Published papers

近年,バイオマーカーに基づきそれぞれの患者に適した治療を行うがん個別化医療の進歩が目覚ましい。進行がんに対しては,殺細胞性抗がん剤に加えて分子標的薬や免疫チェックポイント阻害薬などが開発され,数多くの臨床試験が実施されている。一方,早期がんでは血液中の循環腫瘍DNAを用いた高感度な分子残存病変評価により,周術期治療の精密な層別化が試みられている。本邦では,2015年に始動したSCRUM-Japanプロジェクトから多くの治療薬・診断薬の薬事承認が実現し,バイオマーカーに基づくがん個別化医療の実践に重要な役割を果たしてきた。本稿では,その軌跡と展望を踏まえ,がん個別化医療について概説する。(著者抄録)

進行大腸がんの再発率を抑制するために術後補助化学療法が行われてきた。しかし術後補助化学療法の効果は限定的であるため、現在の進行度分類(ステージ分類)のみの治療適応では、本当に治療が必要な症例を選択することは困難である。ctDNAは血中がん由来遊離DNAで、その存在は再発を鋭敏に予測することが報告されている。CIRCULATE-Japanは大腸がんの術後モニタリングや術後補助化学療法の選択におけるctDNAの有用性を証明する大規模臨床試験である。(著者抄録)

Background: Zolbetuximab plus chemotherapy is the standard of care for unresectable advanced gastric cancer that is human epidermal growth factor receptor 2-negative and claudin-18 isoform 2 (CLDN18.2)-positive (2+/3+ staining intensity in ≥75% of tumor cells). The dynamics of CLDN18.2 expression after zolbetuximab remain poorly understood. Materials and methods: Using immunohistochemistry, we retrospectively assessed CLDN18.2 expression in tumor samples from CLDN18.2-positive advanced gastric cancer collected before and after zolbetuximab-containing chemotherapy. Expression levels were evaluated based on the proportion of cells with ≥2+ staining intensity using multiple cut-off values (75%, 40%, and 25%). Results: Among 65 patients who received zolbetuximab-containing therapy, CLDN18.2 status was assessable at both baseline and disease progression in 15 patients. At disease progression, 53.3% of cases converted to CLDN18.2-negative. CLDN18.2 positivity was retained in 66.7% and 73.3% of patients when applying 40% and 25% cut-off levels, respectively. Conclusions: CLDN18.2 expression above the ≥75% cut-off declined after zolbetuximab, but lower-level expression was often preserved, supporting the potential for subsequent targeted therapy.

Importance: The definition of cure in stage II to III colon cancer (CC) remains unclear due to limitations in conventional end points, which include deaths and second primary tumors as events. These can complicate communication with patients regarding long-term outcomes. Objective: To distinguish relapses from competing health-related events to classify long-term outcomes years after surgery and explore when the incidence of true relapses of the initial CC approaches 0% to define cure in this disease. Design, Setting, and Participants: This pooled analysis of individual patient-level data from 15 phase 3 randomized clinical trials assessed time to CC-related relapse using Kaplan-Meier and Aalen-Johansen methods, with death and second primary tumors treated as competing risks. Cox regression models evaluated prognostic associations, stratified by sex, stage, and tumor. Patients with stage II to III CC who underwent adjuvant chemotherapy were included. All patients had undergone radical surgery for CC and received adjuvant chemotherapy with a median follow-up of at least 6 years. The Adjuvant Colon Cancer Endpoints (ACCENT) and the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) databases included adjuvant studies conducted between 1996 and 2015. Data were analyzed from February 2022 to June 2025. Exposures: Adjuvant chemotherapy regimens varied across trials, including fluoropyrimidines alone or in combination with oxaliplatin or biologic agents. Main Outcomes and Measures: The primary outcome was time to CC-related recurrence. The predefined threshold for cure was a recurrence risk below 0.5%. Results: Of 35213 included patients, 19 346 (54.9%) were male, and the mean (SD) age was 60.2 (10.8) years. The incidence rate of recurrence peaked at 6.4% (1993 of 31373) between month 6 and month 12 and decreased continuously until year 10 of follow-up never exceeding 0.5%. Recurrence rate appeared to increase again after year 10 and peaked at 2.0% during year 12.5 to year 13, a pattern observed exclusively in the MOSAIC trial. Competing-event analysis revealed that death and second primary tumors inflated the apparent recurrence rate, especially for older patients. The overall cumulative incidence of relapse with death as competing risk was lower among female patients (hazard ratio, 0.58; 95% CI, 0.45-0.76; P <.001). Conclusions and Relevance: In this pooled analysis of phase 3 randomized clinical trials, a recurrence rate less than 0.5% occurred after 6 years from surgery, supporting a practical definition of cure. Recognizing this milestone may improve patient communication, guide follow-up duration, and reduce unnecessary long-term surveillance.

Within the last decade, the science of molecular testing has evolved from single gene and single protein analysis to broad molecular profiling as a standard of care, quickly transitioning from research to practice. Terms such as genomics, transcriptomics, proteomics, circulating omics, and artificial intelligence are now commonplace, and this rapid evolution has left us with a significant knowledge gap within the medical community. In this paper, we attempt to bridge that gap and prepare the physician in oncology for multiomics, a group of technologies that have gone from looming on the horizon to become a clinical reality. The era of multiomics is here, and we must prepare ourselves for this exciting new age of cancer medicine.

Clinical cancer genomic testing based on next-generation sequencing can help select genotype-matched therapy and provide diagnostic and prognostic information. Pathological tissue from malignant tumors obtained during routine practice are frequently used for genomic testing. This article is aimed to standardize the proper handling of pathological specimens in practice for genomic medicine based on the findings established in "Guidelines on the handling of pathological tissue samples for genomic medicine (in Japanese)" published by The Japanese Society of Pathology (JSP) in 2018. The two-part practical guidelines are based on empirical data analyses; Part 1 describes the standard preanalytic operating procedures for tissue collection, processing, and storage of formalin-fixed paraffin-embedded (FFPE) samples, while Part 2 describes the assessment and selection of FFPE samples appropriate for genomic testing, typically conducted by a pathologist. The guidelines recommend that FFPE sample blocks be used within 3 years from preparation, and the tumor content should be ≥30% (minimum 20%). The empirical data were obtained from clinical studies performed by the JSP in collaboration with leading Japanese cancer genome research projects. The Japanese Ministry of Health, Labour, and Welfare (MHLW) recommended to comply with the JSP practical guidelines in implementing cancer genomic testing under the national health insurance system in over 200 MHLW-designated core and cooperative cancer genome medicine hospitals in Japan.

The Next Generation Virgo Cluster Survey (NGVS) is a deep, high resolution imaging campaign that used the 1 deg$^2$ MegaCam instrument on the Canada-France-Hawaii Telescope to carry out a comprehensive optical survey of the Virgo cluster, from its core to its virial radius. The NGVS covers a contiguous area of 104 deg$^2$ (8.63 Mpc$^2$ at the 16.5 Mpc distance of Virgo) in the $u^*$-,$g$-,$i$-, and $z$-band, with additional limited coverage in $r$. In this paper, we present the final catalog of Virgo galaxies across the entire NGVS area. The catalog includes 3680 galaxies considered to be $bona~fide$ members of the cluster, spanning a factor of 2.5 million in luminosity, from $g = 8.42$ mag to $g = 24.41$ mag ($M_g = -22.67$ mag to $M_g = -6.68$ mag). With 2100 previously uncataloged galaxies, the NGVS catalog augments the number of known Virgo members by a factor 2.3. The catalog is complete down to $g = 18.6$ mag ($M_g=-12.5$ mag, corresponding to a stellar mass $M_* \sim 1.6\times10^7~M_{\odot}$ for an old stellar population) and 50% complete at $g = 22.0$ mag ($M_g=-9.1$ mag, $M_* \sim 6.2\times10^5~M_{\odot}$), three magnitudes deeper than the venerable Virgo Cluster Catalog (VCC), which for over 40 years has served as the reference standard for Virgo. Photometric and structural parameters are derived for all NGVS galaxies and presented in a series of tables, alongside nuclear and morphological classification, as well as stellar masses and, when available, radial velocities.

What is this summary about? BRAF V600E-mutant metastatic colorectal cancer is difficult to treat as people often do not respond to standard of care treatment and their cancer gets worse. The BREAKWATER study looked at whether encorafenib plus cetuximab with mFOLFOX6 was a better treatment than standard of care to treat this disease. What were the results? More participants in the encorafenib plus cetuximab with mFOLFOX6 group had their tumor shrink after treatment than those in the standard of care group (61% versus 40%). Participants in the encorafenib plus cetuximab and mFOLFOX6 group might live longer after starting treatment than those in the standard of care group. The side effects reported were expected by researchers. What do the results mean? Encorafenib plus cetuximab and mFOLFOX6 is the new standard of care for this cancer.

ERBB2 amplification is a driver oncogenic alteration in many cancers and it has recently been incorporated among therapeutically actionable biomarkers also in metastatic colorectal cancer (mCRC). In contrast, the role of ERBB2 point mutations, which are detectable in up to 3% of CRC patients, remains to be assessed. In this systematic review, we collected preclinical and clinical data addressing the role of ERBB2 point mutations in mCRC patients as a predictive biomarker for anti-EGFR and anti-HER2 targeted agents, and as mechanism of acquired resistance to ERBB2 amplified mCRC treated with any anti-HER2 regimen. In both preclinical and clinical studies, most ERBB2 point mutations were associated with resistance to anti-EGFR agents, particularly L755S and R784G, which occur in the HER2 protein kinase domain. No ERBB2 mutation was associated with tumor response to HER2-targeted agents in mCRC patients, although signals of activity were observed in preclinical models. Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance.

BACKGROUND: Non-metastatic castration-resistant prostate cancer (PCa) has become clinically important in PCa management, with treatments aiming to delay metastasis. However, limited data exist on its prevalence and patient characteristics in real-world settings. METHODS: We retrospectively investigated the clinical records of 1929 patients who were treated for localized PCa between 2005 and 2018. From this population, we counted patients who progressed to non-metastatic castration-resistant PCa, and summarized the characteristics of the patients. RESULTS: Among patients who underwent radical prostatectomy (796 patients), radiation therapy (1021 patients), or primary androgen deprivation therapy (ADT) (112 patients), 0.9%, 0.9%, and 5.4%, respectively, were diagnosed with non-metastatic castration-resistant PCa over a median follow-up of 5.5 years. Including referred cases, a total of 45 non-metastatic castration-resistant PCa patients were analyzed. The median age at non-metastatic castration-resistant PCa diagnosis was 76 years, with a median time of 4.8 years from the initiation of ADT to non-metastatic castration-resistant PCa development. From the initial PCa diagnosis, the median time to non-metastatic castration-resistant PCa was 5.9 years. Median metastasis-free survival was 5.2 years, while overall survival was 6.3 years. CONCLUSION: This study reports the prevalence of non-metastatic castration-resistant PCa at our institution and provides clinical findings of non-metastatic castration-resistant PCa patients by analyzing consecutive localized PCa cases through comprehensive medical chart reviews for every patient.