Therapeutic Advances in Medical Oncology最新文献

Background: Despite the revolutionary impact of immune checkpoint inhibitors (ICIs) on the treatment of metastatic urothelial carcinoma (mUC), the clinical utility of reliable prognostic biomarkers to foresee survival outcomes remains underexplored.

Objectives: The purpose of this study was to ascertain the prognostic significance of serum inflammatory markers in mUC patients undergoing ICI therapy.

Design: This is a retrospective, multicenter study.

Methods: Data were collected from two independent medical centers in Taiwan, encompassing a validation and a training cohort (TC). Patients with histopathologically confirmed urothelial carcinoma who received at least one cycle of ICI monotherapy were included. Serum inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were calculated prior to ICI therapy. Statistical analyses involved the use of receiver operating characteristic (ROC) curves to determine optimal biomarker cutoffs and Cox proportional hazards models to evaluate the independent predictive capability of these markers.

Results: A total of 192 patients were enrolled. In the univariate analysis, serum markers such as NLR, PLR, SII, and Hb were significantly associated with overall survival (OS) in both the training and validation cohorts (VC). White blood cells, NLR, and SII demonstrated a robust correlation with progression-free survival across both cohorts. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status ⩾2 (p < 0.001), visceral metastasis (p < 0.001), leukocytosis (p < 0.001), Hb levels ⩾10 mg/dL (p = 0.008), and NLR ⩾5 (p = 0.032) as independent predictors of OS. A prognostic nomogram integrating these independent factors yielded a C-index for a 3-year OS of 0.769 in the TC and 0.657 in the VC.

Conclusion: Serum inflammatory markers, combined with clinicopathologic factors, provide a practical prognostic tool in mUC treatment with ICIs.

Background: Sex disparities are known modifiers of health and disease. In neuroendocrine neoplasms (NENs), sex-based differences have been observed in the epidemiology and treatment-related side effects.

Objectives: To examine sex differences in demographics, diagnoses present during hospital admission, comorbidities, and outcomes of hospital course among hospitalized patients with NENs.

Design: Retrospective analysis.

Methods: A descriptive analysis of sex differences was performed on patients with NENs discharged from U.S. community hospitals in 2019 from the National Inpatient Sample (NIS), Healthcare Cost and Utilization Project, and Agency for Healthcare Research and Quality.

Results: A total of 7334 patients with NENs were identified; 4284 patients had primary NENs, and 3050 patients had metastatic NENs. In total, 48.7% were males and 51.3% were females. Distributions of race and ethnicity, and payer types differed by sex (p < 0.001 and p = 0.027, respectively). For race and ethnicity, there were more females in White, Black, and Native American races, and Hispanic ethnicity. For payer types, female predominance was seen with Medicare, Medicaid, private insurance, and self-pay groups. Sex differences were seen in diagnosis made during hospital stay. In all NENs, oral (p = 0.036) and neurologic (p < 0.001) diagnoses were more common in females; ascites (p = 0.002), dysphagia (p = 0.002), biliary ductal obstruction (p = 0.014), and jaundice (p = 0.048) were more common in males. In primary NENs, ascites (p < 0.001) was male predominant. In metastatic NENs, dysphagia (p = 0.003) and jaundice (p = 0.034) were male predominant, whereas females had more headaches (p < 0.001). Nausea and vomiting were female predominant in all NENs (p < 0.001), primary (p = 0.044), and metastatic (p < 0.001) NENs. For comorbidities, arthropathies (p < 0.001), depression (p < 0.001), hypothyroidism (p < 0.001), other thyroid disorders (p < 0.001), chronic pulmonary disease (p = 0.002), and obesity (p < 0.001) were female predominant.

Conclusion: There were sex differences in the race and ethnicity, payer types, diagnoses present during hospital admission, and comorbidities among the 2019 NIS hospital discharge sample of patients with NENs.

Background: The androgen receptor pathway inhibitors (ARPI), abiraterone acetate and enzalutamide, are commonly used in first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, early resistance to ARPI treatment occurs frequently. Traditionally, the response is evaluated 3-6 months after the start of treatment. However, recent findings indicate that by detecting circulating tumor DNA (ctDNA) at baseline and 4 weeks after ARPI treatment initiation, patients with a nondurable response can be identified after 4 weeks of treatment, enabling an early switch to alternative treatments.

Objective: This study aims to evaluate the cost-effectiveness of ctDNA-guided treatment switch after 4 weeks of ARPI therapy in mCRPC patients compared to standard of care.

Design: A cost-effectiveness analysis.

Methods: A cost-effectiveness analysis was conducted by creating a Markov state transition model to simulate progression, mortality, and treatment costs over a 5-year time horizon comparing ctDNA-guided care versus standard of care. The outcomes measured were incremental treatment costs per life-years and quality-adjusted life-years (QALYs) gained.

Results: The analysis showed an incremental cost-effectiveness ratio of €65,400.86 per QALY gained and an incremental net monetary benefit of €2716.62. Thereby, the use of ctDNA-guided treatment was cost-effective in comparison to standard care in 74% of the simulations using a willingness-to-pay threshold of €80,000 per QALY gained.

Conclusion: Our study demonstrated the cost-effectiveness of using a ctDNA-guided early therapy switch in non-responders after only 4 weeks of first-line ARPI therapy in mCRPC patients. This paves the way for implementing ctDNA-guided treatment decisions in clinical practice.

Background and objectives: Breast cancer is the most common cancer in women, with one in eight women suffering from this disease in her lifetime. The implementation of centrally organized mammography screening for women between 50 and 69 years of age was a major step in the direction of early detection. However, the participation rate reaches approximately 50% of the eligible women, one reason being the painful compression of the breast, cited as a major issue for not participating in this very important program. Therefore, focusing current research on less painful and less invasive techniques for the detection of breast cancer is highly clinically relevant. Liquid biopsies offer this option by detection of distinct molecules such as microRNAs (miRNAs) or circulating tumor DNA (ctDNA) or disseminated tumor cells.

Design and methods: Here, we present the first proof-of-concept approach for sequencing miRNAs in female urine to detect breast cancer and, subsequently, intrinsic subtype-specific miRNA patterns and implement in this regard a novel random forest algorithm. To this end, we performed miRNA sequencing on 82 urine samples, 32 samples from breast cancer patients (9× luminal A, 8× luminal B, 9× triple-negative, and 6× HER2) and 50 healthy control samples.

Results and conclusion: Using a random forest algorithm, we identified a signature of 275 miRNAs that allows the detection of invasive breast cancer in urine. Furthermore, we identified distinct miRNA expression patterns for the major intrinsic subtypes of breast cancer, specifically luminal A, luminal B, HER2-enriched, and triple-negative breast cancer. This experimental approach specifically validates miRNA sequencing as a technique for breast cancer detection in urine samples and opens the door to a new, easy, and painless procedure for different breast cancer-related medical procedures such as screening but also treatment monitoring.

Background: Given the widespread prevalence of breast cancer as a global malignancy, there is a compelling need to delve into its risk determinants.

Objective: This study aims to investigate the potential relationship between indicators of left-handedness and breast cancer, employing systematic review, meta-analysis, and Mendelian randomization methods.

Design: Systematic review and meta-analysis.

Methods: The systematic review and meta-analysis, encompassing case-control and cohort designs, conducted a database search on June 17, 2022, utilizing Medline and Embase. For Mendelian randomization analysis, the exposure variable, left-handedness, was sourced from the UK Biobank. Data for breast cancer outcomes were obtained from two cohorts: the Breast Cancer Association Consortium and the Finnish Biobank (Finngen).

Results: Eight studies were included in the meta-analysis to investigate the correlation between left-handedness and breast cancer in females. The analysis of cohort studies revealed a hazard ratio (HR) of 1.21 (95% confidence interval (CI): 1.01-1.45), whereas case-control studies showed an odds ratio of 0.81 (95% CI: 0.52-1.26). Subgroup analysis indicated an elevated HR in premenopausal left-handed women. However, Mendelian randomization did not confirm a significant association.

Conclusion: Our findings suggest a potential correlation between left-handedness and breast cancer, particularly in premenopausal women. However, due to limited studies and unclear supporting theories, definitive conclusions are premature.

Patients with genitourinary (GU) malignancies have seen the development of multiple life-prolonging treatments in the past decade. As patients and clinicians consider their treatment options along the cancer journey, time spent with healthcare contact, or "time toxicity," has emerged as a new outcome measure that comprehensively considers time receiving cancer care, including planned visits for evaluation and treatment as well as unplanned urgent care addressing complications. Despite its rising study across cancer populations, there has been a surprising lack of work evaluating time toxicity in patients with GU cancers. This narrative review aims to summarize the available studies on time toxicity in cancer, with a deeper dive into the methodology, strengths and limitations, and future directions of the field. A dedicated section focused on scenarios and best practices to measure and collect data on time toxicity can serve to spark interest in evaluating this novel health outcome on GU cancer survivors. Ultimately, time toxicity is a relevant patient-centered metric that can be incorporated into clinical trial design and routine clinical care to influence clinical decision-making.

Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS-mutated mCRC.

Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS-mutated mCRC.

Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro, and we validated the drugs' efficacy in vivo.

Methods: HTS was performed using three-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with two "clinically ready" libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the drugs' effects on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts.

Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS-mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell-cycle progression. Trametinib also enhanced paclitaxel-mediated microtubule stability resulting in significantly higher defects in mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models.

Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.

Background: Claudin-18 isoform 2 (CLDN18.2) is expressed in multiple cancers and is a promising target for antitumor therapy. However, there is limited knowledge regarding the prevalence and characteristics of CLDN18.2-positive colorectal cancer (CRC).

Objectives: To determine the clinicopathological and molecular features of patients with CLDN18.2-positive CRC.

Design: Single-center retrospective study.

Methods: A total of 805 patients who underwent surgical resection for pathological stage I-III CRC at the National Cancer Center Hospital (Tokyo, Japan) between 1997 and 2019 were identified. Expression of CLDN18.2 was evaluated by immunohistochemistry. The association of CLDN18.2 expression with clinicopathological features and treatment outcomes was assessed. The cutoff for CLDN18.2 positivity was defined as ⩾1%.

Results: Among these patients, 17 (2.1%) had CLDN18.2-positive CRC. Right-sided CRC was significantly more common in patients who were CLDN18.2 positive than in those who were CLDN18.2 negative (76.5% vs 28.3%, p < 0.0001), as was mucinous or poorly differentiated adenocarcinoma (17.6% vs 3.0%; 17.6% vs 2.2%, p < 0.0001), T3-4 disease (100% vs 84.3%, p = 0.075), lymphatic invasion (64.7% vs 24.2%, p < 0.0001), BRAF V600E mutation (29.4% vs 4.1%, p < 0.0001), and deficient mismatch repair (MMR) status (47.1% vs 10.0%, p < 0.0001). Multivariate analysis did not identify CLDN18.2 expression status to be an independent predictor of relapse-free survival (RFS) or overall survival (OS).

Conclusion: Approximately 2% of all CRC cases in this study were CLDN18.2 positive and had unfavorable features (e.g., mucinous or poorly differentiated adenocarcinoma, T3-4 disease, lymphatic invasion, BRAF V600E mutation) and deficient MMR status. CLDN18.2 positivity did not have a significant impact on RFS or OS.

Background: The esophageal mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is an extremely rare but poor prognosis tumor.

Objectives: This retrospective study aimed to analyze the clinical characteristics of MiNEN and to investigate postoperative survival and prognostic factors.

Design: This retrospective study analyzed 69 patients diagnosed with esophageal MiNEN at two major esophageal cancer centers in China from January 2000 to December 2021.

Methods: We assessed demographic data, tumor characteristics, treatment modalities, and survival outcomes. Statistical analyses included Kaplan-Meier survival curves and Cox regression models to evaluate prognostic factors.

Results: The most common histological types were combinations of small-cell carcinoma and squamous carcinoma (91.3%). The correct diagnostic rate of preoperative pathologic biopsy was only 4.3%. The median overall survival (OS) was 24.0 months, and disease-free survival (DFS) was 16.6 months. The 1-, 3-, and 5-year survival rates were 84.1%, 34.8%, and 25.3%, respectively. A peak period of recurrence or metastasis occurs in the first year after surgery, and regional lymph node recurrence is the main route of postoperative recurrence or metastasis. Tumor size, T-stage, N-stage, and tumor, lymph node, metastasis (TNM) stage were significant prognostic factors. Subgroup analyses showed that in patients with limited-stage MiNEN in stages I-III, the postoperative adjuvant treatment modality failed to improve OS and DFS compared with surgery alone. Postoperative adjuvant therapy also failed to prolong OS and DFS in patients with lymph node-positive MiNEN. No significant survival benefits were observed with different surgical techniques or adjuvant chemotherapy regimens.

Conclusion: Esophageal MiNEN has aggressive behavior and a poor prognosis. In China, the pathologic type of esophageal MiNEN may be dominated by a combination of small-cell carcinoma and squamous carcinoma. Early-stage disease significantly correlated with improved survival outcomes. Current treatment protocols, similar to those for other esophageal cancers, show limited efficacy in improving patient survival.

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved treatment-related outcomes of patients with oncogene-driven non-small-cell lung cancer (NSCLC). TKIs are usually well tolerated and used for a prolonged time, although experienced toxicity varies between patients. It is unclear whether patients report all (low grade) toxicities and how these impact their daily lives. The use of therapeutic drug monitoring (TDM) to, for example, manage toxicities is increasingly applied, but there is limited insight into the patient perspective regarding TDM. This qualitative study aims to explore patient perspectives on TKI toxicity and TDM.

Methods: Five semi-structured focus group interviews were held, each with three to four patients with NSCLC using a TKI and their (care) partners. Two researchers independently performed a directive content analysis.

Results: In total, 16 patients and 12 (care) partners participated. Experienced treatment-related toxicities were encountered limitedly and patients felt no boundaries discussing these with their treatment team. However, symptoms were sometimes not reported as they were doubted as treatment related. The concept of TDM-guided dosing to, for example, reduce TKI exposure to account for dosing outside the therapeutic window resulted in feelings of uncertainty regarding treatment efficacy. Patients emphasized the need for thorough research and frequent check-ups to ensure treatment efficacy.

Conclusion: Perceived TKI-related toxicities seem limited, although the treatment team should pay attention to symptoms not directly described by patients as treatment related. In general, patients are open to implement TDM-guided dosing, but only if thorough scientific evidence demonstrates retained or enhanced safety and efficacy.