Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

Abstract

BackgroundMolecular 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.MethodsWe 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.ResultsA 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.ConclusionsWe 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.Trial registrationEuropean 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0729-9) contains supplementary material, which is available to authorized users.

Imaging for the diagnosis and response assessment of renal tumours

“…A radiomic approach synthesising results from a combination of imaging modalities may play a role in future [97]. Recently, Crusz et al noted that in a group of 27 patients with metastatic RCC receiving tyrosine kinase inhibitors, over 50% of individuals demonstrated heterogeneous responses to therapy (defined as lesions in at least two of the following three response categories: responding, progressing and stable), potentially reflecting molecular intra-tumoral heterogeneity [98]. This may have important implications for clinical decision making, such as the choice to continue therapy in individuals with heterogeneous responses.…”

Tumour response in metastatic renal cell carcinoma treated with tyrosine kinase inhibitors – assessment of intra-tumour heterogeneity

“…The underlying tumour biology demonstrates that the majority of somatic gene mutations are not ubiquitously present within a tumour, but is rather characterised by the existence of subclones derived from a common clonal progenitor, with variations between different regions of the same tumour and metastases [2]. As a clinical result, metastatic lesions of the same patients might show heterogeneous progression patterns in radiologic imaging due to different drug sensitivity as reported by Crusz et al [11]. Currently, the RECIST 1.1 classification is widely used to determine response assessment, but does not acknowledge phenotypic ITH.…”

“…In a recent article, Crusz et al [11] hypothesized that the molecular ITH is mirrored by clinical heterogeneity, observed by a subset of metastases responding and progressing within the same patient. In their study, a radiological analysis of patients with two or more assessable metastatic lesions that progressed under therapy with anti-angiogenic TKIs (sunitinib or pazopanib), based on the population of three similar phase II trials, was performed.…”

“…Thus, the identification of cancer types with a respective heterogeneous response pattern is likely to influence clinical decision-making and, therefore, clinical outcome. As shown, a clinical ITH was observed for mRCC upon sunitinib or pazopanib treatment [11]. The occurrence of new lesions, which was the main cause for the definition of progression, questions the applicability of the currently used RECIST 1.1 criteria, particularly considering that progression-free survival, which is one of the main parameters in the assessment of clinical trials, is presently determined by RECIST 1.1 analysis.…”

“…According to this definition, if new, small metastatic lesions occur (defined as PD by RECIST) while the bulk of the disease remains controlled, therapy should not be changed, but rather should be continued. The immune-related response criteria acknowledge heterogeneous response patterns, although their underlying principle is an immune-related event defined as pseudoprogression [10] and not, as shown by Crusz et al [11], of ITH. Likewise, novel imaging approaches like functional imaging, but also the adjustment of current response criteria, which do not automatically consider the appearance of new lesions as a PD, could further assist to detect metastases that differ in their individual biological characteristics.…”