Prognostic analysis of related factors of adverse reactions to immunotherapy in advanced gastric cancer and establishment of a nomogram model

Table 1 Comparison of clinical characteristics between the two groups

Clinical characteristic	irAEs group (n = 63)	Non-irAEs group (n = 69)	P value
Age > 65 yr, n	22	37	0.030
Gender (male/female)	43/20	46/23	0.847
Treatment line (first line/subsequent line), n	46/17	40/29	0.071
TNM staging (III/IV)	6/57	4/65	0.421
Ki-67 index, %	49.4 ± 23.3	58.9 ± 20.8	0.049
Her-2 expression (positive/negative)	9/54	11/58	0.791
PD-1/PD-L1 expression (positive/negative), n	22/21	16/17	0.818
MMR (pMMR/dMMR), n	28/2	32/4	0.535
Tumor marker
AFP (ng/mL)	3.3 (2.1, 7.0)	3.3 (2.5, 4.7)	0.209
CEA (ng/mL)	6.0 (2.5, 68.5)	6.3 (2.3, 21.7)	0.280
CA19-9 (U/mL)	20.6 (8.4, 122.9)	30.0 (9.9, 301.0)	0.254
CA125 (U/mL)	31.1 (13.3, 143.5)	23.3 (10.6, 114.0)	0.116
CA153 (U/mL)	12.8 (9.4, 21.2)	10.9 (7.4, 15.8)	0.165
CA724 (U/mL)	5.7 (2.1, 49.7)	9.1 (4.7, 48.0)	0.549
CYFRA21-1 (ng/mL)	5.1 (2.6, 12.4)	6.7 (3.5, 9.6)	0.648
CA50 (U/mL)	17.6 (5.2, 115.6)	24.6 (6.4, 191.6)	0.153
CA242 (U/mL)	6.4 (3.0, 16.4)	9.9 (4.4, 96.3)	0.262
SCC (ng/mL)	1.0 (0.8, 1.7)	1.2 (0.8, 1.5)	0.933
NSE (ng/mL)	11.4 (9.4, 14.6)	11.5 (9.3, 15.3)	0.693
PSA (ng/mL)	0.7 (0.5, 1.5)	0.8 (0.5, 1.6)	0.712
Endocrine indicator
Sex hormone
Neohombreol (nmol/L)	7.8 (1.2, 12.0)	8.5 (1.2, 13.6)	0.942
Progestin (nmol/L)	2.0 (0.9, 2.8)	2.1 (1.4, 3.4)	0.381
Estradiol (pmol/L)	84.0 (55.1, 105.0)	92.0 (72.3, 124.8)	0.274
Prolactin (ng/mL)	13.6 (9.7, 19.0)	13.7 (9.2, 19.7)	0.812
Folkopoietin (U/L)	12.8 (7.4, 20.7)	20.1 (8.1, 39.2)	0.256
Luteinizing hormone (U/L)	5.0 (2.8, 11.4)	6.3 (4.5, 23.3)	0.456
Cortisol hormone (nmol/L)	369.5 (313.1, 456.5)	414.5 (298.6, 465.4)	0.668
Somatotropic hormone (ng/mL)	1.5 (0.7, 2.0)	0.8 (0.2, 2.4)	0.647
ACTH (pg/mL)	28.5 (23.5, 39.3)	29.1 (21.3, 51.7)	0.269
Amylase (U/L)	83.5 (63.8, 99.3)	63.5 (54.8, 75.2)	0.058
ANA (positive/negative), n	22/24	11/17	0.477
Routine blood index
Leukocyte count (× 109/L)	5.7 (4.4, 8.3)	5.4 (4.1, 6.2)	0.044
Neutrophil count (× 109/L)	3.8 (2.4, 5.4)	3.3 (2.3, 4.0)	0.039
Monocyte count (× 109/L)	0.5 (0.4, 0.6)	0.5 (0.4, 0.7)	0.656
Lymphocyte count (× 109/L)	1.4 (1.1, 1.6)	1.3 (1.0, 1.6)	0.634
CRP (mg/L)	2.9 (0.5, 11.5)	1.6 (0.5, 10.3)	0.569
Neutrophil count/lymphocyte count	2.8 (2.0, 3.9)	2.1 (1.6, 3.6)	0.1
Neutrophil count/CRP	1.7 (0.4, 4.7)	2.0 (0.4, 5.0)	0.712
Leukocyte count/CRP	2.4 (0.5, 8.5)	3.3 (0.6, 8.3)	0.8
Lymphocyte subsets
CD19, %	6.5 (4.4, 10.9)	6.8 (3.9, 9.8)	0.527
CD3, %	69.9 (60.6, 76.4)	67.9 (57.8, 72.8)	0.175
CD4, %	37.8 ± 9.1	36.1 ± 11.9	0.384
CD8, %	26.1 ± 8.9	24.7 ± 10.0	0.404
CD4/CD8	1.4 (1.1, 2.2)	1.5 (1.2, 2.4)	0.37
CD56, %	19.9 (12.9, 27.1)	21.0 (14.1, 32.4)	0.183
Cytokine level
Treg count, %	8.3 ± 2.5	9.8 ± 3.0	0.016
IFN-α (pg/mL)	1.8 (1.2, 2.3)	1.5 (0.9, 2.4)	0.783
IL-17 (pg/mL)	6.0 (1.3, 9.4)	3.5 (1.3, 10.0)	0.666
TNF-α (pg/mL)	1.8 (1.3, 2.5)	1.6 (1.0, 3.0)	0.806
IL-2 (pg/mL)	1.2 (0.8, 1.5)	1.2 (0.8, 1.8)	0.24
IL-4 (pg/mL)	1.8 (1.0, 3.0)	1.6 (0.9, 2.5)	0.349
IL-6 (pg/mL)	8.1 (4.4, 16.2)	6.9 (3.8, 12.2)	0.083
IL-8 (pg/mL)	46.6 (22.4, 67.3)	40.0 (19.0, 74.2)	0.829
IL-10 (pg/mL)	3.4 (2.2, 4.6)	2.9 (2.0, 3.9)	0.299

irAEs: Immune-related adverse reactions; TNM: Tumor-node-metastasis; PD-1: Programmed death protein-1; PD-L1: Programmed death ligand 1; Her-2: Human epidermal growth receptor 2; pMMR: Mismatch repair proficient; dMMR: Mismatch repair deficient; AFP: Alpha-fetoprotein; CEA: Carcinoembryonic antigen; CA: Carbohydrate antigen; CYFRA21-1: Cytokeratin fragment antigen 21-1; SCC: Squamous cell carcinoma; NSE: Neuron-specific enolase; PSA: Prostate-specific antigen; ACTH: Adrenocorticotropic hormone; ANA: Antinuclear antibody; CRP: C-reactive protein; IFN: Interferon; IL: Interleukin; TNF: Tumor necrosis factor.

Table 2 Multivariate logistic regression analysis of the occurrence of immune-related adverse reactions

Variable	OR	95%CI	P value
Age ≥ 65 yr	0.489	0.153-1.558	0.227
Ki-67 index	0.985	0.958-1.013	0.305
Leukocyte count	0.796	0.346-1.799	0.574
Neutrophil count	1.583	0.603-4.154	0.351
Treg count	0.796	0.647-0.977	0.03

OR: Odds ratio; CI: Confidence interval.

Table 3 Adverse reaction spectrum and classification of patients in the immune-related adverse reactions group

irAEs	Incidence, n (%)	Severity, n
		Grade 1-2	Grade 3-4
Erythra	17 (27.0)	15	2
Enteritis	15 (23.8)	10	5
Myocarditis	8 (12.7)	4	4
Thyroid dysfunction	8 (12.7)	4	4
Pneumonia	3 (4.8)	3	0
Others	12 (19.0)	7	5

irAEs: Immune-related adverse reactions.

Table 4 Comparison of therapeutic effects between the two groups

Therapeutic effect	irAEs group (n = 63), n (%)	Non-irAEs group (n = 69), n (%)	χ2/t value	P value
PR	19 (30.1)	10 (14.5)	4.679	0.031
SD	35 (55.6)	39 (56.5)	0.012	0.913
PD	9 (14.3)	20 (29.0)	4.12	0.042

irAEs: Immune-related adverse reactions; PR: Partial remission; SD: Stable disease; PD: Disease progression.

Table 5 Cox proportional hazard regression analysis of the prognostic factors of cancer

Variable	Univariate Cox analysis1		Multivariate Cox analysis1		Univariate Cox analysis2		Multivariate Cox analysis2
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Age ≥ 65 yr	0.907 (0.646-1.286)	0.586	0.805 (0.557-1.164)	0.25	1.205 (0.852-1.705)	0.293	1.142 (0.795-1.640)	0.473
Gender	0.977 (0.677-1.408)	0.899	0.823 (0.560-1.209)	0.32	0.927 (0.643-1.338)	0.687	0.869 (0.523-1.443)	0.588
TNM staging	1.371 (0.715-2.625)	0.342	0.945 (0.651-1.374)	0.769	1.614 (0.816-3.194)	0.169	1.372 (0.666-2.826)	0.391
Treatment line	0.794 (0.552-1.141)	0.213	1.591 (0.794-3.186)	0.19	0.992 (0.686-1.433)	0.965	0.924 (0.636-1.341)	0.677
Her-2 expression	1.001 (0.620-1.617)	0.996	1.045 (0.634-1.723)	0.863	0.815 (0.495-1.341)	0.421	0.988 (0.678-1.439)	0.949
irAEs	0.609 (0.431-0.863)	0.005	0.608 (0.431-0.863)	0.006	0.735 (0.520-1.039)	0.081	0.761 (0.535-1.083)	0.129

¹Progression-free survival.

²Overall survival.

HR: Hazard ratio; CI: Confidence interval; TNM: Tumor-node-metastasis; Her-2: Human epidermal growth receptor 2; irAEs: Immune-related adverse reactions.