Introduction Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. Results The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. Conclusions Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.
Background Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. Methods We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient’s cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug’s efficacies against HER2 E401G. Results We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. Conclusions Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.
Viral cell‐free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus‐associated tumors. We investigated whether the amount of cfDNA of human T‐cell leukemia virus type 1 (HTLV‐1) correlates with disease state in adult T‐cell leukemia‐lymphoma (ATL). HTLV‐1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV‐1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV‐1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones.
Background: Cancer genome profiling using next-generation sequencing (NGS) has become widespread. Multiple genetic abnormalities including variant of unknown significance (VUS) have been detected in various cancer types. However, there is a lack of an integrated analysis system capable of identifying relationships among multiple genetic abnormalities and weighting them appropriately. Here, we report heat map analysis, a new integrated pathway scoring system for cancer genome profiling. Methods: In heat map analysis, approximately 180 cancer-related genes among 324 genes evaluated by FoundationOne CDxTM are scored based on gene annotation and variant allele fraction (VAF), and classified into 16 pathways. This system provides an overall picture of genetic abnormalities and easy recognition of abnormal pathways. To examine the usefulness of the heat map analysis, a retrospective observational study was conducted on 50 patients with solid tumors who underwent cancer genome profiling test at Saga University Hospital from June 2019 to February 2022. The primary end point was the presentation rate of pathways with significantly increased scores. Results: A total of 749 genetic abnormalities including VUS were detected in 50 patients with 15 cancer types: 571 single nucleotide variants (SNVs), 156 copy number variants (CNVs), and 22 fusions. The median number of abnormalities detected was 11 (2-20) SNVs, 2 (0-23) CNVs, and 0 (0-4) fusions, respectively. Heat map analysis presented active pathways with significant score elevation in 42 cases (84%). The TP53 pathway was the most common, followed by the Receptor Tyrosine Kinase pathway, PIK3-AKT, RAS, and DNA repair-related pathways. Conclusion: Heat map analysis could be a promising new method for integrated analysis using cancer genome profiling tests. Citation Format: Chiho Nakashima, Yukimasa Shiotsu, Yohei Harada, Hiroo Katsuya, Emi Ookuma, Masanori Nishi, Akemi Sato, Hideaki Nakamura, Naoko Sueoka-Aragane. Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 262.
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