Therapeutic Advances in Medical Oncology最新文献

Early-stage (I-III) non-small cell lung cancer (NSCLC) can harbor oncogenic driver mutations that have critical implications for patient management and outcomes. Historically, molecular testing in resected NSCLC was limited, often focusing only on EGFR mutations or ALK rearrangements due to the lack of approved targeted therapies in the adjuvant setting until recently. However, with the advent of next-generation sequencing (NGS) and emerging evidence of actionable mutations in early-stage tumors, comprehensive genomic profiling is becoming increasingly relevant in this setting. Identifying these alterations is clinically significant: the presence of specific mutations can directly influence adjuvant treatment planning and refine the role of immunotherapy. Beyond guiding therapy selection, molecular profiles also provide prognostic insight: certain driver subtypes have been associated with higher recurrence risk in early-stage patients, suggesting a need for intensified surveillance. The expanding role of NGS enables personalized postoperative strategies, including tailored follow-up intervals and potential circulating tumor DNA monitoring to detect minimal residual disease. In summary, incorporating broad molecular testing in early-stage NSCLC empowers clinicians to optimize adjuvant treatment decisions and surveillance strategies, ultimately aiming to improve patient outcomes through precision oncology.

Locally advanced rectal cancer (LARC) presents a significant burden on lower gastrointestinal diseases, with current treatment strategies primarily involving neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery. However, patient responses to nCRT exhibit significant variability, highlighting the need for personalized therapeutic approaches. Emerging evidence suggests that the gut microbiota plays a critical role in influencing both treatment outcomes and toxicity in LARC patients. Intestinal dysbiosis has been linked to LARC progression and may affect the efficacy and adverse effects of nCRT. This narrative review critically evaluates the current literature on the relationship between gut microbiota and nCRT in LARC. Certain microbial taxa, such as Alistipes spp., Akkermansia muciniphila, and Faecalibacterium prausnitzii, have been associated with enhanced therapeutic responses, while others, such as Fusobacterium nucleatum and Enterotoxigenic Bacteroides fragilis, may contribute to treatment resistance and exacerbate adverse effects. We also discuss novel mechanisms by which specific gut microbiota and their metabolites modulate nCRT response distinct from conventional immune regulation, alongside emerging strategies for microbiota modulation, including dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation. Despite challenges in standardizing microbiota analysis and fully understanding the precise mechanisms, microbiota-targeted interventions offer a promising avenue for personalized treatment in LARC, with the potential to improve patient outcomes and quality of life.

Background: The effect of vulnerability on the outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemoradiotherapy (CCRT) remains unclear.

Objectives: To examine the impact of vulnerability on the outcomes in patients with locally advanced NSCLC undergoing CCRT.

Design: We analyzed data from the Japan Lung Cancer Society Integrated Clinical Trial Database, which included 1288 patients with locally advanced NSCLC treated with CCRT.

Methods: Vulnerability was defined as meeting one or more of the following: age ⩾75 years; history of chronic obstructive pulmonary disease (COPD) or emphysema; chronic kidney disease with at least one other comorbidity; or cancer cachexia (C-reactive protein >1.0 mg/dL and albumin <3.5 g/dL).

Results: Among 741 eligible patients, 283 (38.2%) were classified as vulnerable. Vulnerable patients had significantly shorter overall survival (OS; 19.7 vs 27.4 months, p = 0.003), whereas progression-free survival (PFS) did not differ significantly (8.8 vs 10.4 months, p = 0.151). In multivariate analysis adjusted for factors including cisplatin (CDDP) use, the association between vulnerability and OS was attenuated (hazard ratio = 1.221, 95% confidence interval: 0.959-1.555, p = 0.105). The vulnerable patients were significantly less likely to undergo subsequent therapies (60.4% vs 71.6%, p = 0.003). Among the vulnerability components, cachexia showed the strongest association with shorter PFS (8.0 vs 10.5 months, p = 0.009) and OS (16.5 vs 27.4 months, p < 0.001).

Conclusion: Clinical vulnerability was associated with poorer OS after CCRT, mediated by multiple factors, including reduced CDDP use, lower subsequent therapy rates, and cachexia. Individualized strategies that balance treatment intensity, supportive care, and access to post-CCRT are essential for improving outcomes.

Background: Head and neck squamous cell carcinoma (HNSCC) remains a global health challenge with rising incidence, especially in HPV-associated subtypes. The mismatch repair (MMR) system maintains genomic stability, and its deficiency has been linked to tumor immunogenicity and response to immunotherapy in several cancers. However, its role in HNSCC, particularly in the context of HPV status, remains poorly defined.

Objectives: The aim of this study was to compare the imbalance expression of MMR proteins and their association with clinical features and survival in HNSCC.

Design: A retrospective, clinicopathological correlation study.

Methods: We retrospectively analyzed 369 HNSCC specimens. Tissue microarrays were constructed and immunohistochemically stained for four key MMR proteins (MSH2, MSH6, PMS2, and MLH1) and p16 (as an HPV surrogate). Expression patterns were correlated with clinicopathological variables, immune cell infiltration, and survival outcomes.

Results: Among all HNSCC patients, MMR protein expression was preserved in all but one case. MSH2 and PMS2 showed consistently higher nuclear positivity than their partners, MSH6 and MLH1. These imbalances were more pronounced in p16-negative tumors (p < 0.001), whereas p16-positive tumors showed balanced expression. Expression patterns varied by sex, tumor site, drinking history, and AJCC stage. Moreover, MSH6 was significantly lower than MSH2 in nondrinkers (p = 0.039), and PMS2 was lower in advanced-stage patients (p = 0.023). Immunologically, MSH2 expression positively correlated with CD8⁺ T cells in nontumor tissue, while MSH6 and PMS2/MLH1 ratios were inversely correlated with CD4⁺ T cells in tumor tissue. Kaplan-Meier survival analysis revealed that lower MSH2 expression was significantly associated with improved overall survival (p = 0.030).

Conclusion: MMR protein expression in HNSCC varies by HPV status and demographic factors and is linked to differential immune infiltration. These findings suggest that MMR protein imbalance may influence tumor immunogenicity and could potentially serve as a biomarker to inform therapeutic strategies in the immunotherapy era, especially in p16-negative tumors.

Radioligand therapy (RLT) has reshaped the treatment landscape of advanced prostate cancer (PCa), offering a precision medicine approach that integrates molecular imaging with targeted radionuclide delivery, in which radioactive isotopes are bound to molecules that aim to selectively target cancer cells. The approval of ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 for metastatic castration-resistant prostate cancer marked a major milestone, with randomized trials (VISION, PSMAfore) demonstrating significant improvements in overall and progression-free survival compared to standard therapies. Beyond beta-emitting agents, next-generation alpha emitters such as actinium-225 and beta/Auger electron-emitting isotopes like terbium‑161 are in active development, aiming to overcome resistance and target micrometastases with greater potency. Combination approaches, pairing RLT with poly(ADP-ribose) polymerase inhibitors, immune checkpoint blockade, or androgen receptor pathway inhibitors, for example, are under intense investigation, with early phase data indicating potential efficacy. Technical advances in imaging, personalized dosimetry, and molecular diagnostics may enable more precise patient selection and adaptive treatment strategies, such as dose adjustment based on dosimetry or target expression. Emerging RLT platforms target additional tumor markers, including human kallikrein 2 and six-transmembrane epithelial antigen of the prostate-2 as well as bispecific ligands, addressing disease heterogeneity and expanding therapeutic reach. Nonetheless, challenges remain around long-term hematologic and renal safety, radionuclide supply, protocol standardization, and global accessibility. Ongoing and future multicenter trials, collaborative consortia, and innovations in theranostics will be critical to defining optimal patient selection, sequencing with existing therapies, and embedding RLT as a key pillar in the management of advanced PCa.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a cornerstone in the treatment of HR+/HER2- advanced breast cancer. While their efficacy is well-established, emerging reports of nephrotoxicity warrant further investigation into its incidence, risk factors, and potential impact on survival outcomes.

Objectives: This study aimed to evaluate the incidence and risk factors for nephrotoxicity in patients receiving CDK4/6 inhibitors (palbociclib or ribociclib) and to analyze its association with progression-free survival (PFS) and overall survival (OS).

Design: This was a single-center, retrospective cohort study.

Methods: We reviewed the medical records of 120 patients with advanced breast cancer treated with palbociclib or ribociclib between October 2018 and July 2024. Nephrotoxicity was defined as a ⩾20% decline in creatinine clearance (CKD-EPI 2021) from baseline. Statistical analyses included descriptive statistics, chi-square tests, t-tests, Kaplan-Meier survival analysis, and Cox regression models.

Results: Nephrotoxicity occurred in 28 patients (23.3%). Older age (⩾65 years) and higher baseline urea and creatinine levels were significant risk factors (p < 0.001). Paradoxically, patients who developed nephrotoxicity showed a trend toward better survival outcomes: median PFS was 30 months versus 20 months (p = 0.188), and the 3-year OS rate was 77.9% versus 63.8% (p = 0.801), though these differences were not statistically significant. In multivariate Cox analysis, the development of nephrotoxicity showed a trend toward a 71% reduction in mortality risk (HR = 0.293, p = 0.078), but it was not statistically significant.

Conclusion: Nephrotoxicity is relatively common in patients treated with CDK4/6 inhibitors, particularly in older individuals and those with elevated baseline renal parameters. Contrary to conventional expectations, its occurrence may be associated with a trend toward improved survival, possibly reflecting higher drug exposure or effective target inhibition. These findings highlight the need for careful renal monitoring and suggest that nephrotoxicity could serve as a potential surrogate marker for treatment efficacy, warranting validation in larger prospective studies.

Background: The 5-year overall survival rates in acute lymphoblastic leukemia (ALL) vary depending on the patient's age group (from 93% to under 30%). However, in the case of relapsed/refractory ALL (R/R ALL), the complete remission (CR) rate in the pediatric patient group is 44% and in the adult population-18%. Therefore, further research on new therapeutic compounds is necessary.

Objectives: This systematic review aims to analyze the results of clinical studies concerning the use of venetoclax alone or in combination with other drugs in the treatment of ALL.

Design: The systematic review was conducted in accordance with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. The Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group by the National Heart, Lung, and Blood Institute was used to assess the quality of included studies.

Data sources and methods: PubMed and Web of Science were used for the literature review. All clinical studies reporting outcomes in patients with ALL treated with venetoclax met the inclusion criteria. As a result of our search process for articles, a total of 989 records were obtained. After excluding records that did not meet the inclusion criteria or met the exclusion criteria, seven articles were finally obtained.

Results: In seven identified clinical trials, CR rate ranged from 22% to 59.6% in patients with R/R ALL, while in the group of patients with newly diagnosed ALL, it ranged from 90.9% to 96%. The most common adverse events of grade 3 or higher were hematological complications, including neutropenia (71 episodes among 110 patients), anemia (70/141), and thrombocytopenia (70/141).

Conclusion: Based on the results of phase I clinical trials, further clinical trials should be conducted to assess the therapeutic potential of venetoclax in the treatment of ALL.

Background: The optimal management of axillary lymph nodes after neoadjuvant systemic therapy (NST) in breast cancer remains controversial. The oncological outcomes of sentinel lymph node biopsy (SLNB) alone compared with axillary lymph node dissection (ALND) after NST are not well established.

Objective: This study comprehensively evaluated the long-term outcomes of SLNB alone versus ALND following NST in breast cancer patients achieving ycN0 status.

Design: A retrospective, multicenter, real-world study.

Methods: Patients initially presenting with clinically node-negative (cN0) or clinically node-positive (cN+) breast cancer who remained or converted to ycN0 after NST (2011-2022) were included. Patients were divided into SLNB-alone and ALND groups. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Secondary endpoints included recurrence rates, local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics.

Results: A total of 1381 patients were included: 461 received SLNB alone, and 920 underwent ALND. Median follow-up was 34.2 months (range: 1.2-142.6 months). Local (2.8% vs 3.3%, p = 0.656) and regional (2.0% vs 1.3%, p = 0.353) recurrence rates were comparable between SLNB and ALND groups; distant metastases occurred in 5.6% versus 8.5% (p = 0.059). No significant differences in DFS, OS, LRFS, RRFS, or DMFS were observed between the SLNB-alone and ALND groups after IPTW adjustment. Subgroup analyses confirmed similar DFS or OS between the two surgical approaches across initial cN0 and cN+ subgroups; however, patients with initial cN2-3 disease exhibited inferior LRFS with SLNB alone.

Conclusion: SLNB alone achieves oncologic outcomes comparable to ALND in ycN0 breast cancer patients after NST, regardless of initial nodal status, with caution warranted in initial cN2-3 disease. This suggests that SLNB alone can safely substitute ALND without compromising oncologic outcomes in appropriately selected patients.

Background: Drug repurposing has emerged as an effective strategy to accelerate drug discovery. Using the pipeline established from a large collaborative drug repurposing project focused on high-grade serous ovarian cancer (HGSOC), we identified ivacaftor, an FDA-approved cystic fibrosis medication, as a drug candidate predicted to interact with the receptor tyrosine kinase-like orphan receptor 1 (ROR1) which we have previously demonstrated as a therapeutic target in ovarian cancer.

Objectives: This study aimed to provide preclinical evidence supporting the potential repurposing of ivacaftor for HGSOC treatment.

Design: Ivacaftor was tested in 2D and 3D preclinical models as well as patient-derived organoid models in vitro.

Methods: Dose-response analysis was undertaken in ROR1 expressing HGSOC cell lines OVCAR4, KURAMOCHI, COV362 and COV318 in both 2D adherent and 3D bioprinted formats. Real-time live/dead and apoptosis cell staining were performed over a 72 h period using the IncuCyte live cell imaging platform. Flow cytometry was used to assess apoptosis, DNA damage and cell proliferation following treatment with either 15 µM ivacaftor or 30 µM carboplatin at 24, 48 and 72 h. Additionally, ROR1-expressing HGSOC patient-derived organoids (OC029, OC043 and OC058) underwent ivacaftor dose-response analysis. Cell apoptosis following 15 µM ivacaftor treatment was measured in real-time using an Annexin V assay in two additional organoid models (OC062 and OC075). Finally, the mechanisms associated with response to ivacaftor were explored in HGSOC cell lines through Western blotting.

Results: The IC50 for ivacaftor ranged from 6.5 to 13.2 µM in 2D cultures and 11.6 to 18.2 µM in 3D cultures. Treatment with 10 and 15 µM ivacaftor resulted in significantly increased cell death and reduced live cell counts compared to the vehicle control over 72 h. Organoids displayed IC50 values between 11.2 and 14.1 µM. Ivacaftor treatment induced apoptosis in organoids, with no significant impact on DNA damage or cell cycle in HGSOC cells. ROR1 signalling associated oncogenic pathways including the BMI-1 and the PI3K/AKT pathways were modulated following ivacaftor treatment.

Conclusion: In summary, ivacaftor demonstrated significant anti-tumour potential in preclinical HGSOC models, supporting its further investigation as a repurposed therapy for ovarian cancer.