Value of Mismatch Repair, KRAS, and BRAF Mutations in Predicting Recurrence and Benefits From Chemotherapy in Colorectal Cancer

2011 ◽  
Vol 29 (10) ◽  
pp. 1261-1270 ◽  
Author(s):  
Gordon Hutchins ◽  
Katie Southward ◽  
Kelly Handley ◽  
Laura Magill ◽  
Claire Beaumont ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Mutational Analysis ◽  
Left Colon ◽  
Rectal Tumors ◽  
Wild Type ◽  
Right Colon ◽  
Kras Mutations ◽  
Risk Of Recurrence ◽  
Braf Mutant

Purpose It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy. Patients and Methods Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial. Results Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% [25 of 218] v 26% [438 of 1,695] recurred; risk ratio [RR], 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% [150 of 542] v 21% [219 of 1,041]; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy. Conclusion MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.

The correlation between mismatch repair status and clinicopathological characteristics in Chinese colorectal cancer patients.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 544-544 ◽  
Author(s):  
Zhi-tao Xiao ◽  
Rong-xin Zhang ◽  
Yang Zhao ◽  
Jian-Hong Peng ◽  
Pei-Rong Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mismatch Repair ◽  
Mucinous Adenocarcinoma ◽  
Clinicopathological Characteristics ◽  
Left Colon ◽  
Stage Ii ◽  
Chinese Patients ◽  
Right Colon ◽  
Significant Difference

544 Background: Our study aimed to explore the relationship between mismatch repair (MMR) status and clinicopathological characteristics in Chinese patients with colorectal cancer (CRC). Methods: A total of 2684 patients with histologically confirmed adenocarcinoma of CRC were consecutively recruited between May 2011 and May 2015 at Sun Yat-sen University cancer center. The exclusion criteria included multiple primary tumors, synchronous and metachronous CRC, and familial adenomatous polyposis. The CRC was defined as left colon with the tumor located below the splenic flexure or rectum, otherwise grouped as right colon. Correlations of MMR status and patient’s demographics, tumor characteristics and TNM staging (exclude 315 CRC patients receiving neoadjuvant therapy) were investigated. Results: We found that deficient MMR (dMMR) status was more likely detected in younger CRC patients compared to the the elderly (12.7% vs 7.5%, P < 0.001). The dMMR rate in right colon cancer was significantly higher than that in left colon cancer and rectal cancer (22.7% vs 7.2% vs 5.2%, P < 0.001).With respect to tumor differentiation, we found that the mucinous adenocarcinoma had the highest rate of dMMR(24.4%), followed by poorly differentiated adenocarcinoma(18.5%), signet-ring cell carcinoma(17.6%), well differentiated adenocarcinoma(9.5%), moderately differentiated adenocarcinoma(8.9%), and neuroendocrine carcinoma (0%) ( P < 0.001). In addition, the proportions in stage I, stage II, stage III and stage IV CRC were 9.7%, 16.5% , 8.5% and 3.9%, respectively ( P < 0.001). There was no significant difference in gender (P = 0.114). Conclusions: At the first time, our study demonstrated that dMMR status was most likely detected at younger age (less than 59 years) and stage II right colon mucinous adenocarcinoma in large volume Chinese patients, which was similar to the results in western countries.

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.

scholarly journals Clinical and prognostic features of patients with detailed RAS/BRAF-mutant colorectal cancer in Japan

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tatsuki Ikoma ◽  
Mototsugu Shimokawa ◽  
Masahito Kotaka ◽  
Toshihiko Matsumoto ◽  
Hiroki Nagai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Driver Mutations ◽  
Wild Type ◽  
Right Colon ◽  
Chain Reaction ◽  
Prognostic Features ◽  
Oncogenic Driver ◽  
Polymerase Chain ◽  
The Right ◽  
Braf Mutant

Abstract Background RAS/BRAFV600E mutations are the most remarkable oncogenic driver mutations in colorectal cancer (CRC) and play an important role in treatment selection. No data are available regarding the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant metastatic CRC (mCRC) in Japan. Methods A total of 152 chemotherapy-naïve patients with mCRC were included in this study between August 2018 and July 2019. Tumor samples were collected, and RAS/BRAFV600E status was investigated. RAS/BRAFV600E status was examined using a MEBGEN RASKET-B kit and polymerase chain reaction reverse sequence-specific oligonucleotide method. Results RAS/BRAFV600E mutations were detected in 54% of cases (KRAS codon 12, 26%; KRAS codon 13, 17%; KRAS non-Exon2, 5%; NRAS, 5%; and BRAFV600E, 7%). BRAFV600E-mutant CRC mainly existed in the right colon, whereas KRAS non-Exon2 and NRAS-mutant CRC was predominantly present in the left colon. KRAS non-Exon2 and NRAS-mutant CRC were associated with shorter survival time than RAS wild-type CRC (hazard ratio [HR], 2.26; 95% confidence interval [CI], 0.64–8.03; p = 0.19; HR, 2.42; 95% CI, 0.68–8.61; p = 0.16) and significantly shorter overall survival than KRAS Exon2-mutant CRC (HR, 3.88; 95% CI, 0.92–16.3; p = 0.04; HR, 4.80; 95% CI, 1.14–20.2; p = 0.02). Conclusions In our multicenter study, the findings elucidated the clinical and prognostic features of patients with detailed RAS/BRAFV600E-mutant mCRC in Japan.

Mutational analysis of clinically relevant cancer related genes in colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 615-615
Author(s):  
Aine O'Reilly ◽  
Colin Barr ◽  
Aoife Carr ◽  
Elaine Kay ◽  
Susan Kennedy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Mutational Analysis ◽  
Stage Iv ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Tp53 Mutations ◽  
Significant Difference

615 Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were genotyped for Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations using the Sequenom platform. Results: Tissue from 68 patients was genotyped. 163 mutations were identified in 21 cancer related genes. 45% of patients had stage III CRC & 10% had stage IV CRC at diagnosis. 17 patients developed metastatic CRC. 59 patients had at least 1 mutation. Mutations occurring in at least 5% of patients included KRAS(35%), PIK3R1(34%), TP53(32%), PHLPP2(32%), BRAF(16%), PIK3CA(13%), APC(13%), IDH1(12%), FBXW(7%) & MET(6%). Less frequent mutations (<5%) included GNAS, PTPN, NRAS, STK11, TBX3, and EGFR. KRAS mutations were associated with mucinous histology (P=0.04). TP53 mutations were associated with nodal disease at diagnosis (p=0.03). There was no statistically significant difference in overall survival in patients with KRAS, PIK3, TP53 or BRAF mutations as compared to their wild type (WT) counterparts. No mutation was predictive of disease progression. In patients with mCRC and TP53 mutations, DFS was significantly shorter when mutations in APC, FBXW7, IDH1, MET and NRAS were present (10 months verses 15.5 months p=0.01). Mutations in APC, FBXW7, IDH1, MET and NRAS only occurred in the presence of other mutations. A trend towards reduced DFS was seen in KRAS WT patients with mCRC when mutations in APC, FBXW7, IDH1, MET and NRAS were present (9 months vs. 22 months, p=0.2). A trend towards reduced DFS was seen in patients with mCRC & 3 or more distinct mutations (10 months vs. 18 months p=0.2). Conclusions: These results suggest that mutations in known cancer related signaling pathways occur frequently in patients with CRC. Mutations in APC, FBXW7, IDH1, MET and NRAS conferred a shorter DFS in patients with mCRC &, TP53 mutations, KRAS wild type patients and patients with multiple distinct mutations

Clinicopathological features in metastatic colorectal cancer patients with KRAS wild type compared with codon 12 and codon 13 mutant: Results from a multicenter, cross-sectional study by the Japan study group of KRAS mutation in colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 407-407 ◽  
Author(s):  
T. Yoshino ◽  
T. Watanabe ◽  
K. Yamazaki ◽  
H. Uetake ◽  
M. Ishiguro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Metastatic Colorectal Cancer ◽  
Logistic Regression Analysis ◽  
Kras Mutation ◽  
Clinicopathological Features ◽  
Wild Type ◽  
Right Colon ◽  
Codon 12 And 13

407 Background: The KRAS mutation mainly located in the codon 12 and 13 indicates unresponsiveness of patients with metastatic colorectal cancer (CRC) to anti-epidermal growth factor receptor (EGFR) antibodies. Many studies have reported that approximately 30%-40% of CRC patients have KRAS mutations. However, the clinicopathological features of KRAS mutant CRC have not been fully clarified, especially in Asian populations. This study aimed to clarify the clinicopathological features of KRAS mutant CRC in comparison with KRAS wild type in large-scale Japanese population. Methods: The key eligibility criteria included histologically confirmed colorectal adenocarcinoma with adequate tumor samples. Formalin-fixed paraffin-embedded tumor blocks or thinly sliced tumor sections from 389 centers were sent to commercial laboratories. Almost all KRAS point mutations in the codon 12 and 13 were investigated by direct sequencing (96%). The logistic regression analysis was used to estimate the odds ratios (ORs) and compute 95% confidential intervals (CIs). Results: Of 5,887 registered tumor samples between Oct. 2009 and Mar. 2010, the KRAS testing were performed for 5,790 samples. As of the cut-off date, Sep. 2010, we have successfully determined the KRAS mutational status of 5,732 samples (99%).The median age was 65 years old, and 61% were male. The primary tumor site was right colon, left colon, and rectum in 30, 38, and 32% patients, respectively. The frequency of KRAS mutation was 37.6% (2,155/5,732), of which the 80% (1,714/2,155) mutations were located in codon 12. On logistic regression analysis, female gender (OR=1.212, 95% CI=1.083-1.356), older age > 50 years (OR=1.312, CI=1.056-1.628) and right colon (versus left: OR=2.177, CI=1.905- 2.489; versus rectum: OR=1.500, CI=1.308-1.720) were independent risk factors of KRAS mutant CRC. Clinicopathological features were similar between codon 12 and 13 mutant CRC. Conclusions: This study disclosed that KRAS mutant CRC was different from KRAS wild type CRC in terms of clinicopathological features. No significant financial relationships to disclose.

Plasma cell-free DNA and fraction of circulating KRAS mutations as prognostic in patients with metastatic colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
David Sefrioui ◽  
Nasrin Vasseur ◽  
Richard Sesboüé ◽  
France Blanchard ◽  
Alice Oden-Gangloff ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Plasma Cell ◽  
Circulating Tumor Dna ◽  
Dna Fragments ◽  
Wild Type ◽  
Kras Mutations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Tumor Dna

490 Background: It has been suggested that detection of circulating tumor DNA may be relevant in patients with metastatic colorectal cancer (mCRC). The main objective of the present study was to evaluate a method based on the TaqMan Mutation Detection Assay (TMDA) for the detection of circulating KRAS mutations in mCRC patients. Moreover, we also investigated the prognostic impact of the plasma cell-free DNA and the fraction of circulating KRAS mutations. Methods: The study was conducted from April to July 2013 and plasma samples were prospectively collected in a series of 35 mCRC patients treated with chemotherapy (CT). QIAamp Circulating Nucleic Acid kit was used for DNA extraction and Quant-iT High Sensitivity dsDNA Assay for cf-DNA quantification. Detection of circulating tumor DNA was based on the KRAS mutations detected in tumour and was performed in plasma by the castPCR Technology TMDA. Response to CT was assessed according to RECIST criteria. The results of plasma cf-DNA and level of mutant DNA fragments were correlated with response and 3-months survival. Results: We isolated and quantified plasma cf-DNA in all patients with a mean concentration of 106 ng/mL. Among them, 18 were wild-type and 17 mutated for KRAS in the tumour. Detection of circulating KRAS mutations was performed with TMDA in 23 patients (10 KRAS wild-type and 13 KRAS mutated). The sensitivity was 62% (8/13) and specificity 100% (0/10) with a level of circulating mutant DNA fragments ranging from 0 to 29%. Plasma cf-DNA and level of circulating mutant DNA were both significantly correlated with the 3-months survival (mean 36 versus 524 ng/mL, p=0.0015 and 2% versus 29%, p<0.0001). There was a non significant trend for response to CT (respectively p=0.14 and p=0.12). Conclusions: TMDA method is a simple, accurate and non-invasive tool for the detection of circulating tumor DNA. Our preliminary results also suggest that plasma cf-DNA and fraction of mutant DNA fragments could be prognostic markers in mCRC patients.

Retrospective study of BRAF-mutant metastatic colorectal cancer patients and influence of the mismatch repair efficiency.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e14677-e14677
Author(s):  
Laetitia Mais ◽  
Matthieu Sarrabi ◽  
Françoise Desseigne ◽  
Pierre Guibert ◽  
Christine Castillo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Retrospective Study ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Repair Efficiency ◽  
Colorectal Cancer Patients ◽  
Braf Mutant

The occurrence of mutant KRAS clones in the blood of RAS wild type colorectal cancer patients: Impact of response or failure under anti-EGFR therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 600-600
Author(s):  
Andreas W. Berger ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Thomas Jens Ettrich ◽  
Peter Moeller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clonal Selection ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Dynamic Monitoring ◽  
Tumor Evolution ◽  
Genetic Profile ◽  
Wild Type ◽  
Initial State ◽  
Kras Mutations

600 Background: Colorectal cancer (CRC) is characterized by a high level of genetic heterogeneity. In addition, changes in the genetic profile induced by chemotherapy affect treatment results. Acquired resistance of tumors is defined as a result of clonal evolution and clonal selection under systemic chemotherapy. Repeated tumor tissue biopsies are difficult to obtain and cannot be easily used for dynamic monitoring of therapy response or failure due to marked tumor heterogeneity. Promising data for circulating cell-free tumor DNA (ctDNA) as a tool for studying tumor evolution were recently published. Methods: In this study we analyzed ctDNA from patients with metastatic CRC during treatment with anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab/panitumumab). By droplet digital PCR we performed genotyping of CRC tissue and tracking of clonal evolution of the most frequent KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61R, A146T and A59T) in plasma ctDNA. Results: In initial KRAS wild type tumors several mutated KRAS clones occurred in plasma under the course of anti-EGFR-therapy indicating an increasing acquired resistance to the given therapy leading to a disease progression. Some of these mutations declined upon discontinuation of anti-EGFR therapy. Conclusions: Based on these results we hypothesize that the initial state of KRAS wild type situation seems to be restored in some cases. This opens up the possibility to reinduce anti-EGFR therapy in later therapy lines.

Treatment monitoring of metastatic colorectal cancer by quantification and genotyping of mutated KRAS in circulating cell-free DNA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15037-e15037 ◽  
Author(s):  
Thomas Seufferlein ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Ralf Marienfeld ◽  
Stefan A. Schmidt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mutational Analysis ◽  
Early Stage ◽  
Therapy Monitoring ◽  
Stage Iv ◽  
Therapy Resistance ◽  
Disease Monitoring ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Non Invasive

e15037 Background: Treatment of stage IV colorectal cancer (mCRC) has made substantial progress over the last years but therapy monitoring still is in its early stage. A facile, non-invasive, repeatable assessment of the mutational state of a given tumor even during treatment could constitute a desirable biomarker for therapy stratification and disease monitoring. "Liquid biopsies" analyzing circulating free and circulating tumor DNA (cfDNA/ctDNA) from patients’ blood have been proposed as a a simple, non-invasive method that could fulfil this requirement. Methods: 27 patients with histologically confirmed mCRC were enrolled into a treatment surveillance cohort. For the analysis of concordance between tumor tissue DNA and cfDNA we analyzed 40 tissue and blood pairs from therapy naïve patients regarding their KRAS mutation status. The course of cfDNA values combined with targeted genotyping of KRAS mutations were assessed during several palliative chemotherapeutic regimens. cfDNA data were correlated with clinical parameters to establish its prognostic and predictive value. Results: Baseline cfDNA levels allow to significantly differentiate mCRC from healthy controls (14.23 ± 6.33 ng/ml vs. 2.60 ± 1.59 ng/ml; p < 0.0001). cfDNA values at baseline in therapy naïve patients correlate well with tumor burden (p < 0.05) and CEA levels (p < 0.05). cfDNA values significantly increased upon disease progression during 1st (p < 0.01) and 2nd line (p < 0.05) treatment, enabling a non-invasive disease monitoring approach. Moreover, there was a significant correlation between the cfDNA levels upon treatment and progression-free survival (p < 0.05). In addition, our data show that KRAS genotyping of cfDNA under therapy is feasible (80% blood-tissue concordance) and might benefit the patient due to early detection of therapy resistance. Conclusions: Repetitive quantitative and mutational analysis of cfDNA is likely to complement current diagnostic standards in stage IV CRC over the whole continuum of treatment.

Genomic alterations after EGFR blockade in patients with RAS wild-type metastatic colorectal cancer: Combined tissue and blood-based analysis from SCRUM-Japan GI-SCREEN and GOZILA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3528-3528
Author(s):  
Yoshiaki Nakamura ◽  
Riu Yamashita ◽  
Wataru Okamoto ◽  
Yukiya Narita ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Integrated Analysis ◽  
Wild Type ◽  
Genomic Alterations ◽  
Kras Mutations ◽  
Copy Numbers ◽  
Oncogenic Pathways

3528 Background: Anti-EGFR therapy (tx) in RAS wild-type (wt) metastatic colorectal cancer (mCRC) induces resistance through acquired genomic alterations. We aimed to define such alterations in Nationwide Cancer Genome Screening Project tissue and blood specimens, using next generation sequencing (NGS). Methods: Tumor specimens in patients (pts) with RAS wt mCRC were obtained from SCRUM-Japan GI-SCREEN (tissue) and GOZILA (circulating tumor DNA [ctDNA] from blood). Genomic alterations were compared using the Oncomine Comprehensive Assay (SCRUM) and Guardant360 (GOZILA), before anti-EGFR tx and after progression. Results: 373 total actionable alterations were identified in 71 pts with available matched tissue and ctDNA; 255 (68%) were acquired after anti-EGFR tx progression. Frequently seen acquired oncogenic alterations included KRAS mutations (27%) and amplifications (amps) of EGFR (41%), CDK6 (24%), BRAF (20%), MYC (17%), MET (14%), PIK3CA (11%), FGFR1 (11%), and KRAS (10%). Fusions of RET, ALK, and FGFR3 were newly acquired in 1-4%. Acquired alterations co-arose in multiple pathways, including the cell cycle, PI3K-AKT, and MAPK, although 29% of pts had none. Acquired mutations were less frequently clonal versus primary mutations (p<0.0001), but clonal acquired mutations were seen in several oncogenes, including EGFR, KRAS, and PIK3CA. A subset of acquired KRAS, MET, CCND2, and EGFR amps had high (>7) adjusted plasma copy numbers (ApCN). Acquired ERBB2 amps were identified in 3 pts (4%) with a median ApCN of 4, one of whom (ApCN=4.2), treated with dual HER2 blockade, progressed after 2 cycles. Conclusions: Our integrated analysis revealed that anti-EGFR tx of pts with RAS WT mCRC led to acquired genomic alterations in multiple oncogenic pathways. Although most acquired alterations were subclonal, a subset of oncogenic alterations had relatively high clonality and ApCN, suggesting potential targets for overcoming acquired resistance to anti-EGFR tx. Early progression in a pt with an ApCN of 4.2 suggests low-level/subclonal acquired alterations may not be effective treatment targets.

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