Clinico-genomic profiling of conventional and dedifferentiated chondrosarcomas reveals ,TP53 mutation to be associated with worse outcomes
Paper recently published in Clinical Cancer Research on genetic sequencing of conventional and dedifferentiated chondrosarcoma from two of our board members at MD Anderson in Houston, Texas: Anthony Conley, M.D. and Shaan Mohahmad Razza, M.D.
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Chondrosarcomas are the most common primary bone tumor in adults. IDH1 and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild type (WT) chondrosarcomas as well as alterations in other genes. Methods: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there was available clinical next generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas. Results: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared to grades 1-3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease. Conclusion: IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes.
In this study, we assessed the clinico-genomic properties of chondrosarcomas. We find that IDH1 and IDH2 mutations are prevalent, are more common in chondrosarcomas arising in the extremities, are associated with higher age at diagnosis, and more common in dedifferentiated than conventional (i.e. grades 1-3) chondrosarcomas. Further, we find that TP53 mutation is more common in dedifferentiated chondrosarcomas and is associated with worse overall survival and metastasis-free survival. However, we did not observe any difference in overall or metastasis-free survival based on IDH mutation status. Further, we find that patients treated with curative-intent surgery had worse outcomes if their tumors harbored a TP53 mutation. Other prior studies in the literature have reported an association with TP53 mutation and higher grade and/or dedifferentiated subtype in chondrosarcoma.30–34 One of these studies also noted that tumors without TP53 alterations had improved local recurrence free, metastasis free, and overall survival.31 All of these prior studies assessed TP53 status by immunohistochemistry and some complemented with Sanger sequencing. Our study is largely concordant with these findings and implements next generation sequencing to identify TP53 alterations and their clinical implications. Multiple previous studies have assessed the clinical impact of IDH mutations in chondrosarcoma. One previous study of 89 chondrosarcomas also found no association between IDH status and overall survival, though IDH mutation was associated with longer relapse-free and metastasis-free survival in high-grade chondrosarcomas.20 Conversely, another study of 80 chondrosarcoma patients showed that IDH mutation is associated with shorter overall survival.19 Additional studies have found no association between IDH mutation and overall survival.17,18 To add further confusion, another study showed that IDH mutation is associated with longer diseaseDownloaded from http://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-1703/3366908/ccr-23-1703.pdf by MD Anderson Cancer Center user on 26 September 2023 free and relapse-free survival.20 Regarding co-alterations, one study found TERT gene amplification, ATRX mutations, CDKN2A/B deletion, and TP53 mutation to be enriched in tumors with IDH mutations.20 On the contrary, two other studies that found no enrichment of CDKN2A/B and TP53 mutations in IDH1/2 mutant chondrosarcomas.13,35 In our study, we did not see significant enrichment of TP53, TERT, ATRX, or CDKN2A/B alterations in IDH mutant tumors. We find that 37.6% of chondrosarcomas in our series had IDH1 mutations and 12.9% had IDH2 mutations, which is similar to a recent meta-analysis of 488 patients that reported 38.7% and 12.1% had IDH1 and IDH2 mutations, respectively.36 Similar to previous studies,20,37 we find that dedifferentiated chondrosarcomas are enriched with IDH1/2 and TP53 mutations. Some studies have also shown that dedifferentiated chondrosarcomas harbor a high rate of alterations in COL2A1 (64%) and CDKN2A deletion (36%).37 IDH mutation has been reported to co-occur with TERT mutation, more so in IDH2 mutant than IDH1 mutant.13 With regard to clinical correlates, we find that IDH mutation was associated with older age and predilection for the extremities as a primary site. Other studies have similarly shown that IDH mutations are more common in older patients, in long bones (e.g. extremities) versus flat bones (e.g. pelvis, cranium), and in high grade or dedifferentiated chondrosarcomas. 13,36 Other studies have used transcriptome profiling for prognostic assessment. An analysis of 102 chondrosarcomas derived two different gene signatures either defined by overexpression of chondrogenic markers or cell cycle-related genes.38 This subset with overexpression of cell cycle-related genes was enriched in grade 3 and dedifferentiated and associated with worse survival. This group was also enriched with CDKN2A deletion, chromosomal instability, and polyploidy. They further integrated miRNA and methylation analyses to describe a multi-omics Downloaded from http://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-1703/3366908/ccr-23-1703.pdf by MD Anderson Cancer Center user on 26 September 2023 classification of 6 different subtypes that can be distinguished by IDH mutation, 14q32 locus silencing, and mRNA profile.38 Methylation profiling has also been performed in other studies, where it was found that IDH1 mutated chondrosarcomas had more methylation than IDH2 mutant or IDH WT chondrosarcomas.13 It will be interesting to see how these technologies, including miRNA and methylation analyses, impact clinical practice as they become available in the clinical setting. There may be a heretofore undiscovered germline genetic predisposition to chondrosarcoma. In a previous study, 21% of patients with chondrosarcoma also had histories of second unrelated malignancies.20 Similarly, we find that 17.2% of patients with chondrosarcoma in our series had at least one other malignancy. A recent study has shed light on heritable alterations in genes involved in telomere biology and mitosis that selectively predispose to sarcoma.39 Additional work will be needed to identify alterations in which genes and pathways that may predispose to chondrosarcoma. Another possible explanation is that patients with chondrosarcoma are older and many have prolonged survival, thereby increasing their chance of a second malignancy by chance. Inhibition of mutant IDH in chondrosarcoma has been interesting. A phase 1 trial of ivosidenib, an IDH1 inhibitor, in chondrosarcoma resulted in a median progression-free survival of 5.6 months.40 By RECIST 1.1, no complete response or partial response was observed, though half of the patients experienced stable disease. Four patients maintained stability for ≥ 2.5 years, and reductions in 2-HG in plasma and from tumor biopsies were observed. As a follow up to the original study, patients with disease stability beyond two years were noted to have an overall response rate of 23.1%, including one patient with a base of skull primary that achieved a complete response. None of these patients had partial response during the first two years of Downloaded from http://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-1703/3366908/ccr-23-1703.pdf by MD Anderson Cancer Center user on 26 September 2023 treatment.41 Additional work will be needed to optimize the use of IDH inhibitors in chondrosarcoma. This study has several limitations. First, we only include results from clinical sequencing assays, which limits the potential for discovery of new genes involved in the pathogenesis of chondrosarcoma. Second, the in-house panel we utilized has evolved over time, and earlier iterations did not profile as many genes nor provided useful metrics such as microsatellite status of tumor mutational burden. This could lead to under-reporting of mutations in some genes. Third, this study retrospectively analyzed clinical sequencing data that had been collected. Because of this, our study likely enriches for patients with metastatic disease, as clinicians are more likely to order molecular profiling in cases of metastatic disease. In conclusion, this study represents one of the largest datasets to evaluate the clinicogenomic characteristics of conventional and dedifferentiated chondrosarcomas with emphasis on IDH1/2 mutations and TP53 mutations. Though interesting clinical characteristics were observed with IDH mutated chondrosarcomas, survival did not correlate with mutational status. TP53 mutations, however, did impact survivorship for patients with conventional or dedifferentiated chondrosarcomas.