- Email: [email protected]
Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy
EUF-286; No. of Pages 4 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Case Series of the Month
Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy Fannie Morin a,b, Jean-Mathieu Beauregard c,d, Michelle Bergeron a,b, Molie`re Nguile Makao a,b, Louis Lacombe a,b, Vincent Fradet a,b, Yves Fradet a,b, Fre´de´ric Pouliot a,b,* a
Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Quebec City, Canada; b Division of Urology, Department of Surgery
and Oncology Axis of CHU de Québec Research Center, CHU de Québec–Université Laval, Quebec City, Canada; c Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Quebec City, Canada; d Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec–Université Laval, Quebec City, Canada
Article info Article history: Accepted February 10, 2017 Associate Editor: James Catto Keywords: Castration-resistant prostate cancer 18 F-Fluorodeoxyglucose Heterogeneity Metastasis Positron emission tomography Prostate cancer Therapeutic response
Abstract Although intrapatient heterogeneity of prostate cancer (PCa) has recently been characterized via genomic and transcriptomic studies, the heterogeneity of systemic treatment responses has yet to be reported or imaged. Our objective was to evaluate the intrapatient intermetastasis response to systemic treatment among patients with metastatic PCa. We evaluated the metabolic response for each individual metastatic lesion (n = 165) in 15 patients with metastatic PCa who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before and at least 3 mo after initiation of a systemic therapy that did not change in that period. Intermetastasis heterogeneity was defined as opposite metabolic responses for at least two metastases from the same compartment (bone or soft tissue) between the two time points. We found intrapatient intermetastasis response heterogeneity in 40% of the cases in our retrospective series. Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful in identifying clinical resistance early after therapy initiation and could also allow targeted biopsy of resistant clones for molecular analysis. Patient summary: Systemic therapies can lead to heterogeneous responses in individual metastases of prostate cancer in a patient. Molecular imaging may be useful for identifying heterogeneity and could allow targeted biopsy for molecular analysis or therapy. © 2017 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). * Corresponding author.: Division of Urology, Department of Surgery, Université Laval and CHU de Québec–Université Laval, 11 Côte du Palais, Quebec City, Quebec G1R 2J6, Canada. Tel.: +1 418 5254444 ext. 15561; Fax:+1 418 6913159. E-mail address: [email protected] (F. Pouliot).
1.
Case report
Recent studies have clearly established that metastatic prostate cancer (mPCa) is a heterogeneous disease according to genomic analyses of individual cells or metastases. In a landmark study, Miyamoto et al. [1] showed that in
patients with metastatic castration-resistant PCa (mCRPC), circulating tumor cells (CTCs) had heterogeneous levels of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) protein expression, and that the ratio of PSMA to PSA in CTCs could predict abiraterone acetate efficacy. In another study, the same group further
http://dx.doi.org/10.1016/j.euf.2017.02.007 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 2
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
characterized mPCa heterogeneity using single-cell exome sequencing of CTCs [2]. The clonal origin of mPCa heterogeneity was extensively characterized by Gundem et al. [3], who performed advanced whole-genome and deep sequencing analyses on metastasis biopsies. They analyzed the clonal spread of PCa between the primary tumor and metastases, and the intra- and intermetastatic subclonal differentiation under selective androgen deprivation therapy pressure. One of their key findings was that, after sharing a common clonal origin, individual metastases could differentiate independently of each other and/or the primary tumor, and subsequently spread to other metastatic niches. A clinical question arising from these groundbreaking findings is how to identify resistant metastases early enough to alter treatment and slow down further systemic spread. Therefore, identification of resistance emergence in oligometastases before the cancer spreads further would be of highly significant clinical and scientific relevance. To this end, molecular imaging using positron emission tomography/computed tomography (PET/CT) has the unique capability to quantitatively measure changes in tumor metabolism in each individual metastasis. Our study in high-risk PCa [4] and that of Jadvar et al. in mCPRC [5] showed that 18F-fluorodeoxyglucose (FDG) PET/CT can discriminate aggressive from more indolent PCa. For this retrospective series, we investigated whether FDG-PET/CT can identify heterogeneous metabolic responses between several metastases in the same patient undergoing systemic therapy for mPCa, and whether response heterogeneity is associated with progression-free survival (PFS). 1.1.
Patients and results
After institutional review board approval, we retrospectively analyzed data for 15 mPCa patients who underwent FDG-PET/CT before and after more than 3 mo of systemic therapy (median 122 d) between 2010 and 2015. If systemic therapy was stopped or changed during the period between the two scans, the patient was excluded. The maximum standardized uptake value (SUVmax) for each lesion was
computed at the two time points using Hybrid Viewer software (Hermes Medical Solutions, Stockholm, Sweden). The percentage SUVmax variations for individual metastases were then calculated. Following PET Response Criteria in Solid Tumors [6], a 30% change in SUVmax was considered clinically significant [6]. Biochemical progression was defined as two successive increases of more than 25% in serum PSA at least 3 mo after therapy initiation [7]. A patient’s response was considered to be heterogeneous when, in the same compartment (bone or soft tissue): (1) at least one lesion progressed (progressive metabolic disease or new lesion) while another showed a decrease in SUVmax; or (2) at least one lesion responded (complete or partial metabolic response) while another had an increase in SUVmax. Thus, for a patient to meet the heterogeneity criteria, one of his metastases had to show an increase and one a decrease in FDG uptake between the two scans. Moreover, the difference in FDG uptake changes between the two divergent lesions had to be greater than 30%. Fig. 1A shows an example of response heterogeneity in a CRPC patient. We analyzed a total of 165 metastases in 15 patients. Fig. 2 shows the patient characteristics for our series. The series included seven patients with castration-sensitive PCa and eight with CRPC (including 1 case of neuroendocrine differentiation). Six CRPC patients were treated with firstline systemic therapy, while one received a second-line and another a third-line systemic therapy. A heat plot was constructed to illustrate heterogeneous responses in each compartment, with each color representing a category of metabolic response (Fig. 2). The patient responses varied from homogeneous (100% metabolic response, patients 11 and 13) to highly heterogeneous (patients 1 and 4). Overall, 40% (6/15) of the mPCa patients showed response heterogeneity to systemic therapy. On univariate statistical analysis, response heterogeneity was associated with lower PFS (p = 0.001, log-rank test; Fig. 3). Therefore, our results show that in patients with response heterogeneity, some metastases regressed under treatment while others progressed. The latter represents the first evidence of therapeutic resistance, which may not be reflected by the initial biochemical response.
Fig. 1 – Intermetastasis metabolic response heterogeneity in a patient with castration-resistant prostate cancer (CRPC). Whole-body FDG-PET/CT (A,B) before and during (C, D) abiraterone acetate therapy in a patient with metastatic CRPC (patient 4). (A,D) Maximum intensity projection (MIP) of wholebody PET (A) before and (D) during treatment. (B,C) Upper scans: transverse PET/CT fusion at level T12 showing a progressive lesion during treatment (red arrow). Lower scans: transverse PET/CT fusion at level L5 showing a responding bone lesion (green arrow). FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography; CT = computed tomography.
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
3
Fig. 2 – Clustering of the metabolic responses of individual prostate cancer metastases to systemic treatments reveals heterogeneous intrapatient behavior.
2.
Discussion
In this retrospective case series, we showed that the metabolic response of mPCa to systemic therapy can be heterogeneous, which supports the polyclonal evolution of advanced PCa. We also observed that intrapatient response heterogeneity was associated with a decrease in biochemical PFS. While PCa heterogeneity between patients or between intraprostatic tumor foci is well accepted, the importance of intrapatient intermetastasis heterogeneity remains unclear. While two studies showed intermetastasis heterogeneity and the polyclonal evolution of mPCa, another found only limited intrapatient heterogeneity [3,8,9]. As these studies were based on omics analyses from a total of 277 metastases in 90 patients (an average of only 3.1 biopsies per patient), it cannot be excluded that some divergent clones (heterogeneous metastases) may not have been sampled. In our study, this limitation was avoided via whole-body molecular imaging. We analyzed 165 metastases from 15 patients (2–41 lesions per patient, 11 on average) challenged by 1.00
+
Non-heterogeneous Heterogeneous
Survival (%)
+ 0.75
0.50
+ 0.25
+
+
p = 0.001
0.00 0
200
400
600
800
Time (d) Fig. 3 – Progression-free survival curves.
systemic therapies. By showing that metabolic response is heterogeneous among individual metastases under treatment pressure and that new metastases may develop while others completely respond, our results support those of Gundem et al. [3] and Beltran et al. [9]. In our opinion, the association between response heterogeneity and PFS further supports the clinical relevance of this observation. Our successful imaging of intrapatient response heterogeneity using FDG-PET/CT suggest that this technique may help to improve biopsy sampling in future molecular studies on the heterogeneity of PCa therapeutic responses. Our results therefore set a basis for the planning of new studies aimed at redefining imaging-based response criteria in PCa and the role of PET/CT with FDG and other promising radiopharmaceuticals for assessing both overall and perlesion responses, which may not be as accurate with conventional imaging [10]. Molecular imaging could then possibly become the earliest indicator of progressive disease and might trigger a treatment change. Further identification of any correlation of early metabolic progression (including heterogeneity) with strong clinical outcomes is required. Our study has some limitations. Because this was a retrospective series in a limited number of patients, the variables associated with response heterogeneity could not be fully elucidated. For example, we cannot exclude that variables other than PFS are associated with response heterogeneity or that the latter is an independent risk factor for shorter PFS. In addition, other PET radiopharmaceuticals such as 18F/11C-choline, 18F-dihydrotestosterone, and prostate-specific membrane antigen–binding tracers may potentially better characterize therapeutic response, as these are more sensitive for imaging of PCa [10]. Nevertheless, FDG could possibly better identify PCa with more aggressive behavior and hence at higher risk of rapid progression [4,5]. Finally, because FDG-PET/CT–guided biopsies
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 4
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
were not performed, we were unable to correlate the PET findings with genomic/proteomic alterations. Despite these limitations, we provided evidence of PCa response heterogeneity in a significant proportion of patients. In conclusion, our results suggest that in many PCa patients, systemic therapies yield heterogeneous responses among individual metastases, supporting the evidence of polyclonal evolution in advanced metastatic PCa. Molecular imaging of intrapatient intermetastasis heterogeneity with FDG-PET/CT therefore shows promise for better and earlier identification of resistant metastases for molecular characterization and redefinition of progressive disease.
(FQRS) for clinician-scientists (FQRS-22830). The sponsors played no direct role in this study.
References [1] Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov 220129951003. [2] Miyamoto DT, Zheng Y, Wittner BS, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 2015;349:1351–6. [3] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353–7. [4] Beauregard JM, Blouin AC, Fradet V, et al. FDG-PET/CT for pre-
Conflicts of interest: Frédéric Pouliot is or has been a speaker for Astellas,
operative staging and prognostic stratification of patients with
Ferring, Amgen, and Sanofi, and a consultant for Amgen, AstraZeneca,
high-grade prostate cancer at biopsy. Cancer Imaging 2015;15:2.
Astellas, Ferring, Janssen, Sanofi, and Pfizer. He holds research agreements with AstraZeneca, Astellas, Janssen, and Sanofi. Louis Lacombe is
[5] Jadvar H. Molecular imaging of prostate cancer with PET. J Nucl Med 2013;54:1685–8.
working on clinical research with Roche, GlaxoSmithKline, AstraZeneca,
[6] Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST:
MedImmune, Janssen, Medivation, Merck, and Astellas. Vincent Fradet is
evolving considerations for PET response criteria in solid tumors. J
a speaker for Abbvie, Bayer, Ferring, Janssen, and Sanofi, and a consultant
Nucl Med 2009;50:122S–50S, Sul 1.
for Amgen, AstraZeneca, Astellas, Bayer, Ferring, Janssen, and Sanofi. He
[7] Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical
has research agreements with Abbvie, Amgen, AstraZeneca, Astellas,
trials for patients with progressive prostate cancer and castrate
Janssen, and Sanofi. Yves Fradet is an advisory board member for Bayer,
levels of testosterone: recommendations of the Prostate Cancer
Astellas, Roche, AstraZeneca, Sanofi, Merck, and Amgen, and has
Clinical Trials Working Group. J Clin Oncol 2008;26:1148–59.
received research funding from Astellas. Fannie Morin, Jean-Mathieu
[8] Kumar A, Coleman I, Morrissey C, et al. Substantial interindividual
Beauregard, Michelle Bergeron, and Molière Nguile Makao have nothing to
and limited intraindividual genomic diversity among tumors from
disclose.
men with metastatic prostate cancer. Nat Med 2016;22:369–78. [9] Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution
Acknowledgments: Frédéric Pouliot was supported by Movember Canada
of castration-resistant neuroendocrine prostate cancer. Nat Med
and Prostate Cancer Canada (PCC Movember New Investigator pilot grant
2016;22:298–305.
2012-9 33 and Rising Star Grant RS2014-04), Canadian Urological Associa-
[10] Beauregard JM, Pouliot F. New developments in the imaging of meta-
tion Scholarship Funds, and Fonds du Québec de la Recherche en Santé
static prostate cancer. Curr Opin Support Palliat Care 2014;8:265–70.
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Case Series of the Month
Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy Fannie Morin a,b, Jean-Mathieu Beauregard c,d, Michelle Bergeron a,b, Molie`re Nguile Makao a,b, Louis Lacombe a,b, Vincent Fradet a,b, Yves Fradet a,b, Fre´de´ric Pouliot a,b,* a
Division of Urology, Department of Surgery and Cancer Research Center, Université Laval, Quebec City, Canada; b Division of Urology, Department of Surgery
and Oncology Axis of CHU de Québec Research Center, CHU de Québec–Université Laval, Quebec City, Canada; c Division of Nuclear Medicine, Department of Radiology and Nuclear Medicine and Cancer Research Center, Université Laval, Quebec City, Canada; d Division of Nuclear Medicine, Department of Medical Imaging and Oncology Axis of CHU de Québec Research Center, CHU de Québec–Université Laval, Quebec City, Canada
Article info Article history: Accepted February 10, 2017 Associate Editor: James Catto Keywords: Castration-resistant prostate cancer 18 F-Fluorodeoxyglucose Heterogeneity Metastasis Positron emission tomography Prostate cancer Therapeutic response
Abstract Although intrapatient heterogeneity of prostate cancer (PCa) has recently been characterized via genomic and transcriptomic studies, the heterogeneity of systemic treatment responses has yet to be reported or imaged. Our objective was to evaluate the intrapatient intermetastasis response to systemic treatment among patients with metastatic PCa. We evaluated the metabolic response for each individual metastatic lesion (n = 165) in 15 patients with metastatic PCa who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before and at least 3 mo after initiation of a systemic therapy that did not change in that period. Intermetastasis heterogeneity was defined as opposite metabolic responses for at least two metastases from the same compartment (bone or soft tissue) between the two time points. We found intrapatient intermetastasis response heterogeneity in 40% of the cases in our retrospective series. Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful in identifying clinical resistance early after therapy initiation and could also allow targeted biopsy of resistant clones for molecular analysis. Patient summary: Systemic therapies can lead to heterogeneous responses in individual metastases of prostate cancer in a patient. Molecular imaging may be useful for identifying heterogeneity and could allow targeted biopsy for molecular analysis or therapy. © 2017 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). * Corresponding author.: Division of Urology, Department of Surgery, Université Laval and CHU de Québec–Université Laval, 11 Côte du Palais, Quebec City, Quebec G1R 2J6, Canada. Tel.: +1 418 5254444 ext. 15561; Fax:+1 418 6913159. E-mail address: [email protected] (F. Pouliot).
1.
Case report
Recent studies have clearly established that metastatic prostate cancer (mPCa) is a heterogeneous disease according to genomic analyses of individual cells or metastases. In a landmark study, Miyamoto et al. [1] showed that in
patients with metastatic castration-resistant PCa (mCRPC), circulating tumor cells (CTCs) had heterogeneous levels of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) protein expression, and that the ratio of PSMA to PSA in CTCs could predict abiraterone acetate efficacy. In another study, the same group further
http://dx.doi.org/10.1016/j.euf.2017.02.007 2405-4569/© 2017 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 2
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
characterized mPCa heterogeneity using single-cell exome sequencing of CTCs [2]. The clonal origin of mPCa heterogeneity was extensively characterized by Gundem et al. [3], who performed advanced whole-genome and deep sequencing analyses on metastasis biopsies. They analyzed the clonal spread of PCa between the primary tumor and metastases, and the intra- and intermetastatic subclonal differentiation under selective androgen deprivation therapy pressure. One of their key findings was that, after sharing a common clonal origin, individual metastases could differentiate independently of each other and/or the primary tumor, and subsequently spread to other metastatic niches. A clinical question arising from these groundbreaking findings is how to identify resistant metastases early enough to alter treatment and slow down further systemic spread. Therefore, identification of resistance emergence in oligometastases before the cancer spreads further would be of highly significant clinical and scientific relevance. To this end, molecular imaging using positron emission tomography/computed tomography (PET/CT) has the unique capability to quantitatively measure changes in tumor metabolism in each individual metastasis. Our study in high-risk PCa [4] and that of Jadvar et al. in mCPRC [5] showed that 18F-fluorodeoxyglucose (FDG) PET/CT can discriminate aggressive from more indolent PCa. For this retrospective series, we investigated whether FDG-PET/CT can identify heterogeneous metabolic responses between several metastases in the same patient undergoing systemic therapy for mPCa, and whether response heterogeneity is associated with progression-free survival (PFS). 1.1.
Patients and results
After institutional review board approval, we retrospectively analyzed data for 15 mPCa patients who underwent FDG-PET/CT before and after more than 3 mo of systemic therapy (median 122 d) between 2010 and 2015. If systemic therapy was stopped or changed during the period between the two scans, the patient was excluded. The maximum standardized uptake value (SUVmax) for each lesion was
computed at the two time points using Hybrid Viewer software (Hermes Medical Solutions, Stockholm, Sweden). The percentage SUVmax variations for individual metastases were then calculated. Following PET Response Criteria in Solid Tumors [6], a 30% change in SUVmax was considered clinically significant [6]. Biochemical progression was defined as two successive increases of more than 25% in serum PSA at least 3 mo after therapy initiation [7]. A patient’s response was considered to be heterogeneous when, in the same compartment (bone or soft tissue): (1) at least one lesion progressed (progressive metabolic disease or new lesion) while another showed a decrease in SUVmax; or (2) at least one lesion responded (complete or partial metabolic response) while another had an increase in SUVmax. Thus, for a patient to meet the heterogeneity criteria, one of his metastases had to show an increase and one a decrease in FDG uptake between the two scans. Moreover, the difference in FDG uptake changes between the two divergent lesions had to be greater than 30%. Fig. 1A shows an example of response heterogeneity in a CRPC patient. We analyzed a total of 165 metastases in 15 patients. Fig. 2 shows the patient characteristics for our series. The series included seven patients with castration-sensitive PCa and eight with CRPC (including 1 case of neuroendocrine differentiation). Six CRPC patients were treated with firstline systemic therapy, while one received a second-line and another a third-line systemic therapy. A heat plot was constructed to illustrate heterogeneous responses in each compartment, with each color representing a category of metabolic response (Fig. 2). The patient responses varied from homogeneous (100% metabolic response, patients 11 and 13) to highly heterogeneous (patients 1 and 4). Overall, 40% (6/15) of the mPCa patients showed response heterogeneity to systemic therapy. On univariate statistical analysis, response heterogeneity was associated with lower PFS (p = 0.001, log-rank test; Fig. 3). Therefore, our results show that in patients with response heterogeneity, some metastases regressed under treatment while others progressed. The latter represents the first evidence of therapeutic resistance, which may not be reflected by the initial biochemical response.
Fig. 1 – Intermetastasis metabolic response heterogeneity in a patient with castration-resistant prostate cancer (CRPC). Whole-body FDG-PET/CT (A,B) before and during (C, D) abiraterone acetate therapy in a patient with metastatic CRPC (patient 4). (A,D) Maximum intensity projection (MIP) of wholebody PET (A) before and (D) during treatment. (B,C) Upper scans: transverse PET/CT fusion at level T12 showing a progressive lesion during treatment (red arrow). Lower scans: transverse PET/CT fusion at level L5 showing a responding bone lesion (green arrow). FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography; CT = computed tomography.
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
3
Fig. 2 – Clustering of the metabolic responses of individual prostate cancer metastases to systemic treatments reveals heterogeneous intrapatient behavior.
2.
Discussion
In this retrospective case series, we showed that the metabolic response of mPCa to systemic therapy can be heterogeneous, which supports the polyclonal evolution of advanced PCa. We also observed that intrapatient response heterogeneity was associated with a decrease in biochemical PFS. While PCa heterogeneity between patients or between intraprostatic tumor foci is well accepted, the importance of intrapatient intermetastasis heterogeneity remains unclear. While two studies showed intermetastasis heterogeneity and the polyclonal evolution of mPCa, another found only limited intrapatient heterogeneity [3,8,9]. As these studies were based on omics analyses from a total of 277 metastases in 90 patients (an average of only 3.1 biopsies per patient), it cannot be excluded that some divergent clones (heterogeneous metastases) may not have been sampled. In our study, this limitation was avoided via whole-body molecular imaging. We analyzed 165 metastases from 15 patients (2–41 lesions per patient, 11 on average) challenged by 1.00
+
Non-heterogeneous Heterogeneous
Survival (%)
+ 0.75
0.50
+ 0.25
+
+
p = 0.001
0.00 0
200
400
600
800
Time (d) Fig. 3 – Progression-free survival curves.
systemic therapies. By showing that metabolic response is heterogeneous among individual metastases under treatment pressure and that new metastases may develop while others completely respond, our results support those of Gundem et al. [3] and Beltran et al. [9]. In our opinion, the association between response heterogeneity and PFS further supports the clinical relevance of this observation. Our successful imaging of intrapatient response heterogeneity using FDG-PET/CT suggest that this technique may help to improve biopsy sampling in future molecular studies on the heterogeneity of PCa therapeutic responses. Our results therefore set a basis for the planning of new studies aimed at redefining imaging-based response criteria in PCa and the role of PET/CT with FDG and other promising radiopharmaceuticals for assessing both overall and perlesion responses, which may not be as accurate with conventional imaging [10]. Molecular imaging could then possibly become the earliest indicator of progressive disease and might trigger a treatment change. Further identification of any correlation of early metabolic progression (including heterogeneity) with strong clinical outcomes is required. Our study has some limitations. Because this was a retrospective series in a limited number of patients, the variables associated with response heterogeneity could not be fully elucidated. For example, we cannot exclude that variables other than PFS are associated with response heterogeneity or that the latter is an independent risk factor for shorter PFS. In addition, other PET radiopharmaceuticals such as 18F/11C-choline, 18F-dihydrotestosterone, and prostate-specific membrane antigen–binding tracers may potentially better characterize therapeutic response, as these are more sensitive for imaging of PCa [10]. Nevertheless, FDG could possibly better identify PCa with more aggressive behavior and hence at higher risk of rapid progression [4,5]. Finally, because FDG-PET/CT–guided biopsies
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007
EUF-286; No. of Pages 4 4
E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 17 ) X X X – X X X
were not performed, we were unable to correlate the PET findings with genomic/proteomic alterations. Despite these limitations, we provided evidence of PCa response heterogeneity in a significant proportion of patients. In conclusion, our results suggest that in many PCa patients, systemic therapies yield heterogeneous responses among individual metastases, supporting the evidence of polyclonal evolution in advanced metastatic PCa. Molecular imaging of intrapatient intermetastasis heterogeneity with FDG-PET/CT therefore shows promise for better and earlier identification of resistant metastases for molecular characterization and redefinition of progressive disease.
(FQRS) for clinician-scientists (FQRS-22830). The sponsors played no direct role in this study.
References [1] Miyamoto DT, Lee RJ, Stott SL, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov 220129951003. [2] Miyamoto DT, Zheng Y, Wittner BS, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 2015;349:1351–6. [3] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature 2015;520:353–7. [4] Beauregard JM, Blouin AC, Fradet V, et al. FDG-PET/CT for pre-
Conflicts of interest: Frédéric Pouliot is or has been a speaker for Astellas,
operative staging and prognostic stratification of patients with
Ferring, Amgen, and Sanofi, and a consultant for Amgen, AstraZeneca,
high-grade prostate cancer at biopsy. Cancer Imaging 2015;15:2.
Astellas, Ferring, Janssen, Sanofi, and Pfizer. He holds research agreements with AstraZeneca, Astellas, Janssen, and Sanofi. Louis Lacombe is
[5] Jadvar H. Molecular imaging of prostate cancer with PET. J Nucl Med 2013;54:1685–8.
working on clinical research with Roche, GlaxoSmithKline, AstraZeneca,
[6] Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST:
MedImmune, Janssen, Medivation, Merck, and Astellas. Vincent Fradet is
evolving considerations for PET response criteria in solid tumors. J
a speaker for Abbvie, Bayer, Ferring, Janssen, and Sanofi, and a consultant
Nucl Med 2009;50:122S–50S, Sul 1.
for Amgen, AstraZeneca, Astellas, Bayer, Ferring, Janssen, and Sanofi. He
[7] Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical
has research agreements with Abbvie, Amgen, AstraZeneca, Astellas,
trials for patients with progressive prostate cancer and castrate
Janssen, and Sanofi. Yves Fradet is an advisory board member for Bayer,
levels of testosterone: recommendations of the Prostate Cancer
Astellas, Roche, AstraZeneca, Sanofi, Merck, and Amgen, and has
Clinical Trials Working Group. J Clin Oncol 2008;26:1148–59.
received research funding from Astellas. Fannie Morin, Jean-Mathieu
[8] Kumar A, Coleman I, Morrissey C, et al. Substantial interindividual
Beauregard, Michelle Bergeron, and Molière Nguile Makao have nothing to
and limited intraindividual genomic diversity among tumors from
disclose.
men with metastatic prostate cancer. Nat Med 2016;22:369–78. [9] Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution
Acknowledgments: Frédéric Pouliot was supported by Movember Canada
of castration-resistant neuroendocrine prostate cancer. Nat Med
and Prostate Cancer Canada (PCC Movember New Investigator pilot grant
2016;22:298–305.
2012-9 33 and Rising Star Grant RS2014-04), Canadian Urological Associa-
[10] Beauregard JM, Pouliot F. New developments in the imaging of meta-
tion Scholarship Funds, and Fonds du Québec de la Recherche en Santé
static prostate cancer. Curr Opin Support Palliat Care 2014;8:265–70.
Please cite this article in press as: Morin F, et al. Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy. Eur Urol Focus (2017), http://dx.doi.org/10.1016/j.euf.2017.02.007