Childhood Cancer Neuroblastoma: Not only DNA, it´s also the age that matters

Childhood Cancer Neuroblastoma: Not only DNA, it´s also the age that matters

(Vienna, 09.09.2020) Scientists at St. Anna Children's Cancer Research Institute provide an important new insight in neuroblastoma, the most common solid tumor in infants and young children: the influence of genome alterations on the course of disease in certain neuroblastomas depends also on age. The results, published in the renowned Journal of Clinical Oncology, should help to better tailor treatment for affected children.

Scientists at St. Anna Children's Cancer Research Institute discovered how certain genetic changes in neuroblastoma, a frequently malignant tumor of the nervous system, influence the course of the disease. The now published study examined localized, operable neuroblastomas without the prognostically unfavorable MYCN amplification. These tumors showed so far a hardly predictable clinical behavior ranging from very favourable to unfavourable. The study revealed an age-dependent influence of the tumor genome on cancer development. The authors thus provide the framework for even more precise therapy decisions based on genomic alterations, age and clinical parameters.

For localized, operable neuroblastomas without MYCN amplification (multiplication of an oncogene), surgery is recommended as the only treatment if the genomic and clinical parameters for such a procedure are fulfilled. Patients with stage 1 tumors usually have excellent long-term results. In contrast, stage 2 tumors are reported to have significantly higher recurrence rates. Until now, it was unclear how the individual gene defects of the tumor and the age of the patient influence the course of the disease.

Children over 18 months with immature neuroblastomas are more at risk
Therefore, an international consortium led by Inge Ambros, MD, and Doz. Peter Ambros, PhD, of St. Anna Children's Cancer Research Institute analyzed the samples of 317 study patients. The samples were taken from three registries of children with operable tumors who did not receive chemotherapy.

  • Patients with stage 1 tumors had excellent results, 99 percent were still alive after five years.
  • In contrast, patients with stage 2 tumors generally had a shorter event-free survival during a five-year monitoring period, i.e. a shorter time to recurrence, disease progression or death.

Focusing on stage 2 patients, in those under 18 months of age, relapses are as frequent as in the older age group and occur also if segmental chromosome aberrations are lacking, but if they are present, a loss of genetic material at a specific chromosomal arm, a so-called 1p loss, was the only segmental chromosomal change associated with a higher recurrence rate. However, these children could almost always be saved regardless of tumor genetics. However, overall survival after five years was significantly reduced to 81 percent in patients over 18 months. In those children, so-called segmental chromosomal aberrations were associated with a relapse and, unfortunately, with a worse course of the disease. A loss of genetic material on chromosome 11 (11q loss) was identified as the strongest risk factor.

Investigation of intensified therapy for higher risk groups
Inge Ambros, MD, summarizes, "The study led to several new insights which show that, in case of localized tumors, genetics in neuroblastoma cannot be judged in the same way as before. This relates to favorable genetics as well as to the unfavorable segmental chromosome aberrations. Thus, a further refining of risk grouping is possible.”
“And, ideally this new concept will have consequences for more exact treatment approaches. Whether, in case of patients who did badly in this study, chemotherapy after surgery will improve the chance of cure will be investigated in a further study”, adds Doz. Peter Ambros, PhD.

Prediction of prognosis in a variety of disease courses
Neuroblastoma accounts for ten percent of childhood cancer deaths. It has a very broad spectrum of different forms, ranging from harmless variants for which watchful waiting is justified to very aggressive forms that require immediate, comprehensive and intensive treatment. Because of these marked differences in the biological/clinical behavior, prognostic markers are essential for the application of therapies specifically tailored to risk groups.

International neuroblastoma networks
The present work was only possible through close international collaboration of the Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. The samples evaluated with modern genome-based techniques were obtained from three sources: the Localized Neuroblastoma European Study Group I and II (LNESGI/II) and the American Children's Oncology Group (COG) under strict quality control.

Publication
Age-dependency of the prognostic impact of tumor genomics in localized resectable MYCN non-amplified neuroblastoma. Report from the SIOPEN Biology Group on the LNESG Trials and a COG validation group.
Inge M Ambros*, MD; Gian P Tonini, PhD; Ulrike Pötschger, PhD; Nicole Gross, PhD; Veronique Mosseri, PhD; Klaus Beiske, MD; Ana Berbegall, PhD; Jean Bénard, PhD; Nick Bown, PhD; Huib Caron, MD; Valérie Combaret, PhD; Jerome Couturier, PhD; Raffaella Defferrari, PhD; Olivier Delattre, MD, PhD; Marta Jeison, PhD; Per Kogner, MD; John Lunec, PhD; Barbara Marques, PhD; Tommy Martinsson, PhD; Katia Mazzocco, PhD; Rosa Noguera, MD; Gudrun Schleiermacher, MD, PhD; Alexander Valent, PhD; Nadine van Roy, PhD; Eva Villamon, PhD; Dasa Janousek, PhD; Ingrid Pribill, PhD; Evgenia Glogova, PhD; Edward Attiyeh, MD; Michael Hogarty, MD; Tom Von Krogh Monclair, MD; Keith Holmes, MD; Dominique Valteau, MD; Victoria Victoria-Castell, MD; Deb Tweddle, MD; Julie Park, MD; Sue Cohn, MD; Ruth Ladenstein, MD; Maja Beck, MD; Bruno De Bernardi, MD; Jean Michon, MD; Andy Pearson, MD; Peter F. Ambros, PhD.
Journal of Clinical Oncology September 09 2020, https://ascopubs.org/doi/abs/10.1200/JCO.18.02132
*First und Corresponding Author: Inge M. Ambros, MD
Inge M. Ambros and Peter F. Ambros contributed equally to this manuscript.
DOI: https://doi.org/10.1200/JCO.18.02132

Förderung
This research work was supported by St. Anna Children’s Cancer Research Institute, the Anniversary Fund of the Oesterreichische Nationalbank (OeNB, Grant No. 13422), the European Commission (Directorate General V) and the Austrian Science Fonds (FWF, Grant No. I 2799-B28).
Funding was also provided by the Italian Neuroblastoma Foundation and die Italian Association for Cancer Research (AIRC), the Fondation Recherche sur le Cancer de l'Enfant (FORCE, Suisse), the National Resource Centre for Childhood Solid Tumors (Norway), the International Society for Children with Cancer (ISCC), the Spanish Association Against Cancer Scientific Foundation (Spain) and the Neuroblastoma Organization, UK.

Picture: Inge Ambros, MD, and Doz. Peter Ambros, PhD
Copyright: St. Anna Children´s Cancer Research Institute

Figure: 5 year outcome in resectable neuroblastoma without MYCN amplification
Copyright: modified from Figure 3, Ambros I et al., Journal of Clinical Oncology September 09 2020

PressRelease_JCO Ambros_St. Anna Children's Cancer Research Institute
5-Year-Survival Rate in Resective Neuroblastoma without MYCN-Amplifikation
Pressemitteilung_JCO Ambros_St. Anna Kinderkrebsforschung