tbuckley/cabot-search huggingface dataset:
Induction chemoimmunotherapy followed by radiotherapy in locally advanced head and neck squamous cell carcinoma: A real-world study.
Authors: Yi Yang, Shun-Xin Wang, Yi-Ming Lei, Yan-Ping Mao
Journal: Journal of Clinical Oncology (2024)

131 Background: Patients with locally advanced head and neck squamous cell cancers (LAHNSCC) present poor prognosis despite multi-disciplinary comprehensive treatment, and novel treatment strategies are urgently needed. Recently, several phase II clinical trials reported encouraging pathological complete response rate of induction chemoimmunotherapy (IC+ICI) in LAHNSCC, suggesting potentially long-term survival benefits. Therefore, we conducted this real-world study to compare the efficacy of IC+ICI followed by radiotherapy (RT) versus induction chemotherapy (IC) followed by RT in LAHNSCC. Methods: We retrospectively included patients with LAHNSCC from Sun Yat-sen University Cancer center database treated with IC+ICI followed by RT or IC followed by RT between 1/2018-12/2021. Survival outcomes and adverse effects (AEs) were compared between the two groups. Results: A total of 262 patients were included: 128 (48.9%) in the IC+ICI group, and 134 (51.1%) in the IC group. Median age for the whole cohort was 60 (53–66) years, and the male-to-female ratio is 8.9:1. Most patients (84.4%) had stage IV disease. The median follow-up time was 26.7 (IQR 25.8-29.6) months. Marginally significant higher objective response rate (ORR) was observed in the IC+ICI group than that in the IC group (81.25% vs 72.39%, P=0.09). Patients in the IC+ICI group had significantly better results than those in the IC group in 2-year overall survival (OS; 88.9% vs. 71.5%, P&lt;0.001), disease-free survival (DFS; 77.5% vs. 58.3%, P=0.005), locoregional relapse-free survival (LRRFS; 78.4% vs. 59.7%, P=0.009) and distant metastasis-free survival (DMFS; 87.5% vs. 64.6%, P&lt;0.001). Multivariate analysis confirmed that combining immunotherapy in the induction stage was an independent prognostic factor for OS (HR 0.40, 95%CI 0.19-0.84), DFS (HR 0.45, 95%CI 0.28-0.72), LRRFS (HR 0.56, 95%CI 0.31-0.99), and DMFS (HR 0.37, 95%CI 0.19-0.73). The incidences of G3/4 AEs between the IC+ICI group and the IC group were comparable during the induction stage (6.25% vs 12.69%, P = 0.076) as well as the radiotherapy stage (14.06% vs 14.18%, P = 0.978). Conclusions: This study firstly reported that IC+ICI followed by RT was superior to IC followed by RT in long-term survival outcome in LAHNSCC.
Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).
Authors: Xiaoyan Li, Weiwei Shi
Journal: Journal of Clinical Oncology (2024)

201 Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.
Racial differences of secondary metastasis in patients with colon cancer: A United States population-based cohort study.
Authors: Thanathip Suenghataiphorn, Narathorn Kulthamrongsri, Narisara Tribuddharat, Pojsakorn Danpanichkul, Tuntanut Lohawatcharagul, Sakditad Saowapa, Jerapas Thongpiya, Natapat Chaisidhivej, Soravis Alm Osataphan
Journal: Journal of Clinical Oncology (2024)

80 Background: Disparities in health outcomes exist among racial and ethnic groups in the United States, notably in patients with colon cancer. Metastasis is the primary cause of cancer morbidity and mortality. However, data on the metastasis risks and clinical outcomes on hospitalized individuals with colon cancer is still limited. Therefore, we aim to assess the association between metastatic colon cancer and racial differences. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to explore patients who have colon cancer as the primary diagnosis. Additionally, we identified evidence of metastasis, as recorded by ICD-10-CM. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was racial differences in organ metastasis and secondary outcomes included mortality and length of stay. Statistical significance was established at p-value of 0.05. Results: We identified 80,130 patients with primary diagnosis of colon cancer at discharge. The mean age was 67.4 years; 49.7% were female. Caucasians accounted for 69.3%, with African Americans at 13.3% and Hispanics at 8.2%. 15% of the patients had liver metastasis, whereas 22% had lung metastasis. In a multivariate analysis adjusting for patient, COVID-19, chemotherapy usage and hospital factors, African Americans had higher risk of lung metastasis (aOR 1.22; 95%CI (1.07, 1.40), p = 0.003), higher risk of liver metastasis (aOR 1.51; 95%CI (1.31, 1.74), p = 0.021) and longer length of stay (b = 0.95; 95%CI (0.56, 1.33), p = 0.001). Hispanics also had higher risk of lung (aOR 1.22, p &lt; 0.05) and liver metastasis (aOR 1.24, p = 0.021). We observed an increase in risk of metastasis and mortality but non-statistically significant in some parameters and races, as shown in table provided. Conclusions: In conclusion, our study revealed that racial difference is associated with higher risk of metastasis, as well as other outcomes. To establish a causal relationship between races, metastasis, and mortality in patients with colon cancer, further longitudinal research is necessary. [Table: see text]
Investigation of a tamoxifen-RACK7/KDM5C-IFN-I axis for ER<sup>+</sup> breast cancer immunomodulation.
Authors: Marvin Angelo Esteban Aberin, Saurabh Singh, Yu-Ling Lee, Kun-Yuan Lin, Yao-Ming Chang, Chandan Guha, Shu-Ping Wang
Journal: Journal of Clinical Oncology (2024)

9 Background: ER+ breast cancer patients generally have good prognosis. However, significant relapse rates (i.e., hormone drugs, Tamoxifen/TMX) and the poor response to immune checkpoint blockade (ICB) remain critical issues to be addressed. Thus, exploration of anti-ICB resistant mechanisms and alternative targets is needed to improve therapeutic efficacy. Methods: To investigate potential cross-resistant mechanisms between hormone and ICB therapy, ER+ cell lines T47D and MCF7 cells were chronically-treated with TMX for 6 months, and subjected to RNA-Seq and pathway enrichment analysis. Dysregulation of identified factors were validated via western blotting, RT-qPCR, and flow cytometry. Target factors were then inhibited or depleted by shRNA knockdown (KD) or small-compound inhibition. Identified ICB resistance mechanisms were further elaborated by in vitro co-culture assays, syngeneic mouse models, and immune-profiling of tumor microenvironment (TME). Results: Chronic exposure to TMX activates Type I interferon (IFN-I) signaling, induces IFN I-stimulated gene (ISG) expression, and downregulates the H3K4 demethylase and ISG repressor complex known as RACK7/KDM5C. Chronic TMX also upregulates CEACAM1, a well-known ligand for the immune checkpoint receptor TIM3. Results prompt us to evaluate whether loss of RACK7 combined with TMX treatment may modulate a lymphocyte-attractive (via IFN-I), but T-cell exhaustive (via CEACAM1-TIM3) TME. Indeed, in vitro treatment of TMX under RACK7-KD conditions triggers STING upregulation, TBK1 hyperphosphorylation, and a more pronounced activation of ISGs and CEACAM1. In vivo, TMX combined with RACK7-KD enhances tumor growth in the TS/A (ER+) syngeneic mouse model, while immune-profiling reveal that this combination promotes lymphocyte infiltration with a higher population of terminally exhausted CD8+ T-cells in the TME. Conclusions: Our data demonstrate that the TMX-induced activation of cGAS/STING pathway and RACK7 downregulation coordinately shape the IFN-I and immune checkpoint signaling axes in ER+ breast cancer. This TMX–RACK7–IFN-I regulatory network promotes a lymphocyte-attractive TME via IFN-I signaling activation, whereas induction of inhibitory ligands renders T-cells to be terminally-exhausted and unable to kill tumors. These findings highlight the potential use of TMX’s STING-agonistic effect in re-shaping the “cold” breast cancer TME, and the use of combined TMX and anti-TIM3 or anti-CEACAM1 blockade to improve ICB therapy.
Dietary pattern and the corresponding gut microbiome in response to immunotherapy in Thai patients with advanced non-small cell lung cancer (NSCLC).
Authors: Piyada Sitthideatphaiboon, Nicha Somlaw, Nicha Zungsontiporn, Pongsakorn Ouwongprayoon, Narittee Sukswai, Krittiya Korphaisarn, Naravat Poungvarin, Chatchawit Aporntewan, Nattiya Hirankarn, Chanida Vinayanuwattikun
Journal: Journal of Clinical Oncology (2024)

204 Background: Gut microbiota is considered a key player modulating the response to immune checkpoint inhibitors (ICI) in cancer. The effects of dietary pattern on this interaction is not well-studied. Methods: A prospective multicenter cohort of 95 patients with advanced non-small cell lung cancer (NSCLC) undergoing ICI therapy were enrolled. Stool shotgun metagenomic sequencing was performed. Three-day dietary patterns before ICI were assessed. Patients were categorized as hyperprogressive disease (HPD) if they exhibited a time to treatment failure of &lt;2 months. All others were categorized as non-hyperprogressive disease (non-HPD). The correlation between dietary patterns, gut microbiome, and response to ICI therapy was analyzed. Results: In the multivariate analysis, high abundance of Firmicutes unclassified and the Ruminococcaceae family correlated with significantly diminished progression-free survival (PFS) with HR of 2.40 [ P=0.006] and 4.30 [ P=0.005], respectively. More specifically, within the subset of NSCLC patients treated solely with ICI therapy, high abundance of Intestinimonas and the Enterobacteriaceae family were associated with reduced PFS with HR of 2.61 [ P=0.02] and HR 3.34 [ P=0.005], respectively. In dietary pattern analysis, HPD group showed increased consumption of cholesterol, sodium, and fats beyond recommended levels compared to non-HPD group. This group also displayed a tendency towards higher food pattern scores characterized by significant intake of fat and dairy products. Conclusions: Our study revealed distinct association between the gut microbiome composition and treatment outcomes. Based on these findings, the overall composition of diet may play a pivotal role in ICI therapeutic outcomes. [Table: see text]
The prognosis of pancreatic neuroendocrine tumors according to the WHO 2017 classification: The multi-center experience in Taiwan.
Authors: Wei-Pang Ho
Journal: Journal of Clinical Oncology (2024)

87 Background: The occurrence of pancreatic neuroendocrine tumors (PanNETs) remains infrequent, there is an upward trend in their diagnosis. Our retrospective study, conducted in Taiwan, focuses on exploring the interplay between clinical characteristics, treatment modalities, and prognosis in PanNET cases. Particularly, we aim to assess the implications of the updated WHO classification system on prognosis. Methods: We conducted a retrospective analysis of 176 PanNET cases from Chang Gung Medical Foundation, encompassing Linkou, Taoyuan, and Tucheng Hospitals, spanning the years 2009 to 2022. Pathology reports for all cases were reevaluated by pathologists according to the WHO 2017 classifications. Clinical features and overall survival outcomes were documented. Additionally, we examined the prognosis of distinct subgroups categorized by the WHO 2017 classification and their respective treatments. Results: The 5-year survival rate for all patients in the cohort stood at 58.7%. Among these, individuals diagnosed with NET G1 exhibited the highest survival rate (n = 78, 83.1%), followed by those with NET G2 (n = 57, 55.0%), NET G3 (n = 25, 14.6%), and NEC (n = 16, 9.4%). Univariate analysis highlighted several significant prognostic factors, including age, absence of symptoms at diagnosis, tumor size, lymph node involvement, distant metastasis, higher Ki-67 index, and cellular morphology. Comparative analysis between the WHO 2017 and WHO 2010 classifications revealed both systems as significant independent predictors of overall survival in PanNET cases. Notably, the 95% confidence interval for the WHO 2017 classification (2.892–9.703) showed a slight improvement in prognostic precision compared to the WHO 2010 classification (3.696–10.067). Under the WHO 2010 classification, NET G3 and NEC were combined, with NEC presenting higher rates of distant metastases, lymph node involvement, and Ki-67 index. Further investigation revealed that patients receiving somatostatin analogs, chemotherapy, or targeted therapy exhibited improved survival rates, particularly notable in NET G3 and NEC subgroups. Furthermore, NEC patients displayed extended treatment durations and higher objective response rates to first-line chemotherapy compared to the NET G3 group. Conclusions: Our retrospective analysis has illuminated the interrelation between prognostic factors and the overall survival rate. Furthermore, the updated WHO 2017 classification elucidates the distinctions between G3 and NEC, thus influencing the selection of clinical interventions.
Osteosarcoma patient-derived orthotopic xenograft (PDOX) models for identification of novel and effective therapeutics.
Authors: Takashi Higuchi, Robert M. Hoffman, Hiroyuki Tsuchiya, Norio Yamamoto, Katsuhiro Hayashi, Shinji Miwa, Kentaro Igarashi
Journal: Journal of Clinical Oncology (2024)

228 Background: Osteosarcoma is the most common malignant primary tumor of bone and mainly occurs in young generations. Due to the heterogeneity, rarity, poor response rate to systemic therapy, and metastatic potential of osteosarcoma, individualized precision medicine and novel drug discovery are greatly needed. Toward this goal, we have established the patient-derived orthotopic xenograft (PDOX) mouse model with surgical orthotopic implantation for all major cancers. The PDOX models recapitulate human tumors better than subcutaneous-transplanted xenografts including patient-derived xenograft (PDX). Metastasis is observed to a greater extent in PDOX models due to the intact histology and correct-organ tumor micro-environment of the orthotopically implanted tissue. Therefore, the PDOX model is highly predictive of drug efficacy and useful for identifying effective drugs for tumors in which new drugs are difficult to develop. Methods: We have reported 18 osteosarcoma PDOX studies evaluating approved and experimental drugs since 2017. The present report reviews our research group’s experience with the osteosarcoma-PDOX model, and the power of the PDOX models to identify effective therapeutics. Results: Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatin, as combinations. Experimental therapy with recombinant methioninase, tumor-targeting S. typhimurium A1-R, or combinations of these agents and other drugs have shown surprising efficacy in the recalcitrant-osteosarcoma PDOX models. Conclusions: Owing to the high concordance of drug efficacy between patients and their corresponding PDOX models, these models provide improved and personalized treatment options for patients with osteosarcoma. The patient does not need to suffer from the potential drug toxicity and morbidity of ineffective chemotherapies. In an era of growing promise of new treatment and precision medicine, PDOX models can offer a unique opportunity to provide specific and individualized therapy and novel therapeutic options for osteosarcoma patients.
Circulating tumor DNA for predicting radiographic and pathologic response to total neoadjuvant therapy in locally advanced rectal cancer: ENSEMBLE-1.
Authors: Yoshinori Kagawa, Jun Watanabe, Mamoru Uemura, Koji Ando, Akira Inoue, Yujiro Nishizawa, Yusuke Suwa, Keigo Chida, Tsuyoshi Hata, Yuki Sekido, Ryota Nakanishi, Koichi Okuya, Masaaki Miyo, Koji Oba, George Laliotis, Yoshiaki Nakamura, Hideaki Bando, Takayuki Yoshino, Ichiro Takemasa, Eiji Oki
Journal: Journal of Clinical Oncology (2024)

71 Background: Total neoadjuvant therapy (TNT) has dramatically shifted the treatment paradigm for locally advanced rectal cancer (LARC), prolonging survival with high rates of pathologic complete response (pCR) and introducing opportunities for nonoperative management (NOM). However, there is a need for robust predictive biomarkers of TNT efficacy, local cancer regrowth in NOM, and overall prognosis. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker used to detect molecular residual disease (MRD) and predict recurrence in colorectal cancer after curative resection. The effectiveness of ctDNA MRD status specifically as a predictive biomarker for TNT was evaluated in the Phase II TNT study, ENSEMBLE-1 (jRCTs051200113), conducted in Japan. Methods: Patients with LARC undergoing TNT were enrolled in ENSEMBLE-1. Protocol treatment was defined as short-course radiotherapy (SCRT: 25Gy) followed by six cycles of CAPOX and total mesorectal excision (TME). NOM was allowed if a clinical complete response (cCR) was achieved after TNT. ctDNA was measured by SignateraTM (Natera, Inc.) at the following time points: baseline (pre-treatment), after SCRT, after 4 cycles of CAPOX, before TME, and post operatively at 4w, 12w, 24, 36 and 48w in the GALAXY trial (UMIN000039205). Results: A total of 30 patients were enrolled in the study. After completing TNT, TME and NOM were performed in 20 and 7 patients, respectively. ctDNA was measured in 26 patients (TME: 19 patients, NOM: 7 patients). ctDNA was detected in 100% (25/25) at baseline, 81% (21/26) after SCRT, 31% (8/26) after 4 cycles of CAPOX, and 45% (9/20) after TNT. The attached table shows the results of statistical analyses of the correlation between ctDNA status, clinical response, TME or NOM, and pathologic complete response (pCR). It was found that ctDNA status after SCRT and after 4 cycles of CAPOX was associated with cCR or non cCR (p=0.007 and p=0.007, respectively). Additionally, ctDNA status after TNT was associated with pCR or non pCR (p=0.029). Conclusions: Our study demonstrates that ctDNA-based MRD may predict TNT response in LARC patients. Negative ctDNA during treatment correlates with favorable responses and may be an aid in NOM decision making. Clinical trial information: jRCTs051200113 . [Table: see text]
CVM-1118: An oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.
Authors: Chia Jui Yen, Yi-Hsiang Huang, Kun-Yun Yeh, Pei-Jer Chen, Sheng-Nan Lu, John Gutheil, Teresa J. Melink, Yen-Ling Chen, Chun-Man Chen, Ting-Yu (Tiffany) Chao, Yi-Wen Chu, Du-Shieng Chien
Journal: Journal of Clinical Oncology (2024)

92 Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n=4) or C (87%, n=27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–17.7 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 5.2 mos (range 5.2–17.7 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 12.1 mos (95% CI 5.2–16.1 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was C max 564 ng/mL and the AUC 0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T 1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .