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1
Landa, Iñigo, Ian Ganly, Timothy A. Chan, Norisato Mitsutake, Michiko Matsuse, Tihana Ibrahimpasic, Ronald A. Ghossein, and James A. Fagin. "Frequent Somatic TERT Promoter Mutations in Thyroid Cancer: Higher Prevalence in Advanced Forms of the Disease." Journal of Clinical Endocrinology & Metabolism 98, no. 9 (September 1, 2013): E1562—E1566. http://dx.doi.org/10.1210/jc.2013-2383.
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Background: TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas. Objectives: The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC. Methods: TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs). Results: TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10−4 vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10−4), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04). Conclusions: TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.
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Calegari, Maria Alessandra, Lisa Salvatore, Brunella Di Stefano, Michele Basso, Armando Orlandi, Alessandra Boccaccino, Fiorella Lombardo, et al. "Clinical, Pathological and Prognostic Features of Rare BRAF Mutations in Metastatic Colorectal Cancer (mCRC): A Bi-Institutional Retrospective Analysis (REBUS Study)." Cancers 13, no. 9 (April 27, 2021): 2098. http://dx.doi.org/10.3390/cancers13092098.
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Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age < 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.
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Maurel, Joan, Vicente Alonso, Pilar Escudero, Carlos Fernández-Martos, Antonieta Salud, Miguel Méndez, Javier Gallego, et al. "Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti–Epidermal Growth Factor Receptor Therapy." JCO Precision Oncology, no. 3 (December 2019): 1–16. http://dx.doi.org/10.1200/po.18.00289.
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PURPOSE RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti–epidermal growth factor receptor therapy. METHODS RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease ( P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD ( P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations ( P = .016). CONCLUSION Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti–epidermal growth factor receptor therapy.
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Kotoula, Vassiliki, Elias Sozopoulos, Helen Litsiou, Galinos Fanourakis, Triantafyllia Koletsa, Gerassimos Voutsinas, Sophia Tseleni-Balafouta, Constantine S. Mitsiades, Axel Wellmann, and Nicholas Mitsiades. "Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas." Endocrine-Related Cancer 16, no. 2 (June 2009): 565–72. http://dx.doi.org/10.1677/erc-08-0101.
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The serine/threonine kinase B-Raf plays a key role in the Ras/Raf/MEK/ERK pathway that relays extracellular signals for cell proliferation and survival. Several types of human malignancies harbor activating BRAF mutations, most frequently a V600E substitution. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small cell lung carcinomas harboring activating EGFR TK domain somatic mutations. We evaluated the presence of mutations in BRAF (exons 11 and 15), KRAS (exons 1 and 2), NRAS (exons 1 and 2), and EGFR (exons 18–21) in adrenal carcinomas (35 tumor specimens and two cell lines) by DNA sequencing. BRAF mutations were found in two carcinomas (5.7%). Four carcinomas (11.4%) carried EGFR TK domain mutations. One specimen carried a KRAS mutation, and another carried two NRAS mutations. No mutations were found in the two adrenocortical cell lines. BRAF- and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases than their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared with wild-type carcinomas. We conclude that BRAF, RAS, and EGFR mutations occur in a subset of human adrenocortical carcinomas. Inhibitors of the Ras/Raf/MEK/ERK and EGFR pathways represent candidate targeted therapies for future clinical trials in carefully selected patients with adrenocortical carcinomas harboring respective activating mutations.
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Bilgetekin, Irem, Mehmet Dogan, Cengiz Karacin, Fatma Bugdayci Basal, Ece Esin, Gokhan Ucar, Ozlem Aydin Isak, et al. "The temporal evaluation of RAS and BRAF mutation by liquid biopsy at progression after bevacizumab combinations in patients with metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15587-e15587. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15587.
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e15587 Background: Expanded RAS analysis is essential for the selection of biologic agents in mCRC. RAS mutations indicates anti-EGFR unresponsiveness. In this study, we aimed to investigate RAS and BRAF mutations by liquid biopsy at progression in patients with RAS mutant mCRC. Methods: Sixty patients with mCRC who harbored tissue RAS mutations were prospectively analyzed between July 2019 and April 2020. All the patients treated with chemotherapy plus bevacizumab combinations . The plasma samples of the patients were analyzed after progression of bevacizumab combinations. RAS mutation profile was evaluated in plasma using Idylla PCR-based molecular diagnostics method, which enables rapid detection of common mutations in RAS and BRAF genes in circulating tumor DNA (ctDNA). Kaplan-Meier method was used for survival analysis and log-rank test was performed for comparison of groups. Results: The median age of the patients was 60 years (IQR:35-83 years) and female was (n=23, 38.3%). Primary tumor was located in the left colon in 81.7% of all patients. There were 95.0% KRAS and 5% NRAS mutations in baseline tissue biopsy. As a result of liquid biopsy after progression, 55.0% of the patients had KRAS, 3.3% NRAS and 3.3% had BRAF mutations. The RAS mutation detected in 58.3% of the patients. While there was no significant difference in terms of clinicopathological features between wild type (RAS/BRAF) and mutant type (RAS/BRAF) determined by liquid biopsy, the overall survival (OS) of the wild type group was significantly longer than mutant group (43.8 vs. 20.4 months, p= 0.002). Conclusions: This study demonstrated that there may be changes in RAS/BRAF mutation from plasma analysis after progression in patients with mCRC. Since better survival in the patient group with wild type was detected compared to the RAS concordance group, the evaluation of RAS mutation status at the time of progression may be important in terms of disease prognosis and treatment options.
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Wang, Chongkai, Jaideep Sandhu, and Marwan Fakih. "Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer." Oncologist 27, no. 2 (February 1, 2022): 104–9. http://dx.doi.org/10.1093/oncolo/oyab028.
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Abstract Background Limited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy. Methods We conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer. Results In comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer. Conclusions Mucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.
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Yoshino, Takayuki, Radka Obermannova, Gyorgy Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, Pilar Garcia Alfonso, et al. "Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—A global, randomized, double-blind, phase III study." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 622. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.622.
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622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]
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Conroy, Jeffrey M., Sarabjot Pabla, Marc S. Ernstoff, Igor Puzanov, Mary Nesline, Sean T. Glenn, Antonios Papanicolau-Sengos, et al. "Comprehensive immune and mutational profile of melanoma." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 182. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.182.
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182 Background: The association between tumor mutational profiles and immune signatures has not been well-characterized. Methods: 306 melanoma samples were tested by NGS using a comprehensive cancer panel for mutational status and an immune response panel which interrogates the expression profile of 54 validated immune-related genes. The ranking of gene expression, mutational burden and 7 immune phenotypes was compared to a reference population. 38% cases were positive for activating BRAF mutations, 12% for RAS, and 6% for NF1. The remaining 44% were considered triple wild type. Principal component analysis (PCA) followed by hierarchical clustering was performed to determine association of BRAF/RAS/NF1 mutations and triple wild type with immune phenotypes, mutational burden and gene expression as measured by the NGS panels. Results: PCA showed that the first and second dimension explain 86% of the variation in the mutation profiles of the 306 melanomas. The first principal component highly correlated with BRAF positive status (pval < 0.001), the second highly correlated with RAS positive status (pval < 0.001), and the third principal component, although not informative, highly correlated with NF1 status (pval < 0.001) and Mutation Burden (pval < 0.001). Hierarchical clustering of the samples resulted in 4 distinct clusters: RAS positive, BRAF Positive, NF1 positive and triple wild type. The RAS positive cluster demonstrated significantly lower expression of ICOSLG, ICOS, CD4, C10orf54, CD40 and CD244 genes. Similarly, the BRAF positive cluster under-expresses immune escape and proinflammatory immune phenotypes, but over-expressed OX40L. The NF1 positive cluster had significantly higher mutational burden than other clusters. On the contrary, the triple wild type cluster over-expressed 6 out of 7 immune phenotypes. Conclusions: BRAF/RAS/NF1 mutation status are immunophenotypically distinct and do not associate with a typical immune phenotype in the tumor microenvironment. Triple wild type samples present with an overall activated immune phenotype, representative of an inflamed tumor. Additional studies are necessary to include additional activating or loss of function mutations to expand these findings.
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Romano, David, Lucía García-Gutiérrez, Nourhan Aboud, David J. Duffy, Keith T. Flaherty, Dennie T. Frederick, Walter Kolch, and David Matallanas. "Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma." Life Science Alliance 5, no. 10 (August 29, 2022): e202201445. http://dx.doi.org/10.26508/lsa.202201445.
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The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAFV600E mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase-independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAFi. We show that the BRAFV600E mutant protein, but not the wild-type BRAF protein, binds to MST2 inhibiting its proapoptotic signalling. Down-regulation of MST2 reduces BRAFi-induced apoptosis. In BRAFi-resistant cell lines, MST2 pathway proteins are down-regulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway–induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAFi resistance in melanoma.
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Dillon, Martha, Antonio Lopez, Edward Lin, Dominic Sales, Ron Perets, and Pooja Jain. "Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers." Cancers 13, no. 20 (October 10, 2021): 5059. http://dx.doi.org/10.3390/cancers13205059.
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The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
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Wang, Chongkai, Ching Ouyang, Jaideep Singh Sandhu, Michael Kahn, and Marwan Fakih. "Wild-type APC and prognosis in metastatic colorectal cancer." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 223. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.223.
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223 Background: Somatic mutations at adenomatous polyposis coli ( APC) gene, found in ~75% of colorectal cancers (CRC), are under-represented in microsatellite instable (MSI-H) tumors. While several studies have suggested worse outcomes for CRC patients (pts) with wild-type APC ( APC-WT), the prognostic implication of this genomic alteration in metastatic CRC (mCRC) is not well defined. Methods: APC prognostic value was evaluated in 331 stage IV microsatellite stable (MSS) CRC pts treated in our institution. Next-generation genomic analysis (FoundationOne) was used to characterize the molecular characteristics of APC-WT and mutant APC ( APC-MT) pts. Findings were validated on a public database of stage IV colon cancer from MSKCC. Results: APC-WT was present in 26% of mCRC patients. In comparison to APC-MT population (n = 244), APC-WT pts (n = 87) tended to be younger (median age: 49 vs. 58 years), right-sided (44% vs. 24%), BRAF-V600E mutated (25% vs. 5%), p53 WT (38% vs. 21%) and RAS WT (66% vs. 53%). APC-WT tumors were associated with other Wnt activating alterations ( CTNNB1, FBXW7, RNF43, ARID1A and SOX9). Among those, RNF43 and CTNNB1 were more significantly represented in the APC-WT vs APC-MT population (12% vs 1% and 11% vs 3%, respectively). APC-WT pts had a worse overall survival (OS) than APC-MT pts (30 vs 48 months, HR = 1.809, 95% CI 1.260-2.596, p < 0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (HR = 1.7, p = 0.001) in our data set. The prognostic implication of APC-WT on OS were confirmed further in a similar multivariate model of 433 stage IV pts from MSKCC public database (HR = 1.6, P = 0.01). Conclusions: APC-WT is associated with poor OS in MSS mCRC regardless of RAS, BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other activating alterations of Wnt pathway, including RNF43 and CTNBB1.
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Tóth, Béla, Norbert Kiss, Judit Hársing, Sarolta Kárpáti, Judit Csomor, Csaba Bödör, József Tímár, and Erzsébet Rásó. "Frequent KIT mutations in skin lesions of patients with BRAF wild-type Langerhans cell histiocytosis." Virchows Archiv 477, no. 5 (May 5, 2020): 749–53. http://dx.doi.org/10.1007/s00428-020-02820-w.
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Abstract Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients.
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Damato, Angela, Angela Damato, Carlo Aschele, Fortunato Ciardiello, Evaristo Maiello, Salvatore Siena, Valter Torri, et al. "Phase III study to compare bevacizumab or cetuximab plus FOLFIRI in patients with advanced colorectal cancer RAS/BRAF wild type (wt) on tumor tissue and RAS mutated (mut) in liquid biopsy: LIBImAb Study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): TPS3636. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.tps3636.
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TPS3636 Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.
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Damato, Angela, Angela Damato, Carlo Aschele, Fortunato Ciardiello, Evaristo Maiello, Salvatore Siena, Valter Torri, et al. "Phase III study to compare bevacizumab or cetuximab plus FOLFIRI in patients with advanced colorectal cancer RAS/BRAF wild type (wt) on tumor tissue and RAS mutated (mut) in liquid biopsy: LIBImAb Study." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): TPS3636. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.tps3636.
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TPS3636 Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.
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Kotani, Daisuke, Yoshinori Kagawa, Yuki Matsubara, Hideaki Bando, Kazuaki Harada, Naoki Takahashi, Yoshiaki Mihara, et al. "TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): TPS264. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.tps264.
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TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .
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Rachiglio, Anna Maria, Laura Forgione, Raffaella Pasquale, Carlo Antonio Barone, Evaristo Maiello, Lorenzo Antonuzzo, Antonino Cassata, et al. "Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies." Cancers 14, no. 4 (February 18, 2022): 1052. http://dx.doi.org/10.3390/cancers14041052.
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Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.
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Tang, Wentao, Ye Wei, Li Ren, Qing-Hai Ye, Tianshu Liu, and Jianmin Xu. "mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS mutant unresectable colorectal liver-limited metastases: A study protocol of a multicenter randomized controlled phase 3 (BECOME2) trial." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): TPS228. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.tps228.
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TPS228 Background: Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined. Methods: BECOME2 is a multicenter, randomized, phase 3 clinical study. RAS mutant and BRAF wild type colorectal cancer patients with initially unresectable liver-limited metastases are eligible. The (un)resectability status is prospectively assessed by a central multidisciplinary team (MDT) consisting of at least one radiologist and three liver surgeons, according to predefined criteria. RAS and BRAF mutation status were evaluated according to primary tumor. Patients with RAS mutant and BRAF wild type will be randomized between modified FOLFOXIRI (IRI, 165mg/m2; Oxa, 85mg/m2; LV, 400mg/m2; 5-FU 2400mg/m2) plus bevacizumab (5mg/kg) and modified FOLFOX6 (mFOLFOX6) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central MDT every eight weeks. The primary study endpoint is conversion resection rate. Secondary endpoints are the ETS, DpR, ORR, PFS, OS, toxicity, perioperative complication, and the proportion of no evidence of disease. Clinical trial information: NCT04781270.
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Hill, Kristen S., Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, and Minjung Kim. "Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR13. http://dx.doi.org/10.1158/1538-7445.mel2019-pr13.
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Abstract Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
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Formica, Vincenzo, Jessica Lucchetti, Elena Doldo, Silvia Riondino, Cristina Morelli, Renato Argirò, Nicola Renzi, et al. "Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients—The Importance of Tissue/Plasma Discordant Cases." Journal of Clinical Medicine 10, no. 1 (December 29, 2020): 87. http://dx.doi.org/10.3390/jcm10010087.
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Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.
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Hwang, Kwangwoo, SeoHyun Jo, Jieun Choi, Ga-young Choi, Jiseon Choi, Ji-Hye Kwon, Dong-Guk Shin, et al. "Abstract LB521: Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB521. http://dx.doi.org/10.1158/1538-7445.am2022-lb521.
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Abstract FDA approved three RAF inhibitors for the treatment of tumors containing BRAFV600 mutations, but one of the major drawbacks of these type I RAF inhibitors is to activate MAPK signaling pathway, instead of inhibiting signaling, which is referred to as paradoxical activation. Such undesired paradoxical activation not only leads to renewed tumor growth but also spurs additional cancer growth in non-cancerous wild-type BRAF tissue. Plus, these first-generation RAF inhibitors targeting BRAFV600 mutants are unable to inhibit oncogenic RAF dimers. This has led to the development of type II RAF inhibitors such as belvarafenib and day101 to block the activity of multiple forms of RAF while avoiding paradoxical activation. Two lead-like stage compounds 1 and 2 were specifically designed as type II RAF inhibitors to have activity across RAF isoforms including BRAFV600E, BRAF wild-type, and CRAF, showing higher potency than competitors. Compounds 1 and 2 potently inhibited the growth of BRAFV600E melanoma cells and NRAS or KRAS mutant cancer cells. Compounds 1 and 2 promoted the formation of BRAF/CRAF heterodimers by directly binding to the RAF kinase domain like other type II RAF inhibitors and inhibited phosphorylation of downstream effectors MEK and ERK in a dose-dependent manner in RAS mutant cancer cells, suggesting less paradoxical activation liability. Compound 2 showed superior on-target inhibitory activity for BRAFV600E, BRAF wild-type, and CRAF than belvarafenib through RAF immunoprecipitation (IP) kinase assay. Inhibition of the RAF downstream signaling was also confirmed by quantifying the level of phospho-ERK in NRAS or KRAS mutant cancer cells. In HCT116 (KRASG13D) subcutaneous xenograft model, compound 1 showed tumor growth inhibition efficacy, suggesting a potential to address RAS mutant driven- as well as BRAFV600 mutant driven tumors. Also, combination treatment with MEK inhibitor and/or immune checkpoint inhibitor would further improve the therapeutic activity and expand target indication for unmet medical needs. Citation Format: Kwangwoo Hwang, SeoHyun Jo, Jieun Choi, Ga-young Choi, Jiseon Choi, Ji-Hye Kwon, Dong-Guk Shin, Jiyeon Kim, Se-Hyuk Kim, Haelee Kim, Ha Yeon Cho, Jung Beom Son, Nam Doo Kim, Hwan Geun Choi, Daekwon Kim, Sunghwan Kim. Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB521.
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ESER, KADIR. "The Effect of Tumor Sideness and Mutational Status on First Line Treatment Response and Survival in The Patients with Metastatic Colorectal Cancer." International Journal of Hematology and Oncology 30, no. 4 (December 30, 2020): 197–206. http://dx.doi.org/10.4999/uhod.204659.
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RAS and BRAF mutation and primary tumour sideness are prognostic and predictive factors in metastatic colorectal cancer (mCRC). We aimed to investigate RAS-BRAF mutation rates and responses to biologic agents the effects of tumour sideness on survival. This was a retrospective study conducted at three Turkish institutes. 303 patients with mCRC who were examined for tumour RAS and 172 examined for tumour BRAF mutations between 2006-2018. A total of 303 (M/F= 186/117) patients were included to study. Median age was 63 (range: 23-86) years. Median follow-up was 22.8 (range: 19.1-26.4) months. In the RAS wild type population; ad- dition to anti-EGFR agents to standard chemotherapy (CT) had better outcomes than Bevacizumab+CT. Median PFS was improved with anti-EGFR agents (Respectively PFS; 14.5 months, 8.7 months) (log rank p= 0.007 HR= 0.59). Median OS was similar between CT+anti-EGFR and CT+Bevacizumab arms (Respectively OS; 29.3 months, 21.7 months) (log rank p= 0.418; HR= 0.75). RAS muta- tion rates were similar between right colon cancer (RCC) and left colon cancer (LCC), BRAF mutation rates were significantly increased in RCC (22.2 vs 2.7%, p< 0.0001). RCC (24.1%) had worse prognosis than LCC (75.9%). However, this difference was not significant (PFS: 10.4 vs 10.0 months (log rank p= 0.136) , OS: 21.5 vs 23.1 months (log rank p= 0.436). We concluded that in the patients with RAS wild type tumours, CT and anti-EGFR combination was reasonable approach for first line treatment. BRAF mutation, irrespective of CT regimen, was associated with poor survival and more common in RCC patients. Keywords: Metastatic colorectal cancer, RAS and BRAF, Sidedness, Prognosis
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Miller, Nichol L. G., Tim S. Wang, Paul Severson, Ping Jiang, Michelle Perez, Noel Timple, Toufike Kanouni, Aleksandra Franovic, Eric S. Martin, and Eric Murphy. "Abstract 2674: Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2674. http://dx.doi.org/10.1158/1538-7445.am2022-2674.
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Abstract Background: In the US in 2021, invasive melanoma will account for an estimated 106,000 new cases and > 7,000 deaths. Somatic mutations that activate the MAPK signaling pathway are a leading cause of melanoma with 50% harboring oncogenic BRAF alterations and another 20% with activating NRAS mutations. Of note, NRAS mutant melanoma has been shown to be dependent upon RAF signaling via CRAF dimers for downstream activation of MEK/ERK. While targeted therapies are approved for V600 (Class I, monomer-driven) BRAF mutant melanoma, no approved targeted therapy exists for patients with melanoma driven by Class II or Class III dimer-dependent BRAF alterations or NRAS mutations. KIN-2787 is a novel, orally available, potent, and selective pan-RAF inhibitor designed to be effective in RAF-dependent cancers, including all classes of BRAF alterations, by targeting mutant BRAF monomers and RAF dimers, regardless of isoform. Methods: KIN-2787 activity was assessed by suppression of downstream MAPK pathway signaling and subsequent cell growth inhibition in a panel of human melanoma cell lines. In vivo KIN-2787 efficacy was evaluated in BRAF and NRAS mutant melanoma cell- and patient-derived xenograft models. Results: KIN-2787 cellular activity was measured by inhibition of ERK phosphorylation across a panel of melanoma cell lines, including those harboring Class I BRAF alterations, Class II and III BRAF alterations, NRAS mutations, KRAS mutations, and wild type RAF/RAS. In contrast to vemurafenib, an approved BRAF inhibitor with activity limited to Class I BRAF alterations, KIN-2787 was active across all classes of BRAF mutant melanoma cells (EC50 values < 100 nM). NRAS and KRAS mutant cell lines were moderately responsive to KIN-2787 inhibition. Melanoma cells expressing wild type RAS/RAF were the least sensitive to MAPK pathway inhibition by KIN-2787. KIN-2787 also inhibited cell proliferation in BRAF and NRAS mutant melanoma in 2D and 3D cell cultures. Daily KIN-2787 treatment resulted in significant tumor growth inhibition in human melanoma xenograft models bearing Class I, II and III BRAF alterations as well as NRAS mutations and was associated with MAPK pathway suppression. Additionally, KIN-2787 was efficacious in a pre-/post-treatment melanoma PDX pair in which the original tumor was Class I BRAF V600E but acquired a Class II BRAF kinase domain duplication upon progression on dabrafenib + trametinib. Details from the above findings will be presented at the meeting. Conclusions: KIN-2787 is a next-generation, pan-RAF inhibitor with in vitro and in vivo activity against human melanoma driven by BRAF and/or NRAS mutations. Data supports KIN-2787 use in acquired BRAF dimer-dependent resistance to BRAF+MEK inhibitor therapy. A Phase I dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285). Citation Format: Nichol L. G. Miller, Tim S. Wang, Paul Severson, Ping Jiang, Michelle Perez, Noel Timple, Toufike Kanouni, Aleksandra Franovic, Eric S. Martin, Eric Murphy. Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2674.
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Karimi, Misagh, Chongkai Wang, Bahareh Bahadini, George Hajjar, and Marwan Fakih. "Integrating Academic and Community Practices in the Management of Colorectal Cancer: The City of Hope Model." Journal of Clinical Medicine 9, no. 6 (June 2, 2020): 1687. http://dx.doi.org/10.3390/jcm9061687.
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Colorectal cancer (CRC) management continues to evolve. In metastatic CRC, several clinical and molecular biomarkers are now recommended to guide treatment decisions. Primary tumor location (right versus left) has been shown to predict benefit from anti-epidermal growth factor receptors (EGFRs) in rat sarcoma viral oncogene homologue (RAS) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) wild-type patients. Anti-EGFR therapy has not resulted in any benefit in RAS-mutated tumors, irrespective of the primary tumor location. BRAF-V600E mutations have been associated with poor prognosis and treatment resistance but may benefit from a combination of anti-EGFR therapy and BRAF inhibitors. Human epidermal growth factor receptor 2 (HER-2) amplification was recently shown to predict relative resistance to anti-EGFR therapy but a response to dual HER-2 targeting within the RAS wild-type population. Finally, the mismatch repair (MMR)-deficient subgroup benefits significantly from immunotherapeutic strategies. In addition to the increasingly complex biomarker landscape in CRC, metastatic CRC remains one of the few malignancies that benefits from metastasectomies, ablative therapies, and regional hepatic treatments. This treatment complexity requires a multi-disciplinary approach to treatment and close collaborations between various stakeholders in large cancer center networks. Here, we describe the City of Hope experience and strategy to enhance colorectal cancer care across its network.
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Peeters, Marc, Frédéric Forget, Meinolf Karthaus, Manuel Valladares-Ayerbes, Alberto Zaniboni, Gaston Demonty, Xuesong Guan, and Fernando Rivera. "Exploratory pooled analysis evaluating the effect of sequence of biological therapies on overall survival in patients with RAS wild-type metastatic colorectal carcinoma." ESMO Open 3, no. 2 (February 2018): e000297. http://dx.doi.org/10.1136/esmoopen-2017-000297.
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BackgroundThe aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first-line bevacizumab (VEGFi) and second-line EGFRi, were conducted.MethodsPatients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first-line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively.ResultsOverall, 104 RAS WT patients were included (n=66 panitumumab→VEGFi, n=38 bevacizumab→EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab→VEGFi versus bevacizumab→EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours.ConclusionAlthough numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first-line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC.
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Guan, Michelle, R. Joseph Bender, Michael J. Pishvaian, David Charles Halverson, Richard Tuli, Samuel Jacob Klempner, Zev A. Wainberg, Aatur D. Singhi, Emanuel Petricoin, and Andrew Eugene Hendifar. "Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 214. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.214.
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214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.
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Mariani, Stefano, Marco Puzzoni, Nicole Liscia, Valentino Impera, Andrea Pretta, Simona Tolu, Anna Grazia Pireddu, et al. "Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3577. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3577.
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3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.
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Kotani, Daisuke, Sebastián Mondaca, Aparna Parikh, Hideaki Bando, Emily Van Seventer, Hiroya Taniguchi, Takayuki Yoshino, Ryan Bruce Corcoran, Rona Yaeger, and Hiromichi Ebi. "Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes in patients with BRAF non-V600 mutated metastatic colorectal cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 659. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.659.
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659 Background: BRAF non-V600 mutations occur in 2-3% of colorectal cancer. These mutants can be classified as RAS independent (class 2) or RAS dependent (class 3). We reported BRAF non-V600 mutations could be a negative predictive factor for anti-EGFR therapy in patients (pts) with pretreated metastatic colorectal cancer (mCRC), while mCRC pts with class 3 BRAF mutations could respond to anti-EGFR therapy because of its dependency on receptors and RAS. Methods: This study evaluates the efficacy to anti-EGFR therapy in a large cohort of pts with BRAF non-V600 mutated mCRC. Pts with mCRC referred to the participating centers from 2010 to 2017 were included. Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes were stratified by BRAF mutational class. Results: One hundred seventeen pts with BRAF non-V600 mutated mCRC were identified. Median age was 58 years (range, 27-83), 68 pts (58%) were male, and 38 pts (33%) had right-sided tumors. Mucinous histology was seen in 11 cases (9%); concurrent RAS mutations occurred in 31 cases (27%), and 3 cases (3%) were MSI-H. Also, TP53 mutations were detected in 74 pts among 90 analyzed cases (82%). Regarding BRAF mutation subtype, 25/63/29 pts were classified as class 2/3/not reported (NR), respectively. Median OS in RAS wild-type/mutant were 44.8/34.6 months, respectively (p=0.082). The median OS in RAS wild-type pts with BRAF non-V600 mutations for class 2, 3, and NR were 25.7, 44.2, and 79.1 months, respectively (class 2 vs. 3, p=0.219). Among 40 pts treated with anti-EGFR therapy, response rates were 14%, 44%, and 40% for class 2, 3, and NR, respectively. Median PFS was 4.4, 8.3, 4.0 months for class 2, 3, and NR, respectively. Moreover, in 25 pts receiving anti-EGFR therapy as third or later line, response rate was 0%, 27%, and 50% in class 2, 3, and NR, and median PFS was 2.8, 3.7, and 4.0 months (p=0.762), respectively. Conclusions: Pts with class 2 BRAF mutations tend to have a poor prognosis compared to those with class 3 mutations. While almost half of pts with class 3 BRAF mutations responded to anti-EGFR therapy, response was rare for pts with class 2 BRAF mutations, and none achieved objective response in the third or later line.
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Brodowicz, Thomas, Damir Vrbanec, Klaus Kaczirek, Tudor-Eliade Ciuleanu, Regina Knittelfelder, Elisabeth Lindner, Diethelm Messinger, Christoph Zielinski, and Berthold Streubel. "FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): LBA391. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.lba391.
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LBA391^ Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.
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Giordano, Guido, Pietro Parcesepe, Giuseppina Bruno, Annamaria Piscazzi, Vincenzo Lizzi, Andrea Remo, Massimo Pancione, et al. "Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era." International Journal of Molecular Sciences 22, no. 14 (July 19, 2021): 7717. http://dx.doi.org/10.3390/ijms22147717.
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Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
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Morano, Federica, Salvatore Corallo, Sara Lonardi, Alessandra Raimondi, Chiara Cremolini, Lorenza Rimassa, Roberto Murialdo, et al. "Negative Hyperselection of Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy." Journal of Clinical Oncology 37, no. 33 (November 20, 2019): 3099–110. http://dx.doi.org/10.1200/jco.19.01254.
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PURPOSE We assessed the prognostic/predictive role of primary tumor sidedness and uncommon alterations of anti–epidermal growth factor receptor (EGFR) primary resistance (primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies [PRESSING] panel) in patients with RAS/ BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who were randomly assigned to panitumumab plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) induction followed by maintenance with panitumumab with or without fluorouracil (FU) plus leucovorin (LV); Valentino trial (ClinicalTrials.gov identifier: NCT02476045 ). PATIENTS AND METHODS This prespecified retrospective analysis included 199 evaluable patients with RAS/ BRAF wt. The PRESSING panel included the following: immunohistochemistry (IHC) and in situ hybridization for HER2/MET amplification, IHC with or without RNA sequencing for ALK/ROS1/NTRKs/RET fusions, next-generation sequencing for HER2/ PIK3CAex.20/PTEN/ AKT1 and RAS mutations with low mutant allele fraction, and multiplex polymerase chain reaction for microsatellite instability. PRESSING status (any positive biomarker v all negative) and sidedness were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the study population and by treatment arm. RESULTS Overall, left- and right-sided tumors were 85.4% and 14.6%, respectively, and PRESSING-negative and -positive tumors were 75.4% and 24.6%, respectively. At a median follow-up of 26 months, inferior outcomes were consistently observed in right- versus left-sided tumors for ORR (55.2% v 74.1%; P = .037), PFS (8.4 v 11.5 months; P = .026), and OS (2-year rate: 50.2% v 65.1%; P = .062). Similar results were observed in the PRESSING-positive versus PRESSING-negative subgroup for ORR (59.2% v 75.3%; P = .030), PFS (7.7 v 12.1 months; P < .001), and OS (2-year rate: 48.1% v 68.1%; P = .021). The PFS benefit of FU plus LV added to panitumumab maintenance, reported in the study, was independent from sidedness and PRESSING status (interaction for PFS P = .293 and .127, respectively). However, outcomes were extremely poor in patients who received single-agent panitumumab and had right-sided tumors (median PFS, 7.7 months; 2-year OS, 38.5%) or PRESSING-positive tumors (median PFS, 7.4 months; 2-year OS, 47.0%). CONCLUSION The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with RAS/ BRAF–wt mCRC who had inferior benefit from initial anti-EGFR–based regimens, particularly after maintenance with single-agent anti-EGFRs.
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Garawin, Tamer, Kimberly Lowe, George Kafatos, and Samuel Murray. "The prevalence RAS and BRAF mutations among patients in the Middle East and Northern Africa with metastatic colorectal cancer." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 598. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.598.
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598 Background: Anti-EGFR therapies are recommended for metastatic colorectal cancer (mCRC) patients with confirmed wild-type RAS (exons 2, 3, 4 of KRAS and NRAS) status. There is limited published information on the prevalence of RAS mutations using real world data. The objective of this study was estimate the prevalence of RAS and BRAF mutations among patients with mCRC in the Middle East and Northern Africa (MENA) in an effort to inform the rationale for biomarker testing and treatment choice. Methods: The study included 1,669 patients from August 2013 to July 2015 with mCRC from Algeria, Bahrain, Egypt, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, and the United Arab Emeritus. Information on RAS mutation status was obtained from one pathology lab using High Resolution Melting Analysis. Extended RAS analysis was conducted in a subset of patients, including: overall RAS (exon 2, 3, 4 of KRAS and NRAS; n = 750), KRAS exon 2 (n = 750), KRAS exon 3 and 4 (n = 507), NRAS exon 2, 3, and 4 (n = 507), and BRAF exon 15 (n = 78). The proportion of patients with each mutation was summarized. Results: The overall RAS mutation in the full sample was 35.3% (n = 589/1669). The observed mutation for KRAS exon 2 in a subset of patients with extended RAS analysis (n = 750) was 32.4% (243/750). Out of the subjects with wild-type exon 2 (n = 507), the observed mutations rates were as follows: KRAS exon 4 (20/507 = 3.9%), KRAS exon 3 (13/507 = 2.6%), NRAS exon 2 (7/507 = 1.4%), NRAS exon 3 (6/507 = 1.2%), and NRAS exon 4 (0%). The prevalence of BRAF exon 15 was 3.8% (3/78). The most robust data on specific RAS mutations was obtained from Algeria, Egypt, and Saudi Arabia. The prevalence of KRAS exon 2 mutations in these countries was as follows: Algeria (n = 33/86 = 38.4%), Egypt (n = 83/303 = 27.4%), Saudi Arabia (n = 85/245 = 34.7%). Conclusions: To our knowledge, this is the first study to evaluate the prevalence of RAS and BRAF mutations in the Middle East using real world data. The results of this descriptive study illustrate that there is variation in the prevalence of RAS and BRAF mutations in MENA.
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Nishina, Tomohiro, Hiroya Taniguchi, Daisuke Sakai, Hisato Kawakami, Naotoshi Sugimoto, Hiroki Hara, Taito Esaki, et al. "Analysis of RAS/BRAF mutations in a randomized phase II WJOG6510G study of panitumumab plus irinotecan versus cetuximab plus irinotecan in chemorefractory metastatic colorectal cancer." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 624. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.624.
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624 Background: A randomized phase II WJOG6510G study demonstrated non-inferiority of panitumumab (Pmab) plus irinotecan (IRI) to cetuximab (Cmab) plus IRI in terms of progression-free survival (PFS) in wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we performed exploratory analyses of updated survival data using KRAS exon 2 and RAS/BRAF statuses. Methods: In this trial, patients with WT KRAS exon 2 mCRC who progressed after failure of fluoropyrimidine, IRI, and oxaliplatin were randomized to receive Pmab or Cmab in combination with IRI. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence specific oligonucleotide method which can detect 48 types of KRAS/NRAS and 34 types of BRAF mutations. Results: In the ITT population, patient characteristics included the following (Pmab/Cmab): number 61/59; male 69%/63%; median age 64 y/64 y; ECOG PS 0 62%/54%; left-sided primary tumor 85%/88%; multiple sites of metastases 51%/66%. At the time of updated analysis, 113 (94%) and 117 (98%) out of 120 patients had OS and PFS events, respectively. Median PFS was 5.42 months in the Pmab arm and 4.27 months in the Cmab arm (HR 0.674, unstratified log-rank p = 0.035). Median overall survival (OS) was 14.85 months in the Pmab arm and 11.53 months in the Cmab arm (HR 0.675, p = 0.037). In 83 patients, RAS/BRAF tests revealed 19 patients (23%) with RAS and 4 patients (5%) with BRAF mutations (two with V600E, two with non-V600E). Patients with RAS and BRAF mutations did not respond to the treatments. In the RAS WT population, a better PFS trend was observed for Pmab treatment (median 6.06 months vs. 5.26 months, HR 0.629, p = 0.08); however, OS was similar in both arms (median 14.85 months vs. 11.26 months, HR 0.818, p = 0.449). Conclusions: In this analysis, a modest survival benefit was found to be associated with Pmab plus IRI compared to Cmab plus IRI in WT KRAS exon2 mCRC, which warrants further evaluation in the WT RAS population. The number of analytic cases of RAS/BRAF status will be updated in the presentation. Clinical trial information: UMIN000006643.
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Townsend, Amanda Rose, Jennifer Hardingham, Niall C. Tebbutt, Christos Stelios Karapetis, Nimit Singhal, Rohit Joshi, Sue Yeend, Pamela Cooper, Hilary Dorward, and Timothy Jay Price. "A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 643. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.643.
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643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P < 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.
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Nakayama, Izuma, Eiji Shinozaki, Takeru Wakatsuki, Yosuke Kumekawa, Mariko Ogura, Takashi Ichimura, Daisuke Takahari, et al. "The significance of EGFR pathway mutations for the efficacy of first line treatment with bevacizumab in metastatic colonrectal cancer." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 699. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.699.
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699 Background: After analysis of minor RAS mutations (KRAS exon3, 4/NRAS) in FIRE-3 or PRIME study, so called all RAS mutation would be being regarded as a biomarker for anti-EGFR antibodies. BRAF and PIK3CA mutation would be a candidate of biomarkers for anti EGFR targeted therapies. However it remains unknown whether EGFR pathway mutations affect the efficacy of bevacizumab in Stage.‡W CRC. Methods: Of the 1,001 consecutive patients of CRC in our institute between Nov 2006 and Dec 2013, we examined RAS, PIK3CA and BRAF mutational status, 141 patients received systemic chemotherapy for the first line treatment of Stage.‡W. Among them, 96 patients were administered chemotherapy with bevacizumab. Overall survival (OS), Time to Treatment Failure (TTF) and Objective Response Rate (ORR) were evaluated by mutational status. Results: Baseline characteristics were as follows (n=141): median age, 63; male/female, 80/61; ECOG PS 0-1/2, 135/4; chemotherapy with bevacizumab/chemotherapy with anti-EGFR antibodies/cytotoxic agent alone, 96/22/23;KRAS (codon 12,13) wild-type (WT)/RAS wild-type(WT), 89/80; PIK3CA mutation (exon 9/exon 20)/BRAF mutation, 11(5/6)/13. Median OS and TTF were 32.1 and 8.0 months respectively. In chemotherapy with bevacizumab, ORRs were 46.3% (all cases), 55.3% (KRAS WT), 54.5% (RAS WT) and 60.6% (all WT) respectively. ORR was gradually improved by focusing therapeutic target on all wild population. However, there were no significant differences in TTF and OS among them. PIK3CA mutation had a trend toward shorter TTF of bevacizumab (p=0.056). This trend was observed in PIK3CA mutation on exon 20 but not observed exon 9. BRAF mutation had significantly associated with poor OS not only for bevacizumab cases but also all therapies. Conclusions: In our study, profiling of EGFR pathway mutations may not contribute to enrich patients with benefit from chemotherapy with bevacizumab.
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Mesti, Tanja, Marko Boc, Martina Rebersek, Zvezdana Hlebanja, Neva Volk, and Janja Ocvirk. "KRAS, NRAS and BRAF mutational status and first line treatment patterns in Slovenian population with metastatic colorectal carcinoma: Five year results." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15546-e15546. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15546.
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e15546 Background: A phase IV non-interventional study was performed from 2013 till 2018 including 650 patients with primary aim to assess KRAS, NRAS and BRAF mutational status in Slovenian population with metastatic colorectal carcinoma (mCRC) suitable for first-line treatment. The evaluation of decisions for first-line treatment regarding the biomarkers status and assessing the possible impact of the time period of the biomarker status analysis report on the treatment decision were also incorporated in the analysis. The molecular analyses for KRAS and NRAS gene mutations were performed on exons 2, 3 and 4, and for BRAF gene mutations on exon 15. The first line systemic treatment options for RAS (KRAS/NRAS) wild type (wt) and mutated type (mt) mCRC subjects were as follows: chemotherapy - Fluoropyrimidine based systemic therapy combined with oxaliplatin and/or irinotecan with/without VEGF inhibitor bevacizumab and for RAS wt subjects, with/without EGFR inhibitors, cetuximab or panitumumab. Methods: To indicate the degree of certainty of KRAS, NRAS and BRAF status frequency as being wild type or mutant type 95% confidence interval was calculated. Results: The KRAS/NRAS/BRAF mutation rates were as follows - The distribution of subjects with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively. Eighty nine percent of the subjects had NRAS wild type tumours and 86.1% had BRAF wild type tumours. The most frequently used treatment regardless the biomarkers status and in accordance with the treatment guidelines was bevacizumab based combination therapy (53.1%). The EGFR inhibitor (cetuximab or panitumumab) based combination therapy was used in one third of mCRC subjects (30.9%), all with mCRC RAS wt. The time period from the initial presentation of the patient until the biomarker status analysis report was two weeks. Conclusions: With this study, we have proven that the distribution of the mutations in exons 2-4 of KRAS and NRAS genes and exon 15 in the BRAF gene in the Slovenian population with metastatic colorectal cancer matches historical data. Based on this, we conclude that the treatment decision in Slovenian population with metastatic colorectal carcinoma should be in the accordance with international treatment guidelines and on evidence based medicine. The molecular analysis performed at the Institute of Oncology Ljubljana was providing necessary biomarkers status report in an acceptable time that didn’t affect the treatment decision or delay the needed cancer treatment.
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Nagasaka, Takeshi, Hiromi Sasamoto, Kenji Notohara, Harry M. Cullings, Masanori Takeda, Keigo Kimura, Takeshi Kambara, et al. "Colorectal Cancer With Mutation in BRAF, KRAS, and Wild-Type With Respect to Both Oncogenes Showing Different Patterns of DNA Methylation." Journal of Clinical Oncology 22, no. 22 (November 15, 2004): 4584–94. http://dx.doi.org/10.1200/jco.2004.02.154.
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Purpose BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.
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Higuchi, Akio, Rika Kasajima, Manabu Shiozawa, Masahiro Asari, Masaaki Murakawa, Yusuke Katayama, Koichiro Yamaoku, et al. "Analysis of correlation between oncogene mutation and response to chemotherapy in all RAS wild type metastatic colorectal cancer, using next-generation sequencing technology." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 553. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.553.
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553 Background: Targeted therapies of monoclonal antibodies have changed the treatment of metastatic colorectal cancer (mCRC). A target therapy with chemotherapy regimen for mCRC was decided by KRAS mutation status (KRAS exon2 [codon12, codon13]). Currently, there are many reports suggesting that in addition to analysis of KRAS mutation status, the evaluation of EGFR gene copy number, levels of EGFR ligands, BRAF, NRAS, PIK3CA mutations could be helpful to have a more accurate selection of patients who may have a benefit from anti-EGFR targeted drugs. Methods: Mutation status of 50 oncogenes were analysed in 35 mCRC patients with all RAS wild type, using next-generation sequencing technology. The response for chemotherapy was classified response group (R group) and non-response group (N group) by RECIST. The relation between mutation status of 50 oncogenes and the response for chemotherapy was assessed. Results: There were 25 oncogene mutations in the 50 genes. Driver mutation associated with oncogenic mutation deeply were 5 oncogenes, which were PIK3CA, AKT1, BRAF, PDGFRA and TP53. Only BRAF mutation was significantly associated with poor chemo response in the 5 oncogenes. A case which had two driver mutations was only in the N group. One of the two driver mutations was tumor suppressor gene, TP53. Conclusions: BRAF mutation and the number of driver mutations are key predictors of chemosensitivity in the mCRC cases with all RAS wild type.
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Loree, Jonathan M., Anthony Dowers, Dongsheng Tu, Christopher J. O'Callaghan, Dan Edelstein, Hannah Quinn, Derek J. Jonker, et al. "Expanded RAS and BRAF V600 testing as predictive biomarkers for single agent cetuximab in the randomized phase III CO.17 trial." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 537. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.537.
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537 Background: KRAS/NRAS ( RAS) testing of exons 2, 3 and 4 is standard prior to anti-EGFR treatment in metastatic colorectal cancer and many consider BRAFV600 ( BRAF) mutations predictive. CO.17 was a randomized phase III trial comparing cetuximab vs best supportive care (BSC) in unselected patients (pts). Re-analysis tested only KRAS exon 2, thus the benefit of cetuximab in RAS/BRAF wild type (WT) pts is unclear. Methods: We retrospectively performed expanded RAS/BRAF testing using a highly sensitive digital PCR method (BEAMing; 1% allele frequency detection limit) on micro-dissected archival tissue from 248 CO.17 pts. Additional pts without available archival tissue, with prior Sanger sequencing or therascreen results were included in analyses if mutations were previously detected (n = 77). Overall survival (OS), progression free survival (PFS), and response rates (RR) were compared by molecular profile. Results: Of 248 sequenced pts, 139 (56%) were RAS mutant, with 112 (45%) exon 2, 11 (4%) exon 3 and 6 (2%) exon 4 KRAS mutant, and 10 (4%) NRAS mutant pts. Seven (3%) BRAF mutant, and 97 (30%) confirmed RAS/BRAF WT pts were identified. Results are summarized below. A test of interaction indicated RAS status was predictive for PFS (p = 0.0001) and OS (p = 0.037) and BRAF status neared significance as a predictive marker for PFS (p = 0.089) but not OS (p = 0.24). Conclusions: These updated results demonstrate an improved PFS (HR 0.25 vs 0.40 previously) and OS (HR 0.51 vs 0.55 previously) for cetuximab in RAS/BRAF WT pts compared to prior analyses that included only KRAS exon 2 mutation status. We provide an estimate of single agent cetuximab efficacy for future anti-EGFR re-challenge studies and demonstrate further support that BRAF mutations may predict lack of benefit from anti-EGFR therapy. Clinical trial information: NCT00079066. [Table: see text]
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Cho, May Thet, Leanne Goldstein, Chie Akiba, S. Cecilia Lau, Milhan Telatar, Michelle Afkhami, Stephen Sentovich, et al. "RAS mutational status and CEA production at initial presentation in metastatic colorectal cancer." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 542. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.542.
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542 Background: Serial CEA testing is recommended in the surveillance of patients with resected stage II-IV colorectal cancer. However, the sensitivity of CEA in identifying metastatic disease has not been evaluated in the settings of RAS mutant (MT) and RAS/BRAF wild-type tumors (WT). In order to evaluate the impact of RAS mutational status on CEA production, we retrospectively evaluated a single-institute metastatic colorectal cancer (mCRC) population. Methods: We retrospectively reviewed, in a single center, all cases with mCRC with known RAS mutational status based on next generation sequencing (ONCO44 and ONCO48). These assays identify clinically relevant mutations in BRAF, KRAS, and NRAS. Additional eligibility criteria included the availability of CEA levels and imaging studies at first diagnosis of mCRC. Patient demographics, primary tumor location and sites of metastatic disease at 1st diagnosis were captured. CEA levels were stratified as normal or elevated based on a cut point of 5ng/ml. Results: 139 mCRC patients satisfied the eligibility criteria (75 RAS-MT, 59 RAS/BRAF-WT, and 5 BRAF-MT). BRAF-MT patients were excluded from the analysis due to their small sample size. Patients with RAS/BRAF-WT tumors were more likely to present with metastatic disease to the liver, but this did not reach statistical significance (p = 0.056). There was no difference in the incidence of normal CEA at presentation in RAS-MT (30%) and RAS/BRAF-WT (28%) cohorts. CEA production was dependent on the pattern of metastatic disease. Elevated CEA was associated with the presence of liver metastases versus no metastases among RAS-MT (92% vs 47% p <.0001) and RAS/BRAF-WT patients (82% vs 50% p = 0.0101). RAS status did not impact the likelihood of CEA production within the hepatic metastases and non-hepatic metastases groups. Conclusions: RAS status does not appear to influence CEA production in patients with mCRC. CEA elevations are highly associated with liver metastases and are less prevalent in patients without hepatic involvement. These findings confirm the limited predictive value of CEA for non-hepatic recurrence, irrespective of RAS status.
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Albitar, Maher, Sucha Sudarsanam, Wanlong Ma, Shiping Jiang, Wayne Chen, Vincent Anthony Funari, and Sally Agersborg. "Expression of PD-L1 in colorectal cancer that lack mutations in RAS or TP53 genes." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14500-e14500. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14500.
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e14500 Background: PD-L1 expression as detected by immunohistochemistry (IHC) is significantly lower in colorectal cancers (CRC) when compared with lung cancer or other types of cancer. We explored if mutations in the RAS/RAF gene family, TP53 or PIK3CA can define a subgroup of CRC that express PD-L1. Methods: Tissue samples collected from 107 patients with CRC were studied for the expression of PD-L1 using clone SP142. The same samples were also tested for mutations in NRAS, KRAS, HRAS, BRAF, TP53, and PIK3CA using Next Generation Sequencing (NGS). Results: Of the 107 CRC samples only 15 (14%) showed PD-L1 positive tumor cells (≥1%) and 8 of the 15 (7.5% of total) had PD-L1 in ≤5% of tumor cells. Detected mutations in these samples were as follows: TP53 65%, KRAS 49.5%, PI3KCA 22.5%, NRAS 5%, HRAS 1%, and BRAF 17%. There was no correlation between PD-L1 expression and mutation status in any of the RAS/RAF genes. There was also no correlation between TP53 mutation and PD-L1 expression. This was true irrespective if PD-L1 expression is considered as a continuous variable or when cut-off points of 5%, 20%, or 50% were used. However, patients without any mutation in RAS or TP53 had significantly (P = 0.005) more expression of PD-L1 when cut-off point of 5% is used. This remained true if PD-L1 expression is considered as a continuous variable (P = 0.04). There was no correlation between PIK3CA and PD-L1 expression. Conclusions: PD-L1 expression is significantly more common in CRC that lack mutations in RAS or TP53. PD-L1 expression is detected in 31% of patients with wild-type RAS/TP53 as compared with 12% in patients with RAS/TP53 mutations (P = 0.04). If a cut-off point of 5% is used, 31% of RAS/TP53-wild-type CRC were positive for PD-L1, while only 6% of RAS/TP53- mutant CRC were positive for PD-L1 (P = 0.005). This suggests that in CRC without RAS/TP53 mutation, the PD-L1 may play a more important role in oncogenesis. Exploring immunotherapy in this group of CRC patients might be justified.
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Fedyanin, M. Yu, H. H. ‑M Elsnukaeva, I. A. Demidova, D. L. Stroyakovskii, Yu A. Shelygin, A. S. Tsukanov, Yu S. Sergeev, et al. "Resection of metastases in patients with BRAF mutated metastatic colon cancer: results of a multicenter retrospective study." Malignant tumours 11, no. 3 (January 4, 2022): 5–14. http://dx.doi.org/10.18027/2224-5057-2021-11-3-5-14.
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Introduction: local treatment of metastases is an integral part of colon cancer treatment. However, there is not enough data on the efficacy of surgical resection of metastases in patients with a BRAF gene mutation to recom‑mend this approach in routine practice. We initiated a retrospective multicenter study to assess the incidence of BRAF gene mutations in patients with metastatic colon cancer and to study the efficacy of metastasectomy in this group of patients.Materials and methods: we selected all patients who underwent surgical resection of metastases in various sites from the database of patients with BRAF gene mutations created as a result of a multicenter retrospective study with participation of 7 clinics in the Russian Federation. All 57 patients with RAS gene mutations and 43 patients with wild‑type RAS and BRAF genes who also underwent surgical resection of metastases at any stage of treatment were selected from the register of the Chemotherapy Department No. 2 of the NMRC of Oncology named after N. N. Blokhin for comparative analysis. Disease‑free survival and overall survival were used as primary efficacy criteria.Results: we found 26 patients with BRAF gene mutations who underwent surgical resection of metastases. When comparing disease‑free survival, the worst median was achieved in the group of patients with BRAF gene mutations: 7 months versus 14 months in patients with RAS gene mutations (HR 0.4, 94 % CI 0.23–0.7, P = 0.006); median disease‑free survival was not achieved in the wild‑type RAS and BRAF group (HR 0.2, 95 % CI 0.11–0.45, P <0.001).The median overall survival in the BRAF gene mutation group was 26 months versus 38 months in the RAS gene mutations group (HR 0.8, 95 % CI 0.33–1.98, P = 0.6) and 49 months in the wtRAS/wtBRAF group (RR 0.46, 95 % CI 0.17–1.24, P = 0.1). Resection of recurrent tumors in patients with metastases in retroperitoneal lymph nodes was associated with extremely low disease‑free survival (2 months); at the same time, disease‑free survival was 7 months after resection of isolated metastases in the liver and 8 months for metastases in the peritoneum.Conclusion: prognosis of patients with a BRAF gene mutation after surgical resection of metastases is worse than in patients with a different mutation phenotype. Nevertheless, literature data, as well as the results of our study, confirm the possibility of performing metastasectomy with careful selection of patients.
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de Sousa, M. J. P., T. Fraga, J. Correia Magalhães, R. Basto, J. Paulo, P. Jacinto, N. Bonito, J. P. Magalhães, P. Figueiredo, and G. Sousa. "69P HER2 status in RAS and BRAF wild-type metastatic colorectal cancer: Portuguese study." Annals of Oncology 32 (October 2021): S1366. http://dx.doi.org/10.1016/j.annonc.2021.08.2065.
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Liu, Jianhua, Weiqiang Zeng, Chengzhi Huang, Junjiang Wang, Dongyang Yang, and Dong Ma. "Predictive and Prognostic Implications of Mutation Profiling and Microsatellite Instability Status in Patients with Metastatic Colorectal Carcinoma." Gastroenterology Research and Practice 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/4585802.
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To investigate whether mutation profiling and microsatellite instability (MSI) status were associated with clinicopathological features and the prognosis in metastatic colorectal cancer (mCRC), mutations in RAS (including KRAS, NRAS, and HRAS) and BRAF were determined by Sanger sequencing. Tumor mismatch repair proteins and MSI status were examined using immunohistochemistry and polymerase chain reaction, respectively. The clinical value of these abnormalities was statistically analyzed, and prognostic value of different treatment regimens was also evaluated. Among 461 mCRC patients, mutations in RAS, BRAF, and MSI-high (MSI-H) status were observed in 45.3% (209/461), 5.6% (26/461), and 6.5% (30/461) of cases, respectively. Brain metastasis and high carcinoembryonic antigen level were highly correlated with KRAS mutation (P=0.011 and P<0.001), and tumors from females or located in the right colon tended to harbor BRAF mutation (P=0.039 and P=0.001). RAS/BRAF mutations may predict brain and/or lung metastases. Although neither clinical nor prognostic importance of MSI status was identified in our study, KRAS and BRAF mutations were demonstrated to be independent prognostic factors for overall survival and progression-free survival. Besides, in wild-type group, patients treated with chemotherapy plus targeted therapy exhibited the most favorable prognosis. Therefore, RAS/BRAF mutations may serve as indicators for prognosis and treatment options in mCRC.
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Sawada, Kentaro, Wataru Okamoto, Yoshiaki Nakamura, Takeharu Yamanaka, Satoshi Yuki, Takayuki Yoshino, Yoshito Komatsu, Naoya Sakamoto, and Satoshi Fujii. "Survival outcome in HER2-amplified metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 642. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.642.
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642 Background: HER2 amplifications have been observed in approximately 3% of patients (pts) with metastatic colorectal cancer (mCRC). Early clinical trials with combined HER2-targeted therapies showed promising activities. However, it remains unclear whether HER2 amplification in mCRC is as prognostic as RAS or BRAF V600E mutant (mt). We aimed to evaluate survival outcome for mCRC pts with HER2 amplification compared to those with RAS or BRAF mt. Methods: mCRC pts who received a palliative resection of the primary tumor with metastatic diseases at presentation, or recurred after curative resection of the primary tumor between 2005 and 2015, were analyzed. HER2 immunohistochemistry (IHC) was performed using formalin-fixed and paraffin-embedded (FFPE) sections obtained from the primary tumor, and HER2 amplification was confirmed by fluorescence in situ hybridization (FISH) in case of IHC 2+ or 3+. Criteria for HER2 amplification were a HER2- to CEP17- signal ratio of 2.0 or higher. RAS / BRAF status was centrally assessed by a PCR-based method. The pts were classified into four subgroups based on RAS, BRAF and HER2 status: Group R , RAS mt; Group B, BRAF V600E mt; Group H, HER2 amplification with RAS / BRAF wild-type (wt); and Group W, RAS / BRAF wt. Results: Among 370 pts, 359 pts (97%) were successfully analyzed. A total of 15 pts (4%) had HER2 amplifications, out of which four pts had overlapped RAS mt (subclassified as Group R). RAS or BRAF mutations are mutually exclusive. The number in Group R, B, H and W was 204 (57%), 13 (4%), 11 (3%) and 131 (36%), respectively. There was no remarkable difference in baseline characteristics among groups. With a median follow-up time of 63 months (mos), the median overall survival of the 359 pts was 27 mos (95%CI 24 - 29 mos); Group R, 24 mos; Group B, 14 mos; Group H, 20 mos; and Group W, 39 mos. The HR of R vs. H is 0.83 (95%CI 0.41-1.70, p= 0.618), B vs. H is 1.16 (95%CI 0.47-2.84, p= 0.748), and W vs. H is 0.52 (95%CI 0.25-1.08, p= 0.080), respectively. Conclusions: This study suggests that the prognosis of mCRC pts with HER2 amplification tends to be worse as compared to those with RAS / BRAF wt, similar to those with RAS mt, and better than those with BRAF mt, although these comparisons were not statistical significant.
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Capdevila, Jaume, Ignacio Matos Garcia, Francesco M. Mancuso, Carmela Iglesias, Paolo Nuciforo, Carles Zafon, Hector G. Palmer, et al. "RNAseq analysis of the sorafenib phase III DECISION trial in differentiated thyroid cancer (DTC): Correlation with clinical outcome." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6083. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6083.
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6083 Background: In DECISION, sorafenib significantly impacted progression-free survival (PFS) and response rate (RR) in radioactive-iodine refractory DTC. The aim of this biomarker study was to identify RNA expression profiles related with PFS, overall survival (OS) and RR and to describe the expression profiles of DTC histologies. Methods: Of the 417 patients in the trial, 247 had sufficient formalin fixed paraffin embedded archival tumor material for RNAseq. We generated on average 77 million paired-end reads for each sample on HiSeq2000 (Illumina). RNAseq reads were mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameters. 125 samples had sufficient quality to be included in the analysis. Results: The analysis subset included 68 sorafenib and 57 placebo patients (PFS 10.3 vs 7.4 months, HR: 0.62 CI 95% 0.38-0.99, p = 0.046). Unsupervised clustering using the 100 most variable genes identified 3 groups: BRAF-like (included most of the BRAF-mutated tumors), RAS-like (included most of the RAS mutated tumors) and non-BRAF-non-RAS-like group (included most wild-type tumors). These groups, based on the mutational profile, can be correlated with tumor type: the papillary BRAF-mutant, the follicular wild-type, and a third group with papillary, follicular and poorly differentiated with predominant RAS mutations. A Student t-test comparing papillary and follicular histologies revealed a signature of 283 genes with significantly different expression that, within the papillary tumors, identifies a subset with an expression profile more similar to follicular. No RNA signatures correlating with benefit from sorafenib were identified. Conclusions: While papillary and follicular thyroid cancers have significantly different RNA expression profiles, a subset of papillary has been identified with an expression profile more similar to follicular. In addition, a unified RAS-like expression profile spans subsets of papillary, follicular, and poorly differentiated thyroid cancers, suggesting that tumor biology can be similar across histologies. Clinical trial information: NCT00984282.
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Carpen, Olli, Annika Ålgars, Jari Sundström, Soili Kytölä, Pia Österlund, Minnamaija Lintunen, Terhi Jokilehto, et al. "EGFR gene copy number to predict response to anti-EGFR treatment and survival in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer." Journal of Clinical Oncology 34, no. 15_suppl (May 20, 2016): e15108-e15108. http://dx.doi.org/10.1200/jco.2016.34.15_suppl.e15108.
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Harle, Alexandre, Celine Gavoille, Olivier Bouche, Meher Ben Abdelghani, Jérôme Edouard Plaza, Aurélien Lambert, Dominique Spaeth, et al. "cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3542. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3542.
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3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.
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Madanahally Divakar, Kiran, Alvin Concepcion, Jessica Shea, Smriti Gupta, and Lilly Kong. "Sensitive, specific, and modular KRAS, NRAS, and BRAF assays for simultaneous detection of 30 important point mutations in colorectal cancer specimens." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 547. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.547.
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547 Background: Point mutations in KRAS, NRAS, and BRAF are implicated in the oncogenic RAS/RAF/MEK/ERK pathway and are prognostic and predictive markers in treating metastatic colorectal cancer patients. Here, we report the performance of three single tube highly multiplex and modular KRAS/NRAS/BRAF Assays capable of detecting 30 point mutations from FFPE-extracted DNA on the fully automated Modaplex System. Methods: Primers for multiplex KRAS/NRAS/BRAF Assays to detect 13, 13, and 4 point mutations for KRAS, NRAS, and BRAF genes, respectively, were designed using proprietary technology. Analytical sensitivity of each mutation was assessed using mutation specific ultramer oligos or Horizon Dx Mockblock specimens. Analytical specificity was determined on known wild-type FFPE DNAs. The assays were tested on DNA extracted from clinical FFPE specimens that were characterized by pyrosequencing. Modaplex data on these specimens were compared to pyrosequencing for concordance. Results: The modular Modaplex KRAS/NRAS/BRAF point mutation panels detect and differentiate 30 mutations in the KRAS, NRAS, and BRAF genes in three wells. Each assay requires just 5 µL of clinical sample extract (10-50ng DNA per assay) with a setup time of 15-30 minutes. The total run time including data analysis and setup is 4 hours. The kit includes an internal control to determine mutation status; and calibration controls to determine amplicon size. Analytical studies demonstrate the assays are sensitive (number of copies detected in one reaction), selective (mutant to wild-type ratio), and specific (relative to wild-type genomic DNA background). Nearly 110 clinical FFPE samples were tested, and the assays showed more than 95% concordance with pyrosequencing method (98% for BRAF, 97% for KRAS, and 100% for NRAS). Conclusions: Modaplex KRAS/NRAS/BRAF assays provide an accurate and sensitive method of mutation detection. These automated multiplexed assays to detect key mutations in three genes can be performed on a single platform facilitating clinical or translational research. *Modaplex KRAS/NRAS/BRAF Assays are for Research Use Only. Not for clinical diagnostic use.
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Lowe, Kimberly, Tamer Garawin, Michael Anthony Kelsh, and Gerry C. Bohac. "Assessment of treatment with panitumumab, cetuximab, and bevacizumab among mCRC patients with wild-type RAS or BRAF treated at community cancer centers in the United States." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 663. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.663.
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663 Background: There is limited observational data on the use of RAS test results and treatment patterns with chemotherapy and biologics among metastatic colorectal cancer (mCRC) patients. Our objective was to use real world data to evaluate the treatment sequences of mCRC patients who have wild-type RAS (KRAS, NRAS), or BRAF and who are treated at community cancer clinics within the United States (U.S.). Methods: The sample included 536 patients in the Oncology Services Comprehensive Electronic Records (OSCER) database who were diagnosed with mCRC between 1/1/2011 and 8/31/2015. All patients had available treatment data and were confirmed to have wild-type RAS or BRAF. Patients were stratified into mutually-exclusive categories based on 1st line treatment with chemotherapy in combination with either bevacizumab (Bmab), cetuximab (Cmab), panitumumab (Pmab), a combination of Pmab, Cmab or Bmab, or no biologics. Descriptive statistics were used to summarize the data. Results: The demographics of the sample were as follows: mean age 67 years (standard deviation = 12), 55% male, 70% White, and 50% with ECOG value of zero. The use of Bmab, Cmab, or Pmab in combination with chemotherapy in 1st line treatment was follows: Bmab only (n = 270, 50%), Cmab only (n = 81, 15%), Pmab only (n = 28, 5%), and a combination of either Bmab, Cmab and/or Pmab (n = 6, 1%). No biologics were administered to 151 (28%) of the sample in 1st line. There were no statistically significant differences in age, gender, race, insurance type, region of the U.S. or ECOG status at mCRC diagnosis across the 1st line treatment categories. Of the 385 patients who received a biologic in 1st line, 94 (24%) of those who survived and selected to continue treatment received a biologic in 2nd line. Of these 94 patients, 25 (27%) of those who survived and selected to continue treatment also received a biologic in 3rd line. Conclusions: Bmab was the most commonly-used biologic among mCRC patients with wild-type RAS or BRAF in this descriptive study. Future research is needed to better understand what factors impact treatment decisions among mCRC patients.
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Braghiroli, Maria Ignez Freitas Melro, Garrett Michael Nash, Martin Morris, Jaclyn Frances Hechtman, Efsevia Vakiani, Michael F. Berger, David B. Solit, Leonard Saltz, and Andrea Cercek. "Genomic profiling and efficacy of anti-EGFR therapy in appendiceal adenocarcinoma." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 574. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.574.
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574 Background: Metastatic appendiceal adenocarcinoma (AAC) is a heterogenous disease and the majority of patients present with diffuse metastases in the peritoneal cavity. Cytotoxic and targeted therapies are typically extrapolated from colorectal adenocarcinoma (CRC), however, it is not known whether this is effective or not. Herein we investigated the genetic profiles of these tumors in an effort to identify molecular characteristics and potentially actionable mutations, as well as the response to anti-EGFR therapy in RAS/BRAF wild type (wt) AAC. Methods: We identified patients (pts) with ACC treated at MSKCC who had tumor who had undergone molecular profiling, either by next generation sequencing using our MSK-IMPACT platform, or by MALDI-TOF mass spectroscopy genotyping (Sequenom). MSK-IMPACT tumors and matched normal samples were analyzed either on 410 gene panel. Sequenom (provided an 8 gene panel including KRAS, NRAS, BRAF, and PIK3CA). Via an IRB approved waiver, we collected tumor histology and evaluated pts who were RAS/RAF wt and had been treated with anti-EGFR therapy. Results: We identified a total 97 AAC pts, of whom 60 had Sequenom testing and 37 had IMPACT. Among pts analyzed with IMPACT, 24 had mucinous adenocarcinoma, 3 adenocarcinoma with signet ring, 7 adenocarcinoma ex goblet cell carcinoid, 3 invasive adenocarcinoma. In total 159 alterations were identified with a median 4.2 alterations/patient (range 0-10). Alterations were seen most commonly in KRAS (21/37), GNAS (12/37), TP53 (10/37), SOX9 (5/37), and SMAD4 (4/37). Potentially treatable alterations were present in 15% of patients and included BRAF V600E (1), MTOR (2), ERBB2 (1) and NTRK(2). Of the total 97 pts, 50 (52%) were RAS/BRAF wt. Of those,13 evaluable patients received anti-EGFR therapy with either panitumumab or cetuximab. There were no responders. Conclusions: Mutational sequencing in AAC indicates that 16% have mutations in genes such as BRAFV600E, MTOR, ERBB2 and NTRK with the potential to expand investigational options through increased access to trials of selectively targeted agents. Additionally, in RAS/BRAF wt pts, panitumumab/cetuximab does not appear to have therapeutic efficacy comparable to historic controls in RAS/RAF wt CRC.