Crusz, S. M., Tang, Y. Z., Sarker, S. J., Prevoo, W., Kiyani, I., Beltran, L., Peters, J., Sahdev, A., Bex, A., Powles, T., Gerlinger, M. (2016) Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma. BMC MEDICINE, 14. ISSN 1741-7015

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Abstract

Background: 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. Methods: We performed a retrospective central radiological analysis of patients with treatment-naive 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. Results: 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. Conclusions: 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.

Item Type:	Article
Authors (ICR Faculty only):	Gerlinger, Marco
All Authors:	Crusz, S. M., Tang, Y. Z., Sarker, S. J., Prevoo, W., Kiyani, I., Beltran, L., Peters, J., Sahdev, A., Bex, A., Powles, T., Gerlinger, M.
Additional Information:	ISI Document Delivery No.: EB9QJ Times Cited: 0 Cited Reference Count: 27 Crusz, Shanthini M. Tang, Yen Zhi Sarker, Shah-Jalal Prevoo, Warner Kiyani, Irfan Beltran, Luis Peters, John Sahdev, Anju Bex, Axel Powles, Thomas Gerlinger, Marco NIHR; Cancer Research UK; UCLH Experimental Cancer Centre; UCLH NIHR Biomedical Research Centre; Prostate Cancer UK; Prostate Cancer Foundation; Schottlander Research Charitable Trust; Royal Marsden NIHR Biomedical Research Centre for Cancer; Wellcome Trust [105104/Z/14/Z]; Cancer Research UK (the Experimental Cancer Medicine Centre) SC was funded by fellowships from NIHR and Cancer Research UK. IK was funded by the UCLH Experimental Cancer Centre and UCLH NIHR Biomedical Research Centre. TP was funded by grants from Cancer Research UK (the Experimental Cancer Medicine Centre). MG was funded by grants from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Schottlander Research Charitable Trust, the Royal Marsden NIHR Biomedical Research Centre for Cancer and the Wellcome Trust (grant number: 105104/Z/14/Z). 0 BIOMED CENTRAL LTD LONDON BMC MED
Uncontrolled Keywords:	Anti-angiogenic treatment Drug resistance Intratumour heterogeneity Kidney cancer RECIST RANDOMIZED PHASE-3 TRIAL INTRATUMOR HETEROGENEITY ANTIANGIOGENIC THERAPY TARGETED THERAPIES INTERFERON-ALPHA SUNITINIB CANCER SORAFENIB PAZOPANIB EVOLUTION
Research teams:	ICR divisions > Molecular Pathology > Centre for Evolution and Cancer ICR divisions > Molecular Pathology > Translational Oncogenomics
Depositing User:	Barry Jenkins
Date Deposited:	12 Dec 2016 10:41
Last Modified:	12 Dec 2016 10:41
URI:	http://publications.icr.ac.uk/id/eprint/15522

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