EURURO-5651; No. of Pages 2 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Opinion
New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician David J. McConkey *, Woonyoung Choi, Colin P.N. Dinney Departments of Urology and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Muscle-invasive bladder cancers (MIBCs) are highly heterogeneous tumors with variable clinical courses and responses to conventional cisplatin-based combination chemotherapy (gemcitabine and cisplatin or methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]) [1]. Current clinical staging systems are woefully inaccurate, leading to understaging (and hence undertreatment) in at least 40% of cases [2]. Neoadjuvant chemotherapy produces meaningful pathologic responses in almost half of the cases, but it remains impossible to prospectively identify the patients who will obtain this benefit, and its impact on overall survival in unselected patients is considered modest at 5–10% [3]. In spite of the availability of level 1 evidence to support its use, perioperative chemotherapy remains underused (currently 20% of patients receive it) [4]. Finally, and unlike the reality in the other major genitourinary cancers, no molecular targeted agents have been approved for the therapy of MIBC, and consequently no transformative changes have been made in its clinical management since the cisplatin-based combinations were introduced more than three decades ago [1]. The introduction of whole-genome approaches has transformed our understanding of cancer heterogeneity in other solid tumors. Using whole genome messenger RNA expression profiling, Perou et al. [5] discovered that human breast cancers can be grouped into five ‘‘intrinsic subtypes’’ (claudin-low, basal, human epidermal growth receptor 2 [HER2]-enriched, luminal A, and luminal B) based on shared gene expression patterns (Fig. 1). Studies performed in the intervening 15 yr have established that these subtypes behave as distinct clinical entities in terms of patterns of progression and response to conventional chemotherapy, HER2 antagonists, and estrogen receptor inhibitors [6]. Put simply, knowledge of a given breast cancer’s intrinsic subtype has significant prognostic and predictive value [6].
Recent studies performed by three independent groups identified intrinsic subtypes of MIBC that are remarkably similar to the intrinsic subtypes of breast cancer [7–9]. The tumors fall into two major basal and luminal subtypes (Fig. 1). Basal MIBCs contain a claudin-low subtype [8] (‘‘cluster IV’’ of The Cancer Genome Atlas [TCGA] research network [9]) characterized by epithelial-to-mesenchymal transition, a biologic process implicated in cancer ‘‘stemness’’ and metastasis. Luminal MIBCs can be segregated into two subtypes that resemble luminal A and luminal B breast
Fig. 1 – Relationships among the intrinsic subtypes identified in bladder cancer and the intrinsic subtypes of breast cancer. Bladder cancer subtype calls made independently by three different groups [7–9] using the bladder cancer RNA sequencing data of The Cancer Genome Atlas research network were compared with each other. The intrinsic subtypes of breast cancer that correspond to the bladder cancer subtypes are indicated in the bottom color bar. MDACC = MD Anderson Cancer Center; TCGA = The Cancer Genome Atlas; UNC = University of North Carolina.
* Corresponding author. University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail address: [email protected] (D.J. McConkey). http://dx.doi.org/10.1016/j.eururo.2014.05.006 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: McConkey DJ, et al. New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.006
EURURO-5651; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Table 1 – Intrinsic subtypes of muscle-invasive bladder cancer Intrinsic subtype Luminal
p53-like Basal
Claudin-low/mesenchymal
Clinical features Enriched with papillary histology and activating FGFR3 mutations and translocations. About half of the tumors are sensitive to neoadjuvant chemotherapy. Infiltrated with stromal fibroblasts. Resistant to neoadjuvant chemotherapy. Enriched with squamous features. More common in women. Associated with advanced stage and metastatic disease at presentation. Associated with shorter disease-specific and overall survival in the absence of chemotherapy. About half of the tumors are sensitive to neoadjuvant chemotherapy. Clinical features are not well defined. Probably enriched with sarcomatoid features and associated with high metastatic potential.
FGFR3 = fibroblast growth factor receptor 3.
validated in additional clinical trial cohorts, patients with these p53-like tumors should be managed with alterative neoadjuvant regimens, perhaps using FGFR inhibitors and/ or other targeted agents. Finally, given their similarities at the molecular level, it may be possible to leverage the larger breast cancer knowledge base to enable more rapid progress in the clinical management of invasive bladder cancers. Conflicts of interest: The authors have nothing to disclose. Funding support: The National Institutes of Health sponsored collection of the data.
References [1] Shah JB, McConkey DJ, Dinney CP. New strategies in muscleinvasive bladder cancer: on the road to personalized medicine. Clin Cancer Res 2011;17:2608–12. [2] Svatek RS, Shariat SF, Novara G, et al. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. BJU Int 2011;107: 898–904.
cancers and appear to be distinguished by different levels of stromal infiltration and proliferation [7,9]. Clinically, basal MIBCs tend to occur more frequently in women [7,8] (Table 1). They are enriched with squamous and sarcomatoid histopathologic features, associated with advanced stage and metastatic disease at presentation, and with shorter disease-specific and overall survival [7,8]. Nevertheless, a significant fraction of them are highly sensitive to neoadjuvant MVAC chemotherapy [7], suggesting that its increased use could dramatically alter the course of basal cancer disease progression. The luminal MIBCs are enriched with papillary histopathologic features and activating mutations in fibroblast growth factor receptor 3 (FGFR3) (Table 1), which are also present in most non– muscle-invasive (‘‘superficial’’) urothelial cancers [10]. They might correspond to non–muscle-invasive cancers that progressed to become invasive, although this has not been elucidated by longitudinal studies. Importantly, one of the luminal subtypes (p53-like/luminal A, corresponding to the TCGA’s cluster II) is resistant to neoadjuvant MVAC [7] (Table 1). Therefore, if the results can be independently
[3] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. [4] Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.009 [5] Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–52. [6] Prat A, Ellis MJ, Perou CM. Practical implications of geneexpression-based assays for breast oncologists. Nat Rev Clin Oncol 2012;9:48–57. [7] Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014;25:152–65. [8] Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A 2014;111:3110–5. [9] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507: 315–22. [10] Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol 2008;4:71–83.
Please cite this article in press as: McConkey DJ, et al. New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.006
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Opinion
New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician David J. McConkey *, Woonyoung Choi, Colin P.N. Dinney Departments of Urology and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Muscle-invasive bladder cancers (MIBCs) are highly heterogeneous tumors with variable clinical courses and responses to conventional cisplatin-based combination chemotherapy (gemcitabine and cisplatin or methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]) [1]. Current clinical staging systems are woefully inaccurate, leading to understaging (and hence undertreatment) in at least 40% of cases [2]. Neoadjuvant chemotherapy produces meaningful pathologic responses in almost half of the cases, but it remains impossible to prospectively identify the patients who will obtain this benefit, and its impact on overall survival in unselected patients is considered modest at 5–10% [3]. In spite of the availability of level 1 evidence to support its use, perioperative chemotherapy remains underused (currently 20% of patients receive it) [4]. Finally, and unlike the reality in the other major genitourinary cancers, no molecular targeted agents have been approved for the therapy of MIBC, and consequently no transformative changes have been made in its clinical management since the cisplatin-based combinations were introduced more than three decades ago [1]. The introduction of whole-genome approaches has transformed our understanding of cancer heterogeneity in other solid tumors. Using whole genome messenger RNA expression profiling, Perou et al. [5] discovered that human breast cancers can be grouped into five ‘‘intrinsic subtypes’’ (claudin-low, basal, human epidermal growth receptor 2 [HER2]-enriched, luminal A, and luminal B) based on shared gene expression patterns (Fig. 1). Studies performed in the intervening 15 yr have established that these subtypes behave as distinct clinical entities in terms of patterns of progression and response to conventional chemotherapy, HER2 antagonists, and estrogen receptor inhibitors [6]. Put simply, knowledge of a given breast cancer’s intrinsic subtype has significant prognostic and predictive value [6].
Recent studies performed by three independent groups identified intrinsic subtypes of MIBC that are remarkably similar to the intrinsic subtypes of breast cancer [7–9]. The tumors fall into two major basal and luminal subtypes (Fig. 1). Basal MIBCs contain a claudin-low subtype [8] (‘‘cluster IV’’ of The Cancer Genome Atlas [TCGA] research network [9]) characterized by epithelial-to-mesenchymal transition, a biologic process implicated in cancer ‘‘stemness’’ and metastasis. Luminal MIBCs can be segregated into two subtypes that resemble luminal A and luminal B breast
Fig. 1 – Relationships among the intrinsic subtypes identified in bladder cancer and the intrinsic subtypes of breast cancer. Bladder cancer subtype calls made independently by three different groups [7–9] using the bladder cancer RNA sequencing data of The Cancer Genome Atlas research network were compared with each other. The intrinsic subtypes of breast cancer that correspond to the bladder cancer subtypes are indicated in the bottom color bar. MDACC = MD Anderson Cancer Center; TCGA = The Cancer Genome Atlas; UNC = University of North Carolina.
* Corresponding author. University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail address: [email protected] (D.J. McConkey). http://dx.doi.org/10.1016/j.eururo.2014.05.006 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: McConkey DJ, et al. New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.006
EURURO-5651; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Table 1 – Intrinsic subtypes of muscle-invasive bladder cancer Intrinsic subtype Luminal
p53-like Basal
Claudin-low/mesenchymal
Clinical features Enriched with papillary histology and activating FGFR3 mutations and translocations. About half of the tumors are sensitive to neoadjuvant chemotherapy. Infiltrated with stromal fibroblasts. Resistant to neoadjuvant chemotherapy. Enriched with squamous features. More common in women. Associated with advanced stage and metastatic disease at presentation. Associated with shorter disease-specific and overall survival in the absence of chemotherapy. About half of the tumors are sensitive to neoadjuvant chemotherapy. Clinical features are not well defined. Probably enriched with sarcomatoid features and associated with high metastatic potential.
FGFR3 = fibroblast growth factor receptor 3.
validated in additional clinical trial cohorts, patients with these p53-like tumors should be managed with alterative neoadjuvant regimens, perhaps using FGFR inhibitors and/ or other targeted agents. Finally, given their similarities at the molecular level, it may be possible to leverage the larger breast cancer knowledge base to enable more rapid progress in the clinical management of invasive bladder cancers. Conflicts of interest: The authors have nothing to disclose. Funding support: The National Institutes of Health sponsored collection of the data.
References [1] Shah JB, McConkey DJ, Dinney CP. New strategies in muscleinvasive bladder cancer: on the road to personalized medicine. Clin Cancer Res 2011;17:2608–12. [2] Svatek RS, Shariat SF, Novara G, et al. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. BJU Int 2011;107: 898–904.
cancers and appear to be distinguished by different levels of stromal infiltration and proliferation [7,9]. Clinically, basal MIBCs tend to occur more frequently in women [7,8] (Table 1). They are enriched with squamous and sarcomatoid histopathologic features, associated with advanced stage and metastatic disease at presentation, and with shorter disease-specific and overall survival [7,8]. Nevertheless, a significant fraction of them are highly sensitive to neoadjuvant MVAC chemotherapy [7], suggesting that its increased use could dramatically alter the course of basal cancer disease progression. The luminal MIBCs are enriched with papillary histopathologic features and activating mutations in fibroblast growth factor receptor 3 (FGFR3) (Table 1), which are also present in most non– muscle-invasive (‘‘superficial’’) urothelial cancers [10]. They might correspond to non–muscle-invasive cancers that progressed to become invasive, although this has not been elucidated by longitudinal studies. Importantly, one of the luminal subtypes (p53-like/luminal A, corresponding to the TCGA’s cluster II) is resistant to neoadjuvant MVAC [7] (Table 1). Therefore, if the results can be independently
[3] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66. [4] Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.009 [5] Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–52. [6] Prat A, Ellis MJ, Perou CM. Practical implications of geneexpression-based assays for breast oncologists. Nat Rev Clin Oncol 2012;9:48–57. [7] Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014;25:152–65. [8] Damrauer JS, Hoadley KA, Chism DD, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A 2014;111:3110–5. [9] Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507: 315–22. [10] Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol 2008;4:71–83.
Please cite this article in press as: McConkey DJ, et al. New Insights into Subtypes of Invasive Bladder Cancer: Considerations of the Clinician. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.05.006
