Prognostic Value of ACVRL1 Expression in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy With Bevacizumab: Results From the Triplet Plus Bevacizumab (TRIBE) Study.

Hanna, Diana L; Loupakis, Fotios; Yang, Dongyun; Cremolini, Chiara; Schirripa, Marta; Li, Meng; Matsusaka, Satoshi; Berger, Martin Dave; Miyamoto, Yuji; Zhang, Wu; Ning, Yan; Antoniotti, Carlotta; Salvatore, Lisa; Moran, Miriana; Zeger, Gary; Astrow, Stephanie H; Falcone, Alfredo; Lenz, Heinz-Josef (2018). Prognostic Value of ACVRL1 Expression in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy With Bevacizumab: Results From the Triplet Plus Bevacizumab (TRIBE) Study. Clinical colorectal cancer, 17(3), e471-e488. Elsevier 10.1016/j.clcc.2018.03.006

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No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-β receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study.


Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database.


High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages.


ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Berger, Martin Dave


600 Technology > 610 Medicine & health








Rebeka Gerber

Date Deposited:

28 Feb 2019 14:38

Last Modified:

03 Nov 2019 09:22

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Activin receptor like-protein 1 Angiogenesis Biomarker Prognostic mCRC




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