Table 2:

Relationship between protein biomarkers and MSI-H, TMB-H, or PD-L1 expression status ^a

Biomarker	Mantel-Haenszel Odds Ratio (95% CI)b	p-value	Number of patients	Potential benefit in combination therapy [Yes/No]
Protein markers and MSI-H status
ERCC1	0.68(0.55 – 0.85)	0.001	21,772	Yes for benefit of combination of immunotherapy and platinum (ERCC1 negativity, which is associated with platinum response 29, 30, was correlated with MSI-H.)
MGMT	0.91 (0.62 – 1.30)	0.59	5,175	No significant correlation between MGMT status and MSI-H
RRM1	3.49 (2.91 – 4.17)	<0.001	17,190	No for benefit of combination of immunotherapy and gemcitabine (RRM1 negativity is associated with gemcitabine response 34. However, data shows that it is RRM1 positivity that was correlated with MSI-H.)
TOPO1	0.77 (0.67 – 0.89)	0.001	22,186	No for benefit of combination of immunotherapy and irinotecan or topotecan. (TOPO1 positivity is associated with irinotecan response 20. However, data shows that TOPO1 negativity was correlated with MSI-H.)
TUBB3	0.71 (0.60 – 0.83)	<0.001	19,839	Yes for benefit of combination of immunotherapy and taxanes (TUBB3 positivity is associated with taxane resistance 26–28. Data shows that TUBB3 negativity was correlated with MSI-H.)
Protein markers and TMB-H status
ERCC1	0.83(0.72 – 0.96)	0.013	21,665	Yes for benefit of combination of immunotherapy and platinum (ERCC1 negativity, which is associated with platinum response 29,30, was correlated with TMB-H.)
MGMT	0.98(0.80 – 1.20)	0.86	5,160	No significant correlation between MGMT status and TMB-H
TOP2A	2.80 (2.15 – 3.66)	<0.001	12,828	Yes for benefit of combination of immunotherapy and doxorubicin (TOPO2A positivity, which is associated with doxorubicin, etoposide, epirubicin response 19, 21, was correlated with TMB-H.)
TOPO1	0.83 (0.75 – 0.93)	0.001	22,090	No for benefit of combination of immunotherapy and irinotecan or topotecan (TOPO1 positivity is associated with irinotecan or topotecan response 20. However, data shows that it TOPO1 negativity was correlated with TMB-H.)
Protein markers and PD-L1 positivity
MGMT	0.78(0.65 – 0.95)	0.011	4,919	Yes for benefit of combination of immunotherapy and temozolomide, dacarbazine. (MGMT negativity, which is associated with response to dacarbazine 31 and temozolomide 32, 33, was correlated with PD-L1 positivity.)
TOPO1	1.01 (0.91 – 1.12)	0.87	18,931	No significant correlation between TOPO1 status and PD-L1 positivity.

^aIf odds ratio of biomarker is less than 1 and p-value is significant, then biomarker negativity is associated with MSI-H or TMB-H. See summary of these results in Table 3.

^bTumor types were pooled and described in this table by the Mantel-Haenszel odds ratio if the Breslow-Day test was not significant; if the Breslow Day test is significant, you cannot pool the tumor types because there are significant differences between histologies. Protein markers with significant Breslow-Day results were not included in the table and relationships are summarized in Supplemental Tables 5–7

Abbreviations: CI=confidence interval, ERCC1=excision repair complementation group 1, H = high, MGMT= O-6-methyl guanine DNA methyltransferase, MSI=microsatellite instability, TMB=tumor mutational burden, TS=thymidylate synthase, TOPO1=topoisomerase 1, TUBB3=tubulin beta 3