The role of the KRAS G13D mutation in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus cetuximab.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 630-630 ◽  
Author(s):  
S. Tejpar ◽  
C. Bokemeyer ◽  
I. Celik ◽  
M. Schlichting ◽  
E. Van Cutsem
Keyword(s):  
Kras Mutation ◽  
Melting Curve ◽  
First Line ◽  
Kras Mutations ◽  
Biologic Effects ◽  
Disease Stabilization ◽  
Table Data ◽  
Kras Codon ◽  
Line Chemotherapy

630 Background: The CRYSTAL and OPUS studies showed that adding cetuximab (cet) to first-line chemotherapy (CT) significantly improved clinical benefit in patients (pts) with KRAS wild-type (wt) mCRC. Pts with KRAS codon 12 or 13 mutations are excluded from cet treatment. Studies suggest that not all KRAS mutations are equivalent in their biologic effects. Occasional responses and prolonged disease stabilization have been recorded following cet treatment of tumors with mainly KRAS codon 13 mutations. We investigated the influence of the most common KRAS codon 13 mutation (G13D) on clinical outcome compared with pts with other KRAS mutations or wt tumors in the CRYSTAL and OPUS trials. Methods: KRAS mutations were detected in tumor DNA from archival material using a PCR clamping and melting curve technique. Treatment arms were compared by KRAS mutation status for progression-free (PFS) and overall survival (OS). Results: In the CRYSTAL study of 1,063 evaluable pts 63% were KRAS wt, 6% were G13D mutant (mt) and 32% had other mutations. In the OPUS study of 315 evaluable pts, 57% were KRAS wt, 7% were G13D mt, and 36% had other mutations. Compared with KRAS wt pts those with G13D mutations did not benefit from the addition of cet to CT (Table). Data of comparisons of the G13D mutation with other KRAS mutations in these studies will be presented. Conclusions: Patients with KRAS G13D mt tumors did not appear to benefit from the addition of cet to first-line CT for mCRC. This analysis confirms the current practice of KRAS mutation testing as the standard diagnostic tool for determining first-line treatment of mCRC pts. [Table: see text] [Table: see text]

scholarly journals The Role of Irinotecan-Bevacizumab as Rescue Regimen in Children With Low-Grade Gliomas: A Retrospective Nationwide Study in 72 Patients

2021 ◽  
Author(s):  
Charles de Marcellus ◽  
Arnault Tauziède-Espariat ◽  
Aurélie Cuinet ◽  
Claudia Pasqualini ◽  
Matthieu P. Robert ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Low Grade ◽  
First Line ◽  
Standard Chemotherapy ◽  
Duration Of Treatment ◽  
Pilot Studies ◽  
Disease Stabilization ◽  
Line Chemotherapy

Abstract Introduction. At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. Methods. We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. Results. 72 patients (median age 7.8 years [range, 1-19]) received a median of 16 courses (range, 3-30). The median duration of treatment was 9 months (range, 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range, 7.6-75.9 months). Younger patients had a worse PFS (p=0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. Conclusion. Bevacizumab-irinotecan is highly effective for children with recurrent LGG who have failed standard chemotherapy regimens whatever their clinical characteristics, only younger children had a worse PFS.

scholarly journals Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Min Lu ◽  
Xinglei Qin ◽  
Yajun Zhou ◽  
Gang Li ◽  
Zhaoyang Liu ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Transcriptional Regulators ◽  
First Line ◽  
Protein Coding ◽  
Gemcitabine Resistance ◽  
Non Coding Rna ◽  
Sphere Formation ◽  
Long Non Coding Rna ◽  
Line Chemotherapy

AbstractGemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients. Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells. The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers. In addition, Wnt/β-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/β-Catenin activation. B-cell CLL/lymphoma 9-like (BCL9L), the nucleus transcriptional regulators of Wnt/β-Catenin signaling, plays a key role in the nucleus translocation of β-Catenin and promotes β-Catenin-dependent transcription. In our study, we found that LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p. Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/β-Catenin activation in resistant CCA cells. In conclusion, our results disclosed the important role of LINC00665 in gemcitabine resistance of CCA cells, and provided a new biomarker or therapeutic target for CCA treament.

scholarly journals Ανίχνευση μεταλλάξεων του EGFR και KRAS σε ασθενείς με μη-μικροκυτταρικό καρκίνο του πνεύμονα και διερεύνηση της αξίας τους ως προβλεπτικών παραγόντων ανταπόκρισης στη θεραπεία

2013 ◽  
Author(s):  
Αριστέα Καλυκάκη
Keyword(s):  
Kras Mutation ◽  
Smoking History ◽  
Egfr Mutations ◽  
Front Line ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Mutation Status ◽  
Kras Mutation Status ◽  
Line Chemotherapy ◽  
Exon 19

The purpose of this study was to investigate whether the EGFR and KRASmutation status are predictive factors for Greeks patients with NSCLC. Initially, wecalculated the rate and the pattern of EGFR and KRAS mutations in 639 patients withNSCLC and then we correlated the mutations status with clinicopathologicalcharacteristics, the response to 1st line chemotherapy and patients’ overall survival.We also investigated the association of EGFR mutations with the EGFR geneamplification. Finally, in a group of 25 patients the mutation status of these genes inthe primary tumors and the corresponding metastasis was evaluated.The genetic analysis performed in FFPE tissue samples of primary tumor ormetastasis. DNA was extracted using universal techniques. For mutation analysis exons18, 19, 20 and 21 of the EGFR and exon 2 of KRAS genes were sequentially amplified bypolymerase chain reaction (PCR) and subjected to direct sequencing. Finally, EGFRamplification was determined by quantitative real time PCR.Analysis of EGFR mutations was successful performed in 634 patients andmutations were detected in 100 (15.8%) of them. Activating mutations were detected in 8.4%. The most common mutations were deletions of 4-5 codons in exon 19 (del 19,71.7%, 38/53) and the missense mutation at position 858 (L858R) in exon 21 (22.6%,12/53). Also in 47 (7.4%) patients other mutations were detected in four exons ofEGFR, which have been reported previously or are new. We found that the incidenceof EGFR mutations was statistically significant in women with no smoking history andwith adenocarcinoma histology.The mutation analysis of the KRAS gene was successfully performed on 399patients and mutations detected in 20.8% of them (83/399). Especially, 92.8% of themutations were found at codon 12 and 7.2% at codon 13. KRAS mutations weresignificantly associated with smoking history with higher incidence in smokers thannonsmokers. There was also a significant association between KRAS mutations andadenocarcinoma histology.The predictive value of EGFR and KRAS mutations was examined in a subgroupof patients (n=162) with NSCLC who received chemotherapy as 1st line therapy.Patients with classical EGFR mutations had a higher probability of response (55.6%) to front-line chemotherapy as compared to those with wild type EGFR (21.8%) (p =0.023). Multivariate analysis revealed the 'classical' activating EGFR mutations as anindependent predictive factor for response to 1st line chemotherapy. There was nosignificant correlation between the EGFR or KRAS mutation status and the time totumor progression. The presence of activating EGFR but not of KRAS mutations wasassociated with a significantly higher overall survival compared to patients withoutmutations treated with platinum-based front-line chemotherapy.Epidermal growth factor receptor and KRAS mutation status was differentbetween primary tumors and corresponding metastases in 7 (28%) and 6 (24%) of the25 patients, respectively. This discrepancy was not statistically significant with theMcNemar’s test.EGFR amplification was found in 7.2% (6/83) of primary tumors. Among thepatients with EGFR gene amplification none carried KRAS mutations while 2 had EGFR exon 19 deletion.

scholarly journals KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1514 ◽  
Author(s):  
Ghimessy ◽  
Gellert ◽  
Schlegl ◽  
Hegedus ◽  
Raso ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kras Mutation ◽  
Antiangiogenic Therapy ◽  
Hazard Ratio ◽  
Wild Type ◽  
First Line ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Platinum Based Chemotherapy

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

Role of Rituximab and Intensification with Autologous Stem Cell Transplantation in Primary Mediastinal B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4851-4851
Author(s):  
Vittorio Ruggero Zilioli ◽  
Chiara Rusconi ◽  
Cristina Gabutti ◽  
Giovanni Grillo ◽  
Elisa Zucchetti ◽  
...  
Keyword(s):  
Autologous Stem Cell Transplantation ◽  
Salvage Therapy ◽  
Progressive Disease ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Fdg Uptake ◽  
Line Therapy ◽  
Line Chemotherapy

Abstract Abstract 4851 Background: Primary Mediastinal B-Cell Lymphoma (PMBL) is an uncommon disease, characterized by aggressive and invasive course but with a good prognosis after anthracycline-based chemotherapy. In the PET era the role of consolidation radiotherapy is under debate and, despite CD20 expression, the efficacy of Rituximab is still unclear. We retrospectively analyzed the outcome of 36 consecutive patients (pts) affected by PMBL treated in the last 10 years at our institution. We focused on anti-CD20 antibody efficacy when added to chemotherapy and on the role of autologous stem cell transplantation (ASCT) in PET positive pts after first-line treatment. Patients and methods: From June 2000 to March 2011 36 pts with biopsy proven PMBL referred to our institution. Median age was 35 years (range: 18–68); 21 pts (58%) were female and a mediastinal bulk at diagnosis was documented in 33 pts (92%). B-symptoms were reported in 16 cases (44%) and an extra-nodal involvement in 19 cases (53%). Age-adjusted IPI score was ≥ 2 in 12 pts (33%). For all patients first line treatment consisted in a third generation anthracycline-based chemotherapy (VACOP-B), with the addiction of 6 Rituximab doses in 15 pts (42%). Pts obtaining complete remission (CR) with negative PET after (R)-VACOP-B were consolidated by radiotherapy (RT), while pts in partial remission (PR) with residual FDG uptake underwent a second-line chemotherapy with 3 DHAP cycles followed by autologous stem cell transplantation (ASCT). Results: In the whole cohort, after first-line therapy overall response rate (ORR) was 97%, with a CR rate of 39%. RT was therefore performed in 14 PET-negative pts. 2/14 pts experienced early relapse and only one of them obtained a second CR after salvage therapy, while the non-responding patient died because of progressive disease. Twenty-one pts (58%) showed a residual FDG uptake after (R)-VACOP-B and underwent second-line therapy. Nineteen pts responding to second-line therapy achieved ASCT, while 2 pts progressed and died after salvage therapy. ORR after ASCT was 86% with a CR rate of 71%. Post-ASCT RT was performed in 10 pts, 7 CR and 3 PR; two PR pts converted to CR after RT. With a median follow-up of 66 months (range: 13–142) 2-year overall survival (OS) and progression free survival (PFS) were respectively 94% and 89%. Among the 15 pts receiving first-line chemotherapy containing Rituximab, ORR after R-VACOP-B was 93% with a CR rate of 40%. RT was therefore performed in 6 PET-negative pts. 1/6 pts experienced early relapse and died of progressive disease. One patient showed progressive disease after R-VACOP-B and underwent second-line therapy with ASCT, obtaining CR. Eight pts (53%) showed a residual FDG-uptake after R-VACOP-B and underwent second-line therapy and ASCT. ORR and CR rate after ASCT were 100% and 75% respectively. Two pts in PR after ASCT converted to CR after RT. Among the 21 pts receiving chemotherapy without Rituximab, ORR after VACOP-B was 100% and CR rate was 38%. RT was therefore performed in 8 PET-negative pts; one of them experienced early relapse and obtained a second CR after salvage therapy. Thirteen pts (62%) showed a residual FDG-uptake after VACOP-B and underwent second-line therapy. Eleven pts responding to second-line therapy achieved ASCT, while 2 pts progressed and died after salvage therapy. ORR and CR rate after ASCT were 77% and 69% respectively. No statistically significant difference in ORR, CR rate, OS and PFS (Figure 1) was found between pts treated with Rituximab plus chemotherapy and pts treated with chemotherapy alone. Conclusions: These data substantially confirm the satisfactory outcome of PMBL, with a 2-year OS and PFS of 94% and 89% for the entire cohort. We registered a residual FDG uptake after first line chemotherapy in a proportion of pts higher than expected (58%). This subgroup of pts clearly take advantage from second line chemotherapy followed by ASCT, obtaining a CR rate of 71%. The addiction of Rituximab to first line chemotherapy instead does not seem to improve PMBL pts outcome in this small and retrospectively analyzed population. The role of immunotherapy in this rare lymphoma subtype and the chance to safely avoid RT consolidation in PET negative pts need to be further investigated in wider prospective trial. Disclosures: No relevant conflicts of interest to declare.

The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15637-e15637
Author(s):  
M. Haas ◽  
S. Boeck ◽  
P. Stieber ◽  
R. P. Laubender ◽  
H. Buchner ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Advanced Pancreatic Cancer ◽  
Rank Test ◽  
First Line ◽  
Predictive Role ◽  
Pre Treatment ◽  
Line Chemotherapy

e15637 Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of > 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC. [Table: see text]

Clinical characteristics of KRAS mutations in NSCLC and their impact on outcomes to first-line chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7588-7588
Author(s):  
Mohit Butaney ◽  
Jennifer Porter ◽  
Neal Ian Lindeman ◽  
Pasi A. Janne ◽  
Michael S. Rabin ◽  
...  
Keyword(s):  
Smoking Status ◽  
Egfr Mutations ◽  
Limited Information ◽  
Wild Type ◽  
First Line ◽  
Kras Mutations ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
The Impact ◽  
Line Chemotherapy

7588 Background: KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). While the impact of EGFR mutations and EML4-alk translocations has been well-described, there is limited information about the impact of these somatic mutations on response to chemotherapy. Methods: We retrospectively reviewed the demographics and clinical outcomes of patients with KRAS mutations and compared these to patients who were KRAS wild-type (WT). Eligible pts received 1st-line IV chemo for stage IV NSCLC at DFCI and had known information about both KRAS and EGFR status. Since the biology and impact of EGFR mutations on response to chemo is well-described, we excluded such pts from the analysis. The primary endpoint was progression-free survival (PFS) with first-line chemo; secondary endpoints included radiographic response rate (RR) and overall survival (OS). Results: Between 2/05 and 8/11, there were 63 eligible KRAS pts and 97 eligible WT pts. The groups were similar in age (median 65yrs in both groups), % female (K 62, WT 54) race (K 89% white/6% black, 5% other; WT 86% white,/6% black/8% other), histology (K 90%adeno/8% NSCLC NOS; WT 86% adeno/9%NSCLC NOS), and % of pts receiving 1/2/3 agents in 1st line (K 11/56/33; WT 18/53/30). KRAS pts were less likely to be never or light smokers (4% vs 33% for WT). Nonsmokers were more likely to harbor KRAS transition rather than transversion mutations (3 transition, 1 transversion), while the converse held for smokers (51 transversions, 8 transitions). Median PFS was similar for KRAS vs WT (K .65 vs WT 4.8 months, p=0.81). RR (29% for both groups), disease control rates (K 73% vs WT 78%), and median OS (K 13.5 vs WT 12.1 months, p=.525) were also similar. Outcomes of KRAS pts to 2nd line chemotherapy (PFS 2.2, OS 8.6) are similar to those seen for WT patients in this setting. There was no significant difference in outcomes based on gender, smoking status, drug received (pemetrexed-based vs taxane based), or specific KRAS genotype. Conclusions: Pts with KRAS mutations experience similar outcomes to standard chemotherapy as those who are wild-type for EGFR and KRAS. Going forward, these data can serve as a reference for control arms of KRAS-specific randomized trials.

KRAS amplification and mutation as independent events in gastroesophageal adenocarcinomas (GEA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15565-e15565
Author(s):  
Joseph Chao ◽  
Russell Madison ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Older Patient ◽  
Kras Mutations ◽  
Independent Events ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Kras Codon

e15565 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV vs KRASa GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV vs KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.3%) vs KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRASSV vs KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.

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