Analysis of Predictors for Immune-related Adverse Events and the Correlation with Efficacy in Progressive Esophageal Squamous Cell Carcinoma

doi:10.12114/j.issn.1007-9572.2025.0208

Abstract

Abstract:

Background

Immunotherapy has become the standard regimen for progressive esophageal squamous cell carcinoma (ESCC), but there is a lack of clear biomarkers to predict immune-related adverse events (irAEs), and the relationship between irAEs and efficacy is also unclear.

Objective

To explore the predictive factors associated with the occurrence of irAEs in patients with progressive ESCC and the correlation between irAEs and prognosis.

Methods

A retrospective study was conducted on 118 patients diagnosed with progressive ESCC and treated with programmed death protein 1 (PD-1) inhibitors at Nanjing Drum Tower Hospital from 2020 to 2023. The enrolled patients were followed up through access to medical records, outpatient visits, re-admissions, phone calls. Clinical data and occurrence of irAEs were collected. Patients were divided into the irAEs-positive group and the irAEs-negative group based on the occurrence of irAEs during treatment. Univariate and multivariate Logistic analysis were conducted to analyze the factors influencing the occurrence of irAEs. The efficacy was evaluated as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Objective remission rate (ORR), disease control rate (DCR) were compared between the two groups. Kaplan-Meier survival curve were plotted, and Log-rank test was conducted to compare the progression free survival (PFS) and overall survival (OS) between the two groups.

Results

Among the 118 patients, 47 cases (39.83%) experienced irAEs. The irAEs with higher incidence were dermal toxicity 21 cases (17.80%), endocrine toxicity 16 cases (13.56%) and pulmonary toxicity16 cases (13.56%). The comparison of autoantibody profiles and antinuclear antibody (ANA) between the irAEs-positive group and the irAEs-negative group showed a statistically significant difference (P<0.05). Univariate Logistic analysis showed that autoantibody profile positivity (OR=3.375, 95%CI=1.527-7.456, P=0.003) and ANA positivity (OR=3.072, 95%CI=1.404-6.722, P=0.005) were risk factors for the development of irAEs (P<0.05). Multivariate Logistic analysis showed that autoantibody profile positivity (OR=2.367, 95%CI=0.841-6.663, P=0.103) and ANA positivity (OR=1.733, 95%CI=0.621-4.837, P=0.293) were not significantly associated with the occurrence of irAEs. However, the incidence of endocrine toxicity was higher in autoantibody-positive patients than in autoantibody-negative patients, and the incidence of endocrine toxicity and myotoxicity was higher in ANA-positive patients than in ANA-negative patients (P<0.05). Moreover, the DCR of irAEs-positive group was longer than that of irAEs-negative group (χ²=6.690, P=0.010). Comparing the ORR of the two groups, the difference was not statistically significant (χ²=2.628, P=0.105). Survival analysis results showed that the median PFS and median OS of the irAEs-positive group were longer than those of the irAEs-negative group, all differences were statistically significant (PFS: χ²=9.521, P=0.002; OS: χ²=4.254, P=0.039).

Conclusion

Autoantibody profiles or ANA positivity may be more likely to develop irAEs after immunotherapy in patients with ESCC, and the occurrence of irAEs is associated with better efficacy.

Key words: Esophageal squamous cell carcinoma, Immunotherapy, Immune-related adverse events, Autoantibody profiles, Antinuclear antibody, Efficacy

摘要：

背景

免疫治疗已成为进展期食管鳞状细胞癌（ESCC）的标准治疗方案，但目前尚缺乏明确的预测免疫相关不良反应（irAEs）的生物标志物，且irAEs与疗效的关系亦不明确。

目的

探讨进展期ESCC患者发生irAEs的预测因素及irAEs与疗效的相关性。

方法

回顾性纳入2020—2023年在南京鼓楼医院接受程序性死亡蛋白1（PD-1）抑制剂治疗的118例进展期ESCC患者为研究对象，通过查阅病历、门诊、再入院、电话等方式对入组患者进行随访，收集患者的临床资料及irAEs情况，根据治疗过程中是否发生irAEs分为irAEs阳性组和irAEs阴性组，采用单因素和多因素Logistic回归分析探讨影响irAEs发生的相关因素。疗效评价为完全缓解（CR）、部分缓解（PR）、疾病稳定（SD）、疾病进展（PD），比较两组的客观缓解率（ORR）、疾病控制率（DCR），采用Kaplan-Meier法绘制生存曲线，采用Log-rank检验比较两组患者无进展生存期（PFS）及总生存期（OS）差异。

结果

118例患者中47例（39.83%）发生irAEs，发生率较高的irAEs为皮肤毒性21例（17.80%）、内分泌毒性16例（13.56%）和肺毒性16例（13.56%）。irAEs阳性组和irAEs阴性组自身抗体谱及抗核抗体（ANA）比较，差异有统计学意义（P<0.05）。单因素Logistic分析显示，自身抗体谱阳性（OR=3.375，95%CI=1.527~7.456，P=0.003）和ANA阳性（OR=3.072，95%CI=1.404~6.722，P=0.005）是irAEs发生的危险因素（P<0.05）；多因素Logistic分析结果显示，自身抗体谱阳性（OR=2.367，95%CI=0.841~6.663，P=0.103）和ANA阳性（OR=1.733，95%CI=0.621~4.837，P=0.293）与irAEs的发生无显著关联；但自身抗体谱阳性患者内分泌毒性的发生率高于自身抗体谱阴性患者，ANA阳性患者内分泌毒性和肌毒性的发生率高于ANA阴性患者（P<0.05）。且irAEs阳性组DCR高于irAEs阴性组（χ²=6.690，P=0.010）；两组ORR比较，差异无统计学意义（χ²=2.628，P=0.105）。生存分析结果显示，irAEs阳性组中位PFS和中位OS长于irAEs阴性组，差异均有统计学意义（PFS：χ²=9.521，P=0.002；OS：χ²=4.254，P=0.039）。

结论

自身抗体谱或ANA阳性的ESCC患者接受免疫治疗后可能更容易发生irAEs，且irAEs的发生与更好的治疗疗效相关。

关键词: 食管鳞状细胞癌, 免疫治疗, 免疫相关不良反应, 自身抗体谱, 抗核抗体, 疗效

CLC Number:

R 735.1

YANG Haifei,SUN Wu,WU Cheng, et al. Analysis of Predictors for Immune-related Adverse Events and the Correlation with Efficacy in Progressive Esophageal Squamous Cell Carcinoma[J]. Chinese General Practice, 2026, 29(06): 710-717. DOI: 10.12114/j.issn.1007-9572.2025.0208.
杨海飞,孙武,吴成等. 进展期食管鳞状细胞癌免疫相关不良反应的预测因素及其与疗效相关性分析[J]. 中国全科医学, 2026, 29(06): 710-717. DOI: 10.12114/j.issn.1007-9572.2025.0208.

Figures/Tables 6

References 42

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组别	例数	年龄（岁）	性别[例（%）]		TNM分期[例（%）]		ECOG评分[例（%）]		CPS[例（%）]
组别	例数	年龄（岁）	男	女	Ⅲ期	Ⅳ期	0~1分	≥2分	阴性	阳性	NA
irAEs阴性组	71	68.0 ± 8.1	60（84.51）	11（15.49）	16（22.54）	55（77.46）	65（91.55）	6（8.45）	20（28.17）	8（11.27）	43（60.56）
irAEs阳性组	47	66.8 ± 8.1	37（78.72）	10（21.28）	10（21.28）	37（78.72）	43（91.49）	4（8.51）	19（40.43）	10（21.28）	18（38.30）
χ²（t）值		0.828^a	0.647		0.026		<0.001		5.855
P值		0.409	0.421		0.872		1.000		0.054
组别	肿瘤分化[例（%）]			肿瘤位置[例（%）]			肝转移[例（%）]
组别	高分化	中分化	低分化	胸上段	胸中段	胸下段	阴性	阳性
irAEs阴性组	14（19.72）	43（60.56）	14（19.72）	16（22.54）	32（45.07）	23（32.39）	63（88.73）	8（11.27）
irAEs阳性组	10（21.28）	24（51.06）	13（27.66）	15（31.91）	19（40.43）	13（27.66）	43（91.49）	4（8.51）
χ²（t）值	1.263			1.296			0.030
P值	0.532			0.523			0.862
组别	肺转移[例（%）]		复发部位数量[例（%）]		自身抗体谱[例（%）]		ANA[例（%）]
组别	阴性	阳性	1个	≥2个	阴性	阳性	阴性	阳性
irAEs阴性组	66（92.96）	5（7.04）	60（84.51）	11（15.49）	40（56.34）	31（43.66）	53（74.65）	18（25.35）
irAEs阳性组	41（87.23）	6（12.77）	38（80.85）	9（19.15）	13（27.66）	34（72.34）	23（48.94）	24（51.06）
χ²（t）值	0.523		0.269		9.401		8.155
P值	0.469		0.604		0.002		0.004
组别	抗Ro-52抗体[例（%）]		治疗线数[例（%）]		PD-1抑制剂[例（%）]
组别	阴性	阳性	一线	二线及以上	卡瑞利珠单抗	特瑞普利单抗	信迪利单抗	替雷利珠单抗
irAEs阴性组	61（85.92）	10（14.08）	69（97.18）	2（2.82）	30（42.25）	9（12.68）	20（28.17）	12（16.90）
irAEs阳性组	41（87.23）	6（12.77）	45（95.74）	2（4.26）	16（34.04）	9（19.15）	12（25.53）	10（21.28）
χ²（t）值	0.042		<0.001		1.629
P值	0.838		1.000		0.653

组别	例数	年龄（岁）	性别[例（%）]		TNM分期[例（%）]		ECOG评分[例（%）]		CPS[例（%）]
组别	例数	年龄（岁）	男	女	Ⅲ期	Ⅳ期	0~1分	≥2分	阴性	阳性	NA
irAEs阴性组	71	68.0 ± 8.1	60（84.51）	11（15.49）	16（22.54）	55（77.46）	65（91.55）	6（8.45）	20（28.17）	8（11.27）	43（60.56）
irAEs阳性组	47	66.8 ± 8.1	37（78.72）	10（21.28）	10（21.28）	37（78.72）	43（91.49）	4（8.51）	19（40.43）	10（21.28）	18（38.30）
χ²（t）值		0.828^a	0.647		0.026		<0.001		5.855
P值		0.409	0.421		0.872		1.000		0.054
组别	肿瘤分化[例（%）]			肿瘤位置[例（%）]			肝转移[例（%）]
组别	高分化	中分化	低分化	胸上段	胸中段	胸下段	阴性	阳性
irAEs阴性组	14（19.72）	43（60.56）	14（19.72）	16（22.54）	32（45.07）	23（32.39）	63（88.73）	8（11.27）
irAEs阳性组	10（21.28）	24（51.06）	13（27.66）	15（31.91）	19（40.43）	13（27.66）	43（91.49）	4（8.51）
χ²（t）值	1.263			1.296			0.030
P值	0.532			0.523			0.862
组别	肺转移[例（%）]		复发部位数量[例（%）]		自身抗体谱[例（%）]		ANA[例（%）]
组别	阴性	阳性	1个	≥2个	阴性	阳性	阴性	阳性
irAEs阴性组	66（92.96）	5（7.04）	60（84.51）	11（15.49）	40（56.34）	31（43.66）	53（74.65）	18（25.35）
irAEs阳性组	41（87.23）	6（12.77）	38（80.85）	9（19.15）	13（27.66）	34（72.34）	23（48.94）	24（51.06）
χ²（t）值	0.523		0.269		9.401		8.155
P值	0.469		0.604		0.002		0.004
组别	抗Ro-52抗体[例（%）]		治疗线数[例（%）]		PD-1抑制剂[例（%）]
组别	阴性	阳性	一线	二线及以上	卡瑞利珠单抗	特瑞普利单抗	信迪利单抗	替雷利珠单抗
irAEs阴性组	61（85.92）	10（14.08）	69（97.18）	2（2.82）	30（42.25）	9（12.68）	20（28.17）	12（16.90）
irAEs阳性组	41（87.23）	6（12.77）	45（95.74）	2（4.26）	16（34.04）	9（19.15）	12（25.53）	10（21.28）
χ²（t）值	0.042		<0.001		1.629
P值	0.838		1.000		0.653

变量	β	SE	Z值	P值	OR（95%CI）
年龄	-0.019	0.023	-0.831	0.406	0.981（0.937~1.027）
性别（以男为参照）
女	0.388	0.484	0.801	0.423	1.474（0.571~3.809）
TNM分期（以Ⅲ期为参照）
Ⅳ期	0.074	0.456	0.161	0.872	1.076（0.441~2.630）
ECOG评分（以0~1分为参照）
≥2分	0.008	0.675	0.011	0.991	1.008（0.269~3.782）
CPS（以阴性为参照）
阳性	0.274	0.572	0.479	0.632	1.316（0.429~4.040）
NA	-0.820	0.426	-1.924	0.054	0.441（0.191~1.015）
肿瘤分化（以高分化为参照）
中分化	-0.247	0.486	-0.507	0.612	0.781（0.301~2.026）
低分化	0.262	0.565	0.464	0.643	1.300（0.429~3.938）
肿瘤位置（以胸上段为参照）
胸中段	-0.457	0.462	-0.990	0.322	0.633（0.256~1.565）
胸下段	-0.506	0.500	-1.013	0.311	0.603（0.226~1.605）
肝转移（以阴性为参照）
阳性	-0.311	0.644	-0.484	0.629	0.733（0.208~2.586）
肺转移（以阴性为参照）
阳性	0.658	1.033	0.637	0.302	1.932（0.554~6.737）
复发部位数量（以1个为参照）
≥2个	0.256	0.495	0.517	0.605	1.292（0.490~3.408）
自身抗体谱（以阴性为参照）
阳性	1.216	0.404	3.007	0.003	3.375（1.527~7.456）
ANA（以阴性为参照）
阳性	1.122	0.399	2.810	0.005	3.072（1.404~6.722）
抗Ro-52抗体（以阴性为参照）
阳性	-0.114	0.554	-0.205	0.838	0.893（0.301~2.647）
治疗线数（以一线为参照）
二线及以上	0.427	1.018	0.420	0.675	1.533（0.208~11.280）
PD-1抑制剂（以卡瑞利珠单抗为参照）
特瑞普利单抗	0.629	0.564	1.115	0.265	1.875（0.621~5.663）
信迪利单抗	0.118	0.479	0.246	0.806	1.125（0.440~2.875）
替雷利珠单抗	0.446	0.528	0.845	0.398	1.562（0.555~4.401）

变量	β	SE	Z值	P值	OR（95%CI）
年龄	-0.019	0.023	-0.831	0.406	0.981（0.937~1.027）
性别（以男为参照）
女	0.388	0.484	0.801	0.423	1.474（0.571~3.809）
TNM分期（以Ⅲ期为参照）
Ⅳ期	0.074	0.456	0.161	0.872	1.076（0.441~2.630）
ECOG评分（以0~1分为参照）
≥2分	0.008	0.675	0.011	0.991	1.008（0.269~3.782）
CPS（以阴性为参照）
阳性	0.274	0.572	0.479	0.632	1.316（0.429~4.040）
NA	-0.820	0.426	-1.924	0.054	0.441（0.191~1.015）
肿瘤分化（以高分化为参照）
中分化	-0.247	0.486	-0.507	0.612	0.781（0.301~2.026）
低分化	0.262	0.565	0.464	0.643	1.300（0.429~3.938）
肿瘤位置（以胸上段为参照）
胸中段	-0.457	0.462	-0.990	0.322	0.633（0.256~1.565）
胸下段	-0.506	0.500	-1.013	0.311	0.603（0.226~1.605）
肝转移（以阴性为参照）
阳性	-0.311	0.644	-0.484	0.629	0.733（0.208~2.586）
肺转移（以阴性为参照）
阳性	0.658	1.033	0.637	0.302	1.932（0.554~6.737）
复发部位数量（以1个为参照）
≥2个	0.256	0.495	0.517	0.605	1.292（0.490~3.408）
自身抗体谱（以阴性为参照）
阳性	1.216	0.404	3.007	0.003	3.375（1.527~7.456）
ANA（以阴性为参照）
阳性	1.122	0.399	2.810	0.005	3.072（1.404~6.722）
抗Ro-52抗体（以阴性为参照）
阳性	-0.114	0.554	-0.205	0.838	0.893（0.301~2.647）
治疗线数（以一线为参照）
二线及以上	0.427	1.018	0.420	0.675	1.533（0.208~11.280）
PD-1抑制剂（以卡瑞利珠单抗为参照）
特瑞普利单抗	0.629	0.564	1.115	0.265	1.875（0.621~5.663）
信迪利单抗	0.118	0.479	0.246	0.806	1.125（0.440~2.875）
替雷利珠单抗	0.446	0.528	0.845	0.398	1.562（0.555~4.401）

变量	β	SE	Z值	P值	OR（95%CI）
自身抗体谱（以阴性为参照）
阳性	0.862	0.528	1.632	0.103	2.367（0.841~6.663）
ANA（以阴性为参照）
阳性	0.550	0.524	1.051	0.293	1.733（0.621~4.837）