- Email: [email protected]
CNS PNET molecular subgroups with distinct clinical features
Comment
CNS PNET molecular subgroups with distinct clinical features In The Lancet Oncology, Daniel Picard and colleagues report an integrative genomic analysis1 of a large cohort of hemispheric CNS primitive neuro-ectodermal brain tumours (PNETs). The investigation substantially increases our knowledge about this cancer, which is an extremely heterogeneous group of aggressive WHO grade IV brain tumours that primarily affect children and adolescents. CNS PNETs account for about 3–5% of childhood CNS tumours, and apart from arising in the cerebral hemispheres, they are rarely located in the brain stem or spinal cord.2 Clinical features common to all CNS PNET variants include aggressive clinical behaviour and poor survival. Histologically, these undifferentiated, highly proliferative embryonal neoplasms are divided into CNS PNET not otherwise specified (International Classification of Diseases for Oncology 9473/3), CNS neuroblastoma (9500/3), CNS ganglioneuroblastoma (9490/3), medulloepithelioma (9501/3), and ependymoblastoma (9392/3).2 Notably, some of these tumours were classified as different subgroups of embryonal tumours in earlier WHO classifications, emphasising the challenge in appropriate classification of these neoplasms. Picard and colleagues1 obtained samples from 20 centres in North America, Asia, and Europe, to identify and define molecular subgroups of CNS PNETs with different clinical features and associated survival. Their gene-expression analysis suggested that there were three molecular subtypes of hemispheric CNS PNET, which were heterogeneous with regards to clinical characteristics (sex, age, and metastasis status) and molecular features (gene expression, genomic copy number aberrations, and immunostaining for the cell lineage markers LIN28 and OLIG2). The most convincing data are available for those tumours defined as group 1 (table). Children who had group 1 tumours were younger and more often female than were children in groups 2 and 3, and more likely to have localised disease than children in group 3. A high-level amplification at chromosome 19q13 was a sensitive and specific marker for this subtype. Korshunov and colleagues3 identified the focal amplification at chromosome 19q13 in almost all ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes (which is not www.thelancet.com/oncology Vol 13 August 2012
listed as a distinct tumour entity in the latest WHO classification), whereas such an amplification was not reported in a large series of more than 300 other paediatric brain tumours assessed by the same arraybased comparative genomic hybridisation platform.4 This high-level amplification presumably leads to an upregulation of the two miRNA clusters, MIR-371-373 and C19MC.5 Because malignant glioma, in particular small-cell glioblastoma, might morphologically resemble CNS PNET, a unique molecular aberration such as the high-level amplification at chromosome 19q13 could be of great value as a diagnostic marker to identify and define biologically distinct subgroups of CNS PNET and to distinguish them from other differential diagnoses. The authors also define and describe distinct clinical and molecular characteristics of group 2 and group 3 CNS PNETs of the cerebral hemispheres.1 The observation that group 3 tumours were associated with the highest incidence of metastases, but were not characterised by the poorest survival, is an important finding. Notably, Northcott and colleagues6 reported similar data in their analysis of medulloblastoma, in which metastatic stage was unable to predict prognosis in a multivariable analysis that included age, metastasis status, histology, extent of resection, and molecular subgroups. In view of the heterogeneity (clinical, histopathological, and molecular) of hemispheric CNS PNETs,5,7–9 the loss of case numbers due to inconclusive immunohistochemical analysis (for 15 [21%] of 72 samples) and incomplete clinical information (age, sex, metastasis status, survival, and survival time), was a limitation of Picard and colleagues’ study.1
Number of samples (%) Median age, years
Published Online June 11, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70260-7 See Articles page 838
Group 1 tumours
Group 2 tumours
Group 3 tumours
29 (27%)
36 (33%)
43 (40%)
2·9
7·9
5·9
Sex prevalence
Females>males
Males>females
Males>females
Metastasis status
Non-metastatic
Non-metastatic
Metastatic (~50%)
Median overall survival, years
0·8
1·8 Increased OLIG2, decreased LIN28
4·3
Cell lineage markers
Increased LIN28, decreased OLIG2
Genetic characteristics
19q13 amplification, +2, +3 +8p, +13, +20, –9p
–9p, –14
Expression characteristics
Increased WNT and SHH signalling
Increased TGFβ, PTEN, and semaphoring signalling
Decreased WNT and SHH signalling
Decreased LIN28 and OLIG2
Table: Key findings of Picard and colleagues’ study1
753
Comment
After prospective validation of the three molecular risk groups, defined by gene expression and/or immunohistochemical analysis of LIN28 and OLIG2, and their prognostic effects have been confirmed, health-care providers might be able to tailor treatment decisions in the future. Such validation should ideally be done in patients with hemispheric CNS PNET who are treated homogenously and have complete clinical information available. Moreover, new molecular targets such as WNT and SHH signalling, which are also relevant in medulloblastoma,10 might be considered as treatment targets, especially in patients with high-risk CNS PNET. Another multicentre effort is needed to collect as many samples as possible to investigate and delineate molecular groups of CNS PNETs of the brain stem or spinal cord— which are less common than are hemispheric CNS PNETs—to better understand the clinical and molecular features of this heterogeneous cancer.
I declare that I have no conflicts of interest. 1
2 3
4 5
6 7
8
9
10
André O von Bueren
Picard D, Miller S, Hawkins CE, et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 2012; published online June 11. DOI:10.1016/S1470-2045(12)70257-7. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. Lyon: IARC Press, 2007. Korshunov A, Remke M, Gessi M, et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 2010; 120: 253–60. Paulus W, Kleihues P. Genetic profiling of CNS tumors extends histological classification. Acta Neuropathol 2010; 120: 269–70. Li M, Lee KF, Lu Y, et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 2009; 16: 533–46. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011; 29: 1408–14. Russo C, Pellarin M, Tingby O, et al. Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999; 86: 331–39. Pfister S, Remke M, Toedt G, et al. Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer 2007; 46: 839–51. Miller S, Rogers HA, Lyon P, et al. Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma. Neuro Oncol 2011; 13: 866–79. Gilbertson RJ. Medulloblastoma: signalling a change in treatment. Lancet Oncol 2004; 5: 209–18.
University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany [email protected]
The Cancer Drug Fund 1 year on—success or failure? Published Online June 29, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70273-5 See Online for appendix
754
On Oct 1, 2010, the English Government introduced ring-fenced funding for procurement of cancer drugs not funded by the National Health Service (NHS). These funds—worth an additional GBP£650 million during 3·5 years—were developed as “a means of improving patient access to cancer drugs”1 and as the start of “plans to address the disparity in patients’ access to cancer drugs in England compared to other countries”.2 They are collectively known as the Cancer Drug Fund (CDF), are additional to existing NHS funding flows, and are allocated regionally through strategic health authorities (SHA). Some feared that demand would outstrip funding,3 others that the so-called postcode lottery would worsen.4 In December, 2011, however, a national newspaper claimed that millions had not been spent and that patients were “paying the price”.5 So what is the real effect of the CDF? Here, we examine actual drug use and compare such use with expectations.
CDF funds are actually spent on only a few drugs. Five—bevacizumab, cetuximab, everolimus, lapatinib, and sorafenib—constituted 59% of applications between April, and December, 2011, with each one the subject of more than 350 applications.6 Use of these drugs has greatly increased since the introduction of the CDF, as recorded in data obtained by IMS Health from almost all English hospitals (figure 1). Mean volumes dispensed within SHAs in the year to November, 2011, were significantly higher than were those in the year before the CDF was launched (p<0·05). Variation between SHAs also declined (figure 2), and differences between the tenth and 90th percentile for each drug seem to be of magnitudes described as normal in previous reports of variation in the uptake of cancer drugs approved by the National Institute of Health and Clinical Excellence (NICE).7 However, growth is less than what would be expected. If every application to the CDF led to a treatment dose and duration similar to those used in clinical trials or in www.thelancet.com/oncology Vol 13 August 2012
CNS PNET molecular subgroups with distinct clinical features In The Lancet Oncology, Daniel Picard and colleagues report an integrative genomic analysis1 of a large cohort of hemispheric CNS primitive neuro-ectodermal brain tumours (PNETs). The investigation substantially increases our knowledge about this cancer, which is an extremely heterogeneous group of aggressive WHO grade IV brain tumours that primarily affect children and adolescents. CNS PNETs account for about 3–5% of childhood CNS tumours, and apart from arising in the cerebral hemispheres, they are rarely located in the brain stem or spinal cord.2 Clinical features common to all CNS PNET variants include aggressive clinical behaviour and poor survival. Histologically, these undifferentiated, highly proliferative embryonal neoplasms are divided into CNS PNET not otherwise specified (International Classification of Diseases for Oncology 9473/3), CNS neuroblastoma (9500/3), CNS ganglioneuroblastoma (9490/3), medulloepithelioma (9501/3), and ependymoblastoma (9392/3).2 Notably, some of these tumours were classified as different subgroups of embryonal tumours in earlier WHO classifications, emphasising the challenge in appropriate classification of these neoplasms. Picard and colleagues1 obtained samples from 20 centres in North America, Asia, and Europe, to identify and define molecular subgroups of CNS PNETs with different clinical features and associated survival. Their gene-expression analysis suggested that there were three molecular subtypes of hemispheric CNS PNET, which were heterogeneous with regards to clinical characteristics (sex, age, and metastasis status) and molecular features (gene expression, genomic copy number aberrations, and immunostaining for the cell lineage markers LIN28 and OLIG2). The most convincing data are available for those tumours defined as group 1 (table). Children who had group 1 tumours were younger and more often female than were children in groups 2 and 3, and more likely to have localised disease than children in group 3. A high-level amplification at chromosome 19q13 was a sensitive and specific marker for this subtype. Korshunov and colleagues3 identified the focal amplification at chromosome 19q13 in almost all ependymoblastoma and embryonal tumour with abundant neuropil and true rosettes (which is not www.thelancet.com/oncology Vol 13 August 2012
listed as a distinct tumour entity in the latest WHO classification), whereas such an amplification was not reported in a large series of more than 300 other paediatric brain tumours assessed by the same arraybased comparative genomic hybridisation platform.4 This high-level amplification presumably leads to an upregulation of the two miRNA clusters, MIR-371-373 and C19MC.5 Because malignant glioma, in particular small-cell glioblastoma, might morphologically resemble CNS PNET, a unique molecular aberration such as the high-level amplification at chromosome 19q13 could be of great value as a diagnostic marker to identify and define biologically distinct subgroups of CNS PNET and to distinguish them from other differential diagnoses. The authors also define and describe distinct clinical and molecular characteristics of group 2 and group 3 CNS PNETs of the cerebral hemispheres.1 The observation that group 3 tumours were associated with the highest incidence of metastases, but were not characterised by the poorest survival, is an important finding. Notably, Northcott and colleagues6 reported similar data in their analysis of medulloblastoma, in which metastatic stage was unable to predict prognosis in a multivariable analysis that included age, metastasis status, histology, extent of resection, and molecular subgroups. In view of the heterogeneity (clinical, histopathological, and molecular) of hemispheric CNS PNETs,5,7–9 the loss of case numbers due to inconclusive immunohistochemical analysis (for 15 [21%] of 72 samples) and incomplete clinical information (age, sex, metastasis status, survival, and survival time), was a limitation of Picard and colleagues’ study.1
Number of samples (%) Median age, years
Published Online June 11, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70260-7 See Articles page 838
Group 1 tumours
Group 2 tumours
Group 3 tumours
29 (27%)
36 (33%)
43 (40%)
2·9
7·9
5·9
Sex prevalence
Females>males
Males>females
Males>females
Metastasis status
Non-metastatic
Non-metastatic
Metastatic (~50%)
Median overall survival, years
0·8
1·8 Increased OLIG2, decreased LIN28
4·3
Cell lineage markers
Increased LIN28, decreased OLIG2
Genetic characteristics
19q13 amplification, +2, +3 +8p, +13, +20, –9p
–9p, –14
Expression characteristics
Increased WNT and SHH signalling
Increased TGFβ, PTEN, and semaphoring signalling
Decreased WNT and SHH signalling
Decreased LIN28 and OLIG2
Table: Key findings of Picard and colleagues’ study1
753
Comment
After prospective validation of the three molecular risk groups, defined by gene expression and/or immunohistochemical analysis of LIN28 and OLIG2, and their prognostic effects have been confirmed, health-care providers might be able to tailor treatment decisions in the future. Such validation should ideally be done in patients with hemispheric CNS PNET who are treated homogenously and have complete clinical information available. Moreover, new molecular targets such as WNT and SHH signalling, which are also relevant in medulloblastoma,10 might be considered as treatment targets, especially in patients with high-risk CNS PNET. Another multicentre effort is needed to collect as many samples as possible to investigate and delineate molecular groups of CNS PNETs of the brain stem or spinal cord— which are less common than are hemispheric CNS PNETs—to better understand the clinical and molecular features of this heterogeneous cancer.
I declare that I have no conflicts of interest. 1
2 3
4 5
6 7
8
9
10
André O von Bueren
Picard D, Miller S, Hawkins CE, et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncol 2012; published online June 11. DOI:10.1016/S1470-2045(12)70257-7. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. Lyon: IARC Press, 2007. Korshunov A, Remke M, Gessi M, et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol 2010; 120: 253–60. Paulus W, Kleihues P. Genetic profiling of CNS tumors extends histological classification. Acta Neuropathol 2010; 120: 269–70. Li M, Lee KF, Lu Y, et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 2009; 16: 533–46. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011; 29: 1408–14. Russo C, Pellarin M, Tingby O, et al. Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999; 86: 331–39. Pfister S, Remke M, Toedt G, et al. Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer 2007; 46: 839–51. Miller S, Rogers HA, Lyon P, et al. Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma. Neuro Oncol 2011; 13: 866–79. Gilbertson RJ. Medulloblastoma: signalling a change in treatment. Lancet Oncol 2004; 5: 209–18.
University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany [email protected]
The Cancer Drug Fund 1 year on—success or failure? Published Online June 29, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70273-5 See Online for appendix
754
On Oct 1, 2010, the English Government introduced ring-fenced funding for procurement of cancer drugs not funded by the National Health Service (NHS). These funds—worth an additional GBP£650 million during 3·5 years—were developed as “a means of improving patient access to cancer drugs”1 and as the start of “plans to address the disparity in patients’ access to cancer drugs in England compared to other countries”.2 They are collectively known as the Cancer Drug Fund (CDF), are additional to existing NHS funding flows, and are allocated regionally through strategic health authorities (SHA). Some feared that demand would outstrip funding,3 others that the so-called postcode lottery would worsen.4 In December, 2011, however, a national newspaper claimed that millions had not been spent and that patients were “paying the price”.5 So what is the real effect of the CDF? Here, we examine actual drug use and compare such use with expectations.
CDF funds are actually spent on only a few drugs. Five—bevacizumab, cetuximab, everolimus, lapatinib, and sorafenib—constituted 59% of applications between April, and December, 2011, with each one the subject of more than 350 applications.6 Use of these drugs has greatly increased since the introduction of the CDF, as recorded in data obtained by IMS Health from almost all English hospitals (figure 1). Mean volumes dispensed within SHAs in the year to November, 2011, were significantly higher than were those in the year before the CDF was launched (p<0·05). Variation between SHAs also declined (figure 2), and differences between the tenth and 90th percentile for each drug seem to be of magnitudes described as normal in previous reports of variation in the uptake of cancer drugs approved by the National Institute of Health and Clinical Excellence (NICE).7 However, growth is less than what would be expected. If every application to the CDF led to a treatment dose and duration similar to those used in clinical trials or in www.thelancet.com/oncology Vol 13 August 2012