title: Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.
abstract: Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient.
  
  
  
  We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed.
  
  
  
  A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions.
  
  
  
  We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours' phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation.
  
  
  
  European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Shanthini M
authors.initials: SM
authors.lastname: Crusz
authors.affiliation: Department of Radiology, St Bartholomews Hospital, London, UK.
authors.forename: Yen Zhi
authors.initials: YZ
authors.lastname: Tang
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Shah-Jalal
authors.initials: SJ
authors.lastname: Sarker
authors.affiliation: Departments of Surgical and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Warner
authors.initials: W
authors.lastname: Prevoo
authors.affiliation: Institute of Nuclear Medicine, University College Hospital, London, UK.
authors.forename: Irfan
authors.initials: I
authors.lastname: Kiyani
authors.affiliation: Department of Surgery, Whipps Cross Hospital, London, UK.
authors.forename: Luis
authors.initials: L
authors.lastname: Beltran
authors.affiliation: Department of Surgery, Whipps Cross Hospital, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Peters
authors.affiliation: Department of Radiology, St Bartholomews Hospital, London, UK.
authors.forename: Anju
authors.initials: A
authors.lastname: Sahdev
authors.affiliation: Departments of Surgical and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK. marco.gerlinger@icr.ac.uk.|The Royal Marsden Hospital, London, UK. marco.gerlinger@icr.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Anti-angiogenic treatment; Drug resistance; Intratumour heterogeneity; Kidney cancer; RECIST