American Journal of Clinical Oncology-Cancer Clinical Trials最新文献

Objectives: KRAS G12C mutations are key oncogenic drivers in multiple solid tumors. Adagrasib, a selective KRAS G12C inhibitor, has demonstrated promising efficacy and safety in clinical studies. This single-arm meta-analysis comprehensively evaluates key clinical outcomes of Adagrasib, including survival benefits and adverse events, in patients with KRAS G12C-mutant solid tumors.

Methods: Literature search was conducted across 4 databases to identify clinical trials and observational studies evaluating Adagrasib performance in patients with KRAS G12C-mutant solid tumors. A single-arm analysis was performed using the inverse variance method in the "meta" package of RStudio. Log Proportion and standardised mean difference (SMD) with a 95% CI were pooled using a random-effects model. Heterogeneity was assessed using I² statistics.

Results: Six studies involving 400 patients were included in our analysis. Adagrasib showed a median overall survival (OS) of 14.74 months (95% CI: 12.06-17.42, I²=40.4%) and progression-free survival (PFS) of 6.80 months (95% CI: 6.14-7.46, I²=0%), indicating significant survival benefits. The disease control rate (DCR) was 83%, reflecting robust tumor response and stabilization. Safety analysis revealed that 97% of patients experienced at least one adverse event of varying grades.

Conclusions: Adagrasib demonstrated robust efficacy in KRAS G12C-mutant solid tumors, with significant survival benefits and high response rates. However, frequent adverse events and dose modifications, along with variability in response rates, highlight tolerability challenges. Further studies are needed to optimize dosing, improve patient selection, and explore combination strategies to enhance outcomes and minimize unwanted effects.

Objectives: The study aims to identify highly synergistic drug combinations for breast cancer treatment using machine learning models. The primary objective is to predict drug synergy scores accurately and rank combinations with the highest potential for therapeutic efficacy.

Methods: Machine learning models, including XGBoost, Random Forest (RF), and CatBoost (CB), were employed to analyze breast cancer drug combination data. Four synergy metrics-ZIP, Bliss, Loewe, and HSA-were used to quantify drug interaction effects. The models were trained to predict these synergy scores, and their performance was evaluated using normalized root mean squared error (NRMSE) and Pearson correlation coefficient. Predicted top-ranking drug combinations were further validated by comparing observed versus expected dose-response curves and calculating the area under the curve (AUC) for synergy assessment.

Results: XGBoost (XGB_5235) outperformed other models, achieving an NRMSE of 0.074 and a Pearson correlation of 0.90 for the Bliss synergy model. Based on average synergy scores, the top 20 drug combinations were identified, with Ixabepilone+Cladribine, SN 38 Lactone+Pazopanib, and Decitabine+Tretinoin emerging as the most promising. These combinations showed high synergy and were supported by biological insights into their mechanisms of action.

Conclusions: The study demonstrates the effectiveness of machine learning in predicting synergistic drug combinations for breast cancer. By accelerating the screening process and reducing experimental burden, the approach offers a promising tool for guiding future in vitro and in vivo validation of combination therapies.

Objectives: Anaplastic thyroid cancer (ATC) is a rare and aggressive type of thyroid malignancy with a very poor prognosis and outcome despite therapy. The rarity of this disease and the poor functional status of ATC patients limit the ability to conduct clinical trials, thus there is a lack of large, controlled trials to guide treatment and evaluate the benefit of combined modality therapy.

Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with ATC at age 18 or older between 2004 and 2018. After excluding patients with unknown number of treatment modalities, Charlson-Deyo score-a weighted summary of 17 chronic disease categories where higher scores denote greater baseline comorbidity burden-of 3 or more and patients lost for follow-up, we split the cohort into 3 groups according to the number of treatment modalities they received. Treatment modalities included surgery, radiation, and systemic therapy. Then, we evaluated the overall survival (OS) between the 3 groups. We studied the OS using Kaplan-Meier estimates and multivariate Cox regression analyses to evaluate factors associated with OS. In addition, propensity score matching (accounting for age, sex, race, Charlson-Deyo score, and clinical M stage) was used for more robust results.

Results: A total of 3460 patients with ATC were included in the analysis, of which 1472 (42.5%) either received one type of therapy or did not receive any therapy (group 1), 1092 (31.6%) received bimodal therapy (group 2), and 896 (25.9%) received trimodal therapy (group 3). We found that group 3 had better OS compared with group 1 and group 2 (median OS 9.1 vs. 1.7 and 4.9 mo, respectively, with P<0.001 for all comparisons). Propensity score matching yielded 896 patients in each group. We found that group 3 had better OS compared with group 1 and group 2 (median OS 9.1 vs. 1.9 and 5.2 mo, respectively, with P<0.001 for all comparisons). Same trend was found in subgroup analysis when we split the cohort according to the metastatic status; in M0 group (median OS was 10.4 vs. 1.9 and 6.1 mo, respectively, with P<0.001 for all), in M1 group (median OS was 5.9 vs. 1.4 and 3.7 mo, respectively, with P<0.001 for all). Modality-specific analyses further demonstrated that surgery, radiation, and systemic therapy each independently prolonged OS in both M0 and M1 cohorts (all P<0.001). These individual benefits explain the additive advantage of trimodal therapy and underscore that offering at least one evidence-based modality is preferable when comprehensive treatment is infeasible. On multivariate analysis, group 1 and group 2 were associated with worse OS compared with trimodal treatment (HR: 2.721; 95% CI: 2.466-3.002 and HR: 1.434; 95% CI: 1.299-1.582, P<0.001 for all).

Conclusions: Patients with ATC who were treated with intensive trimodal therapy had statistically significant improvement in OS compa

Simple summary: The development of contemporary immune and targeted therapies for patients with metastatic extended survival compared to the previous standard of care treatments. Therefore, equitable access to these therapies for all patients with advanced melanoma is of high importance. We aimed to understand the association between SES with treatment receipt and prognosis. Furthermore, we aimed to identify detailed reasons why patients with stage IV melanoma do not undergo systemic treatment. Our findings would help us understand what interventions are most helpful to improve the care of patients with advanced melanoma within our regional hospital system.

Objectives: The Area Deprivation Index (ADI) has not been used to study the effects of socioeconomic status (SES) in the receipt of treatment in melanoma. We set out to understand the effect of SES on the receipt of systemic treatment upon diagnosis of stage IV melanoma patients within our health system.

Methods: We queried patients with stage IV melanoma at our institution between 2010 and 2021. We defined SES based on ADI (highest quartile considered "low SES"). Multivariable regression analysis was performed to identify predictors of systemic therapy receipt. Additionally, we reviewed granular reasons for not receiving systemic treatment.

Results: One hundred seventy-nine patients were included, of whom 119 (66.5%) received any type of systemic treatment. Patients were less likely to receive systemic therapy if they had worse performance status, low SES, or were diagnosed between 2010 and 2017. The majority of barriers to receiving systemic therapy included poor baseline medical condition and advanced disease with recommendation for hospice care (39 patients, 65%). Potentially modifiable reasons included refusal by the patient (5 patients, 8.3%), which did not differ between high and low SES patients, and occurred in only 1 patient ≥2018.

Conclusions: Low SES predicted lower systemic treatment receipt for stage IV melanoma at our institution; however, most limitations to treatment came from nonmodifiable barriers to care at the time of diagnosis. These findings provide valuable insight into equity-focused programming at our institution and others.

The global burden of cancer remains a major public health challenge, with Kirsten rat sarcoma viral oncogene homolog (KRAS) emerging as the most common mutated oncogene across diverse malignancies. Once considered "undruggable" due to its unique structure, KRAS has garnered intense research focus, resulting in significant advancements. This paper aims to review recent developments in our understanding of KRAS biology, including its structural and functional aspects, and to explore the latest insights into its mutations across various cancer types. Emphasis is placed on prognosis, predictive roles, and emerging therapeutic strategies targeting KRAS. This review aspires to deepen our comprehension of KRAS and potentially enhance treatment outcomes for cancer patients harboring KRAS mutations in the future.

Objectives: For single-fraction stereotactic radiosurgery (SRS) for WHO grade I meningiomas, no-GTV or minimal-GTV to PTV margin is an accepted practice. We evaluated whether there is a control difference based on GTV to PTV expansion size for fractionated RT.

Methods: Eighty-seven patients with WHO grade 1 meningioma were identified from an institutional database, treated with either conventional immobilization and radiation treatment delivery techniques (cRT) with 5 to 20 mm PTV expansions or fractionated stereotactic radiotherapy (fSRT) with ≤3 mm GTV to PTV expansions. Kaplan-Meier estimators were used for local failure-free survival (LFFS), marginal-failure-free survival (MFFS), and distant failure-free survival (DFFS) analysis.

Results: The median follow-up duration was 9.0 years. Twenty-five patients (29%) received cRT and 62 patients (71%) received fSRT. The median dose was 54 Gray. There were 4 local (5%), 1 marginal (1%), and 1 distant failure (1%). The fSRT and cRT groups each had 2 local failures; 3/4 local failures occurred in areas near critical organs at risk. For cRT versus fSRT, 5-year and 10-year LFFS were 100% versus 98% ( P =0.46) and 94% versus 96% ( P =0.34), 5-year and 10-year MFFS were 100% versus 100% and 100% versus 92% ( P =0.004), and 5-year and 10-year DFFS were 100% versus 98% at both time points ( P =0.65 and P =0.67, respectively).

Conclusions: In this patient cohort, there was no local control benefit for larger GTV-to-PTV expansions. For patients with tumors not eligible for SRS, fractionated stereotactic treatment workflow with ≤3 mm PTV expansions is an effective approach for WHO grade 1 meningiomas.

Objectives: To understand surveillance practice patterns in melanoma patients with a positive sentinel lymph node (SLN) biopsy.

Methods: A survey was designed, tested for item relevance, readability, and content validity, and subsequently distributed to melanoma surgeons through institutional emails and international societies.

Results: Majority of the 59 respondents were <10 years from training (59.3%), in academia (74.1%), or dedicated >25% of their practice to melanoma (50.8%). Nearly all surgeons (98.3%) would not recommend complete lymph node dissection (CLND) for a 2 mm melanoma with nodal metastasis <1 mm. 79.7% of surgeons claim a significant role in determining the surveillance regimen, and most (57.6%) opt for a combination of nodal basin ultrasound and CT or PET/CT, while 39.0% follow with ultrasound only. No difference in surveillance modality was seen when stratifying time since training (≤10 vs. >10 y; P =0.798). However, for those who dedicate >25% of their practice to melanoma, significantly fewer surgeons report use of ultrasound only (>25%: 13.3% vs. ≤25%: 65.5%; P <0.001). Whereas 33.9% of surgeons state their surveillance strategy is agnostic to patient factors, others claim adherence to appointments (30.5%), distance from hospital (18.9%), and insurance (15.8%) shift their management. Breslow depth >4 mm (27.4%), ulceration (22.2%), and mapping to >1 basin (16.2%) are the most common reasons surgeons obtain cross-sectional imaging. Reasons that deter surgeons against ultrasound as the surveillance modality of choice include reproducibility/interpretation of the results (42.6%), patient preference (25.0%), and medical oncology preference (22.1%).

Conclusions: Despite trials aimed to inform the management of SLN-positive melanoma, surveillance strategies remain largely dependent on provider preference and individual patient factors.

Objectives: Sacituzumab govitecan, an anti-TROP2 antibody-drug conjugate, is approved for metastatic triple-negative breast cancer (TNBC) from the second-line setting and for hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer from the third line. Radiotherapy is frequently required in metastatic settings for symptom control, but its combination with sacituzumab govitecan has not been formally evaluated. This study aims to assess the safety and tolerability of concurrent sacituzumab govitecan and radiotherapy in metastatic breast cancer patients.

Methods: This retrospective, single-center study included all metastatic breast cancer patients who received sacituzumab govitecan and underwent external beam radiotherapy (EBRT) at Institut Curie. Clinical and pathologic data, treatment details, toxicities graded per CTCAE v5.0, and survival outcomes were analyzed. Overall survival (OS) was estimated using the Kaplan-Meier method.

Results: Thirteen patients were included, with a mean age of 54 years. The majority (61.5%) had TNBC. A total of 19 metastatic sites were irradiated, including 10 brain and 9 bone metastases. No radiation-induced toxicity was observed, and no patients required treatment interruption. Grade 3 to 4 toxicities were limited to neutropenia (15.4%). The median OS from radiotherapy completion was 6 months, with a 6-month OS rate of 45.1% and a 12-month OS rate of 16.9%.

Conclusions: The concurrent administration of sacituzumab govitecan and radiotherapy appears well tolerated, with no increased toxicity. This combination may be feasible in metastatic breast cancer patients when clinically indicated. Further studies with larger cohorts are necessary to confirm these findings.