title: Vasoactive peptides associate with treatment outcome ofbevacizumab-containing therapy in metastatic colorectal cancer.
abstract: BACKGROUND
  Hypertension is a common early adverse event of anti-angiogenic treatment of cancer and may associate with treatment response. However, blood pressure measurement as a surrogate response biomarker has methodological limitations, and predictive biomarkers of angiogenesis inhibitors are lacking. In disease associated with hypertension, vasoactive peptides have been linked to cardiovascular pressure load. Here, we have explored potential associations between circulating levels of vasoactive peptides and tumor response during bevacizumab-containing treatment of colorectal cancer.
  
  
  METHODS
  Metastatic colorectal cancer (mCRC) patients with available best objective response (ORR) and time to tumor progression (TTP) data were included from a randomized clinical trial investigating maintenance therapy after first line chemotherapy plus bevacizumab. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial-natriuretic-peptide (MR-proANP), and C-terminal-prepro-vasopressin (Copeptin) vasoactive peptide concentrations were measured in plasma at baseline and after 6 weeks of chemotherapy and bevacizumab treatment (n = 97). We determined associations among clinical outcome (ORR and TTP), peptide levels, and hypertension (NCI-CTCAE 4.0 criteria), using Spearman's test, multiple linear regression, and Mann-Whitney's test.
  
  
  RESULTS
  Increasing levels of vasoactive peptides from baseline and after six weeks of treatment were associated with improved treatment outcome (MR-proADM: ORR, p = .0003; TTP, p = .05; MR-proANP: ORR, p = .05; TTP, p = .03; Copeptin: ORR, p = .10; TTP, p = .02). Patients with increasing levels of all three peptides (n = 28) versus increasing levels of one or two peptides (n = 59) showed a median TTP of 284 and 225 d, respectively (p = .02).
  
  
  CONCLUSIONS
  Our results suggest that increasing systemic levels of vasoactive peptides associate with improved tumor response and TTP in mCRC patients treated with a bevacizumab-containing regimen. These findings support the proposed link between the tumor vasculature and the cardiovascular system of the host. This should motivate further studies that investigate the potential role of vasoactive peptides as a novel class of dynamic biomarkers in the treatment of cancer.
authors.affiliation: a Department of Clinical Sciences Lund, Section of Oncology and Pathology , Lund University , Lund , Sweden.|b Department of Oncology , County Hospital Ryhov , Jönköping , Sweden.
authors.forename: Helga
authors.initials: H
authors.lastname: Hagman
authors.affiliation: a Department of Clinical Sciences Lund, Section of Oncology and Pathology , Lund University , Lund , Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: c Department of Clinical Sciences Malmö, Section of Hypertension and Cardiovascular Disease , Lund University , Malmö , Sweden.|d Department of Emergency Medicine, Skåne University Hospital , Malmö , Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: e Department of Oncology , Skåne University Hospital , Lund , Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Sundberg
authors.affiliation: a Department of Clinical Sciences Lund, Section of Oncology and Pathology , Lund University , Lund , Sweden.|e Department of Oncology , Skåne University Hospital , Lund , Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johnsson
authors.affiliation: a Department of Clinical Sciences Lund, Section of Oncology and Pathology , Lund University , Lund , Sweden.|e Department of Oncology , Skåne University Hospital , Lund , Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
mesh_terms: D053607:Adrenomedullin / Q000097:blood*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D009320:Atrial Natriuretic Factor / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006020:Glycopeptides / Q000097:blood*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011498:Protein Precursors / Q000097:blood*; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006020:Glycopeptides; D011498:Protein Precursors; C048197:copeptins; C088633:proadrenomedullin; D053607:Adrenomedullin; D009320:Atrial Natriuretic Factor; C527517:ofatumumab