Annals of Oncology Advance Access published May 7, 2015
Prioritizing precision medicine for prostate cancer
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Fudan University on May 8, 2015
Prostate cancer is the most commonly diagnosed cancer in men and the third most common cause of male-cancer-related mortality in Europe [1]. Overtreatment of prostate cancer in men who have indolent disease but that would not become clinically manifest in their life-time is a significant health burden with only one life saved for every 33 men treated in a PSA-screened population [2]. A reduction in overtreatment must however not sacrifice current cure rates. To achieve this, improvements in tumor risk stratification require multimodality approaches including better imaging and molecular subtyping. At the other end of the disease spectrum, patients with metastatic disease invariably become resistant to castration, hormonal manipulations and chemotherapy. The successful development of new drugs and improved sequencing of currently approved agents will probably require biomarker-driven strategies to select patients for the next line of treatment based on their underlying molecular aberrations. To achieve these aims for prostate cancer as for several other cancer types, Annals of Oncology is prioritizing precision medicine studies that contribute to treatment optimization through improved characterization of tumors [3]. A significant clinical impact will only become reality with approaches that are broadly applicable to clinical samples (of widely variable quality) and using high-throughput, affordable and rapid turnaround technology. Assays will have to work on formalin-fixed samples, bone biopsies or circulating biomarkers such as circulating tumor cells or circulating cell-free DNA. In this issue of Annals of Oncology, the Tomlins lab describes MiPC that uses targeted next-generation sequencing and RT-PCR to study DNA and mRNA in 53 formalin-fixed and clinically representative prostate cancer samples [4]. Our understanding of the molecular aberrations and drivers that underlie prostate cancer has increased significantly over the past decade so this report is timely. A number of mutually exclusive aberrations have been described that split the disease into the distinct molecular subtypes used in this study (Figure 1 and reviewed in [5]). The most commonly occurring molecular subtype is characterized by fusion of ERG, a member of the ETS family of transcription factors, with a hormone-driven promoter most commonly TMPRSS2. Other subtypes are less common and characterized by fusions involving other ETS or RAF family members or (often co-occurring) overexpression of SPINK1, loss of CHD1 and point mutations in SPOP. Up to a quarter of prostate cancers do not fit into any of these subtypes, as also observed in this current series. Additionally, multiple molecular
aberrations span these subtypes, can occur at various stages of disease progression to the lethal phenotype and some have been associated with a worse prognosis or drug resistance, including for example loss of PTEN or gain of aurora kinase A [6, 7]. There are a number of commercially available assays and companies that have optimized assays for performing targeted exome-sequencing on formalin-fixed tissue with a rapid turnaround (∼2–3 weeks). MiPC improves on these by simultaneously integrating RNA-based data to detect gene fusions and evaluate androgen receptor (AR) signaling and proliferation. This will allow stratification of prostate cancer into the abovedescribed molecular subtypes (Figure 1) and identification of other molecular signatures that could inform on best treatment selection. These could for example lead to selection of patients for AR targeting treatments based on activation of AR signaling with or without increased levels of splice variants lacking the ligand-binding domain [8], for taxanes based on loss of RB1 [9] or for DNA damaging agents such as platinum and PARP inhibitors based on aberrations in BRCA genes [10]. Nucleic acids from decalcified bone marrow biopsies were not amenable to characterization in the current study. In the majority of patients with advanced prostate cancer, the sole metastatic site that tumor tissue can be obtained from is bone and approaches for processing bone biopsies that avoid decalcification are required for MiPC. The one qualification to the imminent broad introduction of MiPC is that none of the defined markers of molecular subtypes have been validated for risk stratification of prostate cancer at diagnosis and prostate cancer does not yet have a biomarker indication that predicts treatment response. The recent approval of several new agents has been achieved in molecularly unselected populations. In the multicenter COU-AA-302 abiraterone phase III clinical trial in chemotherapy-naïve CRPC patients, formalin-fixed paraffin embedded (FFPE) archival samples were collected for evaluation of ERG gene fusions from close to half of the 1088 accrued patients [11]. A subclass detected by fluorescence in situ hybridization (FISH) characterized by an ERG gene fusion with a deletion and duplication or triplication of ERG gene fusion sequences appeared to have a greater benefit than other molecular subtypes but the improvement in benefit was not sufficiently great to warrant evaluation of ERG in isolation. Nonetheless, the study emphasized the feasibility and potential utility of characterizing archival prostate cancer FFPE tissue in large multicenter trials and suggested that multiplex approaches such as MiPC may be required to improve patient selection for AR-targeting therapies. Also, samples collected immediately before treatment initiation will probably be required to identify AR aberrations that associate with resistance and this may require evaluation of both tissues using an adapted MiPC panel and circulating biomarkers [8, 12]. Moreover, several
editorial
Annals of Oncology 00: 1–2, 2015 doi:10.1093/annonc/mdv179
editorial
editorial
Annals of Oncology
Prostate cancer molecular subtypes Spink1+ SPOPmut CHD1–
RAS/RAF+
disclosure
Unknown/Private
ERG+
FLI1+ ETV5+ ETV4+
Damon Runyon Cancer Research Foundation and the U.S. Department of Defense.
ETV1
GA has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Takeda, Abbott and Sanofi-Aventis, and grant support from Janssen, AstraZeneca and Arno. The Institute of Cancer Research has a commercial interest in abiraterone and the development of agents targeting the PI3K-AKT pathway, HSP90 and PARP. GA is on the ICR list of rewards to inventors for abiraterone. HB has received consulting fees from Bayer Healthcare and research funding from Janssen, Astellas, Eli Lilly and Millennium Pharmaceuticals.
Figure 1. Prostate cancer molecular subtypes.
references
1
G. Attard1* & H. Beltran2 The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK; 2 Division of Medicine, Weill Cornell Medical College, New York, USA (*E-mail: [email protected])
funding GA was supported by a Cancer Research UK clinician scientist fellowship and also receives funding from Prostate Cancer UK and Movember. GA and HB both receive funding from the Prostate Cancer Foundation. HB receives funding from the
| Attard and Beltran
1. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann Oncol 2014; 25: 1650–1656. 2. Schroder FH, Hugosson J, Roobol MJ et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981–990. 3. Soria J-C. Annals of Oncology: an editorial perspective. Ann Oncol 2014; 25: 5–6. 4. Grasso CS, Cani AK, Hovelson DH et al. Integrative molecular profiling of routine clinical prostate cancer specimens. Ann Oncol 2015 Mar 3 [epub ahead of print], doi:10.1093/annonc/mdv134. 5. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol 2011; 29: 3659–3668. 6. Beltran H, Rickman DS, Park K et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 2011; 1: 487–495. 7. Ferraldeschi R, Nava Rodrigues D, Riisnaes R et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol 2015; 67: 795–802. 8. Antonarakis ES, Lu C, Wang H et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–1038. 9. de Leeuw R, Berman-Booty LD, Schiewer MJ et al. Novel actions of nextgeneration taxanes benefit advanced stages of prostate cancer. Clin Cancer Res 2015; 21: 795–807. 10. Fong PC, Boss DS, Yap TA et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–134. 11. Attard G, de Bono JS, Logothetis CJ et al. Improvements in radiographic progression-free survival stratified by ERG gene status in castration-resistant prostate cancer patients treated with abiraterone. Clin Cancer Res 2015; 21: 1621–1627. 12. Carreira S, Romanel A, Goodall J et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med 2014; 6: 254ra125.
Downloaded from http://annonc.oxfordjournals.org/ at Fudan University on May 8, 2015
agents are now undergoing evaluation in clinical trials that target distinct molecular aberrations in prostate cancer and strategies such as MiPC could be used to achieve patient enrichment or selection for trials of these agents. Finally, two large PCF-SU2C-AACR dream team consortia are currently extensively characterizing up to 1000 drug-resistant CRPCs. These studies should give more information on clinically applicable targets. The roll-out of these into clinical practice aiming to impact patient management could ultimately be most feasible using targeted molecular characterization approaches such as MiPC. This is therefore an important contribution to the goal of leveraging precision medicine to improve the outcomes of prostate cancer patients.
Prioritizing precision medicine for prostate cancer
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Fudan University on May 8, 2015
Prostate cancer is the most commonly diagnosed cancer in men and the third most common cause of male-cancer-related mortality in Europe [1]. Overtreatment of prostate cancer in men who have indolent disease but that would not become clinically manifest in their life-time is a significant health burden with only one life saved for every 33 men treated in a PSA-screened population [2]. A reduction in overtreatment must however not sacrifice current cure rates. To achieve this, improvements in tumor risk stratification require multimodality approaches including better imaging and molecular subtyping. At the other end of the disease spectrum, patients with metastatic disease invariably become resistant to castration, hormonal manipulations and chemotherapy. The successful development of new drugs and improved sequencing of currently approved agents will probably require biomarker-driven strategies to select patients for the next line of treatment based on their underlying molecular aberrations. To achieve these aims for prostate cancer as for several other cancer types, Annals of Oncology is prioritizing precision medicine studies that contribute to treatment optimization through improved characterization of tumors [3]. A significant clinical impact will only become reality with approaches that are broadly applicable to clinical samples (of widely variable quality) and using high-throughput, affordable and rapid turnaround technology. Assays will have to work on formalin-fixed samples, bone biopsies or circulating biomarkers such as circulating tumor cells or circulating cell-free DNA. In this issue of Annals of Oncology, the Tomlins lab describes MiPC that uses targeted next-generation sequencing and RT-PCR to study DNA and mRNA in 53 formalin-fixed and clinically representative prostate cancer samples [4]. Our understanding of the molecular aberrations and drivers that underlie prostate cancer has increased significantly over the past decade so this report is timely. A number of mutually exclusive aberrations have been described that split the disease into the distinct molecular subtypes used in this study (Figure 1 and reviewed in [5]). The most commonly occurring molecular subtype is characterized by fusion of ERG, a member of the ETS family of transcription factors, with a hormone-driven promoter most commonly TMPRSS2. Other subtypes are less common and characterized by fusions involving other ETS or RAF family members or (often co-occurring) overexpression of SPINK1, loss of CHD1 and point mutations in SPOP. Up to a quarter of prostate cancers do not fit into any of these subtypes, as also observed in this current series. Additionally, multiple molecular
aberrations span these subtypes, can occur at various stages of disease progression to the lethal phenotype and some have been associated with a worse prognosis or drug resistance, including for example loss of PTEN or gain of aurora kinase A [6, 7]. There are a number of commercially available assays and companies that have optimized assays for performing targeted exome-sequencing on formalin-fixed tissue with a rapid turnaround (∼2–3 weeks). MiPC improves on these by simultaneously integrating RNA-based data to detect gene fusions and evaluate androgen receptor (AR) signaling and proliferation. This will allow stratification of prostate cancer into the abovedescribed molecular subtypes (Figure 1) and identification of other molecular signatures that could inform on best treatment selection. These could for example lead to selection of patients for AR targeting treatments based on activation of AR signaling with or without increased levels of splice variants lacking the ligand-binding domain [8], for taxanes based on loss of RB1 [9] or for DNA damaging agents such as platinum and PARP inhibitors based on aberrations in BRCA genes [10]. Nucleic acids from decalcified bone marrow biopsies were not amenable to characterization in the current study. In the majority of patients with advanced prostate cancer, the sole metastatic site that tumor tissue can be obtained from is bone and approaches for processing bone biopsies that avoid decalcification are required for MiPC. The one qualification to the imminent broad introduction of MiPC is that none of the defined markers of molecular subtypes have been validated for risk stratification of prostate cancer at diagnosis and prostate cancer does not yet have a biomarker indication that predicts treatment response. The recent approval of several new agents has been achieved in molecularly unselected populations. In the multicenter COU-AA-302 abiraterone phase III clinical trial in chemotherapy-naïve CRPC patients, formalin-fixed paraffin embedded (FFPE) archival samples were collected for evaluation of ERG gene fusions from close to half of the 1088 accrued patients [11]. A subclass detected by fluorescence in situ hybridization (FISH) characterized by an ERG gene fusion with a deletion and duplication or triplication of ERG gene fusion sequences appeared to have a greater benefit than other molecular subtypes but the improvement in benefit was not sufficiently great to warrant evaluation of ERG in isolation. Nonetheless, the study emphasized the feasibility and potential utility of characterizing archival prostate cancer FFPE tissue in large multicenter trials and suggested that multiplex approaches such as MiPC may be required to improve patient selection for AR-targeting therapies. Also, samples collected immediately before treatment initiation will probably be required to identify AR aberrations that associate with resistance and this may require evaluation of both tissues using an adapted MiPC panel and circulating biomarkers [8, 12]. Moreover, several
editorial
Annals of Oncology 00: 1–2, 2015 doi:10.1093/annonc/mdv179
editorial
editorial
Annals of Oncology
Prostate cancer molecular subtypes Spink1+ SPOPmut CHD1–
RAS/RAF+
disclosure
Unknown/Private
ERG+
FLI1+ ETV5+ ETV4+
Damon Runyon Cancer Research Foundation and the U.S. Department of Defense.
ETV1
GA has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen, Takeda, Abbott and Sanofi-Aventis, and grant support from Janssen, AstraZeneca and Arno. The Institute of Cancer Research has a commercial interest in abiraterone and the development of agents targeting the PI3K-AKT pathway, HSP90 and PARP. GA is on the ICR list of rewards to inventors for abiraterone. HB has received consulting fees from Bayer Healthcare and research funding from Janssen, Astellas, Eli Lilly and Millennium Pharmaceuticals.
Figure 1. Prostate cancer molecular subtypes.
references
1
G. Attard1* & H. Beltran2 The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK; 2 Division of Medicine, Weill Cornell Medical College, New York, USA (*E-mail: [email protected])
funding GA was supported by a Cancer Research UK clinician scientist fellowship and also receives funding from Prostate Cancer UK and Movember. GA and HB both receive funding from the Prostate Cancer Foundation. HB receives funding from the
| Attard and Beltran
1. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann Oncol 2014; 25: 1650–1656. 2. Schroder FH, Hugosson J, Roobol MJ et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981–990. 3. Soria J-C. Annals of Oncology: an editorial perspective. Ann Oncol 2014; 25: 5–6. 4. Grasso CS, Cani AK, Hovelson DH et al. Integrative molecular profiling of routine clinical prostate cancer specimens. Ann Oncol 2015 Mar 3 [epub ahead of print], doi:10.1093/annonc/mdv134. 5. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol 2011; 29: 3659–3668. 6. Beltran H, Rickman DS, Park K et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 2011; 1: 487–495. 7. Ferraldeschi R, Nava Rodrigues D, Riisnaes R et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol 2015; 67: 795–802. 8. Antonarakis ES, Lu C, Wang H et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–1038. 9. de Leeuw R, Berman-Booty LD, Schiewer MJ et al. Novel actions of nextgeneration taxanes benefit advanced stages of prostate cancer. Clin Cancer Res 2015; 21: 795–807. 10. Fong PC, Boss DS, Yap TA et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–134. 11. Attard G, de Bono JS, Logothetis CJ et al. Improvements in radiographic progression-free survival stratified by ERG gene status in castration-resistant prostate cancer patients treated with abiraterone. Clin Cancer Res 2015; 21: 1621–1627. 12. Carreira S, Romanel A, Goodall J et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med 2014; 6: 254ra125.
Downloaded from http://annonc.oxfordjournals.org/ at Fudan University on May 8, 2015
agents are now undergoing evaluation in clinical trials that target distinct molecular aberrations in prostate cancer and strategies such as MiPC could be used to achieve patient enrichment or selection for trials of these agents. Finally, two large PCF-SU2C-AACR dream team consortia are currently extensively characterizing up to 1000 drug-resistant CRPCs. These studies should give more information on clinically applicable targets. The roll-out of these into clinical practice aiming to impact patient management could ultimately be most feasible using targeted molecular characterization approaches such as MiPC. This is therefore an important contribution to the goal of leveraging precision medicine to improve the outcomes of prostate cancer patients.
