Therapeutic side effects may also be used as biomarkers. For example, mTOR inhibitors (mTORi), such as everolimus and temsirolimus—which are frequently used in RCC—have a significant side effect profile, including nausea, diarrhea, mucositis, skin rash lymphopenia, elevated cholesterol and triglycerides, anemia, and pulmonary toxicity.9 Pneumonitis is, interestingly, a “biomarker” for better clinical outcomes among patients receiving everolimus and temsirolimus.
To further evaluate the role of toxicities as a potential biomarker for disease response, one group retrospectively reviewed data from 75 patients with metastatic RCC receiving an mTORi. Patients with the highest onset rate of hyperglycemia and hypophosphatemia had the highest progression-free survival. Progression-free survival was lower among those patients with the quicker onset of lymphopenia. Other studies showed that patients who develop hypertension and hypothyroidism while receiving bevacizumab or sunitinib have better overall RCC outcomes.
As the world of biomarkers in RCC continues to develop, there is no consensus among the urologic and oncology societies on which biomarker(s), if any, should be routinely ordered. The American Urological Association even recommended against the routine use of biomarkers (such as Ki-67, p-53 and VEGF) in a 2013 guideline.10 The European Society of Medical Oncology (ESMO) does not mention biomarkers at all in their 2016 guidelines.11 These guidelines could lead to either under-utilization or a “shotgun” approach, where a multitude of biomarkers are unnecessarily ordered.
As more data regarding biomarkers accumulate, there may be a way to combine several biomarkers into one “panel” that could provide the best outcomes data for patients. One research group derived a biomarker panel that consisted of 5 specific biomarkers (N- and E-cadherin, Ki-67, Cyclin D1, and p-4EB1) that provided prognostic information for a subgroup of patients.12
Despite the efforts and research to date regarding biomarkers in RCC, it would currently be difficult to replace a thorough clinical assessment with any biomarker. But biomarkers will undoubtedly continue to be an important component of determining patient prognosis, identifying the best treatments for each individual patient, and assisting in monitoring how patients respond to treatment.
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New and old biomarkers should be included in clinical trials to help build a database from which oncologists can draw sound clinical recommendations.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. doi: 10.3322/caac.21332
- Cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute website. https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed January, 2016.
- Patard JJ, Leray E, Rioux-Leclercq N, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005;23(12):2763-71.
- van Kuijk SJ, Yaromina A, Houben R, Niemans R, Lambin P, Dubois LJ. Prognostic significance of carbonic anhydrase IX expression in cancer patients: a meta-analysis. Front Oncol. 2016;6:69. doi: 10.3389/fonc.2016.00069
- Chamie K, Klöpfer P, Bevan P, et al. Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial. Urol Oncol. 2015;33(5):204.e25-33. doi: 10.1016/j.urolonc.2015.02.013
- Peña C, Lathia C, Shan M, Escudier B, Bukowski RM. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res. 2010;16(19):4853-63. doi: 10.1158/1078-0432.CCR-09-334
- Gatto F, Maruzzo M, Magro C, Basso U, Nielsen J. Prognostic value of plasma and urine glycosaminoglycan scores in clear cell renal cell carcinoma. Front Oncol. 2016;6:253.
- Kuzman JA, Stenehjem DD, Merriman J, et al. Neutrophil-lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma. BMC Urol. 2017;17(1):1. doi: 10.1186/s12894-016-0192-0
- Jebali M, Elaidi R, Brizard M, et al. Biological toxicities as surrogate markers of efficacy in patients treated with mTOR inhibitors for metastatic renal cell carcinoma. BMC Cancer. 2017;17(1):27. doi: 10.1186/s12885-016-2993-7
- Donat SM, Diaz M, Bishoff JT, et al. Follow-up for clinically localized renal neoplasms: AUA guideline. J Urol. 2013;190(2):407-16. doi: 10.1016/j.juro.2013.04.121
- Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii49-56. doi: 10.1093/annonc/mdu259
- Haddad AQ, Luo JH, Krabbe LM, et al. Prognostic value of tissue based biomarker signature in clear cell renal cell carcinoma. BJU Int. 2017 Jan 11. doi: 10.1111/bju.13776 [Epub ahead of print]