Colorectal cancer (CRC) KRAS mutational status and response to chemotherapy in absence of influence of epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) therapy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 504-504
Author(s):  
Nirit Yarom ◽  
Nana Boame ◽  
Gillian Gresham ◽  
David Hill ◽  
Derek J. Jonker
Keyword(s):  
Small Sample Size ◽  
Tumour Response ◽  
Stage Iv ◽  
Small Sample ◽  
Kras Mutations ◽  
Triple Combination Therapy ◽  
Mutational Status ◽  
Response To Chemotherapy ◽  
Kras Status ◽  
Refractory State

504 Background: KRAS mutations (MUT), present in ~40% of CRC, predict benefit from EGFR MAb treatment. The effect of mutation status on benefit from chemotherapy alone is less clear. Methods: Following ethics approval, 223 CRC patients with known KRAS status treated at a single institution were retrospectively analyzed for response to chemotherapy prior to initiation of EGFR MAb therapy. Tumour response rate and progression-free survival (PFS) were determined retrospectively. Given chemotherapy sequencing variability, a measure of the time to chemotherapy-refractory state (TTCR) was defined as time from start of first line therapy to progression on all drugs; ie fluoropyrimidines (F), irinotecan (I), and oxaliplatin (O), +/- bevacizumab (B). Results: Patients were median age 60 years (25-86), 58/42% male/female, 38% rectal or rectosigmoid, 18% liver-only metastases, 45.6% stage I-III and 54.4% stage IV at initial diagnosis, 43% prior adjuvant chemotherapy, 43/57% KRAS MUT/wild-type(WT) status. With a median follow-up of 27 months, 64 (29%) are alive. TTCR did not vary by KRAS status, with median 16.7 vs 14.8 months in WT vs MUT status patients, respectively, HR 0.85 [0.65-1.12], p=0.26. Overall survival (which now includes influence of any subsequent EGFR MAb therapy, received by 76/126 (60%) of KRAS WT status patients) did not differ significantly by KRAS status, with median survival 34.3 vs 29.2 months for WT vs MUT status, respectively, 0.79 [0.58-1.08], p=0.14. Conclusions: For most treatment strategies KRAS status did not affect 1st line PFS or time to chemotherapy-refractory state. However, for patients who received triple combination therapy, MUT status was associated with early progression. Small sample size, chance or some yet-to-be-elucidated molecular interaction may account for this finding. [Table: see text]

KRAS mutations and outcomes for patients with stage IV NSCLC treated with frontline platinum/pemetrexed based chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18139-e18139 ◽  
Author(s):  
Benjamin Levy ◽  
Nagashree Seetharamu ◽  
Stacie Richardson ◽  
Daniel Jacob Becker ◽  
Walter Choi ◽  
...  
Keyword(s):  
Stage Iv ◽  
Retrospective Chart Review ◽  
Rank Test ◽  
Fisher Exact Test ◽  
Kras Mutations ◽  
Exact Test ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Former Smokers ◽  
Few Data

e18139 Background: KRAS mutations are the most common driver mutation indentified in NSCLC, occurring in 20 - 30% of adenocarcinomas. While several studies suggest KRAS predicts for lack of response to TKI therapy, few data exist regarding its association with outcomes for patients treated with cytotoxic chemotherapy. This study explores the association between KRAS mutations and outcomes (RR, PFS) in a cohort of patients treated with frontline platinum/pemetrexed (PPm) based therapy. Methods: In this retrospective chart review, we evaluated RR and PFS for 16 KRAS + EGFR – pts treated with carboplatin (AUC 5-6) or Cisplatin 75mg/m2 and (Pm)pemetrexed (500 mg/m2) +/- (B)bevacizumab 15mg/kg. For comparators, we identified 19 KRAS - EGFR - patients treated with the same regimen. Maintenance therapy with Pm or Pm+B was given at the discretion of the treating physician. KRAS and EGFR mutational status were assessed by RT-PCR on tumor tissue collected at first diagnosis. RR was assessed using RECIST criteria. Kaplan-Meier estimates for PFS were evaluating using log rank test. Fisher exact test was used to assess the association between KRAS mutation status and response rate. Results: The groups were similar in age (KRAS + mean 61 vs. 60; p=0.87), gender (62% vs. 57% F; p= 0.9), ECOG 2 (0 vs. 10%,p=0.47), smoking hx (93% vs. 94% current/former smokers, p=0.7), brain mets (0% vs. 18% p=0.22), mean number induction cycles (4 in each, p=0.6), cisplatin and bevacizumab use (12% vs 10%, p > 0.1;10% vs. 40%, p=0.10). Pm maintenance was used in 31% KRAS+ (5/16) and 26% KRAS-(5/19) (p=0.79). P+B maintenance was used in 12% (2/16) and 5% (1/19) (p=0.70). RR was 56% in the KRAS + (9/16) vs. 36% KRAS- (7/19) respectively (p=0.3). There was a statistically significant improvement in PFS in the KRAS + group (10.3 mos vs. 5.7 mos, p =0.03). Conclusions: In this small retrospective review, KRAS mutations appeared to be associated with a non-significant improvement in RR and significant improvement in PFS for patients treated with frontline PPm based therapy. Future prospective studies should investigate and validate the predictive value of KRAS for this cytotoxic regimen. [Table: see text]

Genetic profiling of advanced RAI-resistant differentiated thyroid cancer and correlation with axitinib response.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6066-6066 ◽  
Author(s):  
Rebecca B. Schechter ◽  
Madhavi Nagilla ◽  
Loren Joseph ◽  
Poluru L. Reddy ◽  
Arun Khattri ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Clinical Response ◽  
Genomic Dna ◽  
Differentiated Thyroid Cancer ◽  
Novel Mutation ◽  
Small Sample Size ◽  
Small Sample ◽  
Braf V600e ◽  
Kras Mutations ◽  
Molecular Defects

6066 Background: The VEGFR inhibitor axitinib has demonstrated compelling antitumor activity in advanced RAI-resistant differentiated thyroid cancer (DTC). Biomarkers predicting which patients may benefit from axitinib are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Methods: Pretreatment FFPE thyroid cancer blocks from patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta Mutation Panel was used to test for 238 mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR. Genomic DNA was analyzed for coding regions of VEGFR1-3 with custom primers. Clinical response to axitinib, including best response (BR) (RECIST) and progression free survival (PFS), was ascertained from corresponding patients. Fisher’s exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. Results: A total of 22 pathology samples (11 primary, 11 metastatic) were identified. In patients with 2 samples (n = 4), results were concordant and only included once for analysis. Of 18 specimens, 4 tumors (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One sample with mutated KRAS also had a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing showed a possibly damaging non-synonymous SNP in VEGFR2 (G539GR) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350VE) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439IT) in 2 samples (11%). No significant relationship was seen between BR or PFS and the presence of molecular defects. Conclusions: While DTC is genetically heterogenous, primary and metastatic lesions showed identical alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but data were limited by small sample size. We did identify molecular changes in VEGFR that should be further explored. This study was supported by Pfizer, Inc.

Subgroup analysis of patients enrolled in the United States in the CORRECT phase 3 trial of the multikinase inhibitor regorafenib (REG) in metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 767-767
Author(s):  
Heinz-Josef Lenz ◽  
Eric Van Cutsem ◽  
Udit N. Verma ◽  
Marc Saltzman ◽  
Jyotsna Fuloria ◽  
...  
Keyword(s):  
Subgroup Analysis ◽  
Small Sample Size ◽  
The United States ◽  
Small Sample ◽  
Wild Type ◽  
Correct Trial ◽  
Multikinase Inhibitor ◽  
Kras Status ◽  
The Us ◽  
Dose Modifications

767 Background: The CORRECT trial (NCT01103323) showed that REG improves overall survival (OS) vs placebo (PBO) in patients with mCRC who failed approved therapies (OS HR 0.77; 1-sided p=0.0052; Grothey 2013). A total of 760 patients were randomized to REG (n=505) or PBO (n=255) in more than 100 centers across North America, Europe, Asia, and Australia. We conducted a post-hoc exploratory subgroup analysis of the 83 (11%) patients from 18 US centers. Methods: Eligible patients had an ECOG PS ≤1 and had received approved therapies, including a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, and if KRAS wild-type cetuximab and/or panitumumab. Data from the overall cohort, including US patients, are provided for perspective. Descriptive statistics are shown. Results: Of the 83 US patients, 36 (43%) were randomized to PBO and 47 (57%) to REG. Baseline characteristics of the US group were consistent with the overall cohort: median age in the US was 58 yr (range, 34 – 85) vs 61 (22 – 85) overall, 49% of US patients were ECOG PS1 (vs 46%), and 46% received ≤ 3 treatments for mCRC (vs 52%). KRAS status mutant/wild-type was 57%/34% in the US vs 57%/39% overall. All patients in the trial had prior bevacizumab and 57% of US patients also had prior cetuximab and/or panitumumab (vs 51% overall). However, higher proportion of patients in the US were Black (11% vs 2%), KRAS status unknown (10% vs 4%), and had colon as the primary disease site (82% vs 65%). Mean percentages of planned REG dose were similar (76% US vs 79% overall) and mean REG treatment duration was 3.1 mos in US vs 2.8 mos overall. Rates of dose modifications REG/PBO were 87%/47% in the US vs 76%/38% overall and grade ≥3 adverse events REG/PBO were 74%/64% vs 78%/49%, respectively. Based on 44 total death events, the HR for OS in the US subgroup was 0.46 (95%CI 0.25 – 0.84) favoring REG; median OS was 4.7 mos for PBO, but could not be estimated for REG due to censored data. However, this analysis was based on a relatively small sample size and event count. Conclusions: Patients treated in the CORRECT study in the US appear similar to the overall cohort and results are generally consistent with the overall findings of the trial. Clinical trial information: NCT01103323.

An open-label, multicenter, phase II study of ceritinib in patients with advanced ALK+ non-lung solid tumors and hematological malignancies (ASCEND-10).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3520-3520
Author(s):  
Victor Moreno ◽  
Tae Min Kim ◽  
Sun Young Rha ◽  
Federico Longo ◽  
Sith Sathornsumetee ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Small Sample Size ◽  
Stage Iv ◽  
Small Sample ◽  
Gamma Glutamyl Transferase ◽  
Efficacy And Safety ◽  
Open Label ◽  
Glutamyl Transferase

3520 Background: Prior studies have confirmed the efficacy and safety of ceritinib in patients (pts) with advanced ALK+ non-small cell lung cancer (Soria, et al, Lancet 2017; Shaw et al, Lancet Oncol 2017; Cho et al, JTO 2019). Ceritinib also demonstrated antitumor activity in pediatric pts with ALK+ inflammatory myofibroblastic tumor (IMT) and ALCL (Georger et al, ASCO 2015 [abstract#10005]). Long-term clinical benefits of ceritinib treatment were shown in pts with anaplastic large cell lymphoma (ALCL) (Richly et al, Blood 2015). The aim of the current study was to examine ceritinib efficacy and safety in pts with advanced ALK+ non-lung solid tumors and hematological malignancies. Methods: In this open-label, multi-arm, phase 2 (NCT02465528) trial, adult pts with ALK gene abnormalities who had received ≥1 prior systemic therapy were administered oral ceritinib 750 mg/day, under fasted conditions. Primary endpoint: investigator assessed disease control rate (DCR); secondary endpoints: investigator assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), and safety. Results: Overall, 22 pts (ALCL [n = 1], IMT [n = 4], glioblastoma multiforme [GBM, n = 12] and others [n = 5]) were enrolled; median (m) age: 52.5 years; male: 50%; Stage ≥IV: 95.4%. Key efficacy results are shown in the Table. mTTR in pts with confirmed complete response (CR) or partial response (PR) [n = 4] was 7.4 (range, 6–25) weeks. mDOR was not reached. mPFS (95% CI) was 2.6 (1.6, 3.7) weeks. Most common adverse events (AEs; ≥30%) were: diarrhea and nausea (59.1% each), vomiting (50.0%) and increased alanine aminotransferase (31.8%). Most common grade ≥3 AEs (≥10%): hyperglycemia (18.2%), increased gamma-glutamyl transferase, thrombocytopenia, and anemia (13.6% each). Clinical trial information: NCT02465528 . Conclusions: Ceritinib 750 mg/day under fasted conditions showed antitumor activity in pts with ALK+ ALCL and IMT; however, data interpretation is limited due to the small sample size. Safety findings were consistent with the known ceritinib safety profile. [Table: see text]

KRAS mutational status of endoscopic biopsies matches resection specimens

2012 ◽  
Vol 65 (7) ◽  
pp. 604-607 ◽  
Author(s):  
Qing-Hua Yang ◽  
Jason Schmidt ◽  
Genvieve Soucy ◽  
Robert Odze ◽  
Liza Dejesa-Jamanila ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Point Mutations ◽  
Kras Mutations ◽  
Biopsy Material ◽  
Mutation Status ◽  
Biopsy Tissue ◽  
Perfect Correlation ◽  
Mutational Status ◽  
Kras Status ◽  
Resection Specimen

AimsThis study was performed to determine systematically whether KRAS mutational analysis in biopsy tissue is a reliable indicator of KRAS status in subsequent corresponding resection specimens.Methods30 colorectal cancer (CRC) patients with biopsy and corresponding subsequent surgical resection specimens were studied. KRAS mutational analysis was performed on each biopsy sample as well as two separate samples from each resection specimen by PCR and Sanger sequencing.ResultsOverall, KRAS mutations were identified in 12/30 (40%) of the tumours. There was 100% correlation between biopsy and resection specimens regarding the presence or absence of KRAS mutations. In fact, the same point mutation was identified in both biopsy and corresponding resection specimens in 12/12 (100%) cases. In addition, in two cases, there were two different point mutations detected within the same biopsy specimen.ConclusionThis study shows perfect correlation between KRAS mutation status in biopsy and resection specimens from an individual patient, and suggests that biopsy material is adequate for KRAS mutational analysis in CRC patients.

scholarly journals Assessment of the Mutational Status of NSCLC Using Hypermetabolic Circulating Tumor Cells

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 270 ◽  
Author(s):  
Matteo Turetta ◽  
Michela Bulfoni ◽  
Giulia Brisotto ◽  
Gianpiero Fasola ◽  
Andrea Zanello ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Primary Tumor ◽  
Stage Iv ◽  
Kras Mutations ◽  
Mutational Status ◽  
Downstream Analysis ◽  
Nsclc Patients ◽  
New Mutations

Molecular characterization is currently a key step in NSCLC therapy selection. Circulating tumor cells (CTC) are excellent candidates for downstream analysis, but technology is still lagging behind. In this work, we show that the mutational status of NSCLC can be assessed on hypermetabolic CTC, detected by their increased glucose uptake. We validated the method in 30 Stage IV NSCLC patients: peripheral blood samples were incubated with a fluorescent glucose analog (2-NBDG) and analyzed by flow cytometry. Cells with the highest glucose uptake were sorted out. EGFR and KRAS mutations were detected by ddPCR. In sorted cells, mutated DNA was found in 85% of patients, finding an exact match with primary tumor in 70% of cases. Interestingly, in two patients multiple KRAS mutations were detected. Two patients displayed different mutations with respect to the primary tumor, and in two out of the four patients with a wild type primary tumor, new mutations were highlighted: EGFR p.746_750del and KRAS p.G12V. Hypermetabolic CTC can be enriched without the need of dedicated equipment and their mutational status can successfully be assessed by ddPCR. Finally, the finding of new mutations supports the possibility of probing tumor heterogeneity.

Serum biomarkers as predictors of clinical outcome after cetuximab-based therapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6035-6035
Author(s):  
R. L. Ferris ◽  
T. Feinstein ◽  
J. Grandis ◽  
R. Johnson ◽  
B. Branstetter ◽  
...  
Keyword(s):  
Growth Factors ◽  
Multiple Testing ◽  
Small Sample Size ◽  
Locally Advanced ◽  
Stage Iv ◽  
Complete Response ◽  
Serum Biomarkers ◽  
Small Sample ◽  
P Value ◽  
Baseline Serum

6035 Background: We correlated a panel of serum cytokines and growth factors with antitumor activity in patients (pts) with locally advanced SCCHN treated with cetuximab-based therapy. We have shown that similar biomarkers may be promising for the early detection of SCCHN (Linkov, Can Epi Biomarkers 2007). Methods: We used multi-analyte biomarker profiling for measurement of multiple serum biomarkers (Luminex Corp., Austin, TX). 39 pts with stage III-IVB SCCHN were treated with cisplatin, docetaxel, and cetuximab (TPE) for 3 cycles followed by radiotherapy, cisplatin, and cetuximab (XPE) and then maintenance cetuximab (Argiris, ASCO 2008, A6002). 31 cytokines and growth factors were measured before and after 3 cycles (9 weeks) of induction TPE. Clinical results were correlated with biomarkers, including 23 pts with PET response. Results: 31 pts had baseline biomarkers and 25 paired samples, pre- and post-TPE. Median follow-up was 22 months. Median age 54 years (21–74); male: 27; stage IV: 29; primary site: oropharynx, 16; larynx, 4; hypopharynx, 3, nasopharynx, 3; oral cavity, 3; and unknown, 2. Eight analytes changed significantly after induction. Adjusting p values for false discovery, the following analytes retain a p <0.05: MCP1c, IP-10, Leptin, IL-5, Eotaxin, IL-6, GCSF, CXCL5. In 23 pts with PET response assessment, low vascular endothelial growth factor (VEGF) levels or low IL-6 levels at baseline may be associated with complete response: 4/5 pts with low baseline VEGF (<20.9 pg/ml) had a complete response by PET vs 1/18 pts with high baseline VEGF. Of 31 pts, 9 have progressed. Among tests of association of the 31 analytes and progression-free survival (PFS), VEGF was the only one with a raw p value <.05 (p = .027), although the adjusted p value was not significant. A decrease in VEGF with treatment had a weak but not statistically significant association with longer PFS. Conclusions: Baseline serum biomarkers and in particular, VEGF and IL-6, were identified as potentially useful predictive markers of cetuximab-based therapy. Due to the small sample size and multiple testing, these biomarkers need to be validated in a larger study in SCCHN specifically powered for biomarker associations. No significant financial relationships to disclose.

Prediction of response to alkylator-based chemotherapy in metastatic melanoma (MM) using gene expression and promoter methylation signatures

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9009-9009
Author(s):  
H. A. Tawbi ◽  
S. Buch ◽  
P. Pancoska ◽  
Y. Lin ◽  
M. Saul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Promoter Methylation ◽  
Small Sample Size ◽  
Chemotherapy Resistance ◽  
Small Sample ◽  
Data Set ◽  
Response To Chemotherapy ◽  
Impact On Survival ◽  
Individualization Of Therapy ◽  
Methylation Profiling

9009 Background: Temozolomide and dacarbazine (TMZ and DTIC) remain the mainstay of alkylator-based chemotherapy for MM, despite response rates of 10–15% and the absence of any impact on survival. Classification of patients according to responsiveness can guide the individualization of therapy and inform approaches to abrogate mechanisms of chemotherapy resistance. Epigenetic mechanisms play an important role in regulation of genes associated with resistance and were evaluated in tandem with gene expression profiling in biological samples from MM patients (pts) to refine our understanding of the epigenomic-genomic-phenotypic interplay. Methods: We examined promoter methylation and gene expression in tumor tissues of 21 pts with MM treated with TMZ or DTIC, using high throughput technologies (Illumina Inc). The cases were divided into responder (R) and non-responder (NR) groups based on clinical response. The data were analyzed using Prediction Analysis of Microarrays (PAM) from BRB array tools. Results: Differential promoter methylation analysis revealed that 63.6% of promoter sites were hypomethylated in tumors obtained from R pts (p<0.0001). PAM analysis of gene expression data revealed that a classifier set consisting of 82 genes was able to predict NRs from Rs with 83% sensitivity and 89% specificity. Promoter methylation profiling did not independently correlate with R status. A simultaneous analysis of the promoter methylation and gene expression values first stratified into 3 data-driven categories and then combined into a 3 by 3 matrix allowed us to identify a common gene expression/methylation signature of 15 genes that classified both NR and R groups accurately 100% of the time. Conclusions: Gene expression signatures independently predict response to chemotherapy in MM, however promoter methylation profiling alone does not. Analysis of combined gene expression and promoter methylation in a well- annotated clinical data set dichotomized according to response identified a highly predictive signature. The findings from this study are qualified by the relatively small sample size and are currently being validated in an expanded sample set. Supported in part by the ECOG Paul Carbone, MD, Fellowship Award. No significant financial relationships to disclose.

BRAF and KRAS mutations in liver-resected metastatic colorectal cancer (mCRC) patients (pts).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 476-476
Author(s):  
Francesca Bergamo ◽  
Marta Schirripa ◽  
Fotios Loupakis ◽  
Chiara Cremolini ◽  
Mariaelena Casagrande ◽  
...  
Keyword(s):  
Liver Resection ◽  
High Risk ◽  
Braf Mutation ◽  
Prognostic Role ◽  
Kras Mutations ◽  
Curative Intent ◽  
Mutational Status ◽  
Kras Status ◽  
The Impact

476 Background: Up today there are no molecular markers to identify mCRC pts candidate to curative liver surgery at high risk of relapse. There are conflicting results about the prognostic role of KRAS mutation in mCRC pts, while BRAF mutation is a well-known negative prognostic factor characterizing a subgroup of mCRCs with a distinct metastatic spread. We analyzed the impact of BRAF and KRAS mutations on relapse free-survival (RFS) and overall survival (OS) in pts undergoing liver resection with curative intent. Methods: Medical records of pts referred to 3 Italian institutions between 1995 and 2012 were reviewed. 3024 mCRC pts were identified. 401 pts (13.3%) underwent liver resection with curative intent and had adequate follow-up. Mutational status was assessable on 360 samples from primary tumors (n=63), metastases (mts) (n=59) or both (n=238). Primary objective was to evaluate the impact of BRAF mutation on RFS in mCRC pts candidate to liver resection. Secondary objectives were to evaluate the prognostic role of BRAF status on OS, and of KRAS status on RFS and OS in this population. Results: BRAF and KRAS were mutated in 11 (3%) and 116 (32%) out of 360 cases respectively. In 238 cases in which paired samples from primary and metastases were available, no discordance was found in BRAF status while 18 cases (7.6%) showed a discrepancy in KRAS status and were thus excluded from analysis. Pts with BRAF mutation had significantly shorter median RFS compared to pts with BRAF wt tumor (5.7 mos vs 11.7 mos, HR=4.25; 95%CI: 1.52-11.88, p=0.005). OS was significantly reduced in pts with BRAF mutated tumors vs wt (HR=5.39; 95%CI: 1.59-18.27, p=0.007). Mutated KRAS was not prognostic for RFS (HR=1.14; 95%CI: 0.87-1.49, p=0.34), while demonstrated a weak prognostic impact on OS (HR=1.52; 95%CI: 1.05-2.21, p=0.03). In this cohort high-risk Fong score were significantly associated with shorter RFS (p<0.0001) and OS (p<0.0001). Conclusions: BRAF mutation is associated with higher probability of relapse and worse outcome in liver resected mCRC. KRAS mutation was not associated with RFS after liver resection. BRAF mutational status may become a new prognostic marker when planning liver resection in mCRC pts.

ERBB pathway alterations in advanced gastric signet-ring cell carcinoma (SRCC) and the implications for targeted therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15586-e15586
Author(s):  
Jia Wei ◽  
Bo Xu ◽  
Shenying Jin ◽  
Lixia Yu ◽  
Baorui Liu
Keyword(s):  
Targeted Therapy ◽  
Mutation Rate ◽  
Small Sample Size ◽  
Stage Iv ◽  
Signet Ring Cell Carcinoma ◽  
Signet Ring Cell ◽  
Small Sample ◽  
Her2 Positive ◽  
Clinical Prognosis ◽  
Erbb2 Expression

e15586 Background: Studies have shown that ERBB3 mutations are associated with poor clinical prognosis and ERBB3 targeted therapeutics can be effective against ERBB3 mutant-driven tumors. ERBB signal pathway plays a very important role in the initiation and progression of gastric cancer, however the ERBB2 expression and mutation rate is relative low especially in gastric SRCC. Thus, ERBB3 might be a promising target for the treatment in SRCC patients. The aim of this study is to speculate the prognostic and targeted therapy value in gastric SRCC by evaluating the mutation rate and type of ERBB3. Methods: 92 patients with histological diagnosis of advanced gastric SRCC were retrospectively selected. ERBB3 mutation was evaluated by next generation sequencing from formalin-fixed paraffin-embedded (FFPE) samples. ERBB2 expression was tested by immunohistochemistry. Correlations between ERBB2/3 status and clinical pathologic characteristics and overall survival (OS) were performed. Results: All of the 92 patients were diagnosed as local advanced or metastatic gastric SRCC (92.4% were stage III, 7.6% were stage IV). All the patients received 5-FU-based first-line chemotherapy. 14 out of all 92 patients were ERBB3 mutated SRCC, in which only 2 samples were ERBB2 positive. 12 of all the 14 mutations were in the extracellular domain, 2 were in the transmembrane region. There was no correlation between ERBB3 mutation and serosa invasion (P = 0.389) or lymph node metastasis (P = 1.000). The median OS was 20.5 months (95% CI = 10.05to 30.95 months) for patients with ERBB3 mutation, and 19.0 months (95% CI = 15.54 to 22.46 months) for patients without ERBB3 mutation (P = 0.567). There was no difference in OS according to HER2 positive or negative in ERBB3 mutated patients (14.8 months vs 20.5 month, P = 0.374). Conclusions: Our study demonstrated 15.2% of gastric SRCC patients harboring ERBB3 mutation, providing a potential subgroup of gastric SRCC for targeted treatment on ERBB pathway. No difference of OS was observed, probably due to the relative small sample size and low ERBB2 positive rate in SRCC patients. Further investigation on ERBB3 is warranted to clarify mechanisms of ERBB pathway in gastric SRCC.

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