NEWS & VIEWS KIDNEY CANCER
Carbonic anhydrase IX in resected clear cell RCC Refers to Chamie, K. 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. http://dx.doi.org/10.1016/ j.urolonc.2015.02.013
Data from the ARISER trial indicate that carbonic anhydrase IX (CAIX) score predicts risk of recurrence and survival after curative nephrectomy in patients with localized high-risk clear cell renal carcinoma. Should CAIX staining be quantified to stratify risk after nephrectomy in all such patients? Karim Chamie and colleagues report in Urologic Oncology an analysis of carbonic anhydrase IX (CAIX) staining from kidney tumours and its association with survival of patients enrolled in the ARISER study.1 The results of this phase III adjuvant study are unpublished to date but were presented at ASCO in 2013.2 The researchers randomly assigned 864 patients with localized but high-risk clear cell renal cell carcinoma (ccRCC) to the cG250 anti-CAIX monoclonal antibody or to placebo. Tumour staging inclusion criteria specified three high-risk groups: patients with T3/T4, N0, M0 disease; patients with any T, N+, M0 disease; and patients with T1b/T2, N0, M0 disease with high-grade features. Treatment with cG250 was well tolerated but no significant difference in outcome was demonstrated between treatment and placebo arms for either disease-free survival (DFS; HR 0.99) or overall survival in the analysis of the overall study population (HR 1.01).2 In subset analyses, however, a beneficial effect of cG250 treatment on DFS was demonstrated in tumours with high CAIX expression (HR 0.55; P = 0.01).2 CAIX expression has previously been characterized as a prognostic biomarker in metastatic clear cell kidney cancer.3–5 CAIX antigen expression is typically expressed as staining intensity and recorded as a percentage of the tumour tissue sample that has positive CAIX expression. Using this method, CAIX antigen expression of ≤85%, in comparison with >85%, has been associated with poorer cancer-specific survival.3,6
‘‘
…CAIX expression is not a reliable prognostic factor in localized ccRCC
’’
This association has been questioned, 7,8 however, prompting Chamie and colleagues1 to analyse archival paraffin-embedded nephrectomy samples from patients enrolled in the ARISER study to try and resolve this issue in order to clarify the association of CAIX with survival and to quantify any association observed. In addition to analysis of CAIX expression, analysis of a second measure of CAIX—termed CAIX score—was performed. Paraffin-embedded tissue was stained with the M75 anti-CAIX antibody and a central pathologist who was blinded to clinicopathological data derived the CAIX score by multiplying staining intensity (scored as 1, 2 and 3 for none-tofaint, moderate and strong, respectively) with percentage CAIX expression to give a score of between 0 and 300. Scores were categorized as low (0–100), intermediate (101–199) and high (>200). Notably, both CAIX expression and CAIX score were pre-specified as exploratory analyses in the ARISER study design, indicating that the attempt to identify whether measuring CAIX was of either prognostic or predictive value in this clinical setting was not a speculative post hoc analysis but was embedded in the trial design. Such analyses are important given the current lack of any clinically robust, usable makers to predict benefit from systemic therapy in renal cancer.
NATURE REVIEWS | UROLOGY
wildpixel/iStock/Thinkstock
Lisa M. Pickering and James Larkin
Chamie et al.1 report that expression of CAIX at the 85% threshold predicted both DFS and overall survival in univariate analysis. In these analyses, 5‑year DFS was approximately 45% in patients with CAIX ≤85% versus 55% in those with CAIX >85%; 5‑year overall survival rates were approximately 70% versus 80% for patients with CAIX below and above the threshold, respectively. The calculated CAIX score was also predictive of survival, with DFS at 5 years being approximately 42%, 49% and 59% for low, intermediate and high scores, respectively; overall survival at 5 years was 66%, 79% and 81% for low, intermediate and high scores. In multivariate propensity score analysis, CAIX expression was not significantly associated with either DFS (HR 0.85, P = 0.15) or overall survival (HR 0.74, P = 0.06), but those with CAIX scores ≥200 had significantly better DFS (HR 0.69, P = 0.01) and overall survival (HR 0.60, P = 0.01) in comparison with those with CAIX scores ≤100. The reported lack of association between CAIX expression using the traditional 85% threshold and outcome in the study by Chamie and colleagues1 is consistent with previous data from this group and indeed with other analyses,7,9 suggesting that CAIX expression is not a reliable prognostic factor in localized ccRCC. This finding differs from the association between CAIX expression and outcome reported and validated in metastatic clear cell kidney cancer 3–6 and it is unclear why such a difference may exist. The results from Chamie and co-workers1 indicating that the calculated CAIX score is a useful prognostic marker for survival is, however, novel but in our view requires VOLUME 12 | JUNE 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS further investigation in localized high-risk ccRCC. Indeed, the authors themselves acknowledge limitations of their current study and state that the results at present are exploratory.1 Therefore, although theirs is the largest prospective analysis of CAIX staining in this setting, we do not agree with the authors’ final conclusion that CAIX should be quantified for all patients with ccRCC after surgery in order to risk-stratify patients and identify those with the greatest need for adjuvant therapy. Validated prognostic scoring systems that fulfil this function are already available: the Liebovich score,10 which uses readily available clinicopathological criteria of tumour stage, regional lymph node status, tumour size, nuclear grade and presence of histologic necrosis, is in widespread clinical use. Therefore, in our view, the CAIX score, although of undoubted potential interest, requires further validation before it is ready for use in routine clinical practice. Department of Medical Oncology, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK (L.M.P.). Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK (J.L.).
JUNE 2015 | VOLUME 12
Correspondence to: J.L. [email protected] doi:10.1038/nrurol.2015.124 Published online 2 June 2015 Acknowledgements J.L. is supported by the National Institute for Health Research Royal Marsden Hospital/Institute of Cancer Research Biomedical Research Centre for Cancer. Competing interests The authors declare no competing interests. 1.
2.
3.
Chamie, K. 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. http://dx.doi.org/ 10.1016/j.urolonc.2015.02.013. Belldegrun, A. S. et al. ARISER: a randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC: results and implications for adjuvant clinical trials [abstract]. J. Clin. Oncol. 31 (Suppl.), a4507 (2013). Bui, M. H. et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin. Cancer Res. 9, 802–811 (2003).
4.
Klatte, T., Kabbinavar, F. F., Zomordian, N., Belldegrun, A. S. & Pantuck, A. J. Prospective evaluation of carbonic anhydrase IX (CAIX) as a molecular marker in metastatic renal cell carcinoma: interim results. J. Urol. 177, 164 (2007). 5. Shah, R. B., Amin, A., Braun, T. & Redman, B. High carbonic anhydrase (CA) IX protein tissue expression predicts response to interleukin (IL)‑2 based therapy for advanced renal cell carcinoma patients. J. Urol. 175, 235 (2006). 6. Atkins, M., Regan, M., McDermott, D., Mier, J., Stanbridge, E. & Youmans, A. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin. Cancer Res. 11, 3714–3721 (2005). 7. Leibovich, B. C. et al. Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J. Clin. Oncol. 25, 4757–4764 (2007). 8. McDermott, D. et al. The high-dose aldesleukin (HD IL‑2) “Select” trial in patients with metastatic renal cell carcinoma (mRCC). J. Immunother. 33, 903–904 (2010). 9. Zang, B. Y. et al. Carbonic anhydrase IX (CAIX) is not an independent predictor of outcome in patients with clear cell renal cell carcinoma (ccRCC) after long-term follow-up. BJU Int. 111, 1046–1053 (2013). 10. Leibovich, B. C. et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97, 1663–1671 (2003).
www.nature.com/nrurol © 2015 Macmillan Publishers Limited. All rights reserved
Carbonic anhydrase IX in resected clear cell RCC Refers to Chamie, K. 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. http://dx.doi.org/10.1016/ j.urolonc.2015.02.013
Data from the ARISER trial indicate that carbonic anhydrase IX (CAIX) score predicts risk of recurrence and survival after curative nephrectomy in patients with localized high-risk clear cell renal carcinoma. Should CAIX staining be quantified to stratify risk after nephrectomy in all such patients? Karim Chamie and colleagues report in Urologic Oncology an analysis of carbonic anhydrase IX (CAIX) staining from kidney tumours and its association with survival of patients enrolled in the ARISER study.1 The results of this phase III adjuvant study are unpublished to date but were presented at ASCO in 2013.2 The researchers randomly assigned 864 patients with localized but high-risk clear cell renal cell carcinoma (ccRCC) to the cG250 anti-CAIX monoclonal antibody or to placebo. Tumour staging inclusion criteria specified three high-risk groups: patients with T3/T4, N0, M0 disease; patients with any T, N+, M0 disease; and patients with T1b/T2, N0, M0 disease with high-grade features. Treatment with cG250 was well tolerated but no significant difference in outcome was demonstrated between treatment and placebo arms for either disease-free survival (DFS; HR 0.99) or overall survival in the analysis of the overall study population (HR 1.01).2 In subset analyses, however, a beneficial effect of cG250 treatment on DFS was demonstrated in tumours with high CAIX expression (HR 0.55; P = 0.01).2 CAIX expression has previously been characterized as a prognostic biomarker in metastatic clear cell kidney cancer.3–5 CAIX antigen expression is typically expressed as staining intensity and recorded as a percentage of the tumour tissue sample that has positive CAIX expression. Using this method, CAIX antigen expression of ≤85%, in comparison with >85%, has been associated with poorer cancer-specific survival.3,6
‘‘
…CAIX expression is not a reliable prognostic factor in localized ccRCC
’’
This association has been questioned, 7,8 however, prompting Chamie and colleagues1 to analyse archival paraffin-embedded nephrectomy samples from patients enrolled in the ARISER study to try and resolve this issue in order to clarify the association of CAIX with survival and to quantify any association observed. In addition to analysis of CAIX expression, analysis of a second measure of CAIX—termed CAIX score—was performed. Paraffin-embedded tissue was stained with the M75 anti-CAIX antibody and a central pathologist who was blinded to clinicopathological data derived the CAIX score by multiplying staining intensity (scored as 1, 2 and 3 for none-tofaint, moderate and strong, respectively) with percentage CAIX expression to give a score of between 0 and 300. Scores were categorized as low (0–100), intermediate (101–199) and high (>200). Notably, both CAIX expression and CAIX score were pre-specified as exploratory analyses in the ARISER study design, indicating that the attempt to identify whether measuring CAIX was of either prognostic or predictive value in this clinical setting was not a speculative post hoc analysis but was embedded in the trial design. Such analyses are important given the current lack of any clinically robust, usable makers to predict benefit from systemic therapy in renal cancer.
NATURE REVIEWS | UROLOGY
wildpixel/iStock/Thinkstock
Lisa M. Pickering and James Larkin
Chamie et al.1 report that expression of CAIX at the 85% threshold predicted both DFS and overall survival in univariate analysis. In these analyses, 5‑year DFS was approximately 45% in patients with CAIX ≤85% versus 55% in those with CAIX >85%; 5‑year overall survival rates were approximately 70% versus 80% for patients with CAIX below and above the threshold, respectively. The calculated CAIX score was also predictive of survival, with DFS at 5 years being approximately 42%, 49% and 59% for low, intermediate and high scores, respectively; overall survival at 5 years was 66%, 79% and 81% for low, intermediate and high scores. In multivariate propensity score analysis, CAIX expression was not significantly associated with either DFS (HR 0.85, P = 0.15) or overall survival (HR 0.74, P = 0.06), but those with CAIX scores ≥200 had significantly better DFS (HR 0.69, P = 0.01) and overall survival (HR 0.60, P = 0.01) in comparison with those with CAIX scores ≤100. The reported lack of association between CAIX expression using the traditional 85% threshold and outcome in the study by Chamie and colleagues1 is consistent with previous data from this group and indeed with other analyses,7,9 suggesting that CAIX expression is not a reliable prognostic factor in localized ccRCC. This finding differs from the association between CAIX expression and outcome reported and validated in metastatic clear cell kidney cancer 3–6 and it is unclear why such a difference may exist. The results from Chamie and co-workers1 indicating that the calculated CAIX score is a useful prognostic marker for survival is, however, novel but in our view requires VOLUME 12 | JUNE 2015
© 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS further investigation in localized high-risk ccRCC. Indeed, the authors themselves acknowledge limitations of their current study and state that the results at present are exploratory.1 Therefore, although theirs is the largest prospective analysis of CAIX staining in this setting, we do not agree with the authors’ final conclusion that CAIX should be quantified for all patients with ccRCC after surgery in order to risk-stratify patients and identify those with the greatest need for adjuvant therapy. Validated prognostic scoring systems that fulfil this function are already available: the Liebovich score,10 which uses readily available clinicopathological criteria of tumour stage, regional lymph node status, tumour size, nuclear grade and presence of histologic necrosis, is in widespread clinical use. Therefore, in our view, the CAIX score, although of undoubted potential interest, requires further validation before it is ready for use in routine clinical practice. Department of Medical Oncology, St George’s Hospital, Blackshaw Road, London SW17 0QT, UK (L.M.P.). Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK (J.L.).
JUNE 2015 | VOLUME 12
Correspondence to: J.L. [email protected] doi:10.1038/nrurol.2015.124 Published online 2 June 2015 Acknowledgements J.L. is supported by the National Institute for Health Research Royal Marsden Hospital/Institute of Cancer Research Biomedical Research Centre for Cancer. Competing interests The authors declare no competing interests. 1.
2.
3.
Chamie, K. 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. http://dx.doi.org/ 10.1016/j.urolonc.2015.02.013. Belldegrun, A. S. et al. ARISER: a randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC: results and implications for adjuvant clinical trials [abstract]. J. Clin. Oncol. 31 (Suppl.), a4507 (2013). Bui, M. H. et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin. Cancer Res. 9, 802–811 (2003).
4.
Klatte, T., Kabbinavar, F. F., Zomordian, N., Belldegrun, A. S. & Pantuck, A. J. Prospective evaluation of carbonic anhydrase IX (CAIX) as a molecular marker in metastatic renal cell carcinoma: interim results. J. Urol. 177, 164 (2007). 5. Shah, R. B., Amin, A., Braun, T. & Redman, B. High carbonic anhydrase (CA) IX protein tissue expression predicts response to interleukin (IL)‑2 based therapy for advanced renal cell carcinoma patients. J. Urol. 175, 235 (2006). 6. Atkins, M., Regan, M., McDermott, D., Mier, J., Stanbridge, E. & Youmans, A. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin. Cancer Res. 11, 3714–3721 (2005). 7. Leibovich, B. C. et al. Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J. Clin. Oncol. 25, 4757–4764 (2007). 8. McDermott, D. et al. The high-dose aldesleukin (HD IL‑2) “Select” trial in patients with metastatic renal cell carcinoma (mRCC). J. Immunother. 33, 903–904 (2010). 9. Zang, B. Y. et al. Carbonic anhydrase IX (CAIX) is not an independent predictor of outcome in patients with clear cell renal cell carcinoma (ccRCC) after long-term follow-up. BJU Int. 111, 1046–1053 (2013). 10. Leibovich, B. C. et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97, 1663–1671 (2003).
www.nature.com/nrurol © 2015 Macmillan Publishers Limited. All rights reserved
