Variables associated with extreme and short-term survival
Student’s t-tests were performed separately on males and females and compared the following groups: EXS vs Non-EXS, EXS vs STS, and STS vs Non-STS. The results of this analysis can be found in Table 3. When compared to the rest of the male population, EXS were significantly younger (p=0.005) and STS were significantly older (p<0.001). Male EXS had significantly smaller ϱ when compared to male Non-EXS (p=0.004). When compared to the rest of the female population, female EXS were significantly younger (p=0.032) while female STS were significantly older (p<0.001). Female EXS had significantly smaller T1Gd radii compared to female Non-EXS (p=0.010). Compared to the rest of the female population, female EXS had significantly smaller D (p=0.008) and female STS had significantly larger D (p=0.018). Female EXS had significantly smaller ϱ compared to female Non-EXS (p=0.001).
In the female EXS vs Non-EXS DT (Figure 1A and 1B), the nodes that predicted EXS with 100% sensitivity included T1Gd radius < 21.93 mm and age < 28.5 years. Notably, all male EXS had CE thickness shorter than 11.33 mm, PI D/ϱ above 0.3687 mm2, and age below 72 years. In the female EXS vs STS DT (Figure 1C and 1D), the nodes that best predicted female EXS included ϱ < 10.33 year -1 and CE thickness < 4.746 mm and the node that best predicted female STS was age ≥ 47.5 years. In the male DT, the node that best predicted EXS was ϱ < 118.2 year -1 and the node that best predicted STS was D ≥ 11.85 mm2/year. The third pair of DT sorted males and females into STS and Non-STS groups (Figure 1E and 1F). Among females, the nodes that best predicted STS included age ≥ 49.5 years, T2/FLAIR radius ≥ 23.76 mm, and D ≥ 41.23 mm2/year. In the male DT, the nodes that most accurately predicted STS included age ≥ 47.5 years, ϱ ≥ 10.33 year -1, and CE thickness between 11.25 mm and 12.36 mm.
Variables associated with overall survival
Univariate and multivariate CPH analyses (Table 4) were utilized to determine which variables significantly influenced the overall survival of GBM patients. Variables that were significant or almost significant (p<0.10) in univariate analysis were analyzed in multivariate analysis. In the male multivariate CPH, factors found to independently influence survival included: age (HR=1.030, p<0.001) and T1Gd radius (HR=1.027, p=0.044). In the female multivariate CPH analysis, age (HR=1.021, p=0.006) and PIHNA D (HR=1.011, p<0.001) were identified as significant independent prognostic factors.
IDH1 Mutation
Since IDH1 mutation has been previously identified as significant predictor of long-term survival14, we analyzed the impact of sex and IDH1 status on the overall survival of our patient cohort. 120 patients in the main cohort had determined IDH1 status, consisting of 69 wild-type (wt) and 8 mutant (mut) male patients and 39 wt and 4 mut female patients. When looking at the entire population (both males and females), there was a trend towards IDH1 mut patients having better survival (log-rank, p=0.071). Among females, IDH1 mut survived significantly longer than IDH1 wt patients (log-rank, p=0.008), but among males, the survival difference was not significant (log-rank, p=0.924) (Supplement 1). All 4 IDH1 mut females survived at least three years, making them all long-term survivors29.
We also assessed whether IDH1 mut patients had the same features as the extreme survivors in this analysis (younger age, lower PIHNA D, lower PIHNA ϱ, and smaller T1Gd radii). Unlike the female EXS, IDH1 mut females did not have lower PIHNA D (t-test, p=0.402) or smaller T1Gd radii (p=0.584) compared to their wt counterparts, but they did have significantly lower PIHNA ϱ when compared to wt females (p=0.027). Males did not show significantly different PIHNA D (p=0.796) or PIHNA ϱ (p=0.461) between the two IDH1 status groups, but IDH1 mut males did tend to have smaller T1Gd radii (p=0.052) when compared IDH1 wt males. Both male and female IDH1 mut were significantly younger than their wt counterparts (Male p=0.024, Female p=0.007).
MGMT Methylation
Methylation of the MGMT promoter has been found to be more common in long-term survivors30, so we also assessed the impact of MGMT methylation on the survival of our population cohort. Ninety patients from the main cohort had available MGMT methylation status, which comprised of 32 females (12 methylated and 20 unmethylated) and 58 males (18 methylated and 40 unmethylated). Methylated patients had significantly better survival than unmethylated patients among males (log-rank, p=0.013), females (p=0.007), and the entire population (males and females) (p<0.001) (Supplement 4). Multivariate CPH analyses that assessed the impact of MGMT status on survival while accounting for age showed that MGMT status significantly impacted survival for males (p=0.004) and females (p=0.037). Among EXS with available MGMT methylation status (n=15), 50% (n=5) of males and 60% (n=3) of females had MGMT methylation, while among Non-EXS (n=75), 29% (n=14) of males and 33% (n=9) of females had MGMT methylation, suggesting that MGMT methylation was more common among both male and female EXS.
When we tested to see if MGMT methylated patients shared the features of extreme survivors (younger age, lower PIHNA D, lower PIHNA ϱ, and smaller T1Gd radii), we found that MGMT methylated females had significantly lower ϱ (t-test, p=0.026) and tended to have lower D (p=0.057) when compared to MGMT unmethylated females. There was no significant difference in the values of D (p=0.477) or ϱ (p=0.869) between MGMT methylated and unmethylated males. For both males and females, there was no significant difference in age (Male p=0.724, Female p=0.735) or T1Gd radii (Male p=0.397, Female p=0.241) between methylated and unmethylated patients.
Laterality
Using pre-tx T1Gd MR images, we determined the laterality of each patient’s tumor, classifying the tumors as being located in the right hemisphere, left hemisphere, or both hemispheres (bilateral). The impact of tumor laterality on survival was assessed separately for males and females, and the results were compared. Among males, there were 129 left hemisphere GBMs, 154 right hemisphere GBMs, and 11 bilateral GBMs, and among females there were 86 left hemisphere GBMs, 96 right hemisphere GBMs, and 9 bilateral GBMs. Laterality could not be determined for 5 male and 4 female patients.
Male patients with tumors on the left side tended to have better survival than males with tumors on the right side (log-rank, p=0.077) and had significantly better survival than males with bilateral tumors (p=0.010) (Supplement 6). In a multivariate CPH analysis that also accounted for extent of resection, tumor location in the left hemisphere was found to be a significant independent predictor of improved survival outcome for males (p=0.017) (Supplement 14). There were more EXS than STS among males with tumors on the left side and there were almost twice as many STS as EXS among males with tumors on the right side. Laterality did not have a significant impact on survival for female patients (CPH, p=0.299) (Supplement 14). There was no significant difference in survival between females with left and right hemisphere tumors (log-rank, p=0.218), and females with bilaterally located tumors did not have significantly worse survival when compared to females with non-bilateral tumors (bilateral vs left p=0.272, bilateral vs right p=0.471) (Supplement 6).
Extent of Resection
Our investigation evaluated whether the extent of initial surgical intervention, a known prognostic factor among GBM patients, had the same prognostic value for both male and female GBM patients. Patient EOR status, categorized as gross total resection (GTR), subtotal resection (STR), or biopsy, was obtained from the patient records. From the main cohort of 494 patients, 211 males (83 GTR, 83 STR, and 45 biopsy) and 136 females (54 GTR, 55 STR, and 27 biopsy) had available EOR status.
EOR had a significant impact on the survival of male GBM patients. GTR males had significantly better survival than STR males (log-rank, p=0.033) (Supplement 9) and males who received some surgical resection (GTR or STR) had significantly better survival than males who only received a biopsy (p=0.013) (Supplement 8). Cochran-Armitage Trend Test showed that there was significant trend towards male EXS receiving more extensive resections and male STS receiving less extensive resections or biopsies (p=0.027). Female who received resection (GTR or STR) trended towards improved survival compared to biopsy females (log-rank, p=0.077) (Supplement 8), but there was no significant difference in survival between GTR females and STR females (p=0.992) (Supplement 9). Additionally, EOR did not significantly impact female survival in univariate CPH analysis (p=0.180) (Supplement 14). Trend test showed that there was an insignificant trend towards female EXS receiving more extensive resections and female STS receiving less extensive resections or biopsies (p=0.098).
Patients receiving current standard of care
Due to the timespan over which they were collected, the patients in our cohort received a wide variety of treatment protocols. In order to ensure that our results maintain significance among patients who receive the current standard of care (maximal safe resection followed by concurrent temozolomide and radiation therapy), we created a subset of patients who received this treatment protocol (Stupp protocol patients)32 and tested which factors were associated with overall survival among those patients (Supplement 15). In this limited subpopulation, we had 113 males and 66 females (Supplement 15A). Among females, PIHNA D was a significant independent predictor of overall survival and among males, PIHNA ϱ was a significant independent predictor of overall survival (Supplement 15B).