HER2表达水平对化疗失败的转移性尿路上皮癌免疫治疗疗效的影响

Effect of different HER2 expression on the efficacy of immunotherapy for advanced urothelial carcinoma who failed the previous chemotherapy

目的探讨HER2表达水平对既往化疗失败的转移性尿路上皮癌(UC)免疫治疗疗效的影响。方法回顾性分析北京大学肿瘤医院2017年6月至2021年4月行免疫治疗的77例既往化疗失败的转移性UC患者的临床资料。男49例,女28例;中位年龄为62(29~79)岁;肿瘤原发于膀胱28例(36.4%),肾盂25例(32.5%),输尿管24例(31.2%);转移部位为淋巴结45例(58.4%),肺40例(51.9%),骨20例(26.0%),肝16例(20.8%)。膀胱UC患者中,18例行根治性膀胱切除术,4例行膀胱部分切除术,5例仅行经尿道膀胱肿瘤电切术;肾盂和输尿管UC中,38例行根治性患侧肾输尿管全长切除术,3例行部分切除术,2例行姑息性切除术。术后膀胱灌注化疗15例;术后辅助放疗6例;术后膀胱复发行局部放疗3例;转移灶放疗7例,微波消融治疗1例。所有患者既往均接受过一线化疗,既往接受过二线及以上化疗者30例(40.0%);接受过含铂类方案化疗者70例(90.9%)。所有77例均接受PD-1单抗治疗。免疫组化染色(IHC)检测患者初诊时肿瘤组织(74例为原发灶,3例为转移灶)HER2蛋白表达水平;对于HER2 IHC(++)的患者用第二代测序(NGS)检测患者肿瘤组织HER2基因拷贝数(CN),以CN≥4定义为HER2拷贝数扩增[CN(+)],以CN<4为HER2拷贝数非扩增[CN(-)]。将HER2 IHC(0)定义为HER2阴性,IHC(+)或IHC(++)/CN(-)定义为HER2低表达,IHC(++)/CN(+)或IHC(+++)定义为HER2高表达。采用χ2检验或者Fisher精确检验评估患者HER2表达与PD-1单抗治疗后客观缓解率(ORR)的相关性,采用Kaplan-Meier法和log-rank检验比较不同HER2表达状态患者的中位无进展生存时间(PFS)和总生存时间(OS)差异。结果77例接受PD-1单抗治疗的中位时间为6.4(1.5~47.8)个月,中位治疗次数11(2~45)次。77例中位随访时间为30.9(1.4~48.1)个月,ORR为33.8%(26/77)。其中38例PD-1单抗治疗后进展,接受了后续治疗,采用抗体药物偶联剂治疗17例,化疗18例,化疗联合抗血管生成药物治疗12例。免疫治疗后总体中位PFS为5.8(95%CI 3.0~8.6)个月,中位OS为23.6(95%CI 8.5~38.7)个月。对77例初诊肿瘤组织行HER2 IHC检测,(0)、(+)、(++)、(+++)患者分别为33例(42.9%)、19例(24.7%)、20例(26.0%)、5例(6.5%);20例IHC(++)患者行HER2 CN检测,1例为CN(+),19例为CN(-)。HER2阴性、低表达、高表达患者的ORR分别为42.4%(14/33)、31.6%(12/38)、0(0/6)(P=0.08),三者的中位PFS分别为11.0、3.7、1.8个月,整体比较和两两比较差异均有统计学意义(P<0.05)。HER2阴性和HER2低表达患者接受PD-1单抗治疗后的中位OS分别为23.6个月和22.7个月,而HER2高表达患者的中位OS尚未达到,总体比较差异无统计学意义(P=0.623)。结论对于化疗失败后接受PD-1单抗治疗的转移性UC患者,HER2高表达者的PFS显著低于低表达或阴性者。HER2表达有可能预测既往化疗失败后转移性UC免疫治疗的疗效,结论需进一步研究证实。

Objective To explore the effect of different HER2 expression levels and gene amplification on the efficacy of immunotherapy in metastatic urothelial carcinoma(UC).Methods The clinical data of 77 patients with metastatic UC who received immunotherapy from June 2017 to April 2021 after failure to the previous chemotherapy were analyzed retrospectively,including 49 males and 28 females with the median age of 62 years.The primary tumors located in bladder in 28 cases(36.4%),renal pelvis in 25 cases(32.5%)and ureter in 24 cases(31.2%).The common metastatic sites included:lymph nodes(n=45,58.4%),lung(n=40,51.9%),bone(n=20,26.0%)and liver(n=16,20.8%).27 patients with bladder UC received surgery on the primary tumors including radical cystectomy(n=18),partial cystectomy(n=4)and transurethral resection(n=5).43 patients with renal pelvis or ureteral UC received surgery on the primary tumors including radical nephroureterectomy(n=38),local resection(n=3)and palliative resection(n=2).Postoperative intravesical chemotherapy was performed in 15 cases,adjuvant radiotherapy was performed in 6 cases.3 patients who emerged postoperative bladder recurrence received local radiotherapy.7 patients received radiotherapy and 1 case received microwave ablation to their metastatic sites.All patients had received first-line chemotherapy and 30 patients(40.0%)had received at least second-line treatment including 70 cases(90.9%)with platinum containing chemotherapy.All 77 patients received anti-PD-1 treatment.38 patients received sequential regimen after failed to the anti-PD-1 therapy,including antibody-drug conjugate(n=17),chemotherapy(n=18)and chemotherapy combined with anti-angiogenesis drugs(n=12).Immunohistochemical(IHC)staining was used to detect the expression level of HER2 protein in the tumor tissues(74 cases from primary tumors and 3 cases from metastatic tumors)obtained from the initial diagnosis.For patients with HER2 IHC(++),the copy number(CN)of HER2 gene was detected by next-generation sequencing(NGS).HER2 copy number amplification[CN(+)]was defined as CN≥4,and HER2 copy number non-amplification[CN(-)]was defined as CN<4.HER2 IHC(0)was defined as HER2 negative,IHC(+)or IHC(++)/CN(-)was defined as HER2 low expression,while IHC(++)/CN(+)and IHC(+++)were defined as HER2 high expression.Chi-square test or Fisher exact test were used to evaluate the correlation between HER2 expression and objective response rate(ORR)after anti-PD-1 treatment.Kaplan-Meier method and log-rank test were used to compare the differences of median progression free survival(PFS)and overall survival(OS)under different HER2 expression status.Results All the 77 patients received a median of 11(range:2-45)doses of anti-PD-1 treatment with a median duration of treatment of 6.4(range:1.5-47.8)months and the ORR was 33.8%(26/77).The median follow-up time was 30.9 months.The overall median PFS time was 5.8(95%CI:3.0-8.6)months and the median OS time was 23.6(95%CI:8.5-38.7)months.HER2 IHC tests were performed in 77 patients.HER2 IHC levels of(0),(+),(++)and(+++)were found in 33(42.9%),19(24.7%),20(26.0%)and 5(6.5%)patients,respectively.HER2 copy number was detected in 20 patients with IHC(++),while 1 CN(+)and 19 CN(-)were found.The ORR of HER2 negative,low expression and high expression patients were 42.4%(14/33)vs.31.6%(12/38)vs.0(0/6)(P=0.08),respectively.The median PFS of the three groups were 11.0 months,3.7 months and 1.8 months,respectively,with significant differences in overall and pairwise comparison(P=0.001).The median OS of patients with HER2 negative and low expression after anti-PD-1 treatment were 23.6 months and 22.7 months,respectively,while the median OS of patients with HER2 high expression had not been reached,with no significant difference in the overall comparison(P=0.623).Conclusions For patients with metastatic UC received anti-PD-1 treatment,the PFS of patients with high HER2 expression was significantly worse than that of patients with low or negative HER2 expression.HER2 expression may have potential value in predicting the efficacy of immunotherapy for metastatic UC who failed the previous chemotherapy,which needs further research.