Analysis of KRAS and BRAF mutant colorectal cancers in a multiracial population.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1599-1599
Author(s):  
Jared David Acoba ◽  
Christopher A. Lum ◽  
Lambert T Leong
Keyword(s):  
Braf Mutation ◽  
Proportional Hazards ◽  
Mutational Analysis ◽  
Comprehensive Evaluation ◽  
Statistical Significance ◽  
Cox Proportional Hazards ◽  
Racial Groups ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Braf Mutant

1599 Background: We previously demonstrated racial disparities in colorectal cancer (CRC) survival despite adjustments for tumor and socioeconomic factors. Molecular differences in breast and lung tumors contribute to racial survival inequality, yet in CRC, molecular tumor characteristics have not been studied extensively in a racially diverse cohort. We performed a comprehensive evaluation of KRAS and BRAF mutations in a multiracial population to determine the prevalence in CRC and the degree to which these molecular traits impact survival. Methods: A retrospective cohort study of patients diagnosed with CRC between 2008 and 2011 from hospital tumor registries was performed. The prevalence of KRAS and BRAF mutations was determined for the study population and individual racial groups. Multivariable Cox proportional hazards regression models for survival were built for KRAS and BRAF mutation status while adjusting for age at diagnosis, race, and stage of disease. Results: Of 706 patients diagnosed with CRC, KRAS mutational analysis was performed on 148 subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 subjects (32%). The prevalence of mutant tumors among racial groups was W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed a prevalence of W 11%, A 9%, and NH 7%. When compared to published datasets of predominantly white patients, our multiracial cohort had a significantly higher rate of KRAS G13D mutant tumors, p=0.039. Of 74 subjects tested for the BRAF mutation, two mutant tumors were detected (3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 0% NH (p=0.18). BRAF and KRAS G13D mutations were adverse prognostic factors in a multivariate analysis, although the odds ratios failed to meet statistical significance. Conclusions: The prevalence of BRAF and KRAS mutations in this multiracial cohort is similar to what has been previously reported. However the rates of KRAS G13D and BRAF mutant tumors in our cohort are higher than prior reports. Furthermore, KRAS G13D which has been postulated to be a favorable prognostic factor for CRC, may adversely impact survival of minority patients.

Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3612-3612
Author(s):  
Luisa Foltran ◽  
Giuseppe Aprile ◽  
Giovanna De Maglio ◽  
Federica Edith Pisa ◽  
Mariaelena Casagrande ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Advanced Colorectal Cancer ◽  
Mutational Analysis ◽  
Wild Type ◽  
Prognostic Role ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Pik3ca Mutations ◽  
Negative Prognostic Factor ◽  
Impact On Survival

3612 Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]

Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 413-413
Author(s):  
T. Yokota ◽  
T. Ura ◽  
N. Shibata ◽  
D. Takahari ◽  
K. Shitara ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Clinicopathological Features ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Braf Mutant

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p<0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p<0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.

Association of KRAS and BRAF mutations with progression-free survival (PFS) with second-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 196-196
Author(s):  
Federico Innocenti ◽  
Sara R. Selitsky ◽  
Joel S. Parker ◽  
James Todd Auman ◽  
Kelli Hammond ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Braf V600e ◽  
Second Line ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Angiogenic Therapy ◽  
Kaplan Meier ◽  
Significant Difference

196 Background: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line FOLFIRI plus either regorafenib or placebo in mCRC. The addition of regorafenib improved PFS (median PFS 6.1 vs 5.3 mo, HR 0.73, 95% CI 0.53-1.01). However, the effect of somatic mutations on regorafenib activity has not been tested. Methods: We performed whole exome sequencing on archival primary tumor tissue and paired normal tissue in 85 patients of LCCC1029. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and hazard ratios (HR) were estimated using Cox proportional hazards method. Results: Among the 85 subjects, 54 (64%) had tumors wild-type (WT) for KRAS and BRAF, 26 (31%) had tumors with KRAS mutations in exons 2-4, and 5 (6%) had tumors with BRAF V600E. The addition of regorafenib to FOLFIRI improved PFS in the KRAS/ BRAF WT subgroup (median PFS 8.0 vs 4.9 mo, HR 0.68, 95% CI 0.48-0.97, log-rank p=0.028), but not in the KRAS mutant subgroup (median PFS 6.8 vs 5.5 mo, HR 0.90, 95% CI 0.61-1.35, log-rank p=0.617) or the BRAF mutant subgroup (log-rank p=0.156). In all of these subgroups, the addition of regorafenib was not associated with significant difference in OS. BRAF V600E was prognostic and associated with significantly worse OS (median OS 8.4 vs 18.0 mo, HR 2.59, 95% CI 1.01-6.66, log-rank p=0.04). Conclusions: The addition of regorafenib to FOLFIRI improves PFS among the subgroup of patients with KRAS and BRAF dual WT CRC, but not among the KRAS mutant subgroup. These results indicate that the addition of anti-angiogenic therapy to second-line chemotherapy backbones may be more effective in KRAS/ BRAF WT tumors in particular. More confirmatory studies are needed to corroborate this finding.

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4142-4142
Author(s):  
Lucy Xiaolu Ma ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Disease ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
First Line ◽  
Kras Mutations ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Translational Research Program ◽  
The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  
Keyword(s):  
Germ Cell ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

scholarly journals 7 Assessing melanoma BRAF status through ddPCR of cfDNA

2019 ◽  
Vol 95 (1130) ◽  
pp. 686.4-687
Author(s):  
Lauren Passy ◽  
Shobha Silva ◽  
Ian Brock ◽  
Greg Wells ◽  
Angela Cox ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Limit Of Detection ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutation Status ◽  
Gapdh Gene ◽  
Fractional Abundance ◽  
Significant Difference ◽  
Tissue Specimens ◽  
Braf Mutant

IntroductionTreatment of recurrent and metastatic melanoma has been revolutionised by targeted therapy. Inhibitors of mutant BRAF are a systemic treatment offered for patients with stage III/IV melanoma who are known to carry a mutation in BRAF. Currently patients’ BRAF mutation status is assessed through molecular analysis of tissue specimens.Cell-free DNA (cfDNA) released from tumours can be used to non-invasively detect active disease and predict survival in melanoma. cfDNA also provides a method for detecting BRAF mutations. This project aimed to ascertain BRAF mutation status in cfDNA through digital droplet PCR (ddPCR) of plasma samples from patients with melanoma. We aimed to assess the relationship between cfDNA BRAF positivity and disease relapse and progression.MethodsPlasma from 100 patients with active or recently resected melanoma was obtained during previous work. 85 samples had cfDNA extracted. Tissue BRAF status was known for 57 samples. cfDNA was extracted from 1–2 ml plasma with the QIAamp circulating nucleic acid kit (QIAGEN®) following manufacturer protocol, eluting cfDNA into 100µL. cfDNA was quantified with SYBR green quantitative real-time PCR (Life Technologies), based on an 87bp GAPDH gene amplicon. ddPCR™ was performed using the Bio-Rad QX200 Droplet Generator™ and Droplet Reader as per manufacturer protocol. Analysis was performed with Bio-Rad QuantaSoft Version 1.7.4.ResultsMedian yield of cfDNA extracted from 85 samples was 1.97 ng/ml when eluted into 100µL. This was well-correlated with previous cfDNA extraction yields from this sample set (Pearson’s r=0.6687, p<0.0005), where a 200µL elution volume was used. 74 samples yielded >10,000 droplets and were included for analysis. 12 samples contained BRAF mutant positive droplets. A 74% concordance rate between tissue BRAF mutation status and the presence/absence of cfDNA BRAF mutant positive droplets was found. 7/18 tissue BRAF mutant samples contained BRAF mutant droplets, in comparison to 2/32 tissue BRAF wild-type samples. The presence of BRAF mutant positive droplets was significantly different between the tissue BRAF mutant and tissue BRAF wild-type groups (χ2 8.3145, p=0.004).Fractional abundance of BRAF mutant droplets in the samples containing mutant droplets ranged from 0.07–0.74%. When comparing BRAF mutant droplet-containing samples and samples without BRAF mutant droplets, there was no significant difference in rate of relapse (χ2 0.0948, p=0.758), nor mortality rate (χ2 3.3959, p=0.654).Conclusion cfDNA provides a non-invasive snapshot of the tumour genome and any potential therapeutic targets held within. This work demonstrates that a very low volume of cfDNA can be used to detect BRAF mutations in patients with melanoma through ddPCR.Previous work assessing BRAF status in cfDNA has used larger volumes of cfDNA. Though our concordance rates are comparable with other studies, it is possible that using a smaller amount of cfDNA in our ddPCR has resulted in some samples being below the limit of detection for ddPCR.Longitudinal study is warranted to monitor cfDNA BRAF status and mutant fractional abundance, and whether this better correlates with relapse of disease and disease progression.

Digoxin exposure and prostate cancer mortality: A matched cohort study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13096-e13096 ◽  
Author(s):  
Evelyn Flahavan ◽  
Kathleen Bennett ◽  
Linda Sharp ◽  
Thomas Ian Barron
Keyword(s):  
Prostate Cancer ◽  
Cohort Study ◽  
Proportional Hazards ◽  
Statistical Significance ◽  
Hypoxia Inducible Factor ◽  
Epidemiological Studies ◽  
Cox Proportional Hazards ◽  
Response Analysis ◽  
Covariate Balance ◽  
Exposure Response

e13096 Background: Digoxin (DIG) exposure has been associated with reduced prostate cancer (PC) incidence in epidemiological studies. Preclinical data suggests that this anti-cancer effect is mediated through the inhibition of hypoxia-inducible factor 1-α by DIG. This retrospective cohort study examines associations between DIG exposure and mortality in men with PC. Methods: Men diagnosed with PC during 2001–2006 were identified from National Cancer Registry Ireland records and linked prescription claims data. Propensity scores for DIG exposure in the 90 days prior to PC diagnosis were estimated. DIG exposed and unexposed men were matched (1:1) within a calliper of 0.2 standard deviations of the propensity score logit, using greedy matching without replacement. Standardized differences were used to assess covariate balance (z-score <0.1) between matched cohorts. Hazard ratios (HR) for associations between DIG exposure and all-cause (ACM) or PC-specific (PCM) mortality were estimated using Cox proportional hazards models adjusted for age, comorbidity, tumour stage and grade. Categorical exposure-response analyses were carried out using tertiles of exposure (low, intermediate, high) in the 90 days pre-diagnosis. Results: 5734 PC cases were identified from the linked database. 395 cases received DIG in the 90 days pre-diagnosis, of which 391 were matched to unexposed controls. Matched covariate balance was acceptable. In adjusted analyses, DIG exposure was not associated with ACM (HR 1.06, 95% CI 0.88-1.27) but was associated with a small but non-significant reduction in the risk of PCM (HR 0.89, 95% CI 0.68-1.17). In the exposure-response analysis, DIG exposure in the highest tertile, but not in the intermediate or lower tertiles, was associated with a reduced risk of PCM approaching statistical significance (HR 0.69, 95% CI 0.47-1.01, p=0.059). Men in the high DIG exposure group received a supply of DIG for 98% of their eligible follow up in the year post diagnosis. Post diagnostic DIG exposure in the intermediate and lower tertiles was 94% and 80% respectively. Conclusions: DIG exposure was associated with a non-significant decrease in PCM. Stratification by exposure suggests the presence of an exposure-response relationship.

Prognostic value of BRAFV600 mutations in melanoma patients after resection of metastatic lymph nodes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8540-8540
Author(s):  
Philippe Saiag ◽  
Stephanie Moreau ◽  
Philippe Aegerter ◽  
Daphne Bosset ◽  
Christine Longvert ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Prognostic Value ◽  
Proportional Hazards ◽  
Univariate Analysis ◽  
Primary Melanoma ◽  
Stage Iv ◽  
Cox Proportional Hazards ◽  
Stage Iii ◽  
Rank Test ◽  
Braf Mutations

8540 Background: Prognosis of AJCC stage III melanoma is heterogeneous. BRAFV600 mutations are frequent in melanomas. BRAFV600-targeted therapy has dramatic, but often transitory, efficacy in stage IV patients (pts). We aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with sufficient nodal invasion. Methods: We searched all pts with cutaneous melanoma who had radical lymphadenectomy in our institution between 1/1/00 and 15/6/10 and included those with a nodal deposit >2 mm. BRAFV600 mutations were detected by DNA sequencing and pyrosequencing in formalin-fixed nodal samples containing >60% melanoma cells. Samples were considered mutated when >15% of DNA was positive. Endpoints were overall survival (OS) and distant metastasis free survival (DMFS). 92 patients had to be included to demonstrate a doubling of OS in patients without (40 months (m)) and with BRAFV600 mutation (20 m). Log-rank test and multivariate Cox proportional hazards regression model were used. Results: 105 consecutive pts were included, with 72% prospectively followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death occurred in 83% and 60% of pts with and without BRAF mutations, respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF status influenced OS and DMFS in the univariate analysis. The multivariate analysis showed the major prognostic role of BRAF status and of the number of invaded nodes (table). Conclusions: Provided our findings are independently replicated, BRAFV600 status should be used to stage melanoma pts with nodal metastasis. Our results also help to plan adjuvant trials with BRAFV600-targeted therapy in such patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. [Table: see text]

A phase II trial of gemcitabine, irinotecan, and panitumumab in advanced cholangiocarcinoma, with correlative analysis of EGFR, KRAS, and BRAF: An interim report.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4111-4111
Author(s):  
Davendra Sohal ◽  
Ursina R. Teitelbaum ◽  
Takeshi Uehara ◽  
Kristine Mykulowycz ◽  
Christopher D. Watt ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Stage ◽  
Primary Objective ◽  
Response To Therapy ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Tissue Specimens

4111 Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches achieve modest results. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan, in patients with advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes was planned as well. Methods: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m2) and irinotecan (100 mg/m2) on days 1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for correlative molecular analyses. Primary objective is to evaluate the 5-month progression-free survival (PFS) rate. Secondary objectives include overall response rate (ORR), overall survival (OS) and toxicity of the combination. Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and BRAF (V600E) was done on samples with adequate material for testing. Results: There have been 26 (of planned 42) patients recruited to the study. A median of 6 (0-30) cycles were administered. There were no treatment related deaths. The most common gr 3 or higher toxicities were neutropenia (10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%) and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD (disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts. Two pts went on to have surgical resection. Median OS is 12.7 months. Of 13 testable samples, no EGFR or BRAF mutations were identified; however, there were 7 KRAS mutations. Retrospective analysis showed no difference in OS by KRAS mutation status. Conclusions: Interim evaluation of this ongoing study showed encouraging tolerability and efficacy of this regimen. Several patients have KRAS mutations; there appears to be no association with response, however. The pre-specified efficacy criteria to continue enrollment were met.

The association of a 17-gene genomic prostate score with adverse surgical pathology and recurrence following surgery for localized prostate cancer (PCa): A comparison of African American and Caucasian patients.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 86-86
Author(s):  
Jennifer Cullen ◽  
Inger L. Rosner ◽  
Timothy C. Brand ◽  
Amina Ali ◽  
Yongmei Chen ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Proportional Hazards ◽  
Tumor Biology ◽  
Cox Proportional Hazards ◽  
National Database ◽  
Racial Groups ◽  
Logistic Regression Models ◽  
Gleason Pattern ◽  
Medical Centers ◽  
Or Gene

86 Background: Molecular assays can improve risk assessment for newly diagnosed PCa, but it is imperative to characterize assay performance in different racial groups, since tumor biology and clinical outcomes may vary. A racially diverse cohort of men (20% AA) with PCa in the Center for Prostate Disease Research multi-center national database was used to determine the association of GPS with outcomes in men treated with radical prostatectomy (RP) for localized PCa. Methods: Biopsy specimens from 431 men treated with RP for NCCN very low, low or intermediate risk PCa at 2 U.S. military medical centers were tested with a 17-gene RT-PCR assay to validate the association between GPS (scale 0-100) and 1) biochemical recurrence (BCR) following RP, and 2) adverse pathology (AP) at RP. BCR was defined as 2 successive PSA levels > 0.2 ng/mL. AP was defined as high-grade (primary Gleason pattern 4 or any pattern 5) and/or pT3 disease. Cox proportional hazards and logistic regression models were used. Results: GPS was obtained in 402 cases (93%), including 82 AA men. A broad range of GPS results was observed in both AA and CA men; GPS distributions were similar between AA (median GPS = 30.3; inter-quartile range (IQR): 23-38) and CA (median GPS = 30.3; IQR: 23-40); no correlation was observed between GPS and race (r = -0.04, p = 0.45). No differences in expression of individual genes or gene groups in the assay were observed between the two groups. In univariable analysis, PSA, biopsy GS and NCCN risk group were associated with BCR and AP, but race was not. The associations between GPS and clinical outcomes were similarly strong and statistically significant in both AA and CA men - BCR HR/20 GPS units = 3.0 (95% CI: 2.0-4.3) for CA vs. 3.5 (95% CI: 1.0-11.7) for AA; AP OR/20 units = 4.0 (95% CI: 2.6-6.6) for CA vs. 2.9 (95% CI: 1.2-7.6) for AA (p < 0.05 for all). Conclusions: In this cohort of patients treated in a health care system with equal access, clinical outcomes and the tumor biology measured by GPS were similar between AA and CA patients. GPS is a significant predictor of BCR and AP in men treated with RP for localized PCa in both AA and CA men.

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