The neuroblastoma oral papers (OP2) presented on Friday October 22, 2010 at SIOP in Boston covered a range of topics including prognostic factors, targets, and stem cell contamination. This report will focus on the presentation on prognostic significance of segmental alterations in neuroblastoma tumors.

Accumulation of segmental alterations determines progression in neuroblastoma (O024)

Neuroblastoma tumor biology has long been an intense subject of study because of the heterogeneous nature of this disease. Looking at macro, micro, and genetic features reveals the differences in tumors, and why some children with neuroblastoma survive without treatment and others do poorly with the most intense treatments conceived. Now that technology is accessible to analyze genetic profiles, more precise risk can be assigned, and appropriate treatment given. Further, this analysis allows for understanding the evolution of tumor genetics as relapse and progression occurs.

Gudrun Schleiermacher from France presented on a study of numerical and segmental chromosome alterations in neuroblastoma tumors. This subject was a matter of interest at ANR in Stockholm as well, and this abstract was also presented at ASCO in June.[1]  This topic has been the subject of many abstracts at recent meetings, and several recent publications confirm the importance of this work [2-6].

Prior publication in 2009 from this French group included  a comprehensive overview of the genetic alterations of neuroblastoma and clinical significance. A series of 493 neuroblastoma samples was investigated by array-based comparative genomic hybridization and the analysis identified several types of profiles:

Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.[2]

Caren and collegues (Sweden) also concurred that these studies have:

implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. [5]

Schleiermacher and colleagues analyzed 394 neuroblastoma tumors with array-based comparative genomic hybridization and linked the results to clinical data for outcomes. The tumor samples included all risk groups, and analysis was performed again in the event of relapse to discover changes in the tumor profile. The study confirmed that neuroblastoma tumors are characterized by two distinct genetic profiles — either numerical or segmental chromosome alterations.

Tumors were first divided into five groups based on genomic aberrations: numerical only, segmental only, MYCN amplified, numerical and segmental, MYCN and numerical. The tumors with only numerical alterations had the best prognosis. No breakpoint pattern was observed in the segmental-only group which contained up to 1000 breakpoints. Seven or more breakpoints portended a worse prognosis, and was an independent factor in multivariate analysis. More breakpoints were correlated with higher age at diagnosis, higher stage of disease, and higher risk of relapse.

Tumors with only numerical alterations at diagnosis frequently acquired segmental alterations upon relapse. This could not be strictly attributed to chemotherapy since tumors treated with surgery only had acquired segmental aberrations. The authors concluded that tumor progression is directly linked to an accumulation of segmental alterations.

References

1. J Clin Oncol. 2010 Jul 1;28(19):3122-30. Epub 2010 Jun 1. Accumulation of Segmental Alterations Determines Progression in Neuroblastoma. PMID: 20516441

2. J Clin Oncol. 2009 Mar 1;27(7):1026-33. Epub 2009 Jan 26.  Overall genomic pattern is a predictor of outcome in neuroblastoma. PMID: 19171713

3. British Journal of Cancer (2007) 97, 238–246.  Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. [free fulltext]

4. Am J Pathol. 2010 Jun;176(6):2616-25. Epub 2010 Apr 15. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics. PMID: 20395439

5. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4323-8. Epub 2010 Feb 9.  High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. [free fulltext]

6. N Engl J Med 2005; 353:2243-2253.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. [free fulltext]

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Recap of presentations

I have so much more to report on ASCO and ANR (coming soon), but should share information about this conference first. This year’s conference was exceptional.  The presentations covered a wide range of important topics, and I am convinced the 130 parents in attendance walked away with essential information for their families. This conference is extraordinary in that no rare disease organization provides such a quality forum for education by top experts in the field—for free, including hotel, meals, children’s program, bereavement session, and even transportation costs for those with the greatest need.  I have met attendees from Australia, Turkey, and other nations. This concept is unprecedented, and CNCF president Pat Tallungan works incredibly hard at the challenge to raise funds for this conference every year. CNCF accepts and appreciates donations for this conference (see www.nbhope.org ).

Dr Yanik in particular expressed his amazement at the difficult and insightful questions posed by the parents. I was struck by the contrast I had just seen at the ASCO and ANR meetings. Attendees come in and out during presentations, and often no questions are asked so no discussion ensues. I was amazed at how many researchers travel great distances to give five minute presentations, or just show a poster. The presenters at this conference spoke for at least 30 minutes and appreciated a very attentive audience. The impact is significant in that parents learn first hand from experts about this disease, and are exposed to information about new treatments which can facilitate quick enrollment on trials.

Speakers and topics were:

Susan Cohn ~ Overview of Neuroblastoma and Intermediate Risk Study

Yael Mosse ~  ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 Update

Giselle Sholler ~  Update on NMTRC Trials

Patrick Reynolds ~ Adult Oncology Connection/Update on Fenretinide trial

Shakeel Modak ~   3F8, NK Cell Therapy, and 8H9 Update

Sandeep Soni ~  Reduced Intensity Allogeneic Transplant

Kate Matthay ~   Overview of NANT trials

Peter Zage ~  3F8/Accutane Randomized Trial (national)

Greg Yanik ~  MIBG Scoring/Ultratrace Trials

Michael Burke ~  Oncolytic Virus Trial

Melissa Alderfer ~   Post Traumatic Stress Syndrome

David Salsberg ~  Neuropsych/learning issues facing NB Children

A few presentations will be covered in each post.

Overview of neuroblastoma and intermediate risk study update

Dr Sue Cohn gave a great overview on neuroblastoma and an update on the current intermediate risk study ANBL0531 (see http://clinicaltrials.gov/ct2/show/NCT00499616 ). This study opened in 2007, is enrolling at 180 locations, and will accrue 395 children. Intermediate risk is a challenging group to design studies for. The numbers are small, with approximately 10-20% of all neuroblastomas diagnosed as intermediate risk. This means there are roughly 100 intermediate risk children diagnosed each year in the US. The past and current studies are complex, with multiple treatment arms depending on tumor characteristics and response to therapy. This study includes 2, 4, or 8 cycles of outpatient (medium dose) chemotherapy, and cis-retinoic acid (Accutane) for some children. The goal is to accurately assign children to the right treatment arm and see if reducing therapy for some children will result in the same overall high survival seen in previous studies.

ALK inhibitor, Aurora A Kinase inhibitor, and ABT-751 updates

Dr Yael Mosse spoke about the research at CHOP (Children’s Hospital of Philadelphia) on ALK mutation and the remarkable speed in which a trial (ADVL0912) was opened to treat children with a drug already available for the mutation in lung cancer. The drug PF-02341066 now has a name, crizotinib. So far 5 children with NB with ALK aberration have been enrolled, and 5 with other diseases.  Dr Mosse shared some of the same information presented at both ASCO and ANR (see previous post on ALK).

The aurora A kinase inhibitor MLN8237 trial COG-ADVL0812 is closed now that the phase I is complete. The data is under review to determine if the drug is active against neuroblastoma for those who enrolled (11 NB children) on the phase I portion of the trial.  If so, the phase II trial will open for neuroblastoma only. In mice, striking synergy is seen with this inhibitor when combined with irinotecan and temozolomide. This combination is planned for an upcoming new NANT (New Approaches to Neuroblastoma Therapy) trial N09-03 directed by Steven DuBois.

A phase II trial of ABT-751 ran from 2007 to 2009 and accrued 91 children. The response data will be released at the fall COG (Children’s Oncology Group) meeting. Right now compassionate access is open at CHOP for second remission.

INRG Task Force

In 1988 an international task force was formed to standardize the risk group classification for neuroblastoma. The reason this is so important is because international studies could not be compared to each other with different patient cohorts. One “high risk” study might actually include children considered to be intermediate risk by another group, and the outcomes reported may consequently look “better.”

Today there are 64 investigators in the INRG task force which includes North America, Australia, Europe, and Japan. A consensus for a pre-treatment risk assignment has been accomplished, which includes image-defined risk factors (IDRFs) for staging. This believed to be more reproducible with radiologists.

A database of 8800 children diagnosed between 1990 and 2002 was used to characterize the new risk assignment scheme. In all of these children, the EFS was 63% ± 1% for all risk groups. The percentage of children in each risk group for the entire database breaks down to:

• 28% were very low risk
• 26% were low risk
• 9% were intermediate risk
• 36% were high risk

So far there have been many studies and reports using this data set.  Any investigator is invited to submit a bid for the use of the database analysis.

The most significant changes in risk assignment from this work is using IDRFs and including 11q status.

The challenge now is to incorporate and analyze approximately 4000 more children diagnosed since 2004 and added to the database.  This brings the total to over 16,000. New data items included are gender, ethnicity, therapy, and other causes of death.

A web-based interactive INRG database network has been proposed, and the goal is to collect biological data, phenotype, clinical outcome, and have tumor samples available for further analysis. A question for the future: will clinical features be abandoned and only genetic features used to classify risk assignment? This could allow for tweaking frontline therapy for children who have genetic aberrations predicting poor response to a particular therapy.

Clearly, this ambitious project will continue to offer a rich source of data to better predict outcomes and required therapy for children with neuroblastoma.

References:

Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V, Pearson AD, Cohn SL. Br J Cancer. 2010 Apr 27;102(9):1319-26. Review.PMID: 20424613

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London WB, Cohn SL, Pearson AD, Maris JM. Br J Cancer. 2009 May 5;100(9):1471-82.PMID: 19401703

Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL, Pearson AD, Matthay KK; International neuroblastoma Risk Group Task Force. Br J Cancer. 2009 May 19;100(10):1627-37. Epub 2009 Apr 28.PMID: 19401690

The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD; INRG Task Force. J Clin Oncol. 2009 Jan 10;27(2):298-303. Epub 2008 Dec 1.PMID: 19047290