Sustained complete response to first-line immunochemotherapy for highly aggressive TP53/MDM2-mutated upper tract urothelial carcinoma with ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state: a case report and literature review

Abstract

Background: Upper tract urothelial carcinoma (UTUC) is a rare malignancy. The management of metastatic or unresectable UTUC is mainly based on evidence extrapolated from histologically homologous bladder cancer, including platinum-based chemotherapy and immune checkpoint inhibitor alone, whereas UTUC exhibits more invasiveness, worse prognosis, and comparatively inferior response to treatments. First-line immunochemotherapy regimens have been attempted in clinical trials for unselected naïve-treated cases, but their efficacies relative to standard chemo- or immuno-monotherapy still remain controversial. Here, we present a case of highly aggressive UTUC for whom comprehensive genetic and phenotypic signatures predicted sustained complete response to first-line immunochemotherapy.

Case presentation: A 50-year-old man received retroperitoneoscopic nephroureterectomy and regional lymphadenectomy for high-risk locally advanced UTUC. Postoperatively, he developed rapid progression of residual unresectable metastatic lymph nodes. Pathologic analysis and next-generation sequencing classified the tumor as highly aggressive TP53/MDM2-mutated subtype with features more than expression of programmed death ligand-1, including ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state. Immunochemotherapy combining gemcitabine, carboplatin, and off-label programmed death-1 inhibitor sintilimab was initiated, and sintilimab monotherapy was maintained up to 1 year. Retroperitoneal lymphatic metastases gradually regressed to complete response. Blood-based analyses were performed longitudinally for serum tumor markers, inflammatory parameters, peripheral immune cells, and circulating tumor DNA (ctDNA) profiling. The ctDNA kinetics of tumor mutation burden and mean variant allele frequency accurately predicted postoperative progression and sustained response to the following immunochemotherapy, which were mirrored by dynamic changes in abundances of ctDNA mutations from UTUC-typical variant genes. The patient remained free of recurrence or metastasis as of this publishing, over 2 years after the initial surgical treatment.

Conclusion: Immunochemotherapy may be a promising first-line option for advanced or metastatic UTUC selected with specific genomic or phenotypic signatures, and blood-based analyses incorporating ctDNA profiling provide precise longitudinal monitoring.

Keywords: ErbB2; TP53/MDM2; case report; circulating tumor DNA (ctDNA); immunochemotherapy; luminal-infiltrated; sintilimab; upper tract urothelial carcinoma.

Figure 1

Comprehensive analyses of the UTUC lesions from the patient. (A) PET-CT scan performed before surgery for the patient indicating malignant lesions involving left upper-middle ureter and surrounding lymph nodes attaching aorta and psoas major. (B) Surgical specimens of left kidney, ureter, and resected lymph nodes. (C) Pathologic analysis for the primary tumor and staining of markers for tumor subtype, proliferation, EMT, and immune status (in order from top to bottom row). Strongly positive: CK7, CK20, ki-67, p53, EGFR/HER-1, E-cadherin, and PD-L1; mildly positive: HER-2; negative: CK5/6, CK14, PTEN, CD44, N-cadherin, vimentin, and ZEB1; infiltrating lymphocytes: 15% PD-1⁺, 50% CD3⁺, 40% CD4⁺, and 10% CD8⁺. (D) Transcriptome subtype classification for the patient’s primary tumor using TCGA classifier based on RNA sequencing data. Left panel: principal component analysis to visualize separation among subtypes (luminal, luminal-papillary, luminal-infiltrated, basal-squamous, and neuronal) of TCGA UC cohort, and this patient clustered with the luminal-infiltrated subset; right panel: cosine similarity measure classifying the current case into the luminal-infiltrated subtype. (E) Bar charts for GO (left) and KEGG (right) categories significantly enriched in TP53-mutant cases of TCGA-UC dataset. (F) Bar charts for GO (left) and KEGG (right) categories significantly enriched in ERBB2-mutant cases of TCGA-UC dataset. CK, cytokeratin; EGFR/HER, human epidermal growth factor receptor; FDR, false discovery rate; GO, Gene Ontology; HE, hematoxylin-eosin; KEGG, Kyoto Encyclopedia of Genes and Genomes; PD-1, programmed death-1; PD-L1, programmed death-1 ligand; PTEN, phosphatase and tensin homolog; TCGA, The Cancer Genome Atlas; ZEB1, zinc finger E-box-binding homeobox-1.

Figure 2

Longitudinal surveillance of the patient’s treatment course. (A) Preoperative PET-CT and serial MRI scans for monitoring the treatment response of lymphatic metastases at different follow-up time points. (B) Dynamic changes of serum tumor markers, systemic inflammatory indices and ctDNA parameters during the treatment. Postoperative (month 1.5) levels of CEA, CYFRA21-1, and CCF were decreased as compared with baseline values corresponding with surgical resection of primary tumor and most of the lymphatic metastases, whereas increased levels of CA72-4, CA15-3, bTMB, and mVAF were supported by rapid progression of residual metastatic lymph nodes as indicated by MRI scans. Durable response to ICT was supported by constantly ascending NK-cell count and descending trends of all other indices, especially Treg count, bTMB, and mVAF. (C) GEP scores of tumors with different immune status in IMvigor210 cohort with metastatic UC. (D) Overall survival curves for high-GEP and low-GEP subgroups of the anti–PD-1–treated IMvigor210 cohort. bTMB, blood tumor mutation burden; CA, carbohydrate antigen; CBP, carboplatin; CCF, cancer cell fraction; CEA, carcinogenic embryonic antigen; CYFRA21-1, cytokeratin-19 fragments; GEM, gemcitabine; GEP, T-cell–inflamed gene expression profile; ICI, immune checkpoint inhibitor; mVAF, mean variant allele frequency; NK, natural killer; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; Treg, regulatory T cell.