Therapeutic Advances in Medical Oncology最新文献

SMARCA4 deficiency plays a critical role in the oncogenesis of various aggressive tumors that exhibit resistance to conventional chemotherapy and radiotherapy, posing significant challenges to clinical management. The pivotal role of SMARCA4 deficiency in tumorigenesis suggests the need for a paradigm shift from traditional tumor origin-based approaches to novel tumor-agnostic strategies focused on molecular alterations associated with SMARCA4 deficiency. This review explores potential targetable molecular changes and emerging therapeutic strategies for SMARCA4-deficient tumors. Molecular alterations related to SMARCA4 deficiency involve impaired genomic stability, defects in DNA mismatch repair, and elevated tumor mutation burdens, all of which suggest potential sensitivity to immune checkpoint inhibitors (ICIs). Recent studies indicate that combining ICIs with chemotherapy or anti-angiogenic agents as first-line treatments may offer clinical benefits for SMARCA4-deficient tumors. Furthermore, SMARCA4 deficiency epigenetically affects chromatin accessibility, alters the distribution of Polycomb group proteins on chromatin, and modulates histone acetylation, highlighting the potential efficacy of epigenetic regulators such as EZH2 and HDAC inhibitors. In addition, synthetic lethality strategies targeting vulnerabilities in SMARCA4-deficient tumors are promising therapeutic approaches, including inhibitors of SMARCA2, CDK4/6, ATR, CHK1, PARP, and the oxidative phosphorylation pathway. Based on current clinical evidence, ICI-based combination therapies represent the most promising first-line regimens for SMARCA4-deficient tumors. Although a theoretical basis supports the potential of tumor-agnostic therapy as a promising strategy for these tumors, several challenges remain in clinical practice. These include heterogeneous therapeutic responses across tumor types, safety concerns associated with synthetic lethality-based agents, and the absence of any histology-agnostic approved therapy for SMARCA4-deficient tumors. The continued development of novel therapeutics and further large-scale clinical evaluations are essential to overcoming these barriers.

Cutaneous metastases from breast cancer, although relatively uncommon, represent the most frequent form of skin metastases overall and pose a significant clinical and therapeutic challenge. Their presence classifies the disease as stage IV, typically prompting the initiation or modification of systemic treatment. However, current clinical guidelines do not distinguish between cutaneous and visceral metastases, which may lead to unnecessary alterations in systemic therapy-even when visceral disease remains well controlled-potentially compromising an otherwise effective regimen. This review provides a comprehensive overview of systemic and loco-regional treatment options for cutaneous breast cancer metastases, including current guidelines stratified by tumor subtype. Special attention is given to loco-regional therapies such as electrochemotherapy, radiotherapy, surgical excision, photodynamic therapy, intralesional agents, and topical treatments, all of which can be integrated with systemic therapy to improve local disease control, reduce symptoms, and enhance patient quality of life. We propose an integrated and personalized therapeutic model that combines systemic and loco-regional approaches, supported by a decision-making flowchart designed to assist clinicians in optimizing treatment strategies. By adopting a multidisciplinary perspective, this approach aims to improve both local and systemic disease management, clinical outcomes, and patient well-being. Further research is warranted to refine therapeutic combinations, establish standardized protocols, and fully realize the clinical benefits for patients with metastatic breast cancer presenting with cutaneous involvement.

Synthetic lethality (SL) is a promising therapeutic concept that relies on the indirect targeting of vulnerabilities acquired through genetic mutations. Ovarian and endometrial cancers frequently exhibit mutations in the breast cancer (BRCA), phosphatase and tensin homolog (PTEN), AT-rich interactive domain-containing protein 1A (ARID1A) and TP53 genes, as well as DNA repair pathway deficiencies. Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in various cancers with BRCA mutations and homologous recombination deficiency. In addition to PARPi, there has been an expansion of drugs exploiting the selective vulnerability of cancer cells via SL, such as WEE1 kinase and Ataxia Telangiectasia and Rad3-related protein (ATR). WEE1 inhibitors have shown encouraging results in combination with chemotherapy, increasing the objective response rate in patients with platinum-resistant TP53-mutated ovarian cancer. ATR inhibitors are currently being evaluated in ARID1A-mutated tumours, with preliminary results confirming their therapeutic potential.

Epithelial ovarian cancer (OC) comprises molecularly distinct disease types, with high-grade serous ovarian cancer (HGSOC) accounting for ~75% of OC diagnoses; ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC) at ~10% each; mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSOC) at ⩽5% each; and ovarian carcinosarcoma (OCS), the rarest type of OC at 1%-4% of OC diagnoses. LGSOC has the best prognosis, followed by EnOC, MOC and OCCC, with HGSOC then OCS being the most aggressive. For all types of OC, diagnosis at the advanced-stage results in dramatically reduced survival. Initial treatment consists of debulking surgery and platinum-based chemotherapy, usually in combination with a taxane; however, response rates vary depending on the OC type. Treatments specific to the OC type may improve treatment outcomes. For HGSOC, poly(ADP-ribose) polymerase inhibitor (PARPi) therapy has improved survival for women with DNA homologous recombination repair (HRR) defects; however, acquired resistance remains an issue and more effective treatments are needed. Next-generation sequencing of distinct types of OC has revealed the complexity of genetic variants and larger-scale genomic and epigenomic alterations harboured, including proven and putative biomarkers of drug response. A predominance of distinct gene classes is altered in specific OC types: HRR genes (e.g. BRCA1 and BRCA2) in HGSOC; ARID1A and PIK3CA in OCCC; PIK3CA and KRAS in EnOC; CDKN2A and KRAS in MOC and MAPK pathway genes (e.g. BRAF and KRAS) in LGSOC. Generating evidence for effective drug combination therapies targeting relevant aberrations in each OC type is urgently needed. The effects of long-term drug treatment on OC genomes, acquired drug-resistance and OC relapse require clarification, especially in women with HGSOC with acquired resistance to PARPi. This article provides an overview of the main types of OC and their genomic profiles. It highlights recent encouraging clinical trials, with an emphasis on the future of genomically-targeted combination therapies, for both first-line and subsequent treatment of OC. We focus on PARPi combinations for HGSOC, MAPK pathway inhibitors for LGSOC, cell cycle checkpoint inhibitors for OC with CCNE1 amplification, the potential of immune checkpoint inhibitors in OCCC and encouraging, as yet preliminary, responses for antibody-drug conjugate-based therapy. Thus, OC type-specific genomic susceptibilities provide direction for personalised therapy in OC.

Background: The aging population presents significant challenges to healthcare worldwide. Evidence concerning the safety and efficacy of neoadjuvant immunochemotherapy in patients with non-small-cell lung cancer (NSCLC) aged 70 years or older remains limited.

Objectives: To investigate the safety and efficacy of neoadjuvant immunochemotherapy in NSCLC patients stratified by age into three groups, and to identify factors associated with overall survival (OS) and disease-free survival (DFS).

Design: We performed a retrospective cohort study including 171 NSCLC patients with NSCLC who underwent neoadjuvant immunochemotherapy followed by surgical resection. The patients were categorized by age into three groups: ⩾70 years, 60-69 years, and <60 years.

Methods: The safety and efficacy of neoadjuvant immunochemotherapy were comprehensively evaluated. Safety was assessed based on the incidence of treatment-related adverse events (AEs) and complications. Efficacy was determined through analyses of tumor response and survival outcomes. OS and DFS were analyzed using the Kaplan-Meier method, and independent prognostic factors were identified through the Cox proportional hazards model.

Results: The study cohort comprised 24 patients aged ⩾70 years, 73 patients aged 60-69 years, and 74 patients under 60 years. OS and DFS did not differ significantly among the three age groups following neoadjuvant immunochemotherapy. Multivariate analysis identified major pathological response (MPR) as a significant independent predictor of OS (hazard ratio (HR): 0.232, 95% confidence interval (CI): 0.079-0.678, p = 0.008). For DFS, both MPR (HR: 0.342, 95% CI: 0.184-0.638, p = 0.001) and the occurrence of postoperative complications (HR: 2.115, 95% CI: 1.208-3.705, p = 0.009) were independent predictors. Overall, patients across all age groups exhibited acceptable tolerance to neoadjuvant immunochemotherapy.

Conclusion: Neoadjuvant immunochemotherapy demonstrated consistent safety and efficacy across all age groups in this cohort of NSCLC patients. Achieving MPR was associated with improved OS and DFS, whereas the occurrence of postoperative complications was associated with diminished DFS.

Background: Relapsed or refractory (R/R) disease following frontline treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) represents a significant clinical challenge in the management of diffuse large B-cell lymphoma (DLBCL).

Objectives: To address unmet medical needs, comprehensive clinical data on R/R DLBCL in real-world settings are warranted.

Design: A retrospective observational study including patients from a tertiary medical center and a national population-based cohort.

Methods: We conducted a retrospective cohort study of R/R DLBCL, derived from 665 consecutive patients treated with R-CHOP. Furthermore, a population-based cohort from Taiwan's National Health Insurance Research Database was established for external validation. Clinical data were comprehensively analyzed using Cox proportional hazards regression to identify independent predictors of overall survival (OS) and progression-free survival (PFS).

Results: A total of 231 patients were identified from the retrospective cohort. Among them, 88 (38.1%) were found to be primarily refractory to R-CHOP, while 143 (61.9%) experienced recurrent disease. When stratified by time to progression (TTP) after R-CHOP, the 2-year OS rate ranged from 35.4% in patients with TTP <12 months to 74.4% in those with TTP ⩾24 months. Patients with TTP <12 months also demonstrated lower response rates to second-line treatments and were less likely to proceed to stem cell transplantation. In multivariate analysis, TTP was identified as an independent prognostic factor for OS and PFS. The prognostic significance of TTP was further validated in an external, population-based cohort of 723 patients with R/R DLBCL.

Conclusion: This real-world study provides valuable insights into R/R DLBCL outside of clinical trial settings, revealing that TTP after frontline R-CHOP is an easy-to-use and robust prognostic predictor. Patients with a TTP of less than 12 months exhibited a particularly poor prognosis under conventional treatment, highlighting the urgent need to consider novel therapeutic approaches for this high-risk population.

Background: The optimal induction chemotherapy (IC) regimen for locally advanced nasopharyngeal carcinoma (LA-NPC) remains uncertain.

Objectives: The study aims to compare the efficacy and safety of nanoparticle albumin-bound paclitaxel plus cisplatin (NAB-TP) versus gemcitabine plus cisplatin (GP) as IC in locoregionally advanced nasopharyngeal carcinoma (LA-NPC).

Design: A retrospective analysis.

Methods: This study was conducted in LA-NPC patients treated at Sun Yat-sen University Cancer Center between 2012 and 2024. All patients received IC with either the GP or NAB-TP regimen followed by concurrent chemoradiotherapy (CCRT). Propensity score matching (PSM) was used to balance baseline characteristics between the GP and NAB-TP groups.

Results: In total, 908 patients with LA-NPC (197 in the NAB-TP group) were enrolled. Before PSM, no statistically significant differences were observed between the NAB-TP and GP group in 5-year overall survival (OS; 98.67% vs 91.67%; p = 0.647), 5-year progression-free survival (PFS; 84.18% vs 66.22%; p = 0.587), 5-year locoregional relapse-free survival (LRFS; 88.13% vs 81.44%; p = 0.106), or 5-year distant metastasis-free survival (DMFS; 98.05% vs 89.88%; p = 0.106). After PSM, no differences were found in 5-year OS (98.60% vs 86.26%; p = 0.536), PFS (84.18% vs 66.22%; p = 0.587), LRFS (88.82% vs 76.14%; p = 0.757), or DMFS (97.95% vs 91.74%; p = 0.105). In the matched cohort, the NAB-TP group showed significantly lower incidences of anemia and thrombocytopenia than the GP group.

Conclusion: IC with the NAB-TP combined with CCRT showed comparable survival efficacy for LA-NPC patients compared with the GP, with reduced acute toxicity.

Sarcomatoid malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with limited therapeutic options. We describe an exceptionally rare case of sarcomatoid MPM in a man in his 50s who developed three severe immune-related adverse events (irAEs)-Grade 3 pneumonitis, Grade 3 hepatitis, and Grade 4 agranulocytosis-within 55 days of initiating nivolumab plus ipilimumab. Corticosteroid treatment and granulocyte colony-stimulating factor resulted in recovery from these toxicities, while two liver biopsies provided essential diagnostic insights, distinguishing drug-induced liver injury from immune-related hepatitis. Despite receiving only a limited number of immune checkpoint inhibitor doses and discontinuing therapy, the patient exhibited rapid pleural tumor regression and sustained clinical benefit. This case highlights the potential association between severe immune-related side effects and favorable treatment response in MPM, and underscores the importance of pathology-supported diagnosis and shared decision-making in managing complex irAEs.

Background: Next-generation sequencing (NGS) of plasma circulating tumor DNA (ctDNA) shows promise as a minimally invasive alternative to tissue sequencing. However, concordance between genomic alterations in tumor tissue and plasma ctDNA remains incompletely characterized in ovarian cancer, particularly in the pretreatment setting.

Objectives: To identify factors influencing concordance between tissue and ctDNA genomic profiling and explore the potential clinical implications (including treatment and survival outcomes) of this concordance.

Design: A prospective, single-center, observational study.

Methods: A total of 40 matched pretreatment tumor specimens and blood samples were prospectively collected from patients with ovarian cancer and subsequently sequenced using a customized gene panel. Overall and individual concordance rates were calculated as the ratio of total concordant mutations to total tissue mutations, with patients stratified into highly concordant (⩾50%) and poorly concordant (<50%) groups.

Results: The overall tissue-plasma concordance rate was 40.8%, with shared variants exhibiting identical abundance patterns across sample types and capturing the majority of functionally relevant mutations. Single-nucleotide variants in tissue showed a higher detection rate in plasma than structural variants. Individual concordance rates displayed significant inter-patient variability. Higher tissue tumor mutation burden (odds ratio (OR) 2.165, 95% confidence interval (CI) 1.183-3.965) and plasma ctDNA fraction (OR 1.433, 95% CI 1.063-1.933) were independently associated with high concordance rates. In advanced-stage patients, the poorly concordant group showed lower CA125 elimination rate constant K (KELIM) scores (median 0.7 vs 1.3; 15.0% vs 68.8% patients with score ⩾1), indicating reduced chemosensitivity. The poorly concordant group demonstrated a higher disease recurrence rate (40.0% vs 6.2%) and elevated early recurrence risk (12-month progression-free survival rate 82.0% vs 100.0%) compared with the highly concordant group.

Conclusion: In the field of ovarian cancer, NGS of ctDNA showed moderate concordance with tissue-based sequencing in the pretreatment setting, influenced by both technical and biological factors. The tissue-plasma concordance may serve as a chemosensitivity and prognostic indicator.

Immunotherapy has shown inconsistent results in Epstein-Barr virus-associated gastric cancer (EBVaGC) despite being associated with an active tumour microenvironment. This calls for the identification of subtypes within the EBVaGC subtype, and subsequent treatments tailored for their properties. This review identified six different EBVaGC subtypes alongside potential therapeutic opportunities. EBVaGCs, which express immune checkpoints, high microsatellite instability or high tumour mutational burden, are shown to respond better to immune checkpoint inhibitors, each due to their own specific characteristics. Co-infection of EBV and Helicobacter pylori in gastric cancer (GC) can exacerbate their impact on inflammatory stress and has the potential to be treated by antiviral agents and antimicrobials. EBVaGCs are also more likely to express wild-type p53 than other GCs, which suggests potential for lytic-induction therapy, where the EBV genome is kicked out of latency and subsequently killed using antiviral nucleoside analogue prodrugs. Lastly, EBVaGC is more likely to express the PI3K and ARID1A mutations, which can potentially be treated using PI3K/mTOR dual inhibitors and Akt/PARP inhibitors. These six subtypes could aid the selection of more successful treatments for EBVaGC, thereby improving the current overall survival and prognosis of patients.