To our knowledge, this is the first study to investigate the relationship between SUVmax and TMB in patients with diverse cancers. Our hypothesis was that higher mutational load (as reflected by TMB) might correlate with metabolic reconfiguration, and immune inflammatory response, and that either of these features would be associated with a higher SUVmax. Our study confirmed that higher TMB was the only evaluated variable that independently correlated with higher SUVmax. Of interest, one prior study examined this question, albeit in lung cancer alone . They found no significant relationship between SUVmax and TMB. However, there were some major differences between their study and ours: (i) Moon and colleagues confined their observations to lung cancer, whereas our study included a variety of malignancies; and (ii) they did not note the timing of the FDG PET-CT versus the biopsy . In our study, the biopsy was taken ≤ 6 months before the PET scan. Longer time lapse may cause poor correlation between the SUVmax and TMB parameters. In addition, obtaining PET imaging after the biopsy or after starting the treatment could cause false positive or false negative SUVmax results. Indeed, we studied 1923 diverse cancer patients with TMB values, out of which 273 patients met the criteria of having no prior systemic treatment and having SUVmax performed within six months prior to the biopsy. Since having synchronous TMB and SUVmax is ideal, future studies should attempt to obtain biopsies for TMB immediately after PET imaging.
Various cutoffs have been previously established for TMB, including the dichotomization at 12 mutations/mb, to be predictive of immunotherapy response . Upon categorizing patients into three groups based on TMB levels: 0–1, 2–11 and ≥ 12 mutations/mb groups, we found that patients in the higher TMB group have higher SUVmax values and this difference was statistically significant between all three groups with p < 0.0001 (Table 1).
To confirm that the relationship between TMB and SUVmax is independent of confounders, we analyzed the data in multivariate models. The only parameter that showed a significant relationship with SUVmax was TMB (multivariate p < 0.0001), confirming the independent correlation between TMB and SUVmax (Table 3). Further, there was a linear relationship between TMB and SUVmax in the log-scale (r = 0.34, p < 0.001) (Fig. 2). Sex, age and cancer type had no statistically significant association with SUVmax (Table 3).
Several genomic alterations have been related to immunotherapy response, including but not limited to microsatellite instability high (MSI-H) status (which results in high TMB), high TMB itself, PBRM1 mutations and APOBEC-related mutagenesis[12, 13, 17–19]. TMB varies dramatically between tumor types, with skin and lung cancers, having higher median TMBs than most other cancers[20, 21]. Our previous studies indicated that the median TMB for responders vs. non-responders to anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/Mb, with higher TMB predicting favorable outcomes across diverse tumors[12, 22]. Other studies have found that higher TMB was linked to improved survival following immunotherapy in diverse cancers for the top 20% of TMBs in each histology. Various investigations have used different cut offs for defining the relationship between TMB and checkpoint blockade response and our own work has suggested a linear correlation between TMB and response.
We hypothesize that higher TMB promotes metabolic reconfiguration, causing increased glucose metabolism rate (GMR), and thus higher SUVmax. Carbohydrate metabolism has been previously shown to have correlation with TMB . GMR-TMB correlation could explain our finding of SUVmax-TMB correlation, although the exact mechanism for this finding is not understood . An alternative explanation for the correlation between TMB and SUVmax might be based on an innate immune response to tumors with higher TMB. Indeed, higher TMB correlates with better response to immune checkpoint blockade and it is conceivable that innate immunity might also be triggered in the presence of high mutational load. An immune cell infiltrate would create increased glycolytic activity and an inflammatory response that would manifest as higher SUVmax . We have also previously shown increased SUVmax in tumors with higher number of characterized genomic alterations  consistent with this work.
Our study had several important limitations: first it is a retrospective analysis and thus TMB and SUVmax parameters were not fully synchronized; second, although the full cohort included 1923 patients, only 273 patients had PET scans within six months before their biopsies for TMB; third, we do not know the mechanism underlying the relationship between TMB and SUVmax; fourth this study was single –center/single-camera, and fifth, a variety of tumor types were included in the analysis, though the latter two may also suggest the homogeneity of PET results and generalizability of results across histologies, respectively); and fourth, we did not examine variant genes or molecules associated with SUVmax, which could be key markers of SUVmax . Future studies are needed to expand the number of the patients, and to evaluate such relationship in each individual cancer type. Multi-center study and also same-day PET scans/biopsy for TMB are needed would be needed to validate our findings. Furthermore, exploring the direct relationship between SUVmax and immunotherapy response is future step since we found SUVmax is correlated with TMB and it is known that higher TMB is correlated with immunotherapy response.