Abstract
Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum-resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer.
Introduction
Urothelial carcinoma (UC) is a chemosensitive malignancy for which platinum-based combination chemotherapy is the standard first-line treatment for unresectable or or metastatic disease. In contrast, second-line therapies have minimal activity. In 2010, an estimated 70,500 new cases and 14,500 deaths were attributed to UC, and it is the fourth most common cancer among men (1). In addition to the human cost of this disease, UC is estimated to be among the most expensive to treat reflecting the high cost of therapy and invasive surveillance of superficial disease (2). While the majority of patients present with non-muscle invasive disease, 50–70% will have a recurrence of “superficial” disease following initial therapy and up to 20% will progress to muscle-invasion over time. Half of all patients with resected, locally advanced UC die of metastatic disease within two years despite response rates of up to 70% for first-line platinum regimens. Furthermore, the prognosis of patients with advanced disease is extremely poor with a median survival of 14 months despite optimal cisplatin-based combination chemotherapy (3). Responses to second-line cytotoxic agents are 10–20%, and thus far, trials of targeted therapies and novel chemotherapeutics in the second-line setting have produced only modest objective response rates and at most a minimal improvement in overall survival (4). Despite some understanding of the molecular aberrations driving UC, this knowledge has yet to be translated into clinical success with targeted therapies. This is because a strong rationale is required to target a specific biologic pathway. Therefore, future investigations should include multiple correlative studies to confirm that the pathway of interest is truly relevant and abrogated by the agent. UC presents multiple opportunities for drug development along the spectrum from disease prevention and blocking progression of superficial disease to augmenting the efficacy of therapy in both the adjuvant and metastatic setting.
The Current State-of-Affairs: Platinum-based Combination Chemotherapy
The regimen of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), the first breakthrough in the treatment of muscle-invasive UC, was associated with improved progression-free survival (PFS) and overall survival (OS) compared with single-agent cisplatin. The combination of gemcitabine and cisplatin (GC) further advanced the field by reducing toxicity without compromising survival benefit compared with MVAC (3). Von der Masse et al. reported that patients who received MVAC had increased rates of febrile neutropenia and mucositis, while GC was associated with increased anemia and thrombocytopenia. Patients treated with GC demonstrated a response rate of approximately 45% with a median OS of 14 months. As such, platinum-based cytotoxic combination therapy is the standard of care for advanced disease. It also has a proven role in the neoadjuvant setting prior to radical cystectomy (5) and as part of a bladder-preservation approach with chemoradiation for muscle-invasive disease.
Clinical trials have attempted to improve upon the overall survival benefit seen with cisplatin-based regimens through the use of two strategies, namely dose intensification and triplet combinations. An EORTC study of 263 patients compared standard MVAC with a dose dense (DD) MVAC schedule that included granulocyte colony stimulating factor support. They found a statistically significant increase in complete response (21% versus 9%) and overall response rates (64% versus 50%) with DD-MVAC compared to MVAC respectively (6). Seven year follow-up demonstrated borderline statistically significant reduction in the risk of progression and death favoring DD-MVAC (HR 0.76). Given these findings, it is possible that dose-intensification may benefit a subpopulation with good performance status. DD-MVAC regimen is currently being studied in the neoadjuvant setting prior to radical cystectomy for patients with muscle-invasive disease in a number of studies (NCT00808639, NCT01031420, and NCT00506155). The combination of paclitaxel/cisplatin/gemcitabine (PCG) was also compared to GC in a randomized phase III study (EORTC 30987) and demonstrated an improved response rate with PCG (57.1 versus 46.4%) but did not meet predefined improvements in PFS or OS (7). Cisplatin together with ifosfamide and paclitaxel (ITP) produced a response rate of 68% and median survival of 20 months in a phase II study in previously untreated patients with advanced UC (8).
It is also worth noting that since increased age and tobacco exposure are risk factors for UC, many patients present with considerable comorbidities, including cardiac disease, impaired kidney function, and neuropathy, which limit their ability to receive cisplatin therapy. Alternatively, patients in need of salvage therapy may experience residual adverse effects from prior cisplatin treatment. These populations are often excluded from clinical trials and therefore have limited access to novel agents. Current treatment options for patients who are ineligible for cisplatin due to organ dysfunction include gemcitabine with carboplatin (9) or single-agent chemotherapy, such as taxanes which produce response rates of approximately 20%.
Improving Standard Therapy: Overcoming Platinum Resistance
For patients who are able to tolerate cisplatin-based combination chemotherapy, de novo or emergence of cisplatin resistance is a frequent complication that ultimately limits treatment options and life-expectancy. Platinum analogs are the most active agents against urothelial carcinoma, and cisplatin and the less toxic second-generation analogue, carboplatin, share the same mechanisms of action and cross-resistance. Platinums bind to DNA and form monoadducts which distort the conformation of the double helix, impair transcription and replication, and ultimately result in activation of signaling cascades that lead to apoptosis. Several DNA repair pathways that are required to correct DNA crosslinks are thought to mediate platinum resistance, and proteins involved in these processes are being studied as potential biomarkers of cisplatin sensitivity (10).
Excision repair cross-complementation group 1 (ERCC1) is required to excise damaged nucleotides and has been shown to predict for response to cisplatin-based chemotherapy. Bellmunt et al. demonstrated that in patients with advanced UC treated with cisplatin combination chemotherapy those with low levels of ERCC1 mRNA expression had a median survival of 25.4 months versus 15.4 months in those with high levels of expression (11). The same group recently reported that ERCC1 expression by immunohistochemistry predicted disease-specific survival in patients with advanced UC who received cisplatin chemotherapy (12.6 months for patients with no expression of ERCC1 versus 8.6 months for those with high expression) (12). Similar findings were reported by a separate group where elevated expression of ERCC1 was associated with worse outcomes for patients with locally advanced UC treated with cisplatin-based regimens (13).
Over-expression of the tumor suppressor p53 in a human bladder cancer cell line through adenoviral gene transfer has been effective in overcoming platinum resistance (14). However, the use of p53 status in the selection of adjuvant therapy for patients with muscle-invasive, node negative UC following radical cystectomy failed to demonstrate prognostic or predictive value of p53 immunohistochemistry, though the study was compromised by a number of limitations (15).
Cells deficient in DNA double-strand repair processes appear to have increased sensitivity to platinum agents. Accumulating evidence suggests that urothelial carcinomas which exhibit alterations in DNA repair pathways experience improved outcomes to platinum agents. A recently reported retrospective series of patients with locally advanced UC treated with neoadjuvant cisplatin-based combination chemotherapy demonstrated improved survival following cystectomy for patients with low/intermediate BRCA1 mRNA compared to high BRCA1 mRNA levels (64% 5 year survival versus 12%) (16). As highlighted above, efforts to elucidate mechanisms of platinum resistance may identify predictive biomarkers and strategies to restore platinum sensitivity that can help effectively utilize and prolong the transient benefit of these agents. The activity of PARP inhibition with carboplatin and gemcitabine in triple negative breast cancer suggests this may be a viable strategy for UC. Specifically, in UC, homologous recombination may be disrupted due to reduced BRCA levels, and these tumors may be made more sensitive to GC if combined with a PARP inhibitor. Conversely, impairment of DNA repair by PARP inhibition may improve GC activity regardless of BRCA status.
Improving Standard Therapy: Targeting Angiogenesis
Angiogenesis is a rational target in UC given that VEGF is produced by UC and VEGFR inhibition may sensitize UC to treatment with cisplatin (17). The VEGF monoclonal antibody bevacizumab was tested in combination with cisplatin and gemcitabine as first-line therapy against metastatic UC and produced an encouraging overall response rate of 72% with a median overall survival of 20.4 months (Table 1). Based on these results, CALGB is currently sponsoring a randomized phase III trial with the same regimen. Sorafenib, an oral multi-targeted tyrosine kinase inhibitor (TKI) with activity against VEGF, showed no objective responses in first or second-line treatment of UC as a single agent (Table 1). Sunitinib was tested as second-line therapy for patients with relapsed or refractory metastatic UC and lead to partial response or stable disease in 33 of 77 patients (43%), though over half experienced grade 3 or 4 toxicities (Table 1). When given as first-line therapy to patients with UC who were ineligible for cisplatin, sunitinib produced a partial response in 2 of 16 patients and an additional 50% (8 of 16 patients) had stable disease resulting in a clinical benefit rate of 64% with progression free survival of 5.9 months (Table 1).
Table 1.
Summary of clinical trials of agents directed against mediators of angiogenesis
| Reference | Phase and Setting | Treatment | Response Rate |
Median OS (months) |
Median PFS (months) |
Comments | |
|---|---|---|---|---|---|---|---|
| Bevacizumab | Hahn, N.M. et al. American Society of Clinical Oncology 2010 | Phase II 1st line advanced UC | GC + Bev | CR: 9/43 pts (21%) PR: 22/43 (51%) | 20.4 | 8.2 | Grade 3–4 non-hematologic toxicity included: DVT/PE 21%, hemorrhage 7%, hypertension 5%, proteinuria 2%. |
| NCT00942331 | Phase III 1st or 2nd advanced UC | GC +/− Bev | |||||
| NCT00268450 | Phase II neoadjuvant/adjuvant locally advanced UC | neoadjuvant GC + Bev, followed by adjuvant paclitaxel + Bev | |||||
| NCT00588666 | Phase II 1st line advanced UC | Gemcitabine, Carboplatin + Bev | |||||
| Sorafenib | Sridhar (1) | Phase II 1st line advanced UC | single-agent sorafenib | OR: none SD x3mo: 1/17 (6%) SD <3mo: 3/17 (18%) | 5.9 | 1.9 | Most common 3+ toxicities: abdominal pain, back pain, hand-foot reaction, bladder infection. |
| Dreicer (2) | Phase II 2nd line advanced UC | single-agent sorafenib | OR: none | 6.8 | 4-month PFS: 9.5% | Most common 3+ toxicities: fatigue, hand-foot reaction. | |
| Krege, S. et al. American Society of Clinical Oncology 2010 | Phase II 1st line advanced UC | GC +/− sorafenib | NA | NA | NA | 42% received only 1–2 cycles of chemotherapy Similar toxicity between arms: 43% (placebo) vs 49% (sorafenib) | |
| NCT01222676 | Phase II neoadjuvantlocally advanced UC | GC + sorafenib | |||||
| NCT00461851 | Phase II 1st line advanced UC | GC + sorafenib | |||||
| NCT00544609 | Phase I 1st line locally advanced UC | sorafenib with radiotherapy | |||||
| Sunitinib | Gallagher (3) | Phase II 2nd line advanced UC | single-agent sunitinib, either 4 wk on/2 wk off (cohort A) or continuous dosing (cohort B) | PR cohort A: 3/45 pts (7%) PR cohort B: 1/32 (3%) PR + SD: 33/77 (43%) | 7.1 vs 6.0 (A vs B) | 2.4 vs 2.3 (A vs B) | Included 26% renal pelvis or ureter primary urothelial tumors 61% experienced grade 3–4 toxicity |
| Galsky, M.D. et al. American Society of Clinical Oncology 2010 | Phase II 1st line advanced UC | GC + sunitinib (up to 6 cycles), followed by daily sunitinib until progression | PR: 8/15 pts (53%) SD: 1/15 (7%) | NA | NA | Significant toxicity: 40% discontinued tx <3 cycles. Neutropenia (80%), 1 septic death. | |
| Bradley, D. et al. American Society of Clinical Oncology 2009 | Phase II maintenance advanced UC with CR/PR/SD following 4–6 cycles of CT | sunitinib vs placebo, 4wk on/2 wk off | SD×24wk: 2/7 (29%) PR x60wk: 1/7 (14%) | NA | 2.2 (on open label sunitinib) | No grade 4–5 adverse events. | |
| Bellmunt, J. et al. American Society of Clinical Oncology 2008 | Phase II 1st line advanced UC ineligible for cisplatin | sunitinib, 4wk on/2wk off | PR: 2/16 (8%) SD x>3mon: 8/16 (50%) | NA | 5.9 | ||
| NCT00847015 | Phase II neoadjuvant locally advanced UC | GC + sunitinib | |||||
| NCT00526656 | Phase II neoadjuvant locally advanced UC | single-agent sunitinib | |||||
| NCT01042795 | Phase II adjuvant locally advanced UC | single-agent sunitinib following platinum-based neoadjuvant CT and cystectomy | |||||
| NCT01089088 | Phase II 1st line unresectable locally advanced/advanced UC | GC + sunitinib | |||||
| NCT01118039 | Phase II 1st line unresectable locally advanced/locally recurrent/advanced UC ineligible for cisplatin CT | single-agent sunitinib | |||||
| NCT00792025 | Phase II 2nd line locally advanced/ advanced UC | single-agent sunitinib | |||||
| NCT01118351 | Phase II recurrent non-muscle invasive UC | single-agent sunitinib |
Abbreviations: OS, overall survival; PFS, progression free survival; UC, urothelial carcinoma; GC, gemcitabine and cisplatin; Bev, bevacizumab; CR, complete response; PR, partial response; OR, objective response rate; SD, stable disease; pts, patients; DVT, deep venous thrombosis; PE, pulmonary embolus; NA, not available; wk, week; CT, chemotherapy; RT, radiation therapy.
References
Sridhar SS, Winquist E, Eisen A, Hotte SJ, McWhirter E, Tannock IF, et al. A phase II trial of sorafenib in first-line metastatic urothelial cancer: A study of the PMH phase II consortium. Invest New Drugs. 2010 Feb 27.
Dreicer R, Li H, Stein M, DiPaola R, Eleff M, Roth BJ, et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: A trial of the eastern cooperative oncology group. Cancer. 2009 Sep 15;115(18):4090–5.
Gallagher DJ, Milowsky MI, Gerst SR, Ishill N, Riches J, Regazzi A, et al. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol. 2010 Mar 10;28(8):1373–9.
Improving Standard Therapy: Targeting the EGFR axis
Multiple growth factor receptors and ligands have been shown to be overexpressed in UC, including HER2/neu, epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), fibroblast growth factor-3 (FGF-3), insulin-like growth factor receptor (IGF1R) and insulin-like growth factor (IGF). As with VEGF, both monoclonal antibodies and tyrosine kinase inhibitors against the EGFR TKI family have been tested for activity in UC with modest activity to date. Despite immunohistochemical confirmation of strong expression of EGFR on pretreatment biopsies in a second-line trial with the EGFR inhibitor gefitinib for advanced UC median progression-free survival was only 2 months (Table 2). Gefitinib combined with GC in a phase 2 trial failed to improve first-line therapy response rates for advanced UC in CALGB 90102 compared with historical controls (Table 2). In a phase II neoadjuvant study of erlotinib, another EGFR TKI, 5 of 20 patients with clinical stage T2 disease were pT0 upon radical cystectomy, 7 were clinically down-staged, and 15 had organ-confined disease (Table 2). This agent has not yet been evaluated in the setting of metastatic disease. A phase II study of cetuximab, a monoclonal antibody directed against EGFR, in combination with GC in advanced UC is currently underway (NCT00645593).
Table 2.
Summary of clinical trials of agents directed against EGFR and Her2
| Reference | Phase and Setting | Treatment | Response Rate | Median OS (months) |
Median PFS (months) |
Comments | |
|---|---|---|---|---|---|---|---|
| Gefitinib (ZD1839) | Petrylak (1) (SWOG S0031) | Phase II 2nd line advanced UC | single-agent ZD1839 | PR: 1/31 pts (3%) SD: 2/31 (6.5%) | 3 | 2 | Felt to be ineffective as 2nd agent for UC. |
| Philips (2) (CALGB 90102) | Phase II 1st line advanced UC | GC + gefitinib x6 cycles, followed by maintenance gefitinib for responding or SD | OR: 23/54 pts (42.6%) | 15.1 | 7.4 | No improvement in RR or OS compared to historical controls of GC. | |
| Erlotinib | Pruthi (3) | Phase II neoadjuvant locally advanced UC | single-agent erlotinib | pT0 rate: 5/20 pts (25%) <pT1: 7/20 (35%) OCD: 15/20 (75%) | 50% alive with NED at 24.8 months | NA | Most common AE was drug rash; all patients with pT0 or pTis/T1 had rash. |
| NCT00749892 | Phase II neoadjuvant locally advanced or recurrent UC | single-agent erlotinib | |||||
| NCT00380029 | Phase II neoadjuvant/maintenance locally advanced UC | neoadjuvant single-agent erlotinib, followed by maintenance erlotinib | |||||
| Cetuximab | NCT00645593 | Phase II 1st line advanced UC | GC +/− cetuximab | ||||
| Lapatinib | Wulfing (4) | Phase II 2nd line advanced UC | single-agent lapatinib | OR >10%: 1.7% pts SD: 18/59 (31%) | 17.9 | 8.6 | 42% could not be evaluated for response. Clinical benefit correlated with EGFR overexpression. |
| NCT01245660 | Phase 0 Neoadjuvant locally advanced UC | single-agent lapatinib | Primary endpoint is effect on EGFR pathway at molecular level. | ||||
| NCT00949455 (LaMB UK study) | Phase II/III maintenance advanced UC with Her1/2 overexpression | Maintenance lapatinib vs placebo | |||||
| NCT00623064 | Phase I 1st line advanced UC | GC + lapatinib | |||||
| Trastuzumab | Hussain (5) | Phase II 1st line advanced UC with Her-2/neu overexpression | paclitaxel, carboplatin, gemcitabine + trastuzumab | CR: 5/44 pts (11%) PR: 26/44 (59%) | 14.1 | 9.3 | Grade 1–3 cardiac toxicity in 22.7%. |
| Beuzeboc, P. et al. American Society of Clinical Oncology 2007 | Phase II 1st line advanced UC with HER2 overexpression | gemcitabine, platinum CT +/− trastuzumab | NA | NA | NA | No serious cardiac AEs reported in either arm. | |
| NCT00238420 | Phase I/II adjuvant locally advanced UC, ineligible for cystectomy | paclitaxel and RT +/− trastuzumab following transuretheral surgery | |||||
| NCT00004856 | Phase II 2nd line advanced UC | single-agent trastuzumab | |||||
| NCT01195935 | Phase I 2nd line advanced UC | single-agent MGAH22 (anti-HER2 monoclonal antibody) |
Abbreviations: OS, overall survival; PFS, progression free survival; UC, urothelial carcinoma; GC, gemcitabine and cisplatin; Bev, bevacizumab; CR, complete response; PR, partial response; OR, objective response rate; SD, stable disease; pts, patients; DVT, deep venous thrombosis; PE, pulmonary embolus; NA, not available; RR, response rate; OCD, organ confined disease; AE, adverse event; RT, radiation therapy.
References
Petrylak DP, Tangen CM, Van Veldhuizen PJ,Jr, Goodwin JW, Twardowski PW, Atkins JN, et al. Results of the southwest oncology group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell carcinoma of the urothelium. BJU Int. 2010 Feb;105(3):317–21.
Philips GK, Halabi S, Sanford BL, Bajorin D, Small EJ, Cancer and Leukemia Group B. A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: Results of cancer and leukemia group B (CALGB) 90102. Ann Oncol. 2009 Jun;20(6):1074–9.
Pruthi RS, Nielsen M, Heathcote S, Wallen EM, Rathmell WK, Godley P, et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: Clinical and pathological results. BJU Int. 2010 Aug;106(3):349–56.
Wulfing C, Machiels JP, Richel DJ, Grimm MO, Treiber U, De Groot MR, et al. A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer. 2009 Jul 1;115(13):2881–90.
Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN, Jr, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: Results of a multicenter phase II national cancer institute trial. J Clin Oncol. 2007 Jun 1;25(16):2218–24.
The HER2/neu monoclonal antibody trastuzumab was evaluated in a phase II first-line study that required confirmation testing of HER2 overexpression, and the combination of trastuzumab together with PCG produced a response rate of 70% (31 of 44 patients), median time to progression of 9.3 months and overall survival of 14.1 months (Table 2). Lapatinib, a dual EGFR and HER2 TKI, was also shown to possibly benefit patients with EGFR or HER2 overexpression as opposed to those with low expression (median survival 30.3 weeks compared to 10.6) when administered as second-line therapy for patients with advanced UC (Table 2). Ongoing studies of lapatinib include a first-line trial in combination with GC (NCT00623064) and as maintenance after response or stable disease following treatment with GC for patients with HER1 or HER2 overexpression in their tumors (NCT00949455).
Improving Standard Therapy: New Cytotoxics
Thus far, targeted therapies have had only modest effects against UC and newer cytotoxic chemotherapy also have the potential to improve outcomes. Vinca alkaloids, nanoparticle taxanes, epothilones and antifolates are classes of novel chemotherapy agents that have been evaluated. In 2009, the European Medicines Agency granted approval for the use of the Vinca alkaloid vinflunine in the treatment of metastatic UC following treatment with a cisplatin-containing regimen. This decision was based on a randomized, phase III trial that demonstrated a statistically significant overall survival benefit that favored vinflunine and best supportive care (BSC) over BSC alone (6.9 versus 4.3 months, respectively, the eligible patient population (18). Eribulin is a microtubule inhibitor initially derived from a marine sponge in 1986, that was demonstrated to produce a response rate of 34% as a second-line treatment in patients with advanced UC (19). This agent has minimal renal excretion and therefore is being studied as a second-line therapy for patients with UC and renal dysfunction (NCT00365157), as well as first-line therapy in combination with GC (NCT01125749). Nab-paclitaxel, an albumin-bound, nanoparticle formulation of paclitaxel, demonstrated a disease control rate (response rate plus stable disease) of 72% in second-line advanced UC and updated results from this abstract are anticipated (20). Epothilones are active against cells that have developed resistance to taxanes; however, ixabepilone had limited activity as a second-line agent against UC and when combined with gemcitabine in a phase I study resulted in dose-limiting myelosuppression (21). Given the activity of the antifolate methotrexate against UC, pemetrexed has also been studied both in combination with gemcitabine as first-line therapy (22) and as a single-agent in the second-line setting with modest activity (23) (24). Pralatrexate, another antifolate analogue, is currently being assessed in a phase II second-line study with folic acid and vitamin B12 (NCT00722553).
Improving Standard Therapy: Immune modulation
Immune modulation has an established role in the treatment of non-muscle invasive UC (interferon and BCG), and emerging data suggests that strategies to activate the immune system may have a role in the treatment of advanced disease as well. Ipilimumab, an anti-cytotoxic T lymphocyte associated antigen antibody, was tested in the neoadjuvant setting for UC and found to stimulate CD4+ T cells, which was associated with an improved overall survival (25). Other immune therapies currently being evaluated for benefit in UC include vaccines against human chorinonic gonadotropin-beta, which can be produced by urothelial cells, and NY-ESO-1, which is produced by multiple tumor types.
Future Directions
The study of patients with extreme phenotypes is an established approach to the investigation of disease mechanisms and drug response. Combined with the application of new technologies, including comprehensive, integrated, and high-throughput studies of genetic mutations and microRNA profiling, this strategy offers the opportunity to identify prognostic and predictive biomarkers, as well as therapeutic targets for drug design. As an example of such an approach, Dana Farber Cancer Institute has partnered with University Hospital del Mar-IMIM in Barcelona, Spain, to analyze copy number alterations, gene expression profiling, and genetic mutations in a panel of clinically annotated UC tumors from patients treated with platinum-based chemotherapy in order to identify predictive and prognostic factors that may elucidate the drivers of response to therapy and platinum resistance and provide targets for drug development. In essence, further advancements in the treatment of urothelial carcinoma will be realized by capitalizing upon ongoing as well as furthering collaborations between institutions, across disciplines and as part of the clinical trial process.
Key Points.
Unresectable or metastatic urothelial carcinoma is a chemosensitive disease but is lethal for most patients.
Future breakthroughs in the management of unresectable or metastatic urothelial carcinoma are predicated on completion of well-designed clinical trials based on sound biological rationale.
Advances in technology are facilitating drug discovery and targeted therapy development for bladder cancer.
Contributor Information
Elizabeth A. Guancial, Dana Farber Cancer Institute, 450 Brookline Avenue, Smith 353, Boston, MA 02115, 617-632-3779 (telephone), 617-632-5822 (fax), eguancial@partners.org
Jonathan E. Rosenberg, Dana Farber Cancer Institute, 450 Brookline Avenue, Dana 1230, Boston, MA 02115, 617-632-4524 (telephone), Jonathan_Rosenberg@DFCI.HARVARD.EDU
Christopher J. Sweeney, Dana Farber Cancer Institute, 450 Brookline Avenue, Dana 1232, Boston, MA 02115, 617-632-4524 (telephone), 617-632-2165 (fax), Christopher_Sweeney@DFCI.HARVARD.EDU
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