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  • 1
    Online Resource
    Online Resource
    Circulating inflammation signature predicts overall survival and relapse-free survival in metastatic colorectal cancer
    Springer Science and Business Media LLC ; 2019
    In:  British Journal of Cancer Vol. 120, No. 3 ( 2019-2), p. 340-345
    Details
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 120, No. 3 ( 2019-2), p. 340-345
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
    URL: Article
    DOI: 10.1038/s41416-018-0360-y
    RVK:
    XA 33500
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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  • 2
    Online Resource
    Online Resource
    Abstract 2924: Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2924-2924
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2924-2924
    Abstract: Malignant tumors shed cell free DNA into the blood stream. Analyzing this new biological source may have important implications in a shift towards personalized medicine for diagnosing and/or monitoring malignancies. We recently showed the first clinical validation and clinical utility of circulating DNA (cfDNA) analysis in oncology by testing RAS/BRAF hotspot mutations in plasma from metastatic colorectal cancer patients (mCRC) (Nat Med. 2014 Apr;20(4):430-5). In addition, liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. We evaluated under blinded conditions the ability of cfDNA to detect RAS/BRAF mutations in the plasma of 42 mCRC patients treated on a phase Ib/II trial of FOLFOX and dasatnib, with or without cetuximab. Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay was able to detect mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 22 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (50%) developed a second mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) developed new mutations. Patients may harbor mutations at very low frequency down to 0.01% before initiation or during treatment revealing the need of a high sensitive technique to detect mutant subclones. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Combined qualitative and quantitative cfDNA analysis allows tracking acquired resistance by studying the real-time clonal evolution of the tumor and might help physicians to adjust patient treatment. Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern. Note: This abstract was not presented at the meeting. Citation Format: Alain R. Thierry, Brice Pastor, Zhi-Qin Camilla Jiang, anastasia Katsiampoura, Christine Parseghian, Jonathan Loree, Michael J. Overman, Cynthia Sanchez, Safia El Messaoudi, Marc Ychou, Scott Kopetz. Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2017-2924
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2924
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
    Online Resource
    Online Resource
    Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 16 ( 2017-08-15), p. 4578-4591
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 16 ( 2017-08-15), p. 4578-4591
    Abstract: Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. Experimental Design: We evaluated under blinded conditions the ability of cell-free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results: Prior to treatment, sequencing of archival tissue detected mutations in 25 of 42 patients (60%), while the cfDNA assay detected mutations in 37 of 42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41 of 42 patients (98%) had a cfDNA-detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild-type tumors at baseline, 4 of 5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation. Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had preexisting mutations in the pathway, demonstrating a convergent evolutionary pattern. Clin Cancer Res; 23(16); 4578–91. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-0232
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
    Online Resource
    Online Resource
    Association Between Intraoperative Dexamethasone and Postoperative Mortality in Patients Undergoing Oncologic Surgery : A Multicentric Cohort Study
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Annals of Surgery Vol. 278, No. 1 ( 2023-07), p. e105-e114
    Details
    In: Annals of Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 278, No. 1 ( 2023-07), p. e105-e114
    Abstract: We examined the effects of dexamethasone on postoperative mortality, recurrence-free survival, and side effects in patients undergoing oncologic operations. Background: Dexamethasone prevents nausea and vomiting after anesthesia and may affect cancer proliferation. Methods: A total of 30,561 adult patients undergoing solid cancer resection between 2005 and 2020 were included. Multivariable logistic regression was applied to investigate the effect of dexamethasone on 1-year mortality and recurrence-free survival. Effect modification by the cancer’s potential for immunogenicity, defined as a recommendation for checkpoint inhibitor therapy based on the National Comprehensive Cancer Network guidelines, was investigated through interaction term analysis. Key safety endpoints were dexamethasone-associated risk of hyperglycemia 〉 180 mg/dL within 24 hours and surgical site infections within 30 days after surgery. Results: Dexamethasone was administered to 38.2% (11,666/30,561) of patients (6.5±2.3 mg). Overall, 3.2% (n=980/30,561) died and 15.4% (n=4718/30,561) experienced cancer recurrence within 1 year of the operation. Dexamethasone was associated with a −0.6% (95% confidence interval: −1.1, −0.2, P =0.007) 1-year mortality risk reduction [adjusted odds ratio (OR adj ): 0.79 (0.67, 0.94), P =0.009; hazard ratio=0.82 (0.69, 0.96), P =0.016] and higher odds of recurrence-free survival [OR adj : 1.28 (1.18, 1.39), P 〈 0.001]. This effect was only present in patients with solid cancers who were defined as not to respond to checkpoint inhibitor therapy [OR adj : 0.70 (0.57, 0.87), P =0.001 vs OR adj : 1.13 (0.85, 1.50), P =0.40]. A high ( 〉 0.09 mg/kg) dose of dexamethasone increased the risk of postoperative hyperglycemia [OR adj : 1.55 (1.32, 1.82), P 〈 0.001], but not for surgical site infections [OR adj : 0.84 (0.42, 1.71), P =0.63]. Conclusions: Dexamethasone is associated with decreased 1-year mortality and cancer recurrence in patients undergoing surgical resection of cancers that are not candidates for immune modulators. Dexamethasone increased the risk of postoperative hyperglycemia, however, no increase in surgical site infections was identified.
    Type of Medium: Online Resource
    ISSN: 0003-4932
    URL: Article
    DOI: 10.1097/SLA.0000000000005526
    RVK:
    XA 23900
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 5
    Online Resource
    Online Resource
    Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 15 ( 2017-08-01), p. 4146-4154
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 15 ( 2017-08-01), p. 4146-4154
    Abstract: Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT. FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort. Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies. Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146–54. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-3138
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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