ABSTRACT: BACKGROUND: Oligodendroglial tumors harbor IDH mutations and risk of this type of cancer is associated with a germ-line polymorphism at 8q. In addition, when these tumors harbor a co-deletion of 1p19q, they can be highly chemo-sensitive. Indeed, patients with anaplastic tumors (i.e., AO/AOA) with 1p19q co-deletion lived nearly twice as long after chemotherapy and radiation (CRT; 14-16 years) as radiotherapy alone (RT; 7-9 years) in two large randomized trials. In RTOG 9402, some patients with non-co-deleted AO/AOA also lived longer after CRT: for these participants, the survival curves separated after the median had been reached, and significantly more lived 10 years or longer after CRT than RT (25% vs. 10%). Since co-deletion status did not identify all patients benefiting from CRT, we asked whether other molecular hallmarks of AO/AOA – IDH or G-allele status – might be more inclusive markers of benefit from CRT. METHODS: We used tissues and data from RTOG 9402 to explore this hypothesis. RESULTS: IDH status was evaluable in 210 of 291 participants: 156 (74%) had a mutation of IDH1/2. The G allele of rs55705857 was evaluable in 245 of 291 participants: 76 (31%) carried the risk-allele in their germ-line. Presence of either an IDH mutation or the G risk-allele was associated with significantly longer progression-free survival after CRT, and an IDH mutation with much longer overall survival [9.4 vs. 5.7 years, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.40, 0.86), P = 0.006]. For cases in which IDH was intact, CRT did not prolong median survival time [1.3 vs. 1.8 years, HR 1.14, CI (0.63, 2.04), P = 0.67] or 10-year survival rates (CRT 6% vs. RT 4%). As expected, patients with mutated, co-deleted AO/AOA lived longer after CRT than RT (14.7 vs. 6.8 years, HR 0.49, CI (0.28, 0.85), P = 0.01], but so too did those with mutated, non-co-deleted AO/AOA [5.5 vs. 3.3 years, HR 0.56, CI (0.32, 0.99), P < 0.05]. Among the latter, ATRX positive and negative cases had longer overall survival after CRT than RT, but these differences were not significant. CONCLUSIONS: In AO/AOA cases in RTOG 9402, the presence or risk of an IDH mutation was associated with ‘benefit’ from CRT. Wild-type IDH was associated with poor overall and long-term survival, and absence of benefit from CRT. IDH mutation status identified more patients who benefited from CRT than did 1p/19q co-deletion status, but patients with co-deleted AO/AOA lived much longer.
