Published online Jan 14, 2027. doi: 10.3748/wjg.124393
Revised: July 29, 2026
Accepted: September 15, 2026
Published online: January 14, 2027
Processing time: 151 Days and 12.7 Hours
Programmed cell death protein-1 inhibitors are established treatments for advanced microsatellite instability-high (MSI-H) colorectal cancer; however, primary and acquired resistance persist. Recent studies have indicated that combining programmed cell death protein-1 inhibitors with anti-angiogenic targeted agents has been explored as a strategy to improve responses; however, evidence for this approach in MSI-H colorectal cancer remains limited.
We present the case of a 58-year-old female patient with previous primary ovarian and gastric malignancies who was recently diagnosed with malignant adenocarcinoma of the descending and sigmoid colons (cT4N2M1, American Joint Com
This case highlights the potential feasibility of combining immune checkpoint inhibitors with anti-angiogenic agents to achieve a deep radiological response and improve patient prognosis, representing a therapeutic strategy that warrants further exploration.
Core Tip: This case report describes a rare patient with triple primary malignancies, including microsatellite instability-high/KRAS-mutated advanced colorectal cancer, with a history of clinically cured gastric and ovarian cancers, who achieved marked radiological remission following conversion therapy with tislelizumab combined with bevacizumab. The target-lesion longest diameter decreased by 72.3%, meeting Response Evaluation Criteria in Solid Tumors 1.1 criteria for a confirmed partial response. Germline testing identified a pathogenic MSH2 variant, establishing Lynch syndrome. This observation highlights the potential of combining programmed death-1 inhibitors with anti-angiogenic targeted agents in selected patients with advanced microsatellite instability-high colorectal cancer and warrants further investigation.
- Citation: Chen YF, Huang C, Chen ZJ, Wang ZH. Significant response to tislelizumab plus bevacizumab in a patient with microsatellite instability-high colon cancer: A case report and review of literature. World J Gastroenterol 2027; 33(2): 124393
- URL: https://www.wjgnet.com/1007-9327/full/v33/i2/124393.htm
- DOI: https://dx.doi.org/10.3748/wjg.124393
Colorectal cancer (CRC) ranks third in the global cancer incidence rate and is the second leading cause of cancer-related deaths worldwide[1]. This disease is relatively common worldwide, causes numerous deaths, and is prone to distant metastasis at diagnosis or during the course of the disease[2]. Although patients with metastatic CRC (mCRC) typically achieve favorable outcomes with first- and second-line systemic chemotherapy, older patients and those with com
In recent years, the exploration of various targeted therapies and their combination with immunotherapy for deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) mCRC has been established as a key research direction for improving response rates, overcoming drug resistance, and enhancing patient survival outcomes[6]. MSI-H has been identified as a prognostic and predictive biomarker for CRC because tumors with MSI-H status are usually more sensitive to immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) inhibitors. Confirmed dMMR/MSI-H status is a reliable biomarker for the long-term response to ICIs targeting PD-1/programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4. Consequently, ICIs have become the standard treatments for these patients[7,8]. The efficacy of PD-1 inhibitor monotherapy in patients with MSI-H CRC ranges from 40% to 45%[9], indicating that most patients do not achieve the ideal curative effect of this monotherapy. To improve the efficacy of immunotherapy, a combination of anti-angiogenic drugs and ICIs has become a strategy. Anti-angiogenic targeted agents can promote the normalization of the tumor vascular system and improve the hypoxic state of tumors, thus alleviating immunosuppression in the tumor microenvironment and enhancing the activation of immune cells and antitumor effects[6,10]. Commonly used anti-angiogenic drugs for the treatment of CRC include bevacizumab and regorafenib. Bevaci
Intermittent abdominal pain accompanied by nausea and vomiting.
A 58-year-old female patient was admitted to our hospital in January 2025 with intermittent abdominal pain accom
Subsequently, on March 14, 2025, human epidermal growth factor receptor 2 and PD-L1 immunohistochemical testing was performed on the colonoscopic biopsy specimen obtained on February 3, 2025, showing human epidermal growth factor receptor 2 2+ and a PD-L1 combined positive score of approximately 1; PD-L1 staining is shown in Figure 4C and D. Two separate next-generation sequencing (NGS) analyses were conducted. For somatic profiling, formalin-fixed, paraffin-embedded tumor tissue obtained from colonoscopic biopsy on February 3, 2025, was analyzed using hybrid-capture-based NGS on an Illumina-compatible platform (Berry Genomics) with an ADx-SEQ200 Plus sequencer. The assay covered 571 genes at the DNA level and 2660 genes at the RNA level, as well as microsatellite status, tumor mutational burden (TMB), tumor immune microenvironment subtype, gene expression profiles, and polymorphic variants in genes associated with the metabolism of chemotherapeutic agents. Microsatellite instability was assessed across 116 microsatellite loci, with instability at 18 or more loci corresponding to a threshold of 15%, classified as MSI-H. Germline testing was subsequently performed using peripheral whole-blood DNA, with amplicon-based library preparation using the HANDLE System, to analyze the coding regions and exon-intron boundaries of 150 genes associated with hereditary susceptibility to solid tumors and to detect single-nucleotide variants and small insertions and deletions. Both analyses used the hg19 human reference genome, and the variants were described according to the Human Genome Variation Society nomenclature. Somatic variants were classified according to the 2017 AMP/ASCO/CAP guidelines, whereas germline variants were interpreted according to the 2015 ACMG/AMP recommendations[14]. Somatic profiling confirmed MSI-H status and a high TMB of 101.67 mutations/Mb. Alterations of established or potential clinical significance included KRAS c.436G>A p.(A146T) at a variant allele frequency (VAF) of 32.28%; PIK3CA p.(E545A) at 27.69%; PTEN p.(P95 L) at 32.81% and p.(E157Gfs23) at 28.81%; TP53 p.(R267W) at 36.10%; APC p.(R213) at 30.62% and p.(T1556Nfs3) at 29.46%; RNF43 p.(G659Vfs41) at 66.22%; ATR p.(I774Yfs5) at 10.85%; and B2M p.(T93Hfs2) at 63.29%. Two MSH2 alterations were identified in the tumor: The nonsense variant c.1216C>T p.(R406*) at a VAF of 50.85% and the splice-site variant c.1276+1G>A at 34.64%. An MSH6 frameshift variant, p.(F1088 Lfs*5), was also detected at a VAF of 23.64%. Homologous recombination deficiency testing was negative, with a genomic scar score of 6.5. No pathogenic or likely pathogenic variants were identified in BRCA1 or BRCA2. Germline testing identified a heterozygous pathogenic MSH2 variant, c.1216C>T p.(R406*) (NM_000251.3), thereby establishing the molecular diagnosis of Lynch syndrome[14,15]. This loss-of-function variant was absent from the 1000 Genomes Project, ExAC, gnomAD, and iJGVD population databases, and was classified as pathogenic in ClinVar (variation ID: 1755). The patient received genetic counseling regarding the test findings, hereditary cancer risks, and recommendations for ongoing cancer surveillance and risk management.
The regimen was selected on three grounds: MSI-H/dMMR status-supported PD-1 blockade, KRAS p.(A146T) mutation precluded anti-epidermal growth factor receptor monoclonal antibody therapy, and the tumor NGS report annotated bevacizumab as sensitive with level A evidence, thereby informing the selection of this targeted agent. Bevacizumab is an established biological treatment strategy for patients with RAS-mutant, initially unresectable mCRC[16]. Given the patient’s general condition, chemotherapy was considered unsuitable; therefore, a combination of tislelizumab and bevacizumab was selected. Treatment was initiated on March 26, 2025, with the goal of achieving conversion to resectability. In each cycle, bevacizumab 400 mg was administered intravenously, followed 1 day later by intravenous tislelizumab (200 mg), and treatment cycles were repeated every 3 weeks. The patient received a total of 12 cycles between 26 March and 28 November 2025.
Whole-abdominal enhanced CT was reviewed on May 6, 2025, after approximately 6 weeks of treatment, and the scan showed a reduction in the target lesion to 58 mm × 44 mm. Bowel obstruction and rectal dilatation improved and the left ureteral stent remained in situ (Figure 1C). An enhanced abdominal CT scan performed on July 16, 2025, revealed further reduction of the target lesion to 23 mm × 26 mm. Thickening of the sigmoid and rectal walls, pelvic effusion, and thickening of the left renal pelvic wall also decreased. The proximal end of the left ureteral stent was positioned lower than that in the previous scan (Figure 1D). On September 17, 2025, the target lesion remained stable at 23 mm × 26 mm, with no evidence of disease progression (Figure 1E).
Tumor response was retrospectively assessed according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)[17] using the single target lesion. The longest lesion diameter was 94 mm at baseline, 58 mm on May 6, 2025 (a 38.3% decrease), 26 mm on July 16, 2025 (a 72.3% decrease), and 26 mm on September 17, 2025. This reduction met the criteria for a partial response, which was confirmed > 4 weeks later. As no post-treatment resection specimens were available, the pathological response could not be assessed.
The tumor marker trends are shown in Figure 2. CEA peaked at 6.77 ng/mL on March 13, 2025, and subsequently declined to its lowest recorded level of 1.48 ng/mL on September 16, 2025. CA72-4 peaked at 62.43 IU/mL on May 4, 2025, decreased to its lowest recorded level of 5.81 IU/mL on August 6, 2025, and measured 9.36 IU/mL on November 26, 2025. By contrast, CA19-9 increased from its lowest recorded level of 22.57 U/mL on March 13, 2025 to its highest recorded level of 114.70 U/mL on November 26, 2025 despite the radiographic response. This discordant increase was considered more likely to represent treatment-associated pseudo-elevation related to physiological stress or gastrointestinal reactions than tumor progression.
A review of the available medical records revealed the presence of anemia (nadir hemoglobin level, 77 g/L; Common Terminology Criteria for Adverse Events grade 3) and hypoalbuminemia (nadir albumin level, 20.9 g/L; grade 2) before systemic treatment, and both subsequently improved. The pre-treatment fasting glucose level was 7.59 mmol/L, corresponding to grade 1 hyperglycemia. Renal function was monitored and blood pressure remained within the normal range during hospitalization. Proteinuria, rashes, and diarrhea were not observed. No immune-related adverse events or treatment modifications owing to toxicity were noted. Considering the extended duration of the patient’s diagnosis and treatment, which involved targeted immunotherapy and surgical intervention, we created a simplified flowchart to facilitate a clear review of the patient’s treatment history (Figure 5).
The patient had been previously diagnosed with gastric and right ovarian cancers. The patient underwent radical gastrectomy for gastric cancer and hysterectomy with bilateral salpingo-oophorectomy for ovarian cancer, achieving a clinical cure for both malignancies.
Her father had a hematological disorder and her mother had rectal cancer. Germline testing later identified a heterozygous pathogenic MSH2 variant, c.1216C>T p.(R406*), establishing the diagnosis of Lynch syndrome.
The abdomen was soft, with a firm, poorly mobile, palpable mass in the left lower quadrant associated with mild tenderness. No signs of peritoneal irritation or hepatosplenomegaly were observed, and bowel sounds were normal.
The baseline laboratory findings were as follows: Aspartate aminotransferase 9.5 U/L, hemoglobin 100 g/L, total protein 61.8 g/L, carcinoembryonic antigen 4.96 ng/mL, CA72-4 28.90 IU/mL, and CA19-9 43.71 U/mL. Colonoscopic biopsy confirmed mucosal adenocarcinoma. Tumor NGS revealed MSI-H status, a TMB of 101.67 mutations/Mb, and a KRAS c.436G>A p.(A146T) variant. Peripheral blood germline testing revealed a pathogenic heterozygous MSH2 c.1216C>T p (R406*) variant.
Abdominal CT on January 28-29, 2025 showed irregular thickening and a 94 mm × 74 mm mass involving the lower descending and sigmoid colon, accompanied by bowel obstruction, fecal accumulation, and dilatation and obstruction of the left renal pelvis and ureter. After treatment, the target lesion size decreased to 58 mm × 44 mm on May 6, 2025, and to 23 mm × 26 mm on July 16, 2025. On September 17, 2025, it remained stable at 23 mm × 26 mm, with no evidence of disease progression.
Adenocarcinoma of the descending and sigmoid colon, staged as cT4N2M1 according to the American Joint Committee on Cancer 8th edition, with intraoperative findings suggestive of peritoneal metastasis, including a palpable implant-like lesion in the greater omentum; however, histological confirmation was not obtained. Lynch syndrome associated with a germline pathogenic MSH2 variant, c.1216C>T p.(R406*).
Colostomy for intestinal obstruction was followed by 12 cycles of conversion therapy consisting of intravenous tislelizumab 200 mg plus bevacizumab 400 mg every 3 weeks from March 26 to November 28, 2025.
The patient achieved a confirmed partial response according to RECIST 1.1, with a 72.3% reduction in the longest diameter of the target lesion, which was maintained at the most recent imaging assessment on September 17, 2025; no evidence of disease progression was documented. No treatment delays, dose reductions, or discontinuations owing to toxicity were recorded.
CRC is a leading cause of cancer-related mortality worldwide. In selected patients with initially unresectable metastatic disease, conversion therapy aims to achieve tumor downstaging and enable curative-intent resection; however, no standardized regimen has been established, and treatment is typically individualized[18,19]. The MSI-H/dMMR status predicts sensitivity to ICIs; however, not all patients respond to single-agent immunotherapy[20]. Vascular endothelial growth factor (VEGF) blockade may enhance antitumor immunity by normalizing tumor vasculature, alleviating hypoxia, and promoting immune cell infiltration[6,21].
The patient had three metachronous primary malignancies involving the colorectum, ovary, and stomach, and germline testing confirmed a diagnosis of Lynch syndrome. The current malignancy was an unresectable MSI-H and KRAS-mutant colorectal adenocarcinoma, with intraoperative findings suggestive of peritoneal metastasis. As the patient was considered unsuitable for conventional chemotherapy, tislelizumab plus bevacizumab was administered as conversion therapy, resulting in a confirmed partial response according to RECIST 1.1, with a 72.3% reduction in the longest diameter of the target lesion. This case is notable for its distinctive clinical and molecular context and suggests the potential clinical activity of tislelizumab plus bevacizumab. However, the efficacy of this combination and the incremental contribution of bevacizumab require further investigation.
The combination of three metachronous primary malignancies, MSI-H status, and maternal history of rectal cancer raised the suspicion of Lynch syndrome[22,23]. Germline testing of the peripheral blood identified a heterozygous pathogenic MSH2 nonsense variant, c.1216C>T p.(R406*), thereby establishing the diagnosis. The metachronous ovarian, gastric, and CRCs were all within the recognized Lynch syndrome-associated tumor spectrum and were consistent with the clinical phenotype associated with a pathogenic germline MSH2 variant[15]. The same MSH2 variant was detected in the tumor at a VAF of 50.85%, together with a second MSH2 splice-site variant, c.1276+1G>A, a pattern consistent with the biallelic inactivation of MSH2. The patient received genetic counseling regarding the test findings, hereditary cancer risks, and recommendations for ongoing cancer surveillance and risk management. Therefore, cascade testing should be offered to at-risk relatives to facilitate syndrome-specific surveillance.
Several molecular features may have influenced the observed response; however, this interpretation remains exploratory. MSI-H status and high TMB are generally associated with sensitivity to PD-1 blockade[24]. Conversely, PTEN alterations have been associated with reduced effector T-cell infiltration[25,26], and the B2M frameshift variant could impair HLA class I antigen presentation; however, B2M alterations do not necessarily preclude the clinical benefit from immunotherapy in MSI-H CRC[27]. APC and RNF43 alterations were consistent with dysregulation of the WNT signaling pathway. Low PD-L1 combined positive score, negative gene expression profile score, and fibrotic tumor microenvironment subtype are associated with a lower likelihood of response to ICIs[28,29]. However, no individual molecular feature should be considered determinative of the response observed in this patient.
Tumor RNA data were analyzed using R version 4.6.0 and GSVA version 2.6.2. Single-sample gene set enrichment analysis of C8 gene sets showed relative enrichment of myeloid cell-related signatures (Figure 6A). As shown in Figure 6B, TCF7, L2, LEF1, CDKN1A, and MYC exhibited the highest positive relative Z-scores, whereas E2F1, MSH2, APC, and BRCA1 exhibited the lowest relative Z scores. Kyoto Encyclopedia of Genes and Genomes analysis revealed the relative enrichment of the PI3K-Akt, MAPK, Wnt, mTOR, and related signaling pathways (Figure 6C), whereas hallmark analysis highlighted oxidative phosphorylation, glycolysis, MYC-related signaling, and other metabolic and proliferative programs (Figure 6D). The relative enrichment of PI3K-Akt, MAPK, and mTOR signaling was biologically consistent with the growth and survival pathways associated with KRAS and PIK3CA/PTEN alterations, whereas the higher relative Z scores of TCF7, L2, LEF1, and MYC, together with Wnt pathway enrichment, were consistent with APC/RNF43-associated Wnt dysregulation. Moreover, the coexistence of the immunogenic context indicated by MSI-H/TMB-H with myeloid cell and metabolic programs provides a biologically plausible basis for PD-1 inhibition and VEGF blockade to act complementarily through immune activation and modulation of the tumor microenvironment. Because the analysis was based on a single pre-treatment tumor sample without a matched normal control, the Z-scores and enrichment scores represent within-sample relative patterns rather than differential expression compared with normal tissue. These findings are exploratory and may inform mechanistic hypotheses. However, they should not be interpreted as validated predictive biomarkers or as evidence of an independent therapeutic contribution of bevacizumab.
The tumor NGS report annotated bevacizumab as a sensitive therapeutic option with level A evidence in the context of KRAS p.(A146T), and this annotation was considered a factor in treatment selection. This report-derived annotation should not be interpreted as indicating that KRAS p.(A146T) is itself a validated predictive biomarker for the benefit of bevacizumab. In mCRC, the established predictive implication of KRAS mutations is the resistance to anti-epidermal growth factor receptor monoclonal antibodies, whereas bevacizumab remains a guideline-supported treatment option for patients with RAS-mutant disease[16].
The addition of bevacizumab has a biological rationale beyond the established activity of PD-1 blockade in patients with MSI-H CRC. VEGF can impair dendritic cell maturation and promote the accumulation of regulatory T cells and myeloid-derived suppressor cells, whereas VEGF blockade may normalize tumor vasculature, alleviate hypoxia, and enhance T-cell infiltration and drug delivery[6,30-32]. In this tumor, the fibrotic microenvironment subtype, enrichment of myeloid-cell and interferon-γ-related signatures, and relatively high oxidative phosphorylation and glycolysis scores were compatible with hypoxic and metabolic constraints that might potentially be mitigated by vascular normalization (Figure 6A and D). These findings provide a plausible biological basis for the potential effects of bevacizumab. However, the independent contribution of bevacizumab could not be determined in the absence of a PD-1 inhibitor monotherapy comparator. Therefore, prospective comparative studies are warranted.
Clinical and preclinical studies have explored anti-angiogenic strategies, including combinations with immune-based therapies, in CRC and have reported antitumor activity[30,33,34]. Such regimens warrant further investigation in selected patients who are unsuitable for chemotherapy; however, this case alone does not justify the routine use of this combination[20,35,36].
This case report has certain limitations. Its non-comparative design precludes the quantification of the respective contributions of MSI-H-associated sensitivity to PD-1 blockade and VEGF inhibition. No posttreatment resected specimens were obtained; therefore, the pathological response could not be evaluated, and the treatment response was assessed radiologically. The germline panel covered the coding regions and exon-intron junctions of 150 cancer predisposition genes, but was limited to the detection of single-nucleotide variants and small insertions or deletions; exon-level and other large deletions or duplications were outside the scope of the assay. The transcriptomic analyses were based on a single pre-treatment tumor sample without a matched control and should, therefore, be considered exploratory. In summary, this case report describes a marked radiological response to conversion therapy with tislelizumab and bevacizumab in a patient with unresectable MSI-H CRC who was considered unsuitable for conventional chemotherapy, providing a clinically relevant basis for further investigation of this combination.
This case report demonstrates a deep and durable radiological response to tislelizumab plus bevacizumab in a patient with unresectable MSI-H CRC, with no documented toxicity-related treatment interruption. Prospective comparative studies are needed to evaluate the efficacy of this regimen and clarify the contribution of VEGF blockade. Germline mismatch repair testing, genetic counseling, and appropriate cascade testing may help guide individualized surveillance and cancer risk management in patients with multiple primary malignancies.
We sincerely thank the patient and her family for their participation and cooperation, which was essential for the completion of this study. We also thank the radiological technicians for their invaluable technical support throughout this study.
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