Aichi Cancer Center

BackgroundA Japanese phase 2 trial of encorafenib plus binimetinib met the primary endpoint of the centrally assessed objective response rate in patients with unresectable BRAF V600E-mutated thyroid cancer. Consequently, encorafenib plus binimetinib has been approved in Japan. We present the health-related quality of life (HR-QoL) outcomes from the trial.MethodsThe multicenter, open-label, uncontrolled phase 2 trial enrolled patients with unresectable locally advanced or metastatic BRAF V600E-mutated thyroid cancer. HR-QoL score, one of the secondary endpoints, was assessed using the EORTC QLQ-C30 and QLQ-THY34 at baseline and during follow-up. The minimal important change (MIC) threshold was set at 10 points.ResultsWe enrolled 22 patients with BRAF V600E-mutated thyroid cancer. The median follow-up was 11.5 months. Completion rates for the questionnaires were 100% (22 of 22 patients) at baseline and 68% (15 of 22) at week 20. Until week 20, changes from baseline were below MIC at most time points in 29 of all 32 domains in QLQ-C30 and QLQ-THY34. In the other 3 domains, patients showed tendencies toward improvement (social support and appetite loss) or deterioration (joint pain) for consecutive time points. Patients with anaplastic thyroid cancer showed tendencies toward improvement for swallowing, restlessness, body image, and discomfort in the head and neck, from the first assessment after the initial treatment.ConclusionThe combination therapy of encorafenib plus binimetinib for unresectable BRAF V600E-mutated thyroid cancer was associated with generally maintained HR-QoL. Considering the efficacy and safety data from the trial, the regimen may provide clinical benefits while maintaining HR-QoL.

Pulmonary collision tumors are characterized by the coexistence of two morphologically and genetically distinct neoplasms within a single lesion. We report a rare case of primary collision lung adenocarcinoma harboring two mutually exclusive driver mutations, EGFR exon 21 L858R and KRAS G12C. A 77-year-old man with a history of smoking was diagnosed with lung adenocarcinoma. Preoperative molecular testing of a transbronchial biopsy specimen suggested the coexistence of EGFR L858R and KRAS G12C mutations. Pathological findings of the surgically resected tumor exhibited solid and papillary architecture, with a lepidic pattern at the periphery. DNA was extracted separately from the solid/papillary and lepidic components for molecular analysis. The solid/papillary component harbored a KRAS G12C mutation but lacked an EGFR mutation, with a PD-L1 tumor proportion score (TPS) of 5%. In contrast, the lepidic component harbored an EGFR L858R mutation without a KRAS mutation and had a PD-L1 TPS of <1%. These findings supported the diagnosis of a collision tumor composed of KRAS - and EGFR -mutated adenocarcinomas. Despite adjuvant chemotherapy and immunotherapy, the patient developed recurrence of solitary bone metastasis. Molecular testing of the bone biopsy revealed the presence of a KRAS G12C mutation but no EGFR mutation. This case highlights the biological complexity of collision tumors and the clinical importance of repeated biopsies for guiding treatment. Recognizing genetically distinct tumor populations within a single lesion is crucial for accurate diagnosis and optimal therapeutic decision making.

Colorectal cancer (CRC) exhibits substantial molecular heterogeneity, yet detailed single-cell transcriptomic data from Japanese patients remain limited. Here, we performed single-cell RNA sequencing (scRNA-seq) on tumor tissues and adjacent normal tissues from four Japanese CRC patients to characterize malignant cell populations. We identified a common cancer-associated cell cluster observed across all four cases, characterized by high expression of the long noncoding RNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1). Further analysis revealed a marked decrease in Ras Association Domain Family Member 6 (RASSF6) expression within this cluster, despite clinical datasets reporting that elevated RASSF6 expression correlates with poor overall survival in Western cohorts. Reanalysis of publicly available bulk RNA-seq data from independent East Asian cohorts confirmed that RASSF6 expression was consistently reduced in tumor tissues compared with adjacent normal colon tissues, while KCNQ1OT1 expression showed no apparent differences across cohorts. Collectively, our single-cell analysis delineates a recurrent cancer-associated transcriptional state observed within this cohort and highlights distinct gene expression features that may be underappreciated by bulk or population-averaged analyses, underscoring the value of single-cell profiling for refining molecular interpretations of CRC.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, achieving durable remission in patients who are refractory to conventional therapies.However, the limited persistence of infused CAR-T cells, due to T-cell exhaustion and the loss of CAR-T cells, remains a major obstacle to sustained therapeutic efficacy.Recent studies have demonstrated that CAR-T cell products enriched for less-differentiated memory T cell subsets exhibit superior longterm persistence, greater cytotoxicity, and improved clinical outcomes compared with conventional CAR-T cell products.To enrich for less-differentiated memory T cells, various strategies have been explored throughout the manufacturing process.These strategies include selecting cell sources enriched for less-differentiated memory T cells and delaying their differentiation into terminally differentiated states by regulating signaling pathways, remodeling epigenetics, and modulating metabolism.This review provides an overview of current and emerging manufacturing strategies for CAR-T cells, focusing on enhancing their prolonged persistence.Further investigations are warranted to determine the optimal composition of differentiated and lessdifferentiated T cells in CAR-T cell products under the respective clinical conditions.This could facilitate the personalized manufacturing of CAR-T cell products with the ideal cell composition, thereby maximizing the efficacy of CAR-T cell therapy.

Abstract Background: The DESTINY-Breast04 (DB-04) trial established trastuzumab deruxtecan (T-DXd) as the standard of care for patients (pts) with the metastatic breast cancer (mBC) newly classified as HER2-low status (HER2 IHC 1+, or 2+/ISH−). However, in the DB-04 trial, the number of pts with hormone receptor-negative (HR−)/HER2-low mBC was limited, and pts with stable brain metastases (BMs) were included, while those with active BMs were excluded. The HALLOW study (UMIN000051259) is a large-scale ongoing prospective observational study conducted in Japan with the aim of providing effectiveness and safety data for T-DXd in these clinically important populations, which were underrepresented in the DB-04 trial. Here, we report the interim analysis results for pts with BMs. Methods: The HALLOW study enrolled, from June 2023, approximately 600 pts diagnosed with HER2-low mBC (HR+/−, with/without BMs, including active BMs) who had previously received chemotherapy and were scheduled to receive T-DXd treatment. This interim analysis included pts diagnosed with BMs (current or past) by local investigators. For the effectiveness analysis, only those with BMs confirmed by Brain-independent central review (ICR) based on brain MRI and/or CT images were included. Active BMs were defined as cases where no local treatment was performed on the brain lesion or where there was regrowth or symptom worsening after local treatment. Effectiveness outcomes included intracranial progression-free survival (IC-PFS) and intracranial objective response rate (IC-ORR) assessed by Brain-ICR according to RECIST version 1.1, while progression-free survival (PFS) and overall survival (OS) were assessed by investigators. For the safety analysis, pts who had received T-DXd at least once were included. Safety outcomes include incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE, including ≥ grade (Gr) 3 TEAEs, ≥ Gr1 interstitial lung disease (ILD), and ≥ Gr1 TEAEs that led to discontinuation of T-DXd treatment. Follow-up plan will continue until July 2026. Results: At the data cutoff date of August 31, 2024, 42 pts had physician-diagnosed BMs, of whom 33 were Brain-ICR confirmed and met the criteria for active BMs. In this set, the median age was 55 (range: 42-79) years; the median prior line of chemotherapy in the metastatic setting was 2 (range: 0-7); HER2 status at each local site was IHC 2+/ISH− in 7 pts (21%) and IHC 1+ in 26 pts (79%); 25 pts (76%) were HR+, 8 pts (24%) were HR−. 5 pts (15%) had Brain-ICR-confirmed leptomeningeal disease. At a median follow-up period of 4.1 months (mo) (range: 1.4-12.6), the median IC-PFS was 8.0 mo (95% confidence interval [CI]: 3.9-not estimated), and the 6-mo IC-PFS rate was 57.6% (95% CI: 30.7-77.4) until the data cutoff date. A total of 22 pts was eligible for proper tumor evaluation during the follow-up period by Brain-ICR. Among the 22 pts who could be properly evaluated, the IC-ORR was 9.1% (complete response n=0, partial response n=2; 95% CI: 1.1-29.2). The median PFS was 6.7 mo (95% CI: 4.0-11.1), with a 6-mo PFS rate of 59.0% (95% CI: 34.9-76.7). The median OS was not reached, and the 6-mo survival rate was 77.1% (95% CI: 51.5-90.3). In the safety analysis set (n=42; median follow-up period: 4.1 mo [range: 0.4-12.6]), ≥ Gr3 TEAEs and ≥ Gr3 TEAEs related to T-DXd treatment occurred in 18 (43%) and 11 (26%) pts, respectively. ≥ Gr1 ILD occurred in 2 pts (5%), 1 (2%) of whom experienced Gr 5 ILD, and ≥ Gr1 TEAEs that led to T-DXd discontinuation occurred in 3 pts (7%), with two of these being ILD and the other seizure. Conclusions: While longer follow-up and additional data are needed to confirm these findings, the current data provide tentative support for the effectiveness and safety of T-DXd in this BMs population including active BMs, which was not included in the DB-04 trial. Citation Format: N. Niikura, T. Yamanaka, Y. Aoyama, A. Kataoka, T. Toyama, S. Sakai, M. Endo, K. Kaneko, H. Iwata, T. Yamashita, J. Tsurutani, R. Horii, Y. Kikawa, Y. Hirakawa, S. Yamazaki, W. Hashimoto, E. Tokuda, S. Saji. Interim analysis results for the effectiveness and safety of trastuzumab deruxtecan in patients with HER2-low breast cancer and brain metastases: The HALLOW study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-11.

Correction: Overall survival of palbociclib plus endocrine therapy in Japanese patients with HR+/HER2- advanced breast cancer in the first-or second-line setting: a multicenter observational study (P-BRIDGE study)

Invasive cancer is defined by the loss of epithelial cell traits resulting from the ectopic expression of epithelial–mesenchymal transition (EMT)-related transcription factors such as Snail. Although EMT is known to impart chemoresistance to cancer cells, the precise molecular mechanisms remain elusive. We found that Snail expression confers chemoresistance by upregulating the cholesterol efflux pump ABCA1 as a countermeasure to the excess of cytotoxic free cholesterol relative to its major interaction partner in cellular membranes, sphingomyelin. This imbalance is introduced by the transcriptional repression of enzymes involved in the biosynthesis of sphingomyelin by Snail. Inhibiting esterification of cholesterol, which renders it inert, selectively suppresses growth of a xenograft model of Snail-positive kidney cancer. Our findings offer a new perspective on lipid-targeting strategies for invasive cancer therapy.