Alterations in ALK gene emerge as prognostic marker for neuroblastoma survival
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Genetic alterations of ALK, including clonal mutations and amplifications, in high-risk neuroblastoma demonstrated utility as independent predictors of poorer survival, according to a study published in Journal of Clinical Oncology.
The findings from the HR-NBL1/SIOPEN trial provide a rationale for incorporating ALK inhibitors into upfront treatment along with chemotherapy and immunotherapy, researchers wrote.
“We can clearly define the frequency of ALK activating mutations and amplifications in this patient population (10% of patients with clonal mutations, 3% with subclonal mutations, 4% with amplifications),” Gudrun Schleiermacher, MD, PhD, pediatrician, researcher and physician-scientist at Institut Curie in Paris, told Healio.
“These data will be immediately useful for the design of a clinical trial aimed at the introduction of ALK inhibitors in front-line treatment of high-risk neuroblastoma, in parallel with front-line chemotherapy,” Schleiermacher added.
Researchers pursued the study because of a need for new therapeutic approaches for this population; 5-year OS rates with current treatment such as high-dose chemotherapy, surgery, radiation and immunotherapy do not exceed 50%, Schleiermacher said. And, although ALK activating genetic alterations in neuroblastoma were first described in 2008, the prognostic impact and exact frequency in high-risk disease needed further research, she added.
Schleiermacher and colleagues obtained diagnostic tumor samples of 1,092 patients with high-risk neuroblastoma in the ALK analysis cohort of the international, randomized, open-label, phase 3 HR-NBL1/SIOPEN trial. Most of the patients (81%) were aged younger than 18 months at diagnosis, 88% had stage IV disease and 47% had MYCN-amplified disease. Researchers used the tumor samples to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571) and investigate whether ALK alteration was associated with poor prognosis.
Researchers calculated EFS from diagnosis to first relapse, progressive disease, secondary malignancy, death of any cause or last patient contact and calculated OS from diagnosis to death of any cause or last patient contact.
Of those with known ALK amplification status and/or mutational profile, results showed genomic ALK amplification in 4.5% of patients (n = 41), all but one of whom also had MYCN amplification, and ALK mutations in 13.9% (n = 106).
Schleiermacher and colleagues found associations of ALK amplification with significantly poorer OS compared with no amplification (5-year OS, 28% vs. 51%; P < .0001) and noted a stronger prognostic effect among patients with metastatic disease.
Researchers detected ALK mutations at a clonal level (> 20% mutated allele fraction) in 10% of patients and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients, with a strong correlation (P < .001) between the presence of ALK mutations and MYCN amplification.
They also observed a statistically significant difference in 5-year OS among patients with both known ALK amplification and ALK mutation status between those with ALK amplification (n = 19; 26%; 95% CI, 10-47) or clonal ALK mutations (n = 65; 33%, 95% CI, 21-44) and those with subclonal ALK mutations (n = 22; 48%; 95% CI, 26-67) or no ALK alterations (n = 465; 51%, 95% CI, 46-55; P < .001).
Independent predictors of poor outcomes identified in a multivariate model included involvement of more than one metastatic compartment (HR = 2.87; 95% CI, 1.73-4.78), ALK amplifications (HR = 2.38; 95% CI, 1.32-4.27) and clonal ALK mutations (HR = 1.77; 95% CI, 1.25-2.49).
“We were most surprised by the findings concerning ALK amplifications,” Schleiermacher said. “We did not expect a frequency of 4% of cases with ALK amplifications. And we did not expect that ALK amplifications would be associated with such a poor outcome.”
Schleiermacher said researchers would like to continue the work by defining the frequency and prognostic value of other targetable mutations or genetic alterations in high-risk neuroblastoma. Because the abnormalities they found in the current study were associated with lower rates of survival, the research identified what appear to be important prognostic markers that could be targeted in the treatment of the disease.
“This research is an excellent example of personalized medicine,” Deborah A. Tweddle, MBChB, PhD, professor of pediatric oncology in the faculty of medical sciences at Wolfson Childhood Cancer Research Center at Newcastle University in the U.K., said in a press release. “By treating those patients with an ALK inhibitor, we are tailoring the treatment to the patients’ individual tumor type. By combining an ALK inhibitor with the other treatments we currently give for high-risk neuroblastoma, we hope to be able to cure more patients with this aggressive childhood cancer.”
For more information:
Gudrun Schleiermacher, MD, PhD, can be reached at SIREDO Pediatric Oncology Center, Laboratory of Translational Research in Pediatric Oncology— INSERMU830 Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 05, France; email: gudrun.schleiermacher@curie.fr.
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