tbuckley/cabot-search huggingface dataset:
Development and application of an ultra-sensitive ctDNA mutation profiling assay in monitoring therapy response and drug resistance.
Authors: Tom Zhang, Harshabad Singh, Lu Tan, Xiaohong Wang, Zhixin Zhao, Kemin Zhou, Shujun Luo, Shidong Jia, Pan Du
Journal: Journal of Clinical Oncology (2024)

264 Background: Next-generation sequencing (NGS) assays offer efficient high-throughput profiling methods for analyzing circulating tumor DNA (ctDNA) in blood or other liquid biopsy specimens. The ctDNA mutant allele fractions of patients after treatment is often very low and below the detection limit of regular cfDNA assays. Here we report the development and clinical application of a CLIA-certified ultra-sensitive NGS cfDNA assay in detecting the low-frequency ctDNA mutations and monitoring therapy response and drug resistance in patients with metastatic gastroesophageal adenocarcinoma under combined blockade treatments. Methods: PredicineCARE ULTRA cfDNA assay with 100,000X sequencing depth was validated under CLIA settings. Limit of blank (LoB) and limit of detection (LoD) were established by profiling 38 healthy donor plasma samples, 23 contrived human cfDNAs samples from patients with various cancers, and 30 replicates of well-established ctDNA reference standards. In silico down-sampling of FASTQ files was carried out to test the sensitivity of this assay with a lower coverage (50,000X). This assay was then adopted for longitudinal sequencing of 57 serial plasmas from 6 patients with HER2+ gastroesophageal adenocarcinomas (GEC) who underwent combined treatments (capecitabine, oxaliplatin, bevacizumab and trastuzumab) at different time points (baseline, response, and progression). Results: PredicineCARE ULTRA cfDNA assay exhibited exceptional sensitivity in calling single-nucleotide variants and indels, with a 98.0% detection rate at a LoD of 0.075% mutant allele frequency (MAF) for 60 ng cfDNA. This is significantly lower than the LoD (0.25% MAF) of a standard PredicineCARE cfDNA assay. The ultra-sensitive assay also displayed decent analytical specificity (&gt;99.99%) and precision (intra-assay 100%; inter-assay 99.41%). In 6 GEC patients’ longitudinal samples, PredicineCARE ULTRA cfDNA assay detected 36 additional somatic mutations with the MAFs spanning in a range from 0.024% to 0.1% beyond 124 baseline mutations identified using standard PredicineCARE. In two representative cases presented here, all baseline mutations (genes TP53 and PIK3CA etc.) were consistently reported in the follow-up time points with a noticeable MAF reduction (lowest MAFs from 0.046% to 0.024%) during response. Subsequent elevations were observed in more genes, including low-frequency mutations (KRAS and ERBB2) not detected at baseline or only detected in PredicineCARE ULTRA. Conclusions: This study demonstrated the promise and clinical utility of the ultra-sensitive cfDNA molecular profiling at 100,000X sequencing depth in treatment selection, therapy monitoring, and drug resistance studies.
Real world effectiveness of regorafenib in heavily pretreated patients with metastatic colorectal cancer.
Authors: Anastasia Danilova, Daniil Stroyakovsky, Dmitry Kanner, Ilya Chernikovksy, Nikita Savelov, Mikhail Volkonsky, Irina Demidova
Journal: Journal of Clinical Oncology (2024)

141 Background: Metastatic colorectal cancer (mCRC) remains a challenge with a significant impact on patient survival and quality of life. Over the past decade, targeted therapies have emerged as promising treatment options for mCRC, including regorafenib. While clinical trials have established efficacy and safety of regorafenib in mCRC, based on the CORRECT and ReDos trials, the real-world utilization and outcomes associated with this therapy have gained increasing importance. This abstract presents a real-world data analysis focused on the use of regorafenib in patients with metastatic colorectal cancer in a community based comprehensive cancer center in Moscow, Russia. The data were collected from 2 outpatient medical oncology departments from 2018-2022 and we evaluated the real world patterns of use, effectiveness and safety. Methods: We evaluated all patients who were issued Regorafenib at a medical pharmacy of our cancer center. We evaluated all Regorafenib issued from 2018-2022 in our center – 348 patients received Regorafenib and 311 of them were patients with metastatic colorectal cancer and identified patterns of use, toxicity and outcomes in this patient population. Results: The median age was 61.2 and 49.5% were female (50.5 – were male%) Primary tumor was right sided in 20.9% of all patients, left sided – 49.1% and rectum in 29.9% De novo metastatic colorectal cancer was in 208 patients and 103 patients were those who progressed after initial treatment. Mutation status was identified in 91% of all patients. 46% had KRAS mutation, 3.8% were BRAF mutated and 4.2% were NRAS mutated. MSI status was known for 71% of the patients and it was negative. We understand the selection bias, because most of MSI-h patients would have gone on to receive immunotherapy rather than a TKI. The patients identified in our practice were more heavily pretreated (93.5% of them received more than 3 lines of prior therapy) and 1/3 of all patients were ECOG 2-3 performance status. Toxicity data were available only in 61% of the patients which reveals data caveats when using real world data outside of a clinical trial. Any grade toxicity was noted in 53% of all patients. Using Kaplan Myer Survival Analysis, the median PFS was 2 months and median OS was 5.3 months in the evaluated population. Conclusions: The real world data analysis shows that while Regorafenib is another treatment option, and our data confirm the results of clinical trial, its utilization and use provides only modest clinical benefit for patients.[Table: see text]
The usefulness of ctDNA and exosome DNA as biomarkers in esophageal squamous cell carcinoma.
Authors: Tomoki Nakai, Yuji Kitahata, Yuki Nakamura, Hideki Motobayashi, Norio Takemoto, Toshiyasu Ojima, Keiji Hayata, Takeshi Iwaya, Hayato Hiraki, Satoshi Nishizuka, Manabu Kawai
Journal: Journal of Clinical Oncology (2024)

388 Background: Recently, the usefulness of exosome DNA (exo-DNA) for prognostic analysis of various solid tumors has also been reported. In this study, we investigated the usefulness of ctDNA and exo-DNA as biomarkers for esophageal squamous cell carcinoma. Methods: Patients with esophageal squamous cell carcinoma undergoing standard treatment had ctDNA and exo-DNA collected over time. NGS analysis was performed on biopsy or surgical specimens, and mutated genes in individual cases were followed by ddPCR over time. Results: NGS analysis was performed on 16 patients. 12 of 16 cases showed mutations, In 8 cases, ctDNA and exo-DNA could be measured by ddPCR over time. In one case of Stage IVA. both ctDNA and exo-DNA were useful to determine the efficacy of chemotherapy and radiotherapy, and in one case of Stage II, both ctDNA and exo-DNA were useful to predict postoperative recurrence. Conclusions: In esophageal squamous cell carcinoma, ctDNA and exo-DNA may be useful in determining treatment response and predicting recurrence. We will further investigate the usefulness of ctDNA and exo-DNA in esophageal squamous cell carcinoma, including prognostic prediction. Clinical trial information: UMIN000045311 .
Results of a prospective phase II study of total neoadjuvant therapy for locally advanced rectal cancer.
Authors: Huiying Ma, Yuan Tang, Wenjue Zhang, Haitao Zhou, Zheng Liu, Haizeng Zhang, Yong Cai, Yongheng Li, Lichun Wei, Shixin Liu, Wenling Wang, Yongwen Song, Bo Chen, Ningning Lu, Shunan Qi, Yueping Liu, Shulian Wang, Xishan Wang, Yexiong Li, Jing Jin
Journal: Journal of Clinical Oncology (2024)

147 Background: Total neoadjuvant therapy is further accepted for the treatment of locally advanced rectal cancer, which is more valuable for patients with high-risk factors. Optimal schedule of radiotherapy and chemotherapy remains unknown and needs further exploration. Methods: We conducted a multicenter, randomized, phase II trial (ClinicalTrials.gov No.: NCT04543695). Patients aged 18-75 years with initial stage II / III rectal adenocarcinoma (At least one of high-risk factors should be included: mesorectal fascia involvement, T4, N2, positive lateral lymph node, or extramural vessel invasion) were assigned into three groups, 1) Chemoradiotherapy (50 Gy of radiation combined with oral capecitabine) followed by consolidation chemotherapy using six cycles of XELOX(CNCT group), 2) Induction chemotherapy before chemoradiotherapy (INCT group), or 3) Chemoradiotherapy alone (Control group). Then enrolled patients were required to undergo radical surgery after neoadjuvant therapy. Patients in Control group need six cycles of XELOX after surgery. The primary end point was proportion of yp0-II, and watch-and-wait strategy after complete clinical response (cCR) was allowed. Results: Of the 257 patients enrolled, 255 patients were evaluable (Control: CNCT: INCT= 84: 86: 85). Neoadjuvant treatment related grade 3 or 4 toxicity was higher in TNT approach (7.1%, 23.3% and 32.9% in Control, CNCT and INCT, respectively), of with myelosuppression being most common. Compliance of chemoradiotherapy was lower in INCT group (98.8%, 100% and 90.6% in Control, CNCT and INCT, respectively). As to CNCT and INCT, 60.0% and 74.1% of patients completed six cycles of chemotherapy, with 76.7% and 83.5% completing four cycles of chemotherapy, respectively. Proportions of downstage (yp0-II + sustained cCR) were achieved 75.6% in CNCT group and 74.1% in INCT group, respectively, compared to 56.0% in Control group. CR rates (pCR + sustained cCR) were achieved 43.0% in CNCT group and 38.8% in INCT group, respectively, compared to 20.2% in Control group. Both TNT approaches did not increase the incidence of surgical complications (6.0%, 8.1% and 10.9% in Control, CNCT and INCT, respectively), with anastomotic fistula and abdominal infection being of most common. Conclusions: Both TNT approaches increased the probability of ≥ G3 acute toxicities, but most patients could tolerate 4 cycles of neoadjuvant chemotherapy. Both TNT approaches could achieve a higher proportion of downstage and CR rate. Clinical trial information: NCT04543695 .
Association of intensifying supportive care with improved survival in patients with gastric cancer with malignant ascites.
Authors: John D Karalis, Michelle R Ju, Rachel Feig, Raechelle Estrella, Morgan F Pettigrew, Rodrigo Alterio, Andres A Abreu, Emile Farah, Tarek Sawas, Nina Niu Sanford, Aravind Sanjeevaiah, Scott Reznik, Suntrea Hammer, Matthew R. Porembka, Sam C. Wang
Journal: Journal of Clinical Oncology (2024)

294 Background: Gastric cancer patients with malignant ascites often have poor functional status and malnutrition that precludes receipt of systemic therapies. Thus, these patients have a very poor prognosis. Beginning in 2019, our multidisciplinary gastric cancer disease-oriented team implemented a more aggressive supportive care plan for gastric cancer patients with malignant ascites. The initiative included measures such as supplemental enteral nutrition, ascites drainage, and initiation of chemotherapy on an inpatient basis. We compared outcomes for gastric cancer patients who presented with synchronous malignant ascites treated before and after the implementation of the care plan. Methods: We performed a retrospective review of our institutional database to identify patients diagnosed with gastric adenocarcinoma and synchronous malignant ascites between 2010-2022. We compared survival between patients diagnosed from 2010-2018, which will be referred to as the historical control era and patients diagnosed from 2019-2022, which will be called the aggressive supportive care era. Results: 54 patients were included in our analysis; 31 patients were treated in the historical control time frame and 23 patients treated during the aggressive supportive care era. Demographic, clinical, and pathologic characteristics were similar between groups. 3% of historical controls received supplemental tube feeds at diagnosis as compared to 30% of the aggressive supportive care cohort (p=0.008). 3% of historical controls received their first cycle of chemotherapy in the inpatient setting versus 39% of patients treated during the aggressive supportive care era (p=0.001). The median number of chemotherapy cycles received was 5 among historical controls and 9.5 among aggressive supportive care era patients (p = 0.02). There was no difference in the number of days spent as an inpatient between the two groups. The median overall survival for historical control patients was 5.4 months as compared to 10.4 months for patients treated during aggressive supportive care era (p=0.035). Conclusions: Gastric cancer patients with synchronous malignant ascites treated during a timeframe when our multidisciplinary team implemented more aggressive supportive care measures had improved OS as compared to historic controls.Our results suggest that aggressive supportive measures for these patients with highly challenging clinical issues and poor prognosis can prolong survival. Specifically, initiation of chemotherapy in the inpatient setting and supplemental nutrition should be considered for patients at high risk for treatment intolerance.
The interaction of radiotherapy and dual inhibition of BET and HAT/p300 in colorectal cancer.
Authors: Michael Matthew Pennock, Sanjay Pandey, Claes Wahlestedt, Chandan Guha, Chaoyuan Kuang
Journal: Journal of Clinical Oncology (2024)

146 Background: Colorectal cancer (CRC) is characterized by extensive DNA methylation at the promoters of tumor suppressor genes and enhanced activity of histone modifying proteins such as histone acetyltransferases (HATs) or histone readers such as bromodomain and extra-terminal domain (BET) proteins. BET inhibition has been associated with the reduced expression of DNA repair proteins and therefore can be used in combination with radiotherapy (RT) and chemotherapy. In the current study, we have evaluated the therapeutic potential of a clinical stage (phase 1) dual BET and CBP/p300 inhibitor, EP31670 (EP), in combination with RT. Methods: HCT116 CRC 2-D cultures were treated with EP 4 hours before RT. After pretreatment with EP (0, 0.1, 0.5, 1, 2, 5, and 10µM), cells were irradiated with various doses (0, 2, 4, 6, and 8Gy) of RT (300-kv x-rays). Crystal violet (CV) assay at 48 hours post RT was used to determine growth inhibition and viability between the various drug, RT, and combination groups. Synergy between treatments was evaluated by estimating the combination index (CI) values via mass-action law CompuSyn calculations using CV data. CI values of &lt;1 from the growth inhibition assay suggested that EP synergized with RT for enhanced cytotoxicity in HCT116 CRC cells. Flow cytometry was used to assess DNA damage (γH2Ax), apoptosis and total death (Annexin V-PI assay), cell cycle analysis, and proliferation (EdU). Results: There was a significant dose-dependent increase in the residual DNA damage at 6 hours (8Gy + EP 0.5µM vs. 8Gy, p&lt;0.0001) and 24 hours (8Gy + EP 0.5µM vs. 8Gy, p=0.002) for combination therapy over RT alone. Four-hour treatment with EP promoted G2 cell-cycle arrest (8Gy + EP 0.5µM vs. 8Gy, p&lt;0.001) and significantly reduced the number of HCT cells in S-phase (8Gy + EP 0.5µM vs. 8Gy, p&lt;0.001) and proliferation (EdU) of the HCT cells (8Gy + EP 0.5µM vs. 8Gy, p=0.0003) compared to RT alone. There was a significant increase in apoptotic cells the combination group (8Gy + EP 0.5µM vs. EP 0.5µM, p=0.008) when compared to the unirradiated cells. The combination group also showed significant increase in the total death compared to RT alone (8Gy + EP 0.5µM vs. 8Gy, p=0.03) at the G1-S checkpoint. Conclusions: EP31670 enhanced RT-induced growth arrest, reduced proliferation, and enhanced cell death in HCT116 CRC cells in synergy with the RT. Additional preclinical studies, in vivo studies, and eventual clinical studies can be conducted to further exploit this synergistic interaction.
First-line FOLFOX therapy for advanced esophageal squamous cell carcinoma: Multicenter prospective study in Japan.
Authors: Kunihiro Fushiki, Takahiro Tsushima, Yasuhiro Tsubosa, Akifumi Notsu, Shun Yamamoto, Izuma Nakayama, Hiroshi Imazeki, Yoichi Hamai, Masaaki Motoori, Motoo Nomura, Kohei Nakachi, Soichi Fumita, Satoshi Otsu, Yoshihiro Tanaka, Kentaro Murakami, Mitsuhiro Furuta, HIROYA TAKEUCHI, Ken Kato
Journal: Journal of Clinical Oncology (2024)

280 Background: Cisplatin (CDDP) plus fluoropyrimidine was the standard first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). FOLFOX is promising option especially in patients with ESCC intolerant to CDDP but there were limited data on efficacy and safety of FOLFOX. We conducted a multicenter prospective observational study of FOLFOX for Japanese patients with ESCC intolerant to CDDP. Methods: Eligible participants had clinical stage IVB ESCC, with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, intolerant to CDDP, but tolerant to FOLFOX. FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 2400 mg/m²) was administered every 14 days. The primary endpoint was the response rate (RR) by RECIST v1.1 and the null hypothesis of RR was 10%. Based on the assumption of performing a one-sided test with an α of 0.10, 29 patients were needed to ensure the statistical power of 90% assuming RR of 30%. Results: In this study, 31 patients were enrolled from 14 hospitals between Apr. 2021, and Jul. 2022 and 30 patients received FOLFOX. The patient characteristics were: median age, 77 (range 66–89); male/female, 30/1; ECOG PS 0/1/2, 16/12/3; median creatinine clearance, 49.9 ml/min (33.4–80.2); median G8 score, 12 (range 7–17); and median CARG score, 8 (range 6–13). As the data cutoff of Jul 2023, all 30 patients discontinued FOLFOX. The reason for treatment discontinuation was disease progression, 86.7%; adverse events, 13.3%. Median follow-up time (interquartile range: IQR) was 20.2 (IQR 13.7–23.1) months. Median number of cycles administered were 5 (range 1–24). The RR was 22.6% (80%CI 0.13–0.35; p = 0.031) and disease control rate was 42.0%. Median progression-free survival was 3.9 months (95% CI 2.3–6.1). Median overall survival was 13.3 months (95% CI 9.5–not reached). The incidence of grade 3 or higher adverse events was 40% (neutropenia 26.7%, anemia 3.3%, nausea 6.7%, anorexia 6.7%, infection 6.7%, peripheral sensory neuropathy 3.3%). There was no treatment related death. Twenty-three patients (76.7%) received subsequent therapies, such as nivolumab (70%). Conclusions: First-line FOLFOX showed an acceptable safety profile and the prespecified statistical efficacy target was achieved. FOLFOX might be a treatment option for advanced ESCC patients who are intolerant to CDDP. Clinical trial information: UMIN000044485 .
Single-institutional analysis of radiotherapy and orthotopic liver transplant for patients with unresectable cholangiocarcinoma.
Authors: Meng-Lun Hsieh, Sumehra Hannan, Steven I. Hanish, Parsia A. Vagefi, Amit G. Singal, Andrew Zhuang Wang, Jigesh A. Shah, Arjmand R. Mufti, Nina Niu Sanford, Madhukar S. Patel, Nicole E. Rich, Todd Anthony Aguilera
Journal: Journal of Clinical Oncology (2024)

466 Background: There is increasing interest in effective strategies for locoregional therapy for cholangiocarcinoma, particularly given the evolving role of orthotopic liver transplant (OLT) for select patients. This single-institution retrospective study compares the clinical efficacy and toxicity of stereotactic body radiotherapy (SBRT), conventional fractionation chemoradiation (CRT), or SBRT as a bridge to OLT in patients with unresectable early stage and locally advanced cholangiocarcinoma. Methods: We reviewed a total of 31 patients from 2010 to 2023 with intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and perihilar cholangiocarcinoma who were treated with SBRT (n=22) or CRT (n=9). SBRT was delivered in 1-5 fractions, median dose of 40 Gy, and dose ranging from 16 Gy to 60 Gy. CRT was delivered in 13-28 fractions, median dose of 50.2 Gy, and dose ranging from 45 Gy to 52.5 Gy. Kaplan-Meier was used to analyze overall survival (OS), progression-free survival (PFS), and local control (LC). Acute and late G3+ toxicity was scored using CTCAE, version 5.0. Results: We identified 13 patients with ICC, 5 with ECC, and 13 with perihilar disease where SBRT or CRT was part of upfront definitive treatment. With a median follow-up time of 11 months, there was no statistical difference between SBRT vs. CRT for OS (median 21 vs. 22 months; p=0.36), PFS (median 14.2 vs. 11 months; p=0.09), and 1-year LC (73.2% vs. 66.7%; p=0.10). However, SBRT appeared to have lower proportions of acute grade 3+ (9.1% vs. 33.3%) and chronic grade 3+ toxicities (22.7% vs. 33.3%). Four patients with early stage perihilar or ICC underwent SBRT as successful bridge to transplant, with no evidence of disease progression at 5.4 months. An additional 2 out of 8 patients were removed from protocol due to disease progression and 2 others remain on protocol, awaiting OLT. Conclusions: In our series of unresectable cholangiocarcinoma, we found no difference in OS, PFS, and LC for patients treated with SBRT vs. CRT, although the former appeared to have lower toxicity and a trend towards improved PFS. Further research is needed to compare SBRT and CRT as definitive treatment or bridge to OLT for patients with unresectable cholangiocarcinoma.