Oncologist最新文献

Purpose: Age and sex are known to influence outcomes in neuroendocrine neoplasms (NENs), yet their molecular determinants remain poorly defined. We queried a real-world dataset of gastrointestinal (GI) tract and pancreatic (P) NENs and characterized their clinical, molecular, and immune profiles.

Methods: One thousand nine hundred thirty-five cases (GI: n = 1431, P: n = 504) of NENs were analyzed using Next Generation or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n = 917, P: n = 294) underwent Whole Transcriptome Sequencing. We compared the molecular and immune profile with respect to age and sex.

Results: Older age at diagnosis was associated with worse survival in both GI- and P-NENs. In patients with GI-NENs, there was decreased survival in males compared to females. In GI-NENs, TP53, RB1, FAT1, and KMT2D mutations, as well as immune checkpoint gene (ICG) expressions of LAG3, CD80, and HAVCR2 and M1 macrophages increased with increasing age while APC mutations and M2 macrophages decreased with increasing age. In P-NENs, TP53, RB1, KRAS, and SMAD4 mutations and CD4+ T cells increased with increasing age while MUTYH and NTHL1 mutations and M2 macrophages decreased with increasing age. In GI-NENs, TP53, FBXW7, and TERT (promoter) mutations and genomic loss of heterozygosity (gLOH) were increased in males. In P-NENs, PIK3CA mutations and dMMR/MSI-H were increased in females.

Conclusion: Our study queries one of the largest datasets of GI- and P-NENs to date and highlights distinct age- and sex-specific molecular and immune profiles. Given the exploratory nature of these analyses and borderline significance, these results remain hypothesis-generating, providing an initial framework for future validation studies.

Background: Bevacizumab and temsirolimus target angiogenic and mTOR pathways in cancer progression.

Methods: This phase I study enrolled 48 heavily pretreated patients with advanced solid tumors, including an ovarian cancer expansion cohort. Patients received bevacizumab biweekly plus temsirolimus weekly in a 3 + 3 design to assess safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Exploratory analyses included tumor genomic profiling and dynamic contrast-enhanced MRI (DCE-MRI).

Results: Patients had a median age of 59 and median four prior therapies. Common tumor types were ovarian (27%) and head and neck (15%). Treatment-related adverse events occurred in 93.8%, with 31.3% ≥grade 3. Five patients experienced DLTs, including grade 3 enteritis, fatigue, bowel obstruction/abdominal ileus/pulmonary embolism, bowel perforation and grade 3/4 elevated liver enzymes. MTD was bevacizumab 10 mg/kg biweekly plus temsirolimus 20 mg weekly. Overall, objective response rate (ORR) was 7.3% and 19.5% achieved stable disease ≥6 months (clinical benefit rate [CBR] 26.8%). In ovarian cohort, ORR was 16.7% and CBR 33.3%. Patients with tumor regression on DCE-MRI had lower ΔKtrans values.

Conclusion: Combination therapy showed acceptable safety and modest activity. Molecular and imaging findings were exploratory and limited. These preliminary observations could inform future biomarker studies. (ClinicalTrials.gov Identifier: NCT01552434).

Background: Biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CCA), are rare but aggressive malignancies with distinct molecular landscapes and poor prognoses. Genomic profiling has revealed significant molecular alterations, but the genomic landscape of BTC in the Indian population remains underexplored. This study aims to comprehensively characterize the mutation landscape of BTC in the Indian population.

Methods: A total of 154 BTC cases, including 69 CCA and 85 GBC, were retrospectively analyzed using data collected from various targeted sequencing panels. Somatic mutations, copy number variations (CNVs), and gene fusions in key oncogenic and tumor suppressor genes were identified from these panel reports. Downstream analyses were performed to derive key biological insights, including pathway enrichment and mutual exclusivity and co-occurrence analyses of genomic alterations.

Results: TP53 was the most frequently mutated gene (53%), followed by KRAS (18%), ARID1A (9%), IDH1 (7%), and PIK3CA (7%). Recurrent amplifications were observed in MYC (12%) and ERBB2 (9%). Pathway enrichment analysis revealed significant dysregulation in the PI3K-AKT-mTOR, Notch, and Wnt/β-catenin signaling pathways. Notably, IDH1 mutations were primarily observed in CCA, while STK11 mutations were exclusive to GBC, highlighting distinct molecular characteristics between the two subtypes. PD-L1-negative tumors exhibited distinct genomic alterations, notably SMAD4 mutations, which were associated with reduced PD-L1 expression. This loss of SMAD4, involved in TGF-β signaling, could impair immune response regulation and facilitate immune evasion.

Conclusions: This study provides a comprehensive molecular profiling of BTCs in the Indian population, revealing key genomic alterations, subtype-specific differences, and associations with immune features. The findings underscore the importance of molecular profiling in guiding personalized treatment strategies.

Background: Chemotherapy-induced nausea and vomiting (CINV) significantly impact the patients' quality of life. Whether the granisetron transdermal delivery system (GTDS) offers better protection than palonosetron against long-delayed (120-168 hours) CINV after highly or moderately emetogenic chemotherapy (HEC/MEC) had not been prospectively tested.

Methods: A multicenter, randomized clinical study was conducted in China. Patients scheduled to receive either HEC or MEC were randomly assigned (1:1) to GTDS or palonosetron, each in combination with a neurokinin-1 receptor antagonist (NK1-RA) and dexamethasone. The primary endpoint was the complete response (CR; no vomiting and no rescue medication) rate during the long-delayed phase (120-168 hours), stratified by HEC and MEC categories, to demonstrate the superiority of GTDS over palonosetron.

Results: Overall, 150 patients received either GTDS or palonosetron respectively. We found that the GTDS group demonstrated a significantly higher long-delayed CR rate (97.3%) than the palonosetron group (92%) (P = .04). This advantage was driven predominantly by the HEC subgroup (GTDS 97.5% vs palonosetron 90.8%, P = .028). No significant differences were observed between the groups for the acute (0-24 hours, 92.7% vs 90.0%; P = .412), delayed (24-120 hours, 80.0% vs 76.0%; P = .403), extended-delayed (24-168 hours, 80.7% vs 75.3%; P = .265), or overall (0-168 hours, 78.0% vs 74.0%; P = .417) phases.

Conclusion: A GTDS-based triple antiemetic regimen can effectively control CINV associated with HEC or MEC. It provides a convenient alternative route for delivering granisetron for up to 7 days, with superior efficacy in controlling long-delayed CINV.

Trial registration: Clinicaltrials.gov Identifier: NCT04912271 (in-house ethic number: YBCSG-21-04).

Background: A pathological complete response (pCR) following neoadjuvant chemoradiation (CRT) is associated with a favorable prognosis in patients with locally advanced rectal cancer. Patients with metastatic colorectal cancer (mCRC) often receive systemic therapy, and some patients undergo primary tumor resection after preoperative therapy. However, whether oncological outcomes remain favorable in patients with mCRC and pCR in primary tumor site (ypT0N0M1) following preoperative therapy is unknown.

Patients and methods: Patients with mCRC who underwent preoperative therapy followed by primary tumor resection between March 2014 and August 2023, and in whom pCR was confirmed at the primary tumor site, were retrospectively included in this study. The outcome variables investigated were patient demographics, overall survival (OS), and progression-free survival (PFS).

Results: We included 57 patients who met the inclusion criteria. The median follow-up was 27.1 (range, 7.9-120.6) months. The 2-year PFS and 3-year OS rates in all the patients were 62.2% and 84.5%, respectively. Patients with a primary tumor site in the colon (n = 29) had superior OS (p = 0.039) and a trend toward superior PFS (p = 0.149) compared to those with a primary site in the rectum (n = 28).

Conclusion: Patients with mCRC following preoperative therapy, particularly those with colon cancer, who experienced a pCR in the primary tumor site have a favorable prognosis.

Antibody-drug conjugates (ADCs) combine a tumor antigen-specific monoclonal antibody with a cytotoxic payload via a linker, allowing selective delivery of cytotoxic agents to cancer cells while minimizing damage to healthy tissues. This approach has revolutionized cancer treatment. However, despite these advantages, resistance to ADCs has emerged as a significant barrier to long-term efficacy. Understanding and overcoming ADC resistance is crucial, especially for cancers with limited treatment options like triple-negative breast cancer (TNBC), non-small cell lung cancer, pancreatic cancer, and relapsed/refractory acute myeloid leukemia. Moreover, as ADCs expand into new therapeutic areas, overcoming resistance is essential to preserve their effectiveness and explore novel settings, including combination therapies. Identifying molecular pathways involved in ADC resistance and addressing these mechanisms can benefit more patients and extend ADCs' therapeutic lifespan. This review focuses on elucidating these pathways and explores innovative strategies to overcome resistance, including combination therapies and the development of next-generation ADCs. We also highlight key preclinical studies, bridging the gap between basic research and clinical applications, to provide a comprehensive understanding of ADC resistance and its impact on future cancer treatments.

Background: Lutetium-177 (177Lu)-PSMA-617 is a beta-emitting radioligand approved for treatment of metastatic castration resistant prostate cancer (mCRPC), despite the underrepresentation of Black patients in pivotal trials. We analyzed outcomes of 177Lu-PSMA-617 in a racially diverse cohort.

Methods: Retrospective analysis of patients with mCRPC treated with 177Lu-PSMA-617 was conducted at the Emory Winship Cancer Institute. Primary outcomes assessed were PFS, OS, and prostate-specific antigen (PSA) reduction ≥ 50% (PSA50). Cox proportional hazard models were used for univariate and multivariate OS and PFS, and logistic regression was used for PSA50 analysis.

Results: Among 163 patients treated with 177Lu-PSMA-617, 97 (59.5%) self-identified as White or other racial groups and 66 (40.5%) self-identified as Black. On univariate analysis, Black patients had comparable OS, PFS, and PSA50 responses to non-Black patients, with a trend towards improved outcomes (OS HR: 0.82, p = 0.446; PFS HR 0.92, p = 0.655; PSA50 OR = 1.79, p = 0.088). Multivariate analysis demonstrated a non-significant prolonged PFS and reduction in mortality risk for Black patients (PFS HR: 0.65, p = 0.106; OS: HR 0.59, HR p-value 0.081). The odds of a PSA50 response were 2.45 times higher for Black patients (OR = 2.45, p = 0.027).

Conclusions: In our racially diverse cohort of patients with mCRPC, Black patients had PFS and OS comparable to non-Black patients, although wide confidence intervals limit definitive conclusions. Black patients had a significantly greater odds of achieving a PSA50 response. Our findings suggest efficacy of 177Lu-PSMA-617 among Black patients in real-world settings and underscore the importance of improved representation in prospective studies.

Background: There is a high malnutrition risk in patients with gastrointestinal tumors. Yet, it is unknown when malnutrition manifests and how changes in nutritional status are related to quality of life and fatigue at different stages of oncologic therapy.

Patients and methods: In a prospective observational study, we recruited patients with initial diagnosis of any gastrointestinal tumor requiring systemic therapy and respective patients already receiving treatment. Subjects underwent comprehensive nutritional assessment at enrollment and after 3 months. In addition, patients reported data on physical activity (IPAQ-SF), quality of life (SF-12), and fatigue (EORTC QLQ-FA12). Besides baseline associations, relations between changes in nutritional status and patient-reported outcomes during treatment were analyzed.

Results: We included 66 patients (mean(±SD) age: 62.1(±10.6) yrs.; 68% male), of which 29 had received initial diagnosis and 37 were already undergoing treatment. Baseline clinical characteristics and nutritional status were comparable between groups. With 88% of patients, GLIM-defined malnutrition was highly prevalent at baseline and associated with fatigue, reduced physical activity and quality of life (p < 0.01, respectively). Among 36 study completers, only minor fat mass (p = 0.033) and progressed weight loss (p = 0.025) indicated further nutritional deterioration. Development of cachexia, but not malnutrition or sarcopenia, during treatment was associated with impaired patient-reported outcomes, i.e., higher fatigue (rho = 0.400; p = 0.019) and lowered physical activity (rho=-0.423; p = 0.013).

Conclusion: Most patients with gastrointestinal cancer are malnourished already at diagnosis. Impaired nutritional status is closely linked with reduced quality of life and fatigue, especially their physical components. Trials are warranted to test whether optimized nutrition support can halt further aggravation during treatment.