Association between gene fusions and anti-EGFR resistance signature in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Thereasa A. Rich ◽  
Katherine Clifton ◽  
Victoria M. Raymond ◽  
Arvind Dasari ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Ras Mutation ◽  
Exact Test ◽  
Ras Mutations ◽  
Alk 5 ◽  
Tumor Dna ◽  
Fischer Exact Test

3564 Background: Acquired resistance to anti-EGFR therapy in metastatic colorectal cancer (mCRC) has been characterized by a circulating tumor DNA (ctDNA) signature including any sub-clonal RAS mutation, co-existing RAS mutations, or co-existing EGFR mutations. Here, we investigated if fusions in ctDNA are associated with this anti-EGFR signature for CRC patients (pts). Methods: 4289 advanced stage CRC pts underwent molecular profiling using a plasma-based NGS assay that included FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1 fusions. Available clinical histories were reviewed. Correlations between fusions and clinicopathological features were measured with a Fischer exact test. Relative frequencies of genomic alterations were compared between fusion-present vs -absent cases with an unpaired t-test. Clonality for a given alteration was called for a relative variant allele frequency (rVAF) > 50 %, while subclonal was defined as < 50% rVAF. Results: 44 unique fusions were detected in 40 (1.1%) of the 3808 pts with alterations present: RET (N = 16), FGFR3 (N = 12), ALK (N = 10), NTRK1 (N = 3), ROS1 (N = 2), and FGFR2 (N = 1). Relative to non-fusion variants detected, fusions were more likely to be subclonal (OR 8.2, p < 0.0001). Mutations associated with a previously reported anti-EGFR resistance were found in FGFR3 (7/12 pts), RET (7/15 pts) and ALK (5/10 pts). In fusion-present cases, co-existing RAS mutations were more likely to be subclonal than non-fusion cases (OR 14, p < 0.0001). EGFR mutations were more common in fusion present cases (OR 3.7, p = 0.0001) and predominantly subclonal (97%). EGFR mutations aggregated to ectodomain sites (85%) previously linked to acquired anti-EGFR resistance. For 27 pts with available clinical histories, 21 (78%) received anti-EGFR treatment prior to ctDNA testing. Conclusions: Actionable fusions using a ctDNA NGS assay were predominantly subclonal and co-existed with subclonal RAS and EGFR mutations. These clinicopathologic features are consistent with a previously validated signature linked to resistance to anti-EGFR therapies in CRC. We hypothesize that fusions may arise as a previously undescribed mechanism of acquired resistance to anti-EGFR therapies in CRC pts.

RAS Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer

2020 ◽  
pp. 898-911
Author(s):  
Yu Sunakawa ◽  
Masato Nakamura ◽  
Masahiro Ishizaki ◽  
Masato Kataoka ◽  
Hironaga Satake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Circulating Tumor Dna ◽  
Wild Type ◽  
Phase Ii Trials ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Status ◽  
Tumor Dna

PURPOSE Several trials have evaluated the efficacy of rechallenge treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

scholarly journals Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses

JAMA Oncology ◽  
2018 ◽  
Vol 4 (4) ◽  
pp. e175245 ◽  
Author(s):  
Clara Montagut ◽  
Guillem Argilés ◽  
Fortunato Ciardiello ◽  
Thomas T. Poulsen ◽  
Rodrigo Dienstmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Dna Analyses ◽  
Tumor Dna

Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS886-TPS886
Author(s):  
Hiromichi Maeda ◽  
Naoki Nagata ◽  
Takeshi Nagasaka ◽  
Koji Oba ◽  
Hideyuki Mishima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Mutation Status ◽  
Line Therapy ◽  
Tumor Dna

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.

Circulating tumor DNA to monitor treatment response and investigate resistance mechanism in BRAF inhibitor treated colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16112-e16112
Author(s):  
De-Shen Wang ◽  
Yu-Hong Li ◽  
Hua Bao ◽  
Xiaoxi Chen ◽  
Ming-Tao Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Response ◽  
Cancer Patients ◽  
Acquired Resistance ◽  
Resistance Mechanism ◽  
Braf Inhibitor ◽  
Circulating Tumor Dna ◽  
Egfr Inhibition ◽  
Colorectal Cancer Patients ◽  
Tumor Dna

e16112 Background: BRAF mutations are found in about 10% of colorectal cancer (CRC) patients and is a poor prognosis factor in standard chemotherapy. Combination of BRAF and EGFR inhibition exerts a better therapeutic effective, whereas the resistance develops through undefined mechanisms. Circulating tumor DNA (ctDNA) is a non-invasive approach to assess the genetic evolution of tumors and prognosis in response to therapy, which would help better understanding the treatment response and resistance mechanism in BRAF inhibitor treated colorectal cancer patients. Methods: We performed panel next-generation sequencing of 425 cancer-related genes in 39 serial plasma samples collect from 19 patients who have BRAF V600E mutation CRC to track the resistance during the Vemurafenib treatment in combination with Irinotecan and Cetuximab (VIC) and evaluate the treatment response. Tumor responses were assessed radiologically every two months and are used to determine patients with innate or acquired resistance Results: A total of 19 patients were enrolled into the vemurafenib treatment with irinotecan and cetuximab. By January 20, 2020, treatment had been discontinued in 12 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. Among them, four patients with innate resistance (n = 4, 21.1%) were defined as those with PFS of less than 2 months, while patients (n = 15, 78.9%) with acquired resistance were defined as those with PFS of greater than 2 months. The VIC regimen demonstrated efficacy in patients with BRAF-mutant mCRC, with overall response rates was 63.2% (n = 12). Changes in levels of ctDNA at 4 weeks predicts therapeutic responses. CBLB, TP53 and APC baseline mutations were enriched in baseline samples of innate resistant patients. In contrast, MYC and Cell-cycle pathway alterations were enriched in baseline samples of patients with acquired resistance. Acquired RAS and MAPK mutations, known to confer resistance to BRAF inhibitors, were identified in 60% of acquired resistance patients. Moreover, acquired TGFBR2 and SMAD4 loss-of-function mutations were identified as novel resistant mechanism to the combination of BRAF and EGFR inhibition. Experimental validation is ongoing. Conclusions: Longitudinal analysis of ctDNA in BRAF CRC patients provides insights of molecular difference between innate and acquired resistance and gene alternation during resistance requiring. Serial ctDNA monitoring provides early indication of response to BRAF inhibitor in CRC patients.

Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15574-e15574
Author(s):  
Mohamed Bouchahda ◽  
Raphael Saffroy ◽  
Abdoulaye Karaboué ◽  
Jocelyne Hamelin ◽  
Pasquale Innominato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Pilot Study ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Additional Treatment ◽  
Ras Mutation ◽  
Prior Chemotherapy ◽  
Ras Status ◽  
Tumor Dna

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p < 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.

Circulating tumor DNA dynamics, serial testing and evolution on treatment in 322 colorectal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3566-3566
Author(s):  
Pashtoon Murtaza Kasi ◽  
Saivaishnavi Kamatham ◽  
Dorin Colibaseanu ◽  
Amit Merchea ◽  
Faisal Shahjehan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Selective Inhibition ◽  
Circulating Tumor Dna ◽  
Braf V600e ◽  
Egfr Mutations ◽  
Dna Dynamics ◽  
Ongoing Research ◽  
Serial Testing ◽  
American Society ◽  
Tumor Dna

3566 Background: According to the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint review on circulating tumor DNA (ctDNA) issued in March 2018, widespread use of ctDNA assays in most patients with advanced cancer is still an area of ongoing research. However, multiple studies thereafter published and/or presented support its use in patients with metastatic colorectal cancer (CRC). This has led to several institutions adopting it as ‘clinical practice’. The aim of this study is to report on our institution’s adoption of ctDNA testing for every patient at the time of diagnosis and/or time of progression. Methods: We report on results of 322 CRC patients with 607 ctDNA tests at our center from January 2017 to February 2019 using a commercially available platform (Guardant360). Results: Among 322 patients of our cohort, a total of 607 ctDNA tests were done (Table). 127 (39.4%) of these tests were serial analyses. In the CRC patients who had serial testing, at progression, mechanisms of resistance included acquisition of KRAS, NRAS, EGFR mutations; and HER2- and MET-amplifications. The subclonal mutations were noted to disappear when the selective inhibition was stopped. This was seen in patients on targeted therapies/biologics rather than chemotherapy. This was of value in treatment modification, clinical trial selection and/or monitoring of disease progression in these patients. Conclusions: While ctDNA testing may not be ready for primetime in all advanced cancers, it is increasingly being adopted in practice for especially metastatic CRC. Of particular value is the serial ctDNA testing in the RAS/RAF wildtype subset and now BRAF V600E mutant CRC on anti-EGFR based therapies. [Table: see text]

Utility of circulating tumor DNA in genomic profiling of colorectal cancer with peritoneal metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16057-e16057
Author(s):  
Tenghui Ma ◽  
Weiguo Cao ◽  
Jin Huang ◽  
Yuguang Song ◽  
Lingjun Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Detection Rate ◽  
Somatic Mutations ◽  
White Blood Cells ◽  
Circulating Tumor Dna ◽  
The Other ◽  
Molecular Profile ◽  
Braf Mutations ◽  
Exact Test ◽  
Tumor Dna

e16057 Background: Patients (pts) with peritoneal metastatic (PM) colorectal cancer (CRC) have significantly poorer prognosis than those with other metastases. In this study, we aim to investigate genomic profiles of PM-CRC and metastatic CRC without peritoneal involvement (non-PM-CRC) and PM-CRC with other organ involvement (PM-CRC+) using circulating tumor DNA (ctDNA)-based sequencing. Methods: A total of 169 pts with metastatic CRC were enrolled irrespective of treatment history, including 53 pts with non-PM-CRC, 47 pts with PM-CRC, and 69 pts with PM-CRC+. Matched tumor-normal next-generation sequencing of 1021 cancer-related genes was performed on ctDNA and white blood cells derived from plasma samples. The differences of mutation number were examined with student t test, and the differences of mutation detection rate were examined with two tailed Fisher’s exact test. p≤0.05 was considered statistically significant. Results: Somatic mutations were identified in 96% of pts with non-PM-CRC, 77% of pts with PM-CRC, and 97% of pts with PM-CRC+. The number of somatic mutations observed in the PM-CRC cohort was significantly lower than that in the other cohorts with the median value of 2 in the PM-CRC cohort, 9 in the non-PM-CRC cohort, and 7 in the PM-CRC+ cohort (p = 0.0002 and p < 0.0001, respectively). The most frequently mutated genes in these cohorts was listed in Table. The detection rate of APC and TP53 mutations in the PM-CRC cohort was significantly lower than the other cohorts. Significant differences were also observed when comparing TCF7L2 mutations in the non-PM-CRC and the other cohorts, LRP1B mutations in the PM-CRC cohort and PM-CRC+ cohort, and NOTCH4 and PCK1 mutations in the non-PM-CRC and PM-CRC+ cohorts. In addition, BRAF mutations were more commonly observed in the PM-CRC cohort (13%) than the other cohorts (8% for non-PM-CRC cohort, 4% for PM-CRC+ cohort) (p = 0.51 and 0.16, respectively). Conclusions: Pts with PM-CRC exhibit a distinct molecular profile compared with non-PM-CRC and PM-CRC+, which may be helpful to explain their relatively poor prognosis and potentially be used in the early diagnosis of PM. [Table: see text]

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