Limitations of Genomic Models

The commentary also notes that the contemporary use of tissue-based genomic profiling to improve risk stratification may not capture subclonal disease heterogeneity. “Comprehensive genomic profiling of plasma cell-free circulating tumor DNA (ctDNA) is an alternative approach that affords the advantage of capturing subclonal heterogeneity because tumor DNA is shed into circulation by cells from both primary and metastatic sites,” they note.7


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They suggest the development of prognostic and predictive models based on detecting and profiling ctDNA. “Future studies incorporating molecular markers into prognostic models need to be prospective, use contemporary tumor tissue or ctDNA, and assess improvements across different models,” they observed.7

Issues for Clinical Implementation

Implementation of genomically annotated risk stratification in routine clinical practice is a challenge, acknowledged the researchers.3

They observed that panel testing for mutation profiling is gaining momentum and acceptance and is available to clinicians through institutional or commercial assays. The addition of defined mutational signatures to current panels can be adopted by clinicians in routine clinical practice, they suggested.

“The sequencing that went into this is not highly sophisticated and is available commercially to any clinician,” Dr Voss said.

The commentary points out that the MSKCC genomically annotated risk stratification may have come at an inappropriate time, as allocation to regimens such as nivolumab plus ipilimumab is predicted for those who meet the intermediate- or poor-risk classification based on IMDC criteria.7 

“With this development in mind, the genomic markers assessed by Voss and colleagues could warrant reassessment in the context of the studies that are leading to approval of these regimens.”7 Until this happens the use of the IMDC criteria (without genomic markers) will probably prevail, they concluded.

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Dr Gyawali told Cancer Therapy Advisor that the genomically annotated MSKCC prognostication model was not yet ready for clinical practice. “It needs to be prospectively validated before it can be integrated into clinical practice,” he said. “What we do not know is whether this model has therapeutic implications or whether it is only of prognostic significance.”

“As of now, there are no drugs that target the mutations [the researchers have included in their model] and currently this model is of potential prognostic value,” he added.

Dr Uzzo agreed that the genomically annotated MSKCC risk stratification model is not ready for clinical use and does not have wide applicability. “We all would like to be able to predict how a patient will respond to a given treatment and will increasingly be using mutational analysis. Unfortunately, we still have a lot to learn and a long way to go,” he said.

“The appeal is broad, but the use for now is research-limited and not ready for clinical prime time,” Dr Kohli said. “Once validated and especially if the C-index improves further, the clinical application would be quite broad,” he added.

Dr Voss disagreed with Dr Kohli’s conclusion. He explained that the models that are currently used, which include the MSKCC and IMDC models, were based on retrospective cohort data and did not receive prospective validation. “The genomically annotated MSKCC model has been validated with an external dataset and is ready for clinical practice,” he countered. “However, it cannot be used in the treatment setting for immunotherapies, as the datasets used were in patients [who] were treated with targeted therapies,” he cautioned.

References

  1. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530-2540.
  2. Memorial Sloan-Kettering Cancer Center (MSKCC/Motzer) score for metastatic renal cell carcinoma (RCC). https://www.mdcalc.com/memorial-sloan-kettering-cancer-center-mskcc-motzer-score-metastatic-renal-cell-carcinoma-rcc. Accessed December 13, 2018.
  3. Voss MH, Reising A, Cheng Y, et al. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol. 2018;19(12):1688-1698.
  4. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148.
  5. de Velasco G, Culhane AC, Fay AP, et al. Molecular subtypes improve prognostic value of international metastatic renal cell carcinoma database consortium prognostic model. Oncologist. 2017;22(3):286-292.
  6. Zurita AJ, Gagnon RC, Liu Y, et al. Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma. Br J Cancer. 2017;117(4):478-484.
  7. Agarwal N, Nussenzveig R, Pal SK. Biomarkers in renal-cell carcinoma: building on clinical paradigms. Lancet Oncol. 2018;19(12):1560-1561.
  8. The US Food and Drug Administration. FDA approves nivolumab plus ipilimumab combination for intermediate or poor risk advanced renal cell carcinoma. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm. Updated April 16, 2018. Accessed December 13, 2018.