Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions

Singh, Harshabad; Li, Yvonne Y.; Shinagare, Atul B.; Abhyankar, Ritika; Reilly, Emma; Brais, Lauren K.; Nag, Anwesha; Ducar, Matthew D.; Thorner, Aaron R.; Shapiro, Geoffrey I.; Keller, Rachel B.; Siletti, Cheta; Clark, Jeffrey W.; Farago, Anna F.; Lin, Jessica J.; Demetri, George D.; Gujrathi, Rahul; Kulke, Matthew H.; MacConaill, Laura E.; Ligon, Azra H.; Sicińska, Ewa; Meyerson, Matthew; Meyerhardt, Jeffrey A.; Cherniack, Andrew D.; Wolpin, Brian M.; Ng, Kimmie; Giannakis, Marios; Hornick, Jason L.; Cleary, James M.

doi:10.1158/1078-0432.ccr-20-4073

Cited by 26 publications

(40 citation statements)

References 49 publications

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“…We assembled an international data set of 13 published 5,[12][13][14][15] (n = 6) and nonpublished (n = 7) cases of ALK fusionpositive GI cancer patients treated with ALKi. We collected information about social and demographic characteristics of patients, primary tumor site and histology, ALK fusion partner or site of breakpoint, microsatellite status, or other baseline next-generation sequencing (NGS)/mutational data.…”

Section: Patient Populationmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] ALK fusion-positive metastatic colorectal cancers (mCRCs) define a distinct rare subtype together with ROS1 and NTRK rearranged mCRC, characterized by older age at diagnosis, right-sided primary tumor location, RAS and BRAF wild-type status, microsatellite instability high, lymph node spreading, and evidence of significantly worse survival. 11,12 In a series of patients with resected gastric cancer, ALK overexpression (by immunohistochemistry [IHC] with cytoplasmic staining positivity set at ≥ 10% tumor cells) was found in 8.4% of samples and was associated with signet ring cell component and young age, as well as worse disease-free survival and overall survival (OS). 6 Pancreatic cancers with ALK fusions, most frequently with EML4 as the partner gene, may be associated with young onset (, 50 years), male sex, and KRAS wild-type status.…”

Section: Introductionmentioning

confidence: 99%

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ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

Ambrosini

Manca

et al. 2022

JCO Precision Oncology

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PURPOSE In GI cancers, anaplastic lymphoma kinase ( ALK) rearrangements are extremely less frequent than in non–small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis. RESULTS Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response). CONCLUSION Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion–positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.

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Section: Patient Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

Ambrosini

Manca

et al. 2022

JCO Precision Oncology

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“…NCT02370238). An institution-based comprehensive cancer MGP (OncoPanel; Eurofins Panlabs, Inc. , St. Charles, MO, USA) has a sensitivity of 74% to 98% for detection of SNPs, insertions-deletions, copy number variations, and structural variants across 282 genes considered to have roles as pan-cancer drivers [ 76 ]. OncoPanel was used to identify receptor tyrosine kinase (RTK) fusions occurring exclusively in KRAS , NRAS , and BRAF wild-type CRCs, which play critical roles in CRC oncogenesis, predicting likely response to epidermal growth factor receptor-directed therapeutics.…”

Section: Genetic Testsmentioning

confidence: 99%

Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer

Kim

Bodmer

2021

Ann Coloproctol

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The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.

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“…There are also rare instances of druggable gene rearrangements in microsatellite stable cancers[ 75 , 76 ]. CRCs carrying activating gene fusions are responsive to the administration of appropriate tyrosine kinase inhibitors[ 78 , 79 ].…”

Section: Markers For the Choice Of Systemic Therapymentioning

confidence: 99%

Molecular testing for colorectal cancer: Clinical applications

Imyanitov¹,

Kuligina²

2021

WJGO

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Molecular genetic analysis is an integral part of colorectal cancer (CRC) management. The choice of systemic therapy for CRC is largely based on the results of tumor molecular testing. Evaluation of the KRAS and NRAS gene status is mandatory for consideration of anti-epidermal growth factor receptor (EGFR) therapy. Tumors with the BRAF V600E substitution are characterized by aggressive behaviour, may require intensified cytotoxic regimens and benefit from combined BRAF and EGFR inhibition. The inactivation of DNA mismatch repair (MMR), or MUTYH gene, or DNA polymerase epsilon results in excessive tumor mutational burden; these CRCs are highly antigenic and therefore sensitive to immune checkpoint inhibitors. Some CRCs are characterized by overexpression of the HER2 oncogene and respond to the appropriate targeted therapy. There are CRCs with clinical signs of hereditary predisposition to this disease, which require germline genetic testing. Liquid biopsy is an emerging technology that has the potential to assist CRC screening, control the efficacy of surgical intervention and guide disease monitoring. The landscape of CRC molecular diagnosis is currently undergoing profound changes due to the increasing use of next generation sequencing.

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Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions

Cited by 26 publications

References 49 publications

ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer

Molecular testing for colorectal cancer: Clinical applications

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