Integrated Analysis of Molecular and Clinical Prognostic Factors in Stage II/III Colon Cancer

Roth, Arnaud; Delorenzi, Mauro; Tejpar, Sabine; Yan, Ping; Klingbiel, Dirk; Fiocca, Roberto; Giorgini, Dario; Cisar, Laura A.; Labianca, Roberto; Cunningham, David; Nordlinger, Bernard; Bosman, Fred T.; Cutsem, Éric Van

doi:10.1093/jnci/djs427

Cited by 233 publications

(173 citation statements)

References 32 publications

(37 reference statements)

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“…This subtype has predilection to right colon and often shows mucinous differentiation and MSI phenotype, as seen also in the index case. MSI colorectal carcinoma are found in 10% to 15% and usually exhibit an indolent clinical behavior and are less prevalent in more advanced stages of the disease, accounting for <5% in the metastatic setting (5,39). Identification of ALK-rearranged subtype of MSI colorectal carcinoma may define a distinct aggressive subtype of MSI colorectal carcinoma, which may benefit from targeted therapy with ALK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Yakirevich

Resnick

Mangray

et al. 2016

Clinical Cancer Research

109

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Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40.Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Yakirevich

Resnick

Mangray

et al. 2016

Clinical Cancer Research

109

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“…This highlights the possibility that the mechanism responsible for CRC is highly relevant with regards to choosing appropriate therapy and patient outcomes. Though, it must be noted that the criteria for making the diagnosis of Lynch syndrome used in this particular instance were dMMR, age at adjuvant study randomization and BRAF mutation status as opposed to germline analysis (Roth et al, 2012;Saridaki et al, 2014).…”

Section: Universal Screeningmentioning

confidence: 99%

“…In prospectively col- (Andre et al, 2015;Gavin et al, 2013;Guastadisegni et al, 2010;Klingbiel et al, 2015;Popat et al, 2005;Roth et al, 2012;Sinicrope et al, 2015). lected tumor tissue MSI was detected in 314 of 2580 stage-III CRCs and was prognostic overall for time to relapse (TTR), but not for DFS or OS (Sinicrope et al, 2013a).…”

Section: Msi As a Biomarker With Cetuximab Adjuvant Therapymentioning

confidence: 99%

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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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“…For instance, colorectal cancer (CRC) cell lines ordinarily used in preclinical studies often display microsatellite instability (MSI). MSI colorectal tumours are found in 10-15% patients 5 , but they show an indolent clinical behaviour and are less prevalent in more advanced stages of the disease, accounting for o5% in the metastatic setting 6,7 . Consequently, MSI cell lines do not properly recapitulate the clinical setting in which targeted agents are most commonly administered to CRC patients.…”

mentioning

confidence: 99%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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The development of molecularly targeted anticancer agents relies on large panels of tumourspecific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

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Integrated Analysis of Molecular and Clinical Prognostic Factors in Stage II/III Colon Cancer

Abstract: Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.

Cited by 233 publications

References 32 publications

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

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