Publications by authors named "Tomohiro Nishina"
DESTINY-CRC01 (NCT03384940) was a multicentre, open-label, phase 2 study that investigated the safety and efficacy of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing metastatic colorectal cancer (CRC). The present exploratory biomarker analysis aims to investigate relationships between biomarkers and clinical outcomes in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH] positive) Cohort A (N = 53) of DESTINY-CRC01. Higher levels of HER2 biomarkers in baseline tissue and liquid biopsies, including HER2 status (IHC/ISH), HER2/CEP17 ratio, HER2 ISH signals, HER2 H-score, plasma HER2 (ERBB2) amplification status, HER2 adjusted plasma copy number, and HER2 extracellular domain correlate with antitumor activity (indicated by objective response rate, progression-free survival, and overall survival) of T-DXd.
View Article and Find Full Text PDFBackground: While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.
Methods: We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients.
Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study.
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- - Comprehensive genomic profiling using circulating tumor DNA (ctDNA) has potential in capturing tumor diversity and improving therapy choices, but it's not fully utilized in clinical settings, especially for advanced solid tumors.
- - The GOZILA study found that ctDNA profiling led to a 24% match rate for targeted therapies, significantly improving patient outcomes, with those receiving matched treatments experiencing better overall survival rates compared to those who were unmatched.
- - Key ctDNA characteristics, like biomarker clonality and plasma copy number, serve as indicators of treatment effectiveness, suggesting that ctDNA can enhance precision in oncology and should be more widely used to optimize patient survival in advanced solid tumors.
Article Synopsis
- The study analyzed the use and costs of first-line chemotherapy for advanced/recurrent gastric cancer (AGC) in Japan, focusing on patients with HER2-negative AGC treated in 2022.
- A total of 2113 patients were evaluated, revealing that expensive chemotherapy regimens (costing over 500,000 JPY per month) primarily included triplet therapy with fluoropyrimidine, oxaliplatin, and the immune inhibitor nivolumab.
- The findings showed that these costly regimens were utilized by 67% of patients, including a significant portion of older patients, highlighting the need for more research on the economic implications of such drugs.
Purpose: HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data.
Experimental Design: We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project.
Article Synopsis
- The HERALD/EPOC1806 trial evaluated trastuzumab deruxtecan (T-DXd) for patients with progressive solid tumors that were identified as HER2-amplified through cell-free DNA (cfDNA) testing rather than traditional methods.
- A total of 4,734 patients underwent cfDNA testing, with 252 showing HER2 amplification; the study ultimately included 62 patients from various cancer types, who received T-DXd treatment every three weeks.
- The trial reported a 56.5% overall response rate (ORR), with a median progression-free survival of 7 months and noted interstitial lung diseases in 26% of patients, primarily mild to moderate cases.
Article Synopsis
- The study aimed to assess the effectiveness and safety of nanvuranlat, an L-type amino acid transporter 1 inhibitor, as a treatment for advanced biliary tract cancers that are hard to treat.
- Conducted across 14 Japanese medical centers, the trial involved 211 patients, with 105 eligible participants randomly assigned to receive either nanvuranlat or a placebo, focusing on progression-free survival (PFS) as the main measure of success.
- Results showed that nanvuranlat significantly improved PFS compared to placebo, although overall survival rates were similar, suggesting the need for further research, especially in specific cancer subtypes like intrahepatic and extrahepatic cholangiocarcinoma.
Article Synopsis
- The SCRUM-Japan MONSTAR-SCREEN consortium is conducting a nationwide project that uses AI and multi-omics analyses for molecular profiling in patients with advanced cancers, aiming to create new treatments and diagnostics.
- The project includes the CIRCULATE-Japan study, focusing on precision medicine for resectable solid tumors and requires substantial data storage in a high-tech supercomputing system called VAPOR CONE.
- As of December 2023, over 24,000 patients have been registered, with 5.0% of those in advanced solid tumors participating in matched clinical trials, showing a 29.2% response rate and significantly improved survival rates compared to those not receiving matched therapies.
"NeoRAS WT" refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible.
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- Trastuzumab deruxtecan (T-DXd) showed significant improvement in patients with HER2-positive gastric cancer in the DESTINY-Gastric01 trial, with hints of benefit for those with HER2-low cancer.
- The study faced challenges due to the variability in HER2 expression and genetic alterations in gastric cancer, making it hard to identify which patients would benefit from T-DXd.
- Correlations were found between HER2-associated biomarkers in circulating tumor DNA and objective response rates, indicating potential predictors of effectiveness and the need for further research in larger cohorts.
Article Synopsis
- The study evaluated the effectiveness of pembrolizumab combined with chemotherapy in Japanese patients with advanced esophageal cancer compared to a placebo with chemotherapy, showing improved overall survival (OS) and progression-free survival (PFS) over a median follow-up of 36.6 months.!
- Patients receiving pembrolizumab-chemotherapy exhibited better OS and PFS, particularly those who experienced early tumor shrinkage or significant depth of response, indicating a stronger therapeutic benefit from this combination treatment.!
- The safety profile remained manageable, with a slight increase in severe treatment-related adverse events for the pembrolizumab group, but no new safety concerns emerged during the extended follow-up period.!
Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished.
Patients And Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included.
Article Synopsis
- Zinc deficiency is a significant issue for cancer patients undergoing long-term chemotherapy, but its effects on symptoms like skin rash, taste changes, and oral issues need more research.
- A study analyzed gastric and colorectal cancer patients receiving standard chemotherapy, finding that 38% had zinc deficiency before treatment and that serum zinc levels dropped further for those initially non-deficient during treatment.
- The decline in zinc levels was linked to worsening symptoms such as taste changes and skin issues, suggesting that future research should explore the potential benefits of zinc supplementation for these patients.
Article Synopsis
- Treatment strategies and prognoses for metastatic colorectal cancer (CRC) vary depending on whether the primary tumor is left-sided or right-sided.
- A study involving 531 patients found significant differences in overall survival based on tumor sidedness and specific gene alterations.
- The analysis showed that gain-of-function (GOF) variants were poor prognostic factors for left-sided CRC, while non-GOF variants and specific alterations had poor implications for right-sided colon cancer.
Article Synopsis
- FTD/TPI plus bevacizumab has demonstrated clinical benefits for patients with difficult-to-treat metastatic colorectal cancer (mCRC), especially those who have had prior treatments and cannot handle intensive therapy.
- A study involving 93 patients revealed that most were older and had significant health issues, with 68% receiving FTD/TPI as their second-line treatment.
- The treatment had a low objective response rate of 4.9%, but a notable disease control rate of 67.9%, with median overall survival at 18.6 months and manageable safety concerns, primarily neutropenia.
Article Synopsis
- This study focused on identifying plasma angiogenesis factors that could help predict how well traditional chemotherapy combined with biologics works for patients with RAS wild-type metastatic colorectal cancer (mCRC).
- Researchers collected plasma samples before treatment and at the progression stage from 202 patients, analyzing 17 factors using specialized technology to assess their impact on patient survival.
- Results showed that levels of interleukin-8 and soluble vascular cell adhesion molecule-1 were linked to treatment effectiveness, indicating these could serve as important biomarkers for tailoring cancer therapies.
Article Synopsis
- Nivolumab is an effective treatment for advanced gastric cancer, but identifying reliable biomarkers like TP53 mutations could help predict patient response.
- A study involving 913 patients found that those with TP53 wild type (wt) had a higher response rate to nivolumab (24.6%) compared to TP53 mutant patients (14.8%).
- For TP53 mutants, those with the frameshift type had a slightly better response rate and progression-free survival compared to other mutation types, suggesting some variants may still benefit from treatment.
Article Synopsis
- Circulating tumor DNA (ctDNA) genotyping using next-generation sequencing (NGS) may aid in targeted therapy for metastatic colorectal cancer (mCRC), but its effectiveness in assessing the V600E mutation and guiding therapies needs further validation.
- A study compared NGS-based ctDNA testing to traditional tissue testing in 212 mCRC patients, showing high concordance, sensitivity, and specificity rates for detecting V600E mutations, particularly when ctDNA levels were ≥1.0%.
- The results indicate that ctDNA genotyping is a reliable method for identifying V600E mutations and can inform treatment decisions for anti-EGFR and BRAF therapies, highlighting its potential role in improving patient outcomes.
Article Synopsis
- The DESTINY-CRC01 trial tested trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing metastatic colorectal cancer (mCRC) who had previously undergone at least two treatments.
- The primary endpoint was the objective response rate (ORR), which was 45.3% in cohort A (HER2-positive patients), while no responses were observed in cohorts B and C.
- Safety results indicated that the most common severe side effects included decreased neutrophil count and anemia, with some cases of drug-related lung disease, supporting further research on T-DXd's effectiveness in HER2-positive mCRC.
Article Synopsis
- Pembrolizumab, an anti-PD-1 therapy, showed efficacy in treating gastric/gastroesophageal junction cancer in Japanese patients across multiple study phases (KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062).
- The results indicated varying levels of overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) across the studies, with some advantages over chemotherapy.
- Overall, the findings suggest that pembrolizumab is promising for gastric cancer treatment and further evaluation is warranted.
Article Synopsis
- The SCRUM-Japan GI-SCREEN program uses next-generation sequencing (NGS) to profile genomic data for patients with advanced gastrointestinal cancers, aiming to facilitate enrollment in targeted clinical trials and enhance real-world data collection.
- The study involved 5,743 patients, revealing that those enrolled in matched trials after starting their first-line treatment experienced longer overall survival compared to those who enrolled before treatment, indicating possible immortal time bias.
- Results showed significant improvements in survival rates for colorectal cancer patients receiving targeted therapies based on genomic alterations, highlighting the importance of genetic profiling in clinical trial participation.
Article Synopsis
- BRAF mutations, particularly BRAF V600E, are common in colorectal cancers, but a new mutation, BRAF L525R, was identified and studied for its effects on cancer cell behavior.
- The study utilized HEK293 cells with BRAF V600E or L525R mutations, testing their response to various cancer treatments and assessing cell viability and signaling pathways.
- Results indicated that selumetinib effectively inhibited cell growth and ERK activation in BRAF L525R cells, while the AKT pathway played a crucial role in determining sensitivity and resistance to this treatment.
Background: Paclitaxel or nanoparticle albumin-bound paclitaxel combined with ramucirumab (PTX/nab-PTX + RAM) is widely used as second-line chemotherapy for advanced gastric cancer (AGC), but severe neutropenia often develops with this regimen. Although previous studies have reported that severe neutropenia is a favorable prognostic factor in cancer chemotherapy, it is unclear in AGC patients receiving PTX/nab-PTX + RAM. In addition, the risk factors for early-onset of severe neutropenia (EOSN) still remain unknown.
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