tbuckley/cabot-search huggingface dataset:
Clinical phosphoproteomics reveals aberrant signalling pathways and kinases in treatment-resistant cervical cancer.
Authors: Prashant Kumar, Richa Chauhan, Irene A. George, Janani Sambath, Ekta R. Dhawale, Manisha Singh, Vinita Trivedi, R. Venkataramanan
Journal: Journal of Clinical Oncology (2024)

e17529 Background: Cisplatin-based concurrent chemoradiation therapy (CCRT) is the standard for locally advanced cervical cancer. While cisplatin stands out as a highly effective chemotherapeutic option for cervical cancer, resistance to the drug often triggers relapses. Moreover, previous studies have highlighted the detrimental impact of cisplatin's toxicity, which extends beyond treatment efficacy to influence the overall prognosis of patients. Combination treatment with drugs targeting different molecular pathways increases the effectiveness of the treatment by disrupting multiple critical processes that cancer cells rely on for survival. Herein, we analyzed the phosphoproteomic profile of cervical cancer patients resistant to concurrent chemoradiotherapy to identify the crucial kinases responsible for therapeutic resistance. Methods: We used mass spectrometry for phosphoproteomic analysis to study signaling pathways and dysregulated kinases in CCRT resistance. Biopsy samples collected pre-therapy were processed by protein extraction, digestion, and labeling with 10-plex TMT. Peptides were fractionated by basic pH liquid chromatography, enriched using IMAC, and analyzed on an Orbitrap-Fusion-Tribrid mass spectrometer. Data analysis was performed using Proteome Discoverer and various bioinformatics and statistical methods. Results: The phosphoproteomic analysis revealed distinct phosphorylation signatures between the responders and non-responders. In concordance with the phosphoproteomic data the expression of phospho-SMC1A and CSNK2A1 is preserved in non-responder cohort of cervical cancer patients in concordance with the phosphoproteomic data. Further, the pathway analysis showed elevated presence of the DNA repair pathway in the treatment-resistant cohort. Furthermore, dysregulation in the phosphorylation of key DNA repair proteins, such as SMC1A, HMGN1, MGMT, DDB2, and MSH6, suggests their involvement in treatment. The kinase prediction analysis suggested the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Subsequently, cell line based functional experiments indicated the potential of CSNK2A1 inhibitor silmitasertib in sensitizing the cells to cisplatin treatment. Conclusions: Phosphoproteomicanalysis of the cervical cancer revealed distinct phosphorylation signature and kinases involved in treatment resistance. Our findings indicated that dysregulated phosphorylation and increased expression of the kinase CSNK2A1 play a pivotal role in the treatment response of cervical cancer patients. Moreover, CSNK2A1 can sensitizes the cells to cisplatin uncovering the potential of combination treatment strategies. Our study uncovers the potential of clinical phosphoproteomics to design tailored treatment strategies in patients resistant to standard treatments.
Liquid biopsy detection of structural variant breakpoints to monitor ovarian cancer clonal evolution.
Authors: Jian Li, Shiro Takamatsu, Latasha Little, Joseph Celestino, Barrett Lawson, Robert Tyler Hillman
Journal: Journal of Clinical Oncology (2024)

e17538 Background: Chemotherapy is effective at inducing remission for most patients with high grade serous ovarian cancer (HGSOC), yet relapse is frequent. Methods to interrogate the clonal composition and molecular properties of minimal residual disease are needed to better understand the mechanisms of HGSOC relapse. To address this unmet need, we developed and validated a novel cfDNA-based approach for tracking on-treatment clonal evolution using tumor-informed structural variants (SVs). Methods: Genomic DNA (gDNA) was isolated from cryopreserve multisite pre-treatment HGSOC biopsies and matched germline samples and whole genome sequencing (WGS) was performed. cfDNA was isolated from contemporary pre-treatment plasma. High confidence SVs were identified from multisite WGS using a consensus method incorporating five published SV calling algorithms. Tumor-informed bespoke quantitative PCR primer/probe sets were designed to interrogate SVs breakpoints in tumor gDNA and matched cfDNA. Results: Optimization of the methodology was first performed using synthetic cfDNA generated by ultrasonication of DNA from ovarian cancer cell lines. WGS was used to identify SVs and SV breakpoint-spanning PCR assay exhibited 90% sensitivity and 89% specificity in detection of WGS-informed SVs. 11 validated SVs breakpoint-spanning PCR assays had specific amplifications in synthetic cfDNA. 8 SVs breakpoint-spanning quantitative PCR primer/probe sets were synthesized for qPCR (real-time PCR) and ddPCR (digital droplet), the custom TaqMan probe assays had significant increased sensitivity and superior specificity. When cutoff value of negative was set to “undetected” in qPCR and 0 copies/ul in ddPCR, the sensitivity and specificity of custom TaqMan probe assays can still be 100%. . After screening 18 SVs by tumor-informed SV breakpoint-spanning PCR assays, 8 SVs custom TaqMan probe qPCR assays demonstrated 100 % sensitivity and specificity in multisite biopsy samples. 3 shared and 3 private SVs custom TaqMan probe ddPCR assays were selected for absolute quantification, none of these assays had false positive or false negative when 0 copies/ul was used for cutoff value. 1 shared SV custom TaqMan probe ddPCR assay measured 0.947 copies/ul in cfDNA and 0 copies/ul in matched germline control. Altogether, our multi-layer screening approach yields the “perfect”- high sensitivity and specificity- SV breakpoint-spanning assays that are ready to apply for SVs detection in cfDNA. Conclusions: Detection of SVs from pre-treatment cfDNA using tumor-informed breakpoint-spanning ddPCR is feasible and may enable a novel and sensitive method for monitoring on-treatment disease burden. Work is ongoing to extend this method to private SVs with a goal of tracking treatment-induced tumor clonal dynamics using cfDNA.
Reflections on the changes in ascites and serum VEGF1 levels before and after intraperitoneal infusion of bevacizumab.
Authors: Zhenhua Du, Yu Xia, Xiuqin Li
Journal: Journal of Clinical Oncology (2024)

e17539 Background: This study analyzes the levels of VEGF1 in ascites and serum before and after intraperitoneal infusion of bevacizumab, aiming to explore the optimal administration route for treating recurrent ovarian cancer accompanied by ascites. Methods: Sixty-seven patients with advanced recurrent ovarian cancer and significant ascites were treated with intraperitoneal infusion of bevacizumab combined with chemotherapy. Under ultrasound guidance, a peritoneal drainage tube was placed, and the volume of ascites was measured before the infusion. The effects of the treatment were assessed by measuring the ascites volume during the 2nd to 3rd treatment (final ascites drainage) and by analyzing and comparing the levels of Vascular Endothelial Growth Factor 1 (VEGF1) in both ascites and serum. Results: The average volumes of ascites before and after treatment were 4229.97 ml and 5.42 ml, respectively (P&lt;0.0001), with an overall response rate (ORR) of 89.6% (60/67). Before and after treatment, the levels of VEGF1 in ascites were 283.86 pg/mL and 18.76 pg/mL, respectively (P&lt;0.0001). Before and after treatment, serum levels of VEGF1 were 80.67 pg/mL and 61.25 pg/mL, respectively (P&lt;0.0001). Before treatment, the level of VEGF1 in ascites at 283.86 pg/mL was significantly higher than in serum, which was 80.67 pg/mL (P&lt;0.0001). The reduction in VEGF1 levels following intraperitoneal infusion was over tenfold greater in serum compared to ascites. When the cutoff value for VEGF1 in ascites was set at 37.12 pg/mL, the sensitivity was 80.28%, and the specificity was 91.55%. Conclusions: The combined treatment of intraperitoneal infusion of bevacizumab with chemotherapy is an effective strategy for controlling ascites in recurrent ovarian cancer. Keywords: Bevacizumab, Intraperitoneal Infusion, Recurrent Ovarian Cancer, Ascites, Vascular Endothelial Growth Factor 1 (VEGF1).
Improved germline screening for patients with pancreatic cancer through provider driven testing.
Authors: Heather Frazier, Sewanu Anjolaoluwa Toyon, DeJuana Coleman, Martha Thomas, Paul Raymond Kunk, Tri Minh Le, Muneeb Rehman, Matthew Reilley
Journal: Journal of Clinical Oncology (2024)

e16366 Background: National guidelines recommend germline genetic screening for all pancreatic cancer patients. Results provide meaningful insights into pathogenic variants and impacts both treatment selection and family screening recommendations. We previously reported on current state and the need to improve germline screening rates. Since implementing a provider-driven approach, we have seen a significant increase in testing. Our findings demonstrate the feasibility and ongoing need for novel approaches to germline screening. Methods: This is a retrospective review of 223 patients with pancreatic adenocarcinoma evaluated at the University of Virginia Health System within the calendar year of 2022 compared to the 2021 calendar year. Primary endpoints include the rate of genetic counseling referral placement, the rate of attendance of outpatient genetic counseling, and the rate of individuals who completed germline screening. Our primary data points will be compared with outcomes obtained from a prior study evaluating 210 patients with pancreatic adenocarcinoma in the calendar year of 2021 at the same academic medical center. Results: Of the 223 patients with pancreatic adenocarcinoma, only 30% (69/223) had genetic counseling referrals present in the electronic health record system (EHR). This was an improvement from the 2021 calendar year, where 19% (39/210) had referrals present in the EHR. Of those with referrals present, an improvement in the rate of genetic counseling attendance was found, from 51% (20/39) in 2021 to 58% (40/69) in 2022. There was also an improvement in the rate of germline screening completion rates; 38% (85/223) of patients evaluated in 2022 completed testing, compared to 21% (44/210) in 2021. Six percent (5/85) of tested patients in 2022 had pathogenic findings, consistent with historical incidence rates. The main provider barriers were time and testing logistics. Conclusions: Our data shows an improvement in the rates of genetic counseling referrals, the rates of genetic counseling attendance, and the rates of germline screening completion. This modest improvement is primarily related to increased awareness by our providers. We acknowledge the need for further improvements and are developing a prospective clinical trial to better educate and empower patients to understand the need and results of germline testing.
Improved detection of homologous recombination deficiency using WES sequencing: Insights into a Chinese pan-cancer cohort.
Authors: Yaru Chen, Peisu Suo, Jiasheng Zhong, Huiya Cao, Haoyang Ye, Shifu Chen, Yanqing Zhou
Journal: Journal of Clinical Oncology (2024)

e17503 Background: Homologous recombination (HR) deficiency has emerged as a novel biomarker for the clinical use of PARP inhibitors in advanced ovarian cancer, and may also be of value in guiding the clinical use of PARP inhibitors and platinum-based drugs in breast cancer, prostate cancer, and other tumors. This significant finding assists in precision medication and prognosis judgments for patients. Methods: This research incorporated a Chinese pan-cancer cohort comprising 1033 patients diagnosed across thirteen cancer types. All matched tumor tissues and peripheral blood samples were processed for the whole exome sequencing. The HRD scoring was conducted with ScarHRD R package with defined parameters for the heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) status. HR deficiency were defined as an HRD-score ≥50 or BRCA1/2 deficient, while HR proficiency were defined as an HRD-score &lt;50 and BRCA1/2 intact. Results: Ovarian cancer demonstrates the highest HRD prevalence at 51.85%, surpassing the BRCA1/2 mutation rate of 20.37%. Breast cancer follows with an HRD rate of 45.45%, yet no BRCA1/2 mutations are detected. Other cancers like pancreatic, gastric, and sarcomas also present notable HRD rates (29.41%, 36.84%, and 29.79%, respectively) without corresponding BRCA1/2 mutations. In contrast, cancers such as urological, lung, intestinal, and neurological tumors exhibit a mismatch between HRD rates and BRCA1/2 mutation presence, few patients with notable BRCA1/2 mutations did not have consisted HR-deficient rate, and vice versa. Conclusions: Analysis HRD-score can help to screen a larger population of PARP inhibitor beneficiaries and provide hope to more patients. In the future we will do more dimensional data analysis statistics on this cohort. [Table: see text]
Anlotinib combined with penpulimab as first-line treatment for persistent, recurrent, or metastatic cervical cancer: Preliminary results from ALTER-GO-020, a single-arm, open-label, multi-cohort, multi-center phase II clinical study.
Authors: Dengfeng Wang, Hong Liu, Lihong Chen, Mian He, Weidong Zhao, Yang Xiang, Guonan Zhang
Journal: Journal of Clinical Oncology (2024)

e17506 Background: The BEATcc trial demonstrated the combination of atezolizumab plus bevacizumab and platinum regimen as first-line treatment for recurrent, or metastatic cervical cancer significantly improves progression-free survival (PFS) and overall survival (OS) regardless of PD-L1 status. ALTER-GO-020 is an ongoing open-label, single-arm, multi-cohort phase II study evaluating the combination of anlotinib (a multitarget anti-angiogenic TKI) and penpulimab (anti-PD-1 antibody) as a chemotherapy-free regimen for patients (pts) with recurrent or metastatic gynecological cancer. Here, we report the preliminary results of the cohort of patients with recurrent or metastatic cervical cancer from ALTER-GO-020. Methods: Eligible pts were histologically confirmed persistent, recurrent, or metastatic cervical cancer (including adenocarcinoma, adenosquamous carcinoma, or squamous-cell carcinoma), not amenable to curative treatment, and had no prior systemic treatment for metastatic, persistent, or recurrent disease. Pts were treated with anlotinib (12mg, po qd, d1-14, q3w) plus penpulimab (200mg, IV, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included PFS, duration of response (DOR), disease control rate (DCR), OS and safety. Results: From May 2022 to Nov 2023, 17 pts were enrolled. The median age was 52 years (range, 31-70), 65% of pts were squamous-cell carcinoma, 88% received previous chemoradiotherapy with or without surgery, and 71% had previously received neoadjuvant/adjuvant platinum-containing chemotherapy. As of date cutoff (Dec, 2023), the median follow-up time was 6.8 months (range, 1.4-18.3 months). In the efficacy analysis (n=17), the preliminary ORR was 58.8% (95% CI: 32.9%-81.6%), DCR was 88.2% (95% CI: 63.6%-98.5%). The mPFS was 11.0 months (95% CI: 5.4-16.7 months). The mOS was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in all 17 pts, in which 8 (47.1%) were grade ≥3. The most common grade ≥3 TRAEs were hypertension (29.4%), hand foot syndrome (11.8%), fatigue (11.8%), and diarrhea (5.9%). TRAEs led to dose reduction and interruption were 29.4%, and 35.3% of pts, respectively. No TRAEs leading to death. Conclusions: The preliminary results demonstrated that anlotinib plus penpulimab as a first-line therapy for persistent, recurrent, or metastatic cervical cancer showed promising antitumor efficacy and manageable safety profile. Clinical trial information: NCT05028504 .
Clinical efficacy and safety analysis of immune checkpoint inhibitors combined with concurrent chemoradiotherapy for stage IIIC1-IVA cervical cancer: A prospective cohort study.
Authors: YiMing Ma, Mingchuan Zhang, Hao Wu, Huimin Chen, Dandan Wang, Yuanyuan Xu, Shuxia Cheng
Journal: Journal of Clinical Oncology (2024)

e17505 Background: Stage IIIC1 with larger/more short lymph node diameters and IIIC2-IVA cervical cancer patients had a particularly poor prognosis. Clinical practices have found that stage IIIC1-IVA patients diagnosed with pelvic lymph node short diameter ≥ 1.5cm/number of positive lymph nodes ≥ 3, or paraaortic lymph node metastasis, had a higher recurrence rate and lower overall survival rate. The overall survival rate is approximately 29% -52%. Sequential systemic chemotherapy after concurrent chemoradiotherapy (CCRT) can not improve survival in such patients. However, the current research results on the combination of CCRT with immune checkpoint inhibitors for cervical cancer are not ideal, which may be due to the lack of stratified analysis. This study compared the efficacy and safety of CCRT and combined use of immune checkpoint inhibitors (non sequential) for stage IIIC1-IVA cervical cancer through the cohort analysis, and analyzed the prognostic factors. Methods: Patients diagnosed with stage IIIC1-IVA cervical cancer who underwent concurrent chemoradiotherapy from October 2019 to October 2022 were enrolled. Patients were divided into the study group (35 cases) receiving Sintilimab concurrently with chemoradiotherapy and the control group (35 cases) receiving standard treatment. The primary endpoints were the assessment of one-year progression-free survival (PFS), objective response rate (ORR), and associated influencing factors. Secondary endpoints included treatment-related adverse events (TRAEs). Results: The one-year PFS rates were 88.6% in the study group and 62.9% in the control group, showing a significant difference (χ2=6.293, P=0.012). The median PFS was not reached. The ORR for tumor response was 74.30% in the study group, significantly higher than the 51.43% in the control group (P=0.048). Univariate analysis identified tumor maximum diameter (p = 0.01) and concurrent use of ICIs (p = 0.039) as prognostic factors for PFS. Multivariate Cox analysis also revealed tumor maximum diameter (p = 0.0121) and concurrent use of ICIs (p=0.049) as independent predictors of PFS. The most common TRAEs in both groups included leukopenia, decreased appetite, nausea/vomiting, and fatigue, with no significant differences in incidence (P&gt;0.050). Grade ≥3 TRAEs were most frequently leukopenia (47.5%) and thrombocytopenia (17.1%) in the study group and leukopenia (51.4%) in the control group. All adverse reactions were alleviated after symptomatic treatment, dose reduction, or discontinuation, and no TRAE-related deaths occurred. Conclusions: In patients with stage IIIC1-IVA cervical cancer undergoing definitive concurrent chemoradiotherapy, the addition of ICIs may improve patient survival with manageable safety.
Impact of treatment setting on survival outcomes in undifferentiated pancreatic carcinoma: An analysis of the National Cancer Database.
Authors: John Paul Braun, Christopher Reese Bine, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2024)

e16333 Background: Undifferentiated carcinoma of the pancreas is a rare and highly aggressive form of pancreatic cancer, characterized by its low degree of cellular differentiation. The prognosis for this condition remains poor, with median survival times typically not exceeding one year. While existing research indicates that treatment at academic institutions may lead to improved survival outcomes compared to non-academic settings, there is scant research on this topic in the context of undifferentiated carcinoma of the pancreas. Addressing this research gap, this study analyzes data from the National Cancer Database (NCDB) to compare long-term survival rates between patients treated at academic institutions and those at other facilities. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with undifferentiated carcinoma of the pancreas from 2004 to 2019 using the histology code 8020 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA, and Chi-Square tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: In this analysis of 284 patients, 124 (43.7%) received care at academic centers, while 160 (56.3%) were treated at non-academic institutions. Individuals treated at academic centers had a significantly extended mean overall survival of 27 months compared to 13.9 months for those treated elsewhere (p &lt; 0.05). Additionally, patients at academic centers were more likely to be insured, undergo surgical interventions, receive chemotherapy, and be initially diagnosed at a different facility (p &lt; 0.05). Conversely, patients at non-academic centers were more likely to be white, live closer to their care facility, and exhibit greater metastatic regional lymph nodes (p &lt; 0.05). However, there was no significant association between treatment at academic centers and variables such as median income, cancer grade, and Charlson-Deyo Comorbidity Index (CDCI) (p &gt; 0.05). Conclusions: This study revealed that individuals with undifferentiated carcinoma of the pancreas receiving treatment at academic centers exhibit a significantly improved overall survival rate compared to those treated at non-academic centers. This disparity in survival rates might be attributed to the higher prevalence of chemotherapeutic treatments and surgical interventions at academic institutions. While these observations are based on correlational data, they underscore the necessity for further investigation to establish causality.