Editorials
Targeted Therapies for Metastatic Bladder Cancer THERE have been no new approved drugs for bladder cancer of any stage since the approval of valrubicin for bacillus Calmette-Gu erin refractory carcinoma in situ in 1998. Patients with measurable metastatic disease have at best a 20% 2-year survival probability and less than 12 months in patients with metastatic disease who progress after first line chemotherapy. An attempt to move the field forward has been the comprehensive characterization of the genomic landscape of muscle invasive bladder cancer.1 The Cancer Genome Atlas (TCGA) project reported an integrated analysis of 131 muscle invasive urothelial cancers and described 32 significantly mutated genes, including 16 not previously reported in bladder cancer.1 Bladder cancer has one of the highest mutation rates of all TCGA tumor types, similar to lung adenocarcinoma, lung squamous cell cancer and melanoma. We identified potential therapeutic targets in 69% of tumors, including alterations in the RTK/Ras and PI3 kinase pathways, cell cycle regulatory genes and chromatin remodeling, including histone modifying genes and the SWI/SNF nucleosome remodeling complex. There are multiple challenges for translating these findings and implementing targeted therapies, including but not limited to 1) access to low cost CLIA (Clinical Laboratory Improvement Amendments) approved NextGenÒ sequencing (NGS) and reporting, 2) the need for validated assays to identify targets and predict responses that can preferably be run on NGS, 3) the lack of targeted agents with validated predictive assays tested in urothelial cancer in phase I and II studies, 4) target and pathway prioritization to determine appropriate treatment and 5) what tissue should be tested (primary vs metastasis). There is also a host of regulatory and funding challenges for implementing NGS based targeted therapy trials. The NCI (National Cancer Institute) is moving quickly to implement clinical trials leveraging these genomic data. It is addressing many of these challenges in a unique partnership with philanthropy, the advocacy community, oncology cooperative groups, pharmaceutical organizations,
0022-5347/15/1931-0008/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
8
j
www.jurology.com
AND
RESEARCH, INC.
CLIA approved sequencing centers and the FDA (Food and Drug Administration). MATCH (Molecular Analysis for Therapy Choice) is a global effort designed to test up to 30 validated targets in phase II trials across all locally advanced or metastatic solid and liquid tumor types. Eligible patients must have received failed treatment. The trial will screen 3,000 patients to accumulate 1,000 who are eligible with actionable mutations, amplifications or translocations. The alliance plans a similar baskettype trial in patients with metastatic urothelial cancer in whom front line therapy failed. The 3 arms will target alterations in fibroblast growth factor receptor 3 (FGFR3), the PIK3CA/AKT/MTOR pathway and Rb inactivation. Cytotoxic chemotherapy, another form of targeted therapy, attacks perturbed cell cycle regulation and proliferation. Phase III trials of neoadjuvant cisplatin based chemotherapy (NAC) demonstrated that no more than 40% of patients achieve a complete clinical and pathological response in the primary tumor. Host and tumor factors have a significant role in this response. An example is the expression of nucleotide excision repair genes (eg ERCC1), which may result in cisplatin resistance.2 Lee et al defined a gene expression profile based on COXEN (co-expression extrapolation) that was associated with the response to cisplatin based chemotherapy in the NAC and metastatic settings.3 SWOG-NCI sponsored clinical trial S1314 was activated to validate this predictive biomarker. If the trial meets its primary end point, a followup trial (NCT02177695) will test the hypothesis that COXEN can be used to select patients most likely to respond to NAC. This is the ultimate goal of targeted therapy and personalized medicine. Intratumor genomic heterogeneity is highly relevant for targeted therapy. The recent study by Gerlinger et al demonstrated the potential to underestimate the genomic landscape from a single biopsy in renal cell carcinoma cases.4 In this issue of The Journal Turo et al (page 325) address this important issue of target identification in primary tumors vs metastases.5 They and others previously
http://dx.doi.org/10.1016/j.juro.2014.10.056 Vol. 193, 8-9, January 2015 Printed in U.S.A.
TARGETED THERAPIES FOR METASTATIC BLADDER CANCER
reported that FGFR3 mutations are present in up to 80% of low grade nonmuscle invasive bladder cancers and in 15% to 20% of muscle invasive cancers. This is consistent with observations in the TCGA cohort, in which FGFR3 alterations (amplification, mutations and fusion with TACC-3) were identified in 15% of high grade muscle invasive urothelial cancers.1 In that series increased mRNA expression was seen in a higher percent of tumors, often in the absence of alterations at the gene level. Turo et al evaluated FGFR3 expression at the protein level using immunohistochemistry in 150 matched tumor/node metastasis pairs.5 They observed high expression in 45% of the central portion of primary tumors and in 31% in the invasive front with concordant expression in 75% (OR 8.6). Discordant expression in 25% of tumors suggests at least a modest risk of genomic heterogeneity related to sampling. When primary tumors are used, multiple cores from all tumor regions should be analyzed. For tumors with at least 1 core evaluated 41% of node metastases had high expression. The group found concordance for FGFR3 immunohistochemistry between primary tumor and lymph node metastases in 79 of 106 patients (OR 8.45), suggesting that in most patients the primary tumor may be an appropriate surrogate tissue. There have been several FGFR3 inhibitors in clinical trials. Recent data from 2 early phase trials presented at the 2014 American Association of Cancer Research annual meeting suggest that JNJ42756493 and BGJ398 have significant activity in patients with tumors harboring FGFR3 mutation
9
and/or amplification. While there is ample evidence that FGFR3 inhibitors are active in preclinical models based on high immunohistochemistry (IHC) expression, it is not clear that this level of activity translates to patients with high expression on IHC in the absence of amplification or mutation. In the TCGA muscle invasive bladder cancer cohort we identified 4 expression clusters with integrated expression data, including mRNA, miRNA and reverse phase protein array (IHC). Of these tumors 25% had a predominant papillary phenotype. FGFR3 perturbations were prominent in the tumors, including mutation and amplification. Three tumors showed translocations involving TACC3, which results in constitutive activation of the kinase domain of FGFR3 and was previously reported by Williams et al.6 Tumors harboring these translocations may be particularly sensitive to FGFR3 targeted therapy. The remaining tumors shared genomic alterations and expression patterns similar to those of other tumor types, including lung adenocarcinoma, lung squamous cancer and breast cancer. This was recently corroborated in a pancancer TCGA analysis of 12 common tumor types.7 These observations suggest that the effective targeted therapies in use for these other organ site cancers may provide similar benefit in patients with advanced bladder cancer. Seth P. Lerner Scott Department of Urology Baylor College of Medicine Houston, Texas
REFERENCES 1. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315.
2. Bellmunt J, Paz-Ares L, Cuello M et al: Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol 2007; 18: 522.
3. Lee JK, Havaleshko DM, Cho H et al: A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci U S A 2007; 104: 13086. 4. Gerlinger M, Rowan AJ, Horswell S et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883. 5. Turo R, Harnden P, Thygesen H et al: FGFR3 expression in primary invasive bladder cancers
and matched lymph node metastases. J Urol 2015; 193: 325. 6. Williams SV, Hurst CD and Knowles MA: Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Gen 2013; 22: 795. 7. Hoadley KA, Yau C, Wolf DM et al: Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014; 158: 929.
Targeted Therapies for Metastatic Bladder Cancer THERE have been no new approved drugs for bladder cancer of any stage since the approval of valrubicin for bacillus Calmette-Gu erin refractory carcinoma in situ in 1998. Patients with measurable metastatic disease have at best a 20% 2-year survival probability and less than 12 months in patients with metastatic disease who progress after first line chemotherapy. An attempt to move the field forward has been the comprehensive characterization of the genomic landscape of muscle invasive bladder cancer.1 The Cancer Genome Atlas (TCGA) project reported an integrated analysis of 131 muscle invasive urothelial cancers and described 32 significantly mutated genes, including 16 not previously reported in bladder cancer.1 Bladder cancer has one of the highest mutation rates of all TCGA tumor types, similar to lung adenocarcinoma, lung squamous cell cancer and melanoma. We identified potential therapeutic targets in 69% of tumors, including alterations in the RTK/Ras and PI3 kinase pathways, cell cycle regulatory genes and chromatin remodeling, including histone modifying genes and the SWI/SNF nucleosome remodeling complex. There are multiple challenges for translating these findings and implementing targeted therapies, including but not limited to 1) access to low cost CLIA (Clinical Laboratory Improvement Amendments) approved NextGenÒ sequencing (NGS) and reporting, 2) the need for validated assays to identify targets and predict responses that can preferably be run on NGS, 3) the lack of targeted agents with validated predictive assays tested in urothelial cancer in phase I and II studies, 4) target and pathway prioritization to determine appropriate treatment and 5) what tissue should be tested (primary vs metastasis). There is also a host of regulatory and funding challenges for implementing NGS based targeted therapy trials. The NCI (National Cancer Institute) is moving quickly to implement clinical trials leveraging these genomic data. It is addressing many of these challenges in a unique partnership with philanthropy, the advocacy community, oncology cooperative groups, pharmaceutical organizations,
0022-5347/15/1931-0008/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
8
j
www.jurology.com
AND
RESEARCH, INC.
CLIA approved sequencing centers and the FDA (Food and Drug Administration). MATCH (Molecular Analysis for Therapy Choice) is a global effort designed to test up to 30 validated targets in phase II trials across all locally advanced or metastatic solid and liquid tumor types. Eligible patients must have received failed treatment. The trial will screen 3,000 patients to accumulate 1,000 who are eligible with actionable mutations, amplifications or translocations. The alliance plans a similar baskettype trial in patients with metastatic urothelial cancer in whom front line therapy failed. The 3 arms will target alterations in fibroblast growth factor receptor 3 (FGFR3), the PIK3CA/AKT/MTOR pathway and Rb inactivation. Cytotoxic chemotherapy, another form of targeted therapy, attacks perturbed cell cycle regulation and proliferation. Phase III trials of neoadjuvant cisplatin based chemotherapy (NAC) demonstrated that no more than 40% of patients achieve a complete clinical and pathological response in the primary tumor. Host and tumor factors have a significant role in this response. An example is the expression of nucleotide excision repair genes (eg ERCC1), which may result in cisplatin resistance.2 Lee et al defined a gene expression profile based on COXEN (co-expression extrapolation) that was associated with the response to cisplatin based chemotherapy in the NAC and metastatic settings.3 SWOG-NCI sponsored clinical trial S1314 was activated to validate this predictive biomarker. If the trial meets its primary end point, a followup trial (NCT02177695) will test the hypothesis that COXEN can be used to select patients most likely to respond to NAC. This is the ultimate goal of targeted therapy and personalized medicine. Intratumor genomic heterogeneity is highly relevant for targeted therapy. The recent study by Gerlinger et al demonstrated the potential to underestimate the genomic landscape from a single biopsy in renal cell carcinoma cases.4 In this issue of The Journal Turo et al (page 325) address this important issue of target identification in primary tumors vs metastases.5 They and others previously
http://dx.doi.org/10.1016/j.juro.2014.10.056 Vol. 193, 8-9, January 2015 Printed in U.S.A.
TARGETED THERAPIES FOR METASTATIC BLADDER CANCER
reported that FGFR3 mutations are present in up to 80% of low grade nonmuscle invasive bladder cancers and in 15% to 20% of muscle invasive cancers. This is consistent with observations in the TCGA cohort, in which FGFR3 alterations (amplification, mutations and fusion with TACC-3) were identified in 15% of high grade muscle invasive urothelial cancers.1 In that series increased mRNA expression was seen in a higher percent of tumors, often in the absence of alterations at the gene level. Turo et al evaluated FGFR3 expression at the protein level using immunohistochemistry in 150 matched tumor/node metastasis pairs.5 They observed high expression in 45% of the central portion of primary tumors and in 31% in the invasive front with concordant expression in 75% (OR 8.6). Discordant expression in 25% of tumors suggests at least a modest risk of genomic heterogeneity related to sampling. When primary tumors are used, multiple cores from all tumor regions should be analyzed. For tumors with at least 1 core evaluated 41% of node metastases had high expression. The group found concordance for FGFR3 immunohistochemistry between primary tumor and lymph node metastases in 79 of 106 patients (OR 8.45), suggesting that in most patients the primary tumor may be an appropriate surrogate tissue. There have been several FGFR3 inhibitors in clinical trials. Recent data from 2 early phase trials presented at the 2014 American Association of Cancer Research annual meeting suggest that JNJ42756493 and BGJ398 have significant activity in patients with tumors harboring FGFR3 mutation
9
and/or amplification. While there is ample evidence that FGFR3 inhibitors are active in preclinical models based on high immunohistochemistry (IHC) expression, it is not clear that this level of activity translates to patients with high expression on IHC in the absence of amplification or mutation. In the TCGA muscle invasive bladder cancer cohort we identified 4 expression clusters with integrated expression data, including mRNA, miRNA and reverse phase protein array (IHC). Of these tumors 25% had a predominant papillary phenotype. FGFR3 perturbations were prominent in the tumors, including mutation and amplification. Three tumors showed translocations involving TACC3, which results in constitutive activation of the kinase domain of FGFR3 and was previously reported by Williams et al.6 Tumors harboring these translocations may be particularly sensitive to FGFR3 targeted therapy. The remaining tumors shared genomic alterations and expression patterns similar to those of other tumor types, including lung adenocarcinoma, lung squamous cancer and breast cancer. This was recently corroborated in a pancancer TCGA analysis of 12 common tumor types.7 These observations suggest that the effective targeted therapies in use for these other organ site cancers may provide similar benefit in patients with advanced bladder cancer. Seth P. Lerner Scott Department of Urology Baylor College of Medicine Houston, Texas
REFERENCES 1. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315.
2. Bellmunt J, Paz-Ares L, Cuello M et al: Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol 2007; 18: 522.
3. Lee JK, Havaleshko DM, Cho H et al: A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci U S A 2007; 104: 13086. 4. Gerlinger M, Rowan AJ, Horswell S et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883. 5. Turo R, Harnden P, Thygesen H et al: FGFR3 expression in primary invasive bladder cancers
and matched lymph node metastases. J Urol 2015; 193: 325. 6. Williams SV, Hurst CD and Knowles MA: Oncogenic FGFR3 gene fusions in bladder cancer. Hum Mol Gen 2013; 22: 795. 7. Hoadley KA, Yau C, Wolf DM et al: Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 2014; 158: 929.
