mutant allele fractions (MAFs) of a driver gene may influence response to matched targeted therapies, such as KRAS and anti-EGFR antibodies in CRC. We performed a comprehensive ...

e20582Background: Median age at diagnosis of lung cancer is 70 years (y) and approximately 45% of patients (pts) are 70y or older. No consensus guidelines for the management of these older pts exis...

537Background: Fibroblast growth factors (FGFs) and FGFRs play an essential role in cancer cell proliferation and survival, with FGFR1 and FGFR2 gene amplifications being the most frequent genomic ...

Background: Aberrant MET activation occurs in many types of malignancies and includes protein overexpression, increased gene copy number, amplifications, mutations and deletions. The frequency of genomic alterations in MET varies widely among solid tumors. The criteria for MET amplification and MET overexpression have not been established as well as the relationship between MET amplification, MET expression and additional genomic alterations known to be important in tumor biology. Previous and current phase 1 clinical trials have selected patients without matching MET criterion. Materials and Methods: From Dec/2012 to Dec/2014, 203 formalin fixed paraffin embedded tumor samples from 197 patients consented to undergo targeted MET analysis. Samples were 117 primary and 86 metastatic tumors. Tumor types included colorectal, gastric, lung, glioblastoma, and breast. Samples were analyzed by fluorescence in situ hybridization (FISH) for MET gene amplification (MET/CEN-7 FISH Zytolight SPEC assay Z-2087, Zytovision), and by immunohistochemistry (IHC) for MET protein expression [Met (D1C2) XP® Rabbit mAb #8198, Cell signaling]. Mutations in key oncogenes were determined using Sequenom (Mass Array) and Amplicon-Mi Seq (Illumina) Cancer Panel. Results: MET gene copy number variation (>5copies) was found in 11 of 203 samples (5%) and MET gene amplification (based on the definition of MET/CEN-7 ≥2.2) was found in 6 of 203 samples (3%). Eleven (5%) samples had ≥4 or ≤5 copies of MET gene. KRAS mutation was found in 28 of 167 samples (17%) and PIK3CA mutation in 6 of 167 samples (4%). Both mutations were observed in tumor samples with < 4 copies of MET gene. MET IHC positive (≥ 50% positive cells 3+) was found in 11 of 203 samples (5%). Seven of 203 samples (3%) had MET IHC positive (≥ 50% positive cells 3+ and 2+). MET protein expression showed statistical association with MET gene copy number (P Conclusion: MET expression is higher in metastatic than primary tumor samples. There is a significant association between MET expression and gene copy number. High MET copy number was more frequent in tumors without KRAS and PIK3CA mutation. Quantitative MET protein expression data will be presented. MET IHCMET FISH≥ 50% cells 3+≥ 50% cells 3+ and 2+< 50% cells 3+and 2+< 2 copies01 (0.7%)40 (28.2%)2- 5 copies5 (3.5%)04 (2.8%) Citation Format: Analía Azaro, Guillem Argilés, María Alsina, Elena Elez, Teresa Macarulla, Cristina Cruz, Donatella Marino, Cinta Hierro, Susana Cedres, Alejandro Navarro, María Ochoa de Olza, Irene Braña, Juan Martín-Liberal, Marta Vilaró, Debora Moreno, Paola Martínez, María Díaz, Ana Vivancos, Jordi Rodón, Josep Tabernero, Ludmila Prudkin, Paolo Nuciforo. Prevalence of MET copy number variation, MET expression and MET related genomic alterations in all solid tumors pre-screening program. VHIO experience. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B187.

3602 Background: Biomarker-driven selection of new MTAs has not been widely successful in CRC as we reported in 2012. New screening platforms and drugs have reached early drug development. We aimed...

605 Background: To be eligible for an anti-HER therapy, tumors have to be HER2-positive as determined by IHC or in situ hybridization (ISH) analyses. Although gene amplification is generally consid...

4063 Background: AGC represents the third leading cause of cancer related deaths. Chemotherapy for AGC is active but still of limited efficacy and targeted agents Trastuzumab and Ramucirumab have s...

5562 Background: The broad spectrum of actionable molecular alterations (MA) detected with new techniques has increased interest in matched targeted therapies (MTT) after failure to standard treatm...

e18540 Background: Malignant pleural mesothelioma (MPM) frequently expresses elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggests that PTEN/PI3K pathw...

587 Background: BRAF mutation (mt) occurs in 5-8% of mCRC and its role as a negative prognostic factor is well known. The up-front detection of BRAF mt is not standardized beyond the boundaries of research. However, since novel emerging specific therapies are increasingly available in clinical trials, the prior determination of this mutation is now warranted. Methods: From 07/2010 to 01/2014, 581 patients (pts) with advanced refractory mCRCunderwent genetic tumor profiling as part of the VHIO Phase I Trial Molecular Prescreening Program. BRAF mt was determined by Sanger sequencing or multiplex PCR and mass detection (MassARRAY, Sequenom) of 268 frequent hotspots in 25 oncogenes including, KRAS, NRAS, and PIK3CA. PTEN status was also assessed by immunohistochemistry. Results: 581 samples were analyzed detecting BRAF mt in 56 (9.6%). In the BRAF mt population, median age was 61 years (45-80) and 54% had right-sided CRC. Metastatic sites were found at: liver 61%; peritoneum 52%; lung 39%. Median number of standard treatment was 4 (0-8) including cetuximab and/or panitumumab in 73%. BRAF V600E mutation was detected in 53 samples whereas V600K, D594V and D594G were seen in one sample each. PTEN was analyzed in 44.6% of samples resulting in low expression (H-score

5578 Background: In the wake of personalized medicine in Oncology, genetic tumor profiling has become a cornerstone to select patients (pts) for clinical trials, exploring new molecular targeted ag...

1509 Background: Women with a BRCA1 or BRCA2 mutation are at high risk of developing ovarian carcinoma (OC) and a residual risk of PC after PBSO has been reported. We aimed to analyze the incidence of PC after PBSO and the clinical, pathological and molecular risk factors associated to PC in our series. Methods: Between April 2005 and December 2012, 100 patients with BRCA1 or BRCA2 mutation (50 each) underwent PBSO and were followed in the High Risk Clinics for the development of PC. PBSO pieces were submitted to pathological examination for presence of pathological and molecular risk factors like in situ or invasive Fallopian Tube Carcinoma (isFTC, inFTC) and p53 signature. Patients’ medical charts included in the High Risk Clinics Database were revised retrospectively for clinical, pathological and molecular characteristics. We analyzed the incidence of PC and the odds ratio (OR) for PC after PBSO in univariate analysis. Results: Overall, 2 patients (2%, 1 BRCA1, 1 BRCA2) were found to have isFTC, while 5 out 34 had a positive p53 signature (15%, 1 BRCA1, 4 BRCA2). With a median follow-up of 40 months (1-90) since PBSO, 2 patients developed PC (2%, both BRCA2). They underwent PBSO at age of 63 and 64 years and developed the PC 2 and 9 years after. One had a history of isFTC with p53 signature and 5 children, while the other had a prior history of bilateral breast cancer and no children. None had a family history of OC. Performing PBSO at an age older than 50 years was associated with an OR 8.56 (3.29-22.27) of PC. Conclusions: Fifteen and 2% percent of our patients had a positive p53 signature or an occult isFTC in the PBSO piece. Our analysis suggests that delaying PBSO to women older than 50 years may be associated with a higher risk of PC. Further analysis in a larger cohort is warranted.