EURURO-6057; No. of Pages 2 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Research Letter Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation We report on a 60-yr-old female who initially presented with muscle-invasive bladder cancer. The patient received two cycles of neoadjuvant cisplatin and gemcitabine (CG), followed by cystectomy and extended lymphadenectomy. Pathologic staging suggested a pT3bN0 Mx high-grade urothelial carcinoma, with 58 lymph nodes examined. The patient then had two additional cycles of adjuvant CG. Within 2 mo of adjuvant chemotherapy, the patient developed pelvic pain, and computed tomography (CT) imaging suggested a 1.9-cm lesion in the left lateral wall of the vagina, which was confirmed by magnetic resonance imaging (MRI). Positron emission tomography (PET) showed uptake in the vaginal cuff lesion and several external iliac lymph nodes. The patient was started on docetaxel monotherapy, and also received pelvic radiotherapy for palliation of pain. After 2 mo, imaging indicated an increase in the vaginal cuff lesion. With patient permission, a cystectomy specimen was submitted for comprehensive genomic profiling (FoundationOne) [1] performed in the Foundation Medicine laboratory, which is certified by Clinical Laboratory Improvement Amendments and accredited by the College of American Pathologists [1]. The profiling revealed alterations in NF2 Y153*fs1, ATM V2119fs*8, ATR splice site 7349+2T>C, and TP53 R280K. Preclinical work has suggested that NF2 loss may be associated with sensitivity to rapamycin treatment,
so the patient was transitioned to a combination of everolimus (a rapamycin analog) and paclitaxel according to a dosing regimen currently being examined in a phase 2 study in urothelial carcinoma [2]. Imaging over 13 mo of therapy with this regimen showed continual regression of the vaginal cuff lesion and disappearance of the previously noted iliac adenopathy (Fig. 1). According to Response Evaluation Criteria in Solid Tumors, a partial response was observed, with a 65% decline from baseline according to cumulative measurement of the index lesion. The lesion was initially markedly PET avid, but uptake diminished substantially during the course of therapy (Fig. 1). After progression on platinum-based therapy in the firstline setting, no standard of care exists for second-line treatment of metastatic urothelial carcinoma (MUC). A multitude of cytotoxic agents and targeted therapies have been explored in single-arm phase 2 trials, with typical progression-free survival of 3–6 mo and overall survival of 6–9 mo [3]. Response rates in this setting range from 0% to 25%. This report describes an MUC patient with ATM, ATR, NF2, and TP53 alterations who exhibited disease progression over a short interval during platinum-based chemotherapy and further progression on single-agent taxane. Addition of everolimus to her systemic regimen led to a profound response that is ongoing after 13 mo. For two recently described bladder cancer patients, retrospective genomic analysis identified mTOR pathway alterations (NF2 and TSC1 truncating mutations) after the patients were singled out as extreme responders in clinical trials of targeted
Fig. 1 – Serial positron emission tomography images for a patient with metastatic urothelial carcinoma possessing an NF2 mutation (A) before initiation of paclitaxel/everolimus and (B) after 10 mo of therapy.
http://dx.doi.org/10.1016/j.eururo.2015.01.015 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Ali SM, et al. Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.01.015
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EUROPEAN UROLOGY XXX (2015) XXX–XXX
therapy [4,5]. For this case, by contrast, therapeutic decisionmaking was made directly on the basis of her genomic profile after exhaustion of standard-of-care options, and led to an extreme response. The results for this case support planned efforts such as the Alliance MATCH-UP protocol, which will prospectively treat MUC patients using targeted therapies directed at specific molecular aberrations.
metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol 2010;11:861–70. [4] Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 2012;338:221. [5] Wagle N, Grabiner BC, Van Allen EM, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 2014;4:546–53.
Conflicts of interest: Siraj M. Ali, Vincent A. Miller, and Jeffrey S. Ross are
Siraj M. Alia
employees of and have equity interest in Foundation Medicine Inc.
Vincent A. Millera
Sumanta K. Pal is involved in research collaboration with Foundation
Jeffrey S. Rossa Sumanta K. Palb,*
Medicine Inc. a
References [1] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and
b
Foundation Medicine, Cambridge, MA, USA
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31: 1023–31. [2] NCT01215136. First-line everolimus +/– paclitaxel for cisplatinineligible patients with advanced urothelial carcinoma. http:// clinicaltrials.gov/ct2/show/NCT01215136
*Corresponding author. Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel. +1 626 2564673; Fax: +1 626 3018233. E-mail address: [email protected] (S.K. Pal).
[3] Sonpavde G, Sternberg CN, Rosenberg JE, Hahn NM, Galsky MD, Vogelzang NJ. Second-line systemic therapy and emerging drugs for
January 13, 2015
Please cite this article in press as: Ali SM, et al. Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.01.015
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Research Letter Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation We report on a 60-yr-old female who initially presented with muscle-invasive bladder cancer. The patient received two cycles of neoadjuvant cisplatin and gemcitabine (CG), followed by cystectomy and extended lymphadenectomy. Pathologic staging suggested a pT3bN0 Mx high-grade urothelial carcinoma, with 58 lymph nodes examined. The patient then had two additional cycles of adjuvant CG. Within 2 mo of adjuvant chemotherapy, the patient developed pelvic pain, and computed tomography (CT) imaging suggested a 1.9-cm lesion in the left lateral wall of the vagina, which was confirmed by magnetic resonance imaging (MRI). Positron emission tomography (PET) showed uptake in the vaginal cuff lesion and several external iliac lymph nodes. The patient was started on docetaxel monotherapy, and also received pelvic radiotherapy for palliation of pain. After 2 mo, imaging indicated an increase in the vaginal cuff lesion. With patient permission, a cystectomy specimen was submitted for comprehensive genomic profiling (FoundationOne) [1] performed in the Foundation Medicine laboratory, which is certified by Clinical Laboratory Improvement Amendments and accredited by the College of American Pathologists [1]. The profiling revealed alterations in NF2 Y153*fs1, ATM V2119fs*8, ATR splice site 7349+2T>C, and TP53 R280K. Preclinical work has suggested that NF2 loss may be associated with sensitivity to rapamycin treatment,
so the patient was transitioned to a combination of everolimus (a rapamycin analog) and paclitaxel according to a dosing regimen currently being examined in a phase 2 study in urothelial carcinoma [2]. Imaging over 13 mo of therapy with this regimen showed continual regression of the vaginal cuff lesion and disappearance of the previously noted iliac adenopathy (Fig. 1). According to Response Evaluation Criteria in Solid Tumors, a partial response was observed, with a 65% decline from baseline according to cumulative measurement of the index lesion. The lesion was initially markedly PET avid, but uptake diminished substantially during the course of therapy (Fig. 1). After progression on platinum-based therapy in the firstline setting, no standard of care exists for second-line treatment of metastatic urothelial carcinoma (MUC). A multitude of cytotoxic agents and targeted therapies have been explored in single-arm phase 2 trials, with typical progression-free survival of 3–6 mo and overall survival of 6–9 mo [3]. Response rates in this setting range from 0% to 25%. This report describes an MUC patient with ATM, ATR, NF2, and TP53 alterations who exhibited disease progression over a short interval during platinum-based chemotherapy and further progression on single-agent taxane. Addition of everolimus to her systemic regimen led to a profound response that is ongoing after 13 mo. For two recently described bladder cancer patients, retrospective genomic analysis identified mTOR pathway alterations (NF2 and TSC1 truncating mutations) after the patients were singled out as extreme responders in clinical trials of targeted
Fig. 1 – Serial positron emission tomography images for a patient with metastatic urothelial carcinoma possessing an NF2 mutation (A) before initiation of paclitaxel/everolimus and (B) after 10 mo of therapy.
http://dx.doi.org/10.1016/j.eururo.2015.01.015 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Ali SM, et al. Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.01.015
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EUROPEAN UROLOGY XXX (2015) XXX–XXX
therapy [4,5]. For this case, by contrast, therapeutic decisionmaking was made directly on the basis of her genomic profile after exhaustion of standard-of-care options, and led to an extreme response. The results for this case support planned efforts such as the Alliance MATCH-UP protocol, which will prospectively treat MUC patients using targeted therapies directed at specific molecular aberrations.
metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol 2010;11:861–70. [4] Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 2012;338:221. [5] Wagle N, Grabiner BC, Van Allen EM, et al. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 2014;4:546–53.
Conflicts of interest: Siraj M. Ali, Vincent A. Miller, and Jeffrey S. Ross are
Siraj M. Alia
employees of and have equity interest in Foundation Medicine Inc.
Vincent A. Millera
Sumanta K. Pal is involved in research collaboration with Foundation
Jeffrey S. Rossa Sumanta K. Palb,*
Medicine Inc. a
References [1] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and
b
Foundation Medicine, Cambridge, MA, USA
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31: 1023–31. [2] NCT01215136. First-line everolimus +/– paclitaxel for cisplatinineligible patients with advanced urothelial carcinoma. http:// clinicaltrials.gov/ct2/show/NCT01215136
*Corresponding author. Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Tel. +1 626 2564673; Fax: +1 626 3018233. E-mail address: [email protected] (S.K. Pal).
[3] Sonpavde G, Sternberg CN, Rosenberg JE, Hahn NM, Galsky MD, Vogelzang NJ. Second-line systemic therapy and emerging drugs for
January 13, 2015
Please cite this article in press as: Ali SM, et al. Exceptional Response on Addition of Everolimus to Taxane in Urothelial Carcinoma Bearing an NF2 Mutation. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.01.015
