Abstract Exhaustive analysis of somatic mutation pairs (MC3, [1]) in The Cancer Genome Atlas (TCGA,[2]) revealed significant relationships between the efficacy of drug treatment (PFS/DSS from TCGA-CDR, [3]) and the presence of particular somatic mutation-pairs for each [cancer type + drug treatment] (CANxDRG). For each combination of [CANxDRG + somatic gene mutation-pair], patients were split into 8 categories based on the efficacy (HIT, H) or inefficacy (MISS, M) of the drug treatment (i.e. in the top or bottom ≈33rd percentile of PFS/DSS over all drugs for a given cancer type) and on the presence (1) or absence (0) of mutations in each gene of the pair. Analysis of the resulting 4x2 table of patient counts for each [CANxDRG + gene-pair] provided a probability that the frequency of appearance of patients differed between each [mutation-presence x HIT] class and the corresponding [mutation-presence x MISS] class. Mutations for some critical genes, when considered individually for a CANxDRG, led to patient outcomes mixed between the HIT and MISS classes, but patient outcomes were almost entirely in only one of the HIT or MISS classes on considering the combined presence of a second gene. (e.g. CAN=coad {colon adenocarcinoma} DRG=5-Fluorouracil, "class:pat.count": // APC&KRASH00:7 M00:3, H10:26 M10:1, H01:4 M01:0, H11:12 M11:6 // APC&TTN H00:8 M00:1, H10:17 M10:6, H01:3 M01:2, H11:21 M11:1 // KRAS&TTN H00:17 M00:2, H10:8 M10:5, H01:16 M01:2, H11:8 M11:1 // ) Some single genes appeared often in such critical gene-pairs across many CANxDRGs, but some single genes, while clearly outcome-determining, were critical for a smaller number of CANxDRGs:["GENE ID","count of CANxDRGs with GENE ID in top-appearing, critical gene-pairs for cases categorized as Stage 3 or Stage 4 cancer": TP53 33; TTN 33; MUC16 14; APC 12; CSMD3 12; RYR2 12; PIK3CA 10; SYNE1 8 . . . ] Also, some gene classes with many gene isotypes had a high collective rate of significance across isotypes of the gene class, although each individual isotype might be present in top-appearing critical gene-pairs for many fewer CANxDRGs. ["GENE CLASS ID", "count of CANxDRGs with GENE CLASS ID in top-appearing, critical gene-pairs": TP# 33; TTN 33; cadherins (CDH# + PCDH# + PCDHA# + PCDHB# + PCDHGA# + FAT#) 35 total / 21 unique; CSMD# 19; MUC# 17; DNAH# 16; ZNF# 16; APC 12; RYR# 12; . . . ] Gene pairs found to be critical in TCGA for a CANxDRG, when present (or absent) in GDSC database [4] cell lines, sometimes indicated relative drug sensitivity, but sample sizes were small. Top critical genes are consistent with those inferred by others [5] from the ratios of non-silent to silent mutation frequencies.