Emergence of KRAS mutations and acquisition of resistance to EGFR blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3598-3598
Author(s):  
Takeshi Yamada ◽  
Goro Takahashi ◽  
Takuma Iwai ◽  
Kohki Takeda ◽  
Kohji Ueda ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Braf Mutations ◽  
Primary Resistance ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Ras Mutation ◽  
Epidermal Growth ◽  
Digital Polymerase Chain Reaction

3598 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance. Although RAS mutation is established as a main cause of primary resistance, the mechanisms of this acquired resistance remain unclear. Here, we aimed to identify the mechanisms underlying acquired resistance to EGFR blockade by using circulating cell-free (ccf)DNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy. Methods: We enrolled 33 patients with metastatic CRC and no RAS mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ccfDNA from each patient before they started chemotherapy, and every 2–3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and S492R mutations using digital polymerase chain reaction. Results: KRAS mutations were detected in the ccfDNA of 4 of the 33 patients (12%) before chemotherapy. The response rate was 88% (29/33); all four non-responders had KRAS mutations in their ccfDNA and one of the four had both KRAS and BRAF mutations before starting chemotherapy. A response was detected in all patients (29/29) with no KRAS or BRAF mutations in their ccfDNA before chemotherapy. Of the 29 initial responders, 14 (48%) acquired resistance. Emerging KRAS mutations were detected in the ccfDNA of 13 of these 14 patients (93%); eight of these patients had multiple mutations (e.g. G12D and G12V; G13D and Q61H). BRAF mutations were also detected in six patients (43%); none of the patients had solo BRAF mutations. Six patients (43%) had S492R mutations; none of the patients had solo S492R mutations. Only one patient had no KRAS, BRAF or S492R mutations. Conclusions: Emergence of KRAS, BRAF or S492R mutations that were undetectable before the start of chemotherapy may be a mechanism underlying acquisition of resistance to EGFR blockade. Notably, emerging KRAS mutations were detected in most of the patients (93%) who acquired resistance. This indicates that KRAS mutation emergence may play a major role in the acquisition of resistance to EGFR blockade.

Tracking emerging KRAS, BRAF and EGFR mutations through ccfDNA in colorectal cancers treated with EGFR blockade.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 547-547
Author(s):  
Takeshi Yamada ◽  
Goro Takahashi ◽  
Takuma Iwai ◽  
Kouki Takeda ◽  
Michihiro Koizumi ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Braf V600e ◽  
Egfr Mutations ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Primary Tumors ◽  
Epidermal Growth ◽  
Digital Polymerase Chain Reaction ◽  
Codon 61

547 Background: Epidermal growth factor receptor (EGFR) blockade can achieve considerable tumor shrinkage in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance within a year through emerging KRAS, BRAF or EGFR ( S492R) mutations. We have shown that patients with KRAS or BRAF mutations in circulating cell-free DNA (ccfDNA) do not respond favorably to EGFR blockade. In this study, we aimed to detect acquired resistance to EGFR blockade early by using ccfDNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy. Methods: We enrolled 24 patients with metastatic CRC and no KRAS mutations in their primary tumors who were to be treated with systemic chemotherapy that included EGFR blockade. We purified ccfDNA from 1 mL of serum from each patient before they started chemotherapy. We also extracted ccfDNA from these patients every 2–3 months until disease progression. We detected nine KRAS, BRAF (V600E) and S492R mutations using digital polymerase chain reaction. Results: We detected KRAS mutations in ccfDNA of three patients before chemotherapy (12.5%; 3/24). The response rate was 83% (20/24); the four non-responders comprised the three with KRAS mutations and the other with BRAF mutations in their ccfDNA before chemotherapy. All patients with no KRAS or BRAF mutations in their ccfDNA before chemotherapy responded to the chemotherapy (20/20). Of these 20 initially responsive patients, 12 (60%) acquired resistance. We detected emerging KRAS mutations in the ccfDNA of eight of these 12 patients (67%) prior to relapse, six of them having multiple mutations. Five of these patients had mutations in codon 61 and one had solo codon 61 mutations. We also detected BRAF mutations in five patients; none had solo BRAF mutations. Four patients had S492R mutations; none had solo S492R mutations. Conclusions: If KRAS or BRAF mutation do not detected in primary tumor, EGFR blockade has no beneficial effect in patients with KRAS or BRAF mutations in their ccfDNA prior to commencing chemotherapy. Emerging KRAS, BRAF or S492R mutations that were undetectable before starting chemotherapy are associated with acquired resistance to EGFR blockade.

scholarly journals KRAS and BRAF Concomitant Mutations in a Patient with Metastatic Colon Adenocarcinoma: An Interesting Case Report

2020 ◽  
Vol 13 (2) ◽  
pp. 595-600
Author(s):  
Concetta Cafiero ◽  
Agnese Re ◽  
Gerardo D’Amato ◽  
Pier Luigi Surico ◽  
Giammarco Surico ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Hepatic Metastases ◽  
Growth Factor Receptor ◽  
Colon Adenocarcinoma ◽  
Liver Lesion ◽  
Interesting Case ◽  
Braf V600e ◽  
Braf Mutations ◽  
Negative Prognostic Factor ◽  
Epidermal Growth

A 68-year-old female patient with tenesmus and blood in the stool was admitted to the S.G. Moscati Hospital of Taranto. Investigations revealed infiltrative mucinous colon adenocarcinoma accompanied by lymph node metastases. Following surgery and adjuvant chemotherapy, computed tomography (CT) and carcinoembryonic antigen screening were negative. Two years later, CT demonstrated a liver lesion. Histologic and genetic analyses confirmed the diagnosis of metastatic colorectal cancer with the coexistence of KRAS and BRAF mutations in hepatic metastases and the presence of the BRAF V600E in the primary tumour. It is unclear whether the lack of response was due to BRAF mutations, but the data suggest that mutated BRAF confers resistance to anti-epidermal growth factor receptor therapy. In our patient, BRAF mutation turned out to be a negative prognostic factor, and it may have been the cause of clinical implications for disease progression and therapeutic responses.

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.

KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15077-e15077
Author(s):  
Liu Yang ◽  
Jiahong Jiang ◽  
Lianpeng Chang ◽  
Yaping Xu ◽  
Chao Ni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Function Analysis ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Sequencing Analysis ◽  
Kras Mutations ◽  
Target Capture ◽  
Epidermal Growth

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.

scholarly journals Impact of KRAS Mutations on Management of Colorectal Carcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Kevin M. Sullivan ◽  
Peter S. Kozuch
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Antibody Therapy ◽  
Growth Factor Receptor ◽  
Monoclonal Antibody Therapy ◽  
Novel Therapies ◽  
Wild Type ◽  
Primary Resistance ◽  
Kras Mutations ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not sufficient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed.

Significance of epidermal growth factor receptor in advanced ovarian cancer.

1992 ◽  
Vol 10 (4) ◽  
pp. 529-535 ◽  
Author(s):  
G Scambia ◽  
P Benedetti Panici ◽  
F Battaglia ◽  
G Ferrandina ◽  
G Baiocchi ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Residual Tumor ◽  
Primary Tumors ◽  
Primary Surgery ◽  
Risk Of Progression ◽  
Epidermal Growth ◽  
Postoperative Residual

PURPOSE The purpose of this study was to investigate the significance of epidermal growth factor receptor (EGF-R) expression in a group of advanced ovarian carcinomas. PATIENTS AND METHODS The study was conducted on 72 previously untreated patients with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV disease. The median follow-up was 24 months (range, 4 to 75 months). EGF-R was measured by a radioreceptorial assay. A cutoff of 1.5 fmol per milligram of protein was chosen to define EGF-R positivity. Medians and life tables obtained with the Kaplan and Meier method were analyzed by the log-rank test. The risk of progression was estimated by Cox's proportional hazards model. RESULTS EGF-R was detected in 54% of primary tumors. When EGF-R was analyzed in different tissue specimens of the same tumor, consistent findings were noted in 88% (seven of eight) of cases. A lower concordance rate (nine of 15; 60%) was found between primary tumors and omental metastases, with a tendency toward higher EGF-R levels in the latter. The EGF-R expression did not significantly correlate with age, stage, grading, and residual tumor after primary surgery. In the univariate analysis, stage IV disease, postoperative residual tumor diameter greater than 2 cm, presence of ascites, and EGF-R positivity were found to be significantly associated with a greater risk of disease progression. In the multivariate analysis, only the postoperative residual tumor and the EGF-R expression remained significantly associated with a high risk of progression. CONCLUSION Data reported here suggest that the presence of EGF-R in advanced ovarian tumor at the time of the primary surgery identifies a subset of patients with a particularly poor prognosis.

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