鈴木 浩一

PURPOSE: Cancer stem cells (CSCs) are suggested to contribute to therapy resistance in rectal cancer. However, histopathological analysis of CSCs is still lacking in rectal cancer. METHODS: The expression of leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5), proto-oncogene, polycomb ring finger 1 (BMI1), yes-associated transcriptional regulator (YAP) and its paralog TAZ (hereafter, YAP/TAZ), and nuclear β-catenin was compared in untreated and chemoradiation-treated (CRT) rectal cancer by in situ hybridization and immunostaining. Niche factors were also compared in human rectal cancer specimens and the embryonic intestine. RESULTS: The mean ratios were 15% and 14% for LGR5, 30% and 33% for BMI1, 2.7% and 7.6% for YAP/TAZ, and 38% and 32% for nuclear β-catenin in untreated and CRT rectal cancer, respectively, showing no significant differences for these stem markers following CRT. The stromal expression ratios of YAP/TAZ were 9.7% and 23% in untreated and CRT rectal cancer, which indicated significant upregulation and confirmation of the damage response in the stroma of CRT tumors. In addition, cancer cells co-expressing LGR5 and CDKN1B are also comparable in untreated and CRT rectal cancer. For niche factors, we found that WNT2B and GREM1 were uniformly expressed in rectal cancer with a pattern similar to that of the early embryonic intestine. CONCLUSION: The expression of LGR5, BMI1, CDKN1B, and YAP/TAZ was comparable in untreated and CRT rectal cancer. The uniform expression of mesenchymal niche factors might prevent the zonation of the stem cell niche in rectal cancer.

HER2-targeted therapies have improved outcomes in metastatic gastric cancer (mGC), yet assessment of HER2 status in tumor tissues remains limited by heterogeneity and temporal changes. This study aimed to evaluate real-time HER2 expression on circulating tumor cells (CTCs) using the On-chip Sort system. CTCs were enriched from blood samples of 27 mGC patients, identified by cytokeratin staining, and assessed for HER2 expression via fluorescent labeling. The epithelial-mesenchymal transition (EMT) index was calculated based on co-expression of vimentin and cytokeratin. CTCs also underwent whole-genome amplification and targeted sequencing using a cancer gene panel. Patients were stratified into three groups: Group A (n = 13), HER2-positive in tissue; Group B (n = 8), tissue HER2-negative but CTC HER2-positive; and Group C (n = 6), HER2-negative in both tissue and CTCs. All patients received cytotoxic chemotherapy; only Group A received additional HER2-targeted therapy. Group B showed the poorest progression-free survival (PFS: 7.0 months), compared to Group A (15.7 months) and Group C (not reached). CTC HER2 expression correlated with EMT index; Groups A and B also exhibited higher EMT indices and shared EMT-related mutations. These findings suggest that CTC-based HER2 monitoring reflects tumor aggressiveness and may help identify patients who could benefit from HER2-targeted therapy despite negative tissue HER2 status.

Nivolumab monotherapy is a standard treatment of metastatic gastric cancer, and this type of cancer involves vascular endothelial growth factor (VEGF) signaling in the tumor immunological environment. The subgroup analysis of the ATTRACTION-2 trial revealed that prior treatment with ramucirumab (RAM), a VEGF inhibitor, affected the therapeutic effect of nivolumab. The present retrospective study aimed to review patients with metastatic gastric cancer who were treated with paclitaxel (PTX) and RAM followed by nivolumab. A total of 29 patients with metastatic gastric cancer were treated with PTX + RAM as second-line treatment, followed by nivolumab monotherapy as third-line treatment. The therapeutic efficacy of nivolumab was compared in 13 patients with progression-free survival (PFS) of <5 months and 16 patients with PFS ≥5 months after PTX + RAM therapy. The present study included 22 male and seven female patients, with a median age of 68 years (range, 45-82 years). Human epidermal growth factor receptor 2 positivity was observed in six patients. The disease control rate was 62.1%. The PFS and overall survival (OS) were 4.4 and 11.9 months, respectively. Patients with PFS ≥5 months after PTX + RAM therapy showed better outcome in both PFS (5.3 months vs. 2.8 months, P=0.039) and OS (6.9 months vs. 15.2 months, P=0.066) after nivolumab treatment than patients with PFS of <5 months after PTX + RAM therapy. However, no significant relationship was observed between the outcome of first-line treatment and nivolumab. The therapeutic effect of nivolumab was associated with prior PTX + RAM treatment in advanced gastric cancer.

Molecular assessment using circulating tumor DNA (ctDNA) has not been well-defined. We recruited 61 pancreatic cancer (PC) patients who underwent initial computed tomography (CT) imaging study during first-line chemotherapy. Initial molecular assessment was performed using droplet digital PCR and defined as the change in KRAS-mutated ctDNA before and after treatments, which was classified into five categories: mNT, molecular negative; mCR, complete response; mPR, partial response; mSD, stable disease; mPD, progressive disease. Of 61 patients, 14 diagnosed with PD after initial CT imaging showed significantly worse therapeutic outcomes than 47 patients with disease control. In these 47 patients, initial molecular assessment exhibited significant differences in therapeutic outcomes between patients with and without ctDNA (mPD + mSD vs. mCR + mNT; 13.2 M vs. 21.7 M, P = 0.0029) but no difference between those with mPD and mSD + mCR + mNT, suggesting that the presence of ctDNA had more impact on the therapeutic outcomes than change in its number. Multivariate analysis revealed that it was the only independent prognostic factor (P = 0.0405). The presence of ctDNA in initial molecular assessment predicted early tumor progression and identified PC patients more likely to benefit from chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.