Therapeutic Advances in Medical Oncology最新文献

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.

Background: The efficacy and safety of poly (ADP-ribose) polymerase inhibitors (PARPis) in the Chinese real-world setting have not been well characterized.

Design: This is a retrospective analysis of PARPis efficacy in metastatic breast cancer (MBC) patients with homologous recombination repair (HRR) gene pathogenic variants (PVs).

Objectives: We aimed to evaluate the efficacy and toxicities of PARPis in real-world MBC patients.

Methods: Patients who received PARPi for MBC at the National Cancer Center and two other centers between January 1, 2019, and December 31, 2024, were consecutively included. The primary endpoint was progression-free survival (PFS). Univariable and multivariable Cox proportional hazard models were used to evaluate the predictive impact of clinicopathologic characteristics on PFS.

Results: In total, 62 MBC patients treated with olaparib (N = 55), talazoparib (N = 4), pamiparib (N = 2), and fluzoparib (N = 1) were enrolled. The median PFS (mPFS) in all patients was 6.0 months (95% confidence interval: 4.1-7.9). mPFS in the germline BRCA1 (gBRCA1; N = 19), gBRCA2 (N = 30), gBRCA (N = 4), somatic BRCA2 (sBRCA2; N = 1), gPALB2 (N = 4), and other HRR gene (N = 4) PVs carriers were 3.7, 8.0, 2.8, 2.7, 5.3, and 7.1 months, respectively (p = 0.334). In multivariate analysis, ⩽40 years old (hazard ratio (HR): 2.281, p = 0.008), third-line or later therapy (HR: 2.429, p = 0.019), and prior platinum-based treatment (HR: 2.172, p = 0.014) were independently associated with shorter PFS. The incidence of adverse events (AEs) of all grades was 62.5% (35/56). The most common AEs in all grades were anemia (30.4%), nausea (21.4%), and leukopenia (17.9%). Hematologic toxicity was the most common grade ⩾3 AEs.

Conclusion: PARPis showed promising PFS and tolerable toxicity in the real-world treatment of Chinese MBC patients with HRR-related gene mutations.

Background: In non-metastatic pancreatic adenocarcinoma (PDAC), the appropriate evaluation of tumor response to neoadjuvant treatment (NAT) has a substantial prognostic impact, but the tools used to assess it are imperfect and sometimes discordant.

Objectives: We aimed to explore the prognostic impact of morphological and pathological evaluations of tumor response to NAT.

Design: Single-center retrospective observational study.

Methods: We retrospectively studied all patients with borderline or locally advanced PDAC who underwent surgery after neoadjuvant chemotherapy (NAC) with FOLFIRINOX, ±additional chemoradiation (NACR) between 2016 and 2022 in a tertiary center. Morphological response was evaluated according to RECIST 1.1, and pathological response was assessed according to the CAP score and proportion of viable tumor cells (VTC). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). Factors associated with the risk of recurrence were analyzed using ROC curves and multivariable Cox proportional hazard models.

Results: We included 91 patients (52% male, median age 66, 83% with borderline PDAC) who underwent surgery following NAC with additional NACR in 85% of patients. Overall, 38% of patients had an objective morphological response according to RECIST 1.1, which was not associated with prolonged RFS HR 1.16, 95% CI (0.62-2.10), p = 0.64). Conversely, poor pathological response was associated with shorter RFS on multivariable analysis, notably VTC ⩾ 30% (HR 2.28, 95% CI [1.08-5.13], p = 0.037). Median OS was 62.2 months with VTC ⩾ 30% versus 45.1 months with VTC < 30% (p = 0.025). Identifying PDAC with VTC < or ⩾30% had a strong reproducibility (kappa 0.86).

Conclusion: Morphological response per RECIST should not be the aim of NAT in patients with PDAC. Conversely, the proportion of VTC could be a reproducible, simple, and effective prognostic tool. Should this marker be further confirmed as valuable, it may help inform the adaptation of adjuvant treatment and follow-up in this setting.

The treatment landscape for patients with advanced gastric or gastroesophageal junction adenocarcinoma is evolving, driven by a deeper understanding of molecular profiling and the introduction of novel anticancer drugs. Systemic chemotherapy has improved survival compared to supportive care; however, overall survival worldwide remained limited to approximately 1 year. Recently, the introduction of upfront immune checkpoint inhibitors (ICIs) and/or targeted agents in biomarker-enriched populations has led to clinically meaningful survival improvements. The expansion of treatment options for metastatic disease, combined with the identification of biomarker-selected populations, underscores the importance of tailoring first-line, maintenance, and sequential therapies across multiple lines. In this context, the delivery of an effective first-line treatment is crucial, as less than half of patients retain fitness for additional anti-cancer therapies due to the morbidity associated with disease progression to the initial regimen even within modern clinical trials regardless of the use of targeted therapy or immunotherapy combined with chemotherapy. On the other hand, the expanding therapeutic armamentarium including ICIs, antibody-drug conjugates, and targeted therapies for molecularly selected subgroups, will enable the development of sequential treatment strategies across multiple lines of therapy. This review summarizes the current knowledge about maintenance strategies and subsequent lines of treatment in either biomarker selected and unselected populations.

Background: Patients with epithelial ovarian cancer (EOC) receiving neoadjuvant platinum-based chemotherapy (NACT) who remain ineligible for complete interval cytoreductive surgery (ICS) due to poor chemosensitivity (CA-125 KELIM™ score <1.0) have a poor prognosis (~20% 5-year survival). A weekly dose-dense carboplatin-paclitaxel regimen may improve outcomes in this high-risk subgroup.

Objectives: To demonstrate the superiority of a salvage weekly dose-dense carboplatin-paclitaxel regimen over continuation of the standard 3-weekly regimen in poor-prognosis EOC patients after 3-4 cycles of standard NACT.

Design: SALVOVAR is a pragmatic, open-label, multicenter, international, randomized phase III trial.

Methods and analysis: Patients with stages III-IV high-grade EOC are eligible if they present (1) an unfavorable standardized KELIM score <1.0, and (2) a disease not amenable to complete ICS after 3-4 cycles of standard 3-weekly carboplatin-paclitaxel. Patients are randomized (1:1) to either the experimental arm (dose-dense carboplatin AUC5 day 1 plus paclitaxel 80 mg/m² on days 1, 8, and 15, every 3 weeks) or the control arm (continuation of the standard regimen) for 3 cycles. Bevacizumab use is allowed at investigator discretion. Stratification factors include planned bevacizumab administration, BRCA mutation status, and KELIM strata. The two co-primary endpoints are (1) improvement in late complete cytoreduction rates (from 5% in the control arm to 20% in the experimental arm), and (2) overall survival (target hazard-ratio, 0.61). Total 250 patients will be randomized. Secondary endpoints include objective response rate, progression-free survival, and safety. Additional planned analyses include quality-of-life, cost-effectiveness, surgical standardization, human sciences, and biology studies.

Ethics: The protocol was approved by the national ethics committee and health authorities.

Discussion: SALVOVAR will evaluate whether chemotherapy densification improves outcomes in poorly chemosensitive advanced EOC. If positive, this pragmatic strategy could be implemented in large-scale studies, independent of resource setting.

Trial registration: ClinicalTrials.gov NCT06476184 (June-2024). Available at: https://clinicaltrials.gov/study/NCT06476184.