tbuckley/cabot-search huggingface dataset:
Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53.
Authors: Colin P. Bergstrom, Ethan Samuel Lin, Eric G. Mehlhaff, Dyan M. Lesnik, Noelle K. LoConte, Sam Joseph Lubner, Kristina A. Matkowskyj, Monica Arun Patel, Sean Ronnekleiv-Kelly, Nataliya Volodymyrivna Uboha, Megan Wachsmann, David H. Wang, Albert Y. Lin, Jeremy D. Kratz
Journal: Journal of Clinical Oncology (2024)

546 Background: Cholangiocarcinoma (CCA) has poor prognosis and limited treatment options. The US Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize pathogenic drivers across the integrated VA network. Here, we summarize an important subgroup of CCA with homologous recombination deficiency (HRD) and its impact on overall survival (OS). Methods: Next-generation sequencing (NGS) was performed using FoundationOne CDx Analysis included clinicopathological, molecular alterations including, single nucleotide variants, gene amplification/loss, and gene fusion/rearrangements obtained from centralized data of the VHA’s Corporate Data Warehouse. Homologous recombination deficiency was defined by pathogenic variant mutations (MT) in ARID1A, ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANC, NBN, PALB2, and RAD51. Statistical analysis was performed using Chi-squared test for concurrent gene enrichment and log-rank Kaplan-Meier analysis. Results: 483 CCA samples underwent tissue NGS as standard of care. Pathogenic variants in HRD genes included ARID1A (15.5%, n=75), BAP1 (9.5%, n=46), ATM (2.7%, n=13), PALB2 (2.3%, n=11) and BRCA (2.0%, n=10), representing 31.7% (n=153) of the population. HRD mutations were found in similar proportions of localized (31.8%) and metastatic (31.5%) clinical presentations at diagnosis. OS was not significantly different between CCA with HRD mutations (12.3 mo WT vs. 13.8 months with HRD MT, p=64). KRAS MT (n=77, 15.9% of population) did not impact OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. There was increased frequency in KRAS MT with HRD WT 18.5% versus HRD MT10.4% (p&lt;0.03). Additionally, there was increased frequency in TP53 MT with HRD WT 54.8% versus HRD MT 28.1% (p&lt;0.00001). TP53 MT (n=224, 46.3% of population) conferred inferior OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. Subgroup analysis of TP53 MT had worsened OS with concurrent HRD MT (n=39, 4.1 mo) v. HRD WT (n=158, 9.0 mo; p&lt;0.04). Conclusions: Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD. Future analysis should consider mutation signatures of HRD, loss in heterozygosity of HRD, and platinum exposure to further define the subgroups of CCA with mutations in HRD. [Table: see text]
PD-L1 as a predictor of chemo-immunotherapy response in biliary tract cancers: A systematic review and meta-analysis.
Authors: Juan Jose Juarez, Soravis Alm Osataphan, Ben Ponvilawan, Nipith Charoenngam, Mary Linton Bounetheau Peters
Journal: Journal of Clinical Oncology (2024)

541 Background: Advanced biliary tract cancers (BTCs) are rare and aggressive malignancies with limited treatment options. Recently, immune checkpoint inhibitors in combination with chemotherapy (ICI-C) gained approval as first-line therapy for unresectable or metastatic BTCs. Two large phase III clinical trials of ICI-C in BTCs did not show a significant correlation between PD-L1 expression and therapeutic response. However, in a phase II study of single-agent nivolumab, there was an association. In light of these conflicting findings, we conducted a comprehensive systematic review and meta-analysis of clinical trials investigating ICI-C in BTCs to assess whether PD-L1 expression could predict treatment response. Methods: We searched PubMed, Web of Science, EMBASE, and Cochrane databases to identify relevant studies. Patient characteristics, method of PD-L1 assessment, and measures of treatment response including hazard ratio (HR), objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS) were extracted. Pooled ORR and HR were calculated using random effect model and assessed for study heterogeneity. Results: Among the 4,882 studies screened, seven clinical trials evaluating the efficacy of ICI-C in BTCs were identified. Of these trials, two randomized phase III trials report HR between PD-L1 positive and negative patients, while five phase II clinical trials reported ORR based on PD-L1 expression. Out of the 1,069 patients included in these trials, 954 underwent assessment for PD-L1 expression. 66.4% (n=634) exhibited PD-L1 expression level ≥ 1% as determined by either tumor proportion score (TPS) or combined positive score (CPS), while 33.5% (n=320) were classified as PD-L1 negative. Notably, 115 patients were not tested for PD-L1 expression, a variety of PD-L1 assays were used across the studies, and only some studies reported multiple PD-L1 cutoffs. Pooled analysis of two-phase III trials demonstrated that PD-L1 expression ≥ 1% was associated with improved OS (pooled HR 0.83, 95% CI 0.72-0.95) compared to PD-L1 &lt; 1% (pooled HR 0.85, 95% CI 0.67-1.07). Additionally, pooled ORR from five phase II studies showed a trend towards an improved response in patients with PD-L1 expression ≥ 1% (pooled ORR 64%, 95% CI 52-74%) compared to PD-L1 &lt;1% (pooled ORR 46%, 95% CI 31-62%) with a subgroup difference p-value of 0.08. Conclusions: This meta-analysis suggests that BTCs patients with PD-L1 expression ≥ 1% may exhibit a more favorable response to chemo-immunotherapy, and that a majority of BTCs have this level of expression. These findings support further investigation of the use of PD-L1 as a biomarker, and in particular investigation of different PD-L1 levels, which may inform treatment for patients with relative contraindications to immunotherapy use.
Analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) and Child–Pugh (CP)-B liver function treated with regorafenib in routine clinical practice in the observational REFINE study.
Authors: Yoon Jun Kim, Philippe Merle, Richard S. Finn, Masatoshi Kudo, Heinz-Josef Klümpen, Ho Yeong Lim, Matthias Pinter, Svetlana Babajanyan, Javeed Khan, Maria Awan, Kirhan Özgürdal, Shukui Qin
Journal: Journal of Clinical Oncology (2024)

452 Background: Pts with HCC and compromised liver function are typically excluded from clinical trials. The REFINE real-world study (NCT03289273) assessed a more varied pt population treated with regorafenib than the phase 3 RESORCE trial. 1 Median overall survival (OS) in REFINE was 13.2 months and treatment-emergent adverse events (TEAEs) were consistent with RESORCE. We present a subgroup analysis of outcomes in pts from REFINE with CP-B liver function. Methods: REFINE is an international, prospective observational study of pts with uHCC for whom the decision to treat with regorafenib according to the local health authority approved label was made by their physician before enrollment. The primary endpoints were safety (Medical Dictionary for Regulatory Activities v25) and dose modifications due to drug-related TEAEs. Secondary endpoints included OS and duration of treatment (DoT). Results: Of 1005 evaluable pts, 123 (12%) were classified as CP-B at study entry, with most being CP-B7 (Table). Of the CP-B pts, 40/123 (9%), 9/123 (18%), and 58/123 (15%) initiated regorafenib at 160 mg, 120 mg, and 80 mg, per day, respectively. Median DoT with regorafenib was 2.3 months in CP-B pts and 3.7 months in the overall cohort. Incidence rates of TEAEs in CP-B pts and the overall cohort were similar (93% and 92%) and TEAEs were drug-related in 70% and 74% of pts, respectively. Grade 3–4 TEAEs occurred in 41% of CP-B pts and 39% of the overall cohort and were drug-related in 27% and 26% of pts, respectively. Serious TEAEs were observed in 48% of CP-B pts and 37% of the overall cohort, and were drug-related in 11% and 9% of pts, respectively. Drug-related TEAEs led to less frequent dose modifications in CP-B pts than in the overall cohort (28% vs 37%), but more frequent permanent discontinuations (28% vs 16%). Median OS in CP-B pts was 6.3 (95% confidence interval [CI] 4.9, 7.8) months and in CP-B7 pts was 6.7 (95% CI 5.1, 8.7) months. Conclusions: In REFINE, pts with uHCC and CP-B liver function had similar rates of grade 3–4 TEAEs, but a higher occurrence of serious TEAEs due to underlying cirrhosis led to more frequent permanent discontinuations in CP-B pts. Median OS in CP-B7 pts was comparable with OS in CP-B pts overall. The evaluation of prognostic models to identify CP-B pt subgroups who may benefit from regorafenib treatment is a subject for further research. 1. Kim YJ, ILCA 2022. [Table: see text]
Improving timeliness and equity in germline genetic testing for pancreatic ductal adenocarcinoma patients: A comparative analysis and future strategies.
Authors: Xianghui Zou, Baho Sidiqi, Cathy Nguyen, Ellen Chen, Noah D. Kauff, Daniel King
Journal: Journal of Clinical Oncology (2024)

611 Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). Our previous study identified delays in germline testing for socioeconomically disadvantaged patients. We aimed to compare delays before and after implementing recommendations for same-day germline testing and identify reasons why germline testing was not performed. Methods: Using an IRB-approved protocol, PDAC patients were identified from Jan 2022 to Dec 2022 in our EMR system. Median income was estimated by zip code. Delays were calculated as the difference between diagnosis and germline test date. Social work needs were assessed through EMR review. An in-depth chart review was conducted to identify why tests were not performed. Results: An additional 100 patients were found with tests performed. Compared to our previous 135-patient study with a median delay of 27 days (d) in testing, our recent data showed a median delay of 15d (p=0.0215). In our previous study, 50 out of 135 patients (37%) received testing within two weeks of their PDAC diagnosis, whereas our recent data showed that 49 out of 100 patients (49%) received testing within two weeks (c 2 =3.372, p=0.0663), a 32% relative increase. The negative correlation between median income and delays in testing (r=-0.2578, p=0.0025) found in our previous study no longer existed in our recent analysis (r=0.0419, p=0.6802). Compared to our previous study in underserved minority (UM) patients (African American and Hispanic), our recent data showed a significant decrease in the delays for testing in UM patients (66d vs 19d, p=0.0041). We did not identify a difference in delays for testing between UM and not UM patients in the recent dataset (UM: 19d vs not UM: 15d, p=0.8075). In addition, compared to our previous study in patients with social work (SW) needs, our recent data showed a significant decrease in the delays for patients with SW needs (104d vs 13d, p=0.0004). We did not detect a significant difference between patients with SW needs and without SW needs in our recent data (SW: 13d vs no SW: 15d, p=0.8041). Finally, in our analysis of 87 patients without documented tests, 51 (59%) received care elsewhere, 25 (29%) were never offered tests, 5 (6%) refused tests, and 6 (7%) pursued a palliative approach. Conclusions: Our recent analysis showed a significant decrease in delays of testing, as more patients received prompt testing after PDAC diagnosis. Socioeconomically disadvantaged patients and those with social work needs no longer experienced significant delays in testing. To further mitigate delays, we plan to initiate germline testing during the first visit by providing introductory videos to increase understanding of consent. Furthermore, the substantial number of patients who were not offered tests will raise physician awareness regarding the necessity of offering germline tests.
RAS mutation specific survival in patients with metastatic colorectal cancer treated with trifluridine/tipiracil.
Authors: Peter Grell, Stanislav Batko, Alina Pirsthuk, Simona Borilova, Katerina Polachova, Blanka Mazuchova, Jiri Tomasek, Pavel Fabian, Jitka Berkovcova, Miroslav Bardelcik, Radka Obermannova, Tomas Buchler, Igor Kiss
Journal: Journal of Clinical Oncology (2024)

197 Background: Trifluridine/tipiracil (T/T) is effective in patients with pretreated metastatic colorectal cancer (mCRC). RAS mutational status could predict magnitude of T/T effect (van de Haar et al, Nat Med. 2023), but the data are conflicting. Methods: We retrospectively reviewed the clinical data of 402 patients consecutively treated with T/T in two institutions in the Czech Republic and analysed the potential predictive value of different RAS mutations. Results: Baseline characteristics: median age 65 (range 28-84), female 32.8%, ECOG PS 0 in 32.8% and 1 in 64.9%, primary tumor location left colon in 76.3%. The median line in which T/T was administered was 3 (range 2-8). Median number of T/T cycles administered was 3 (range 2-27). Median follow-up was 32.4 months, 358 patients died (89.1%). Overall survival (OS) was 9.3 months (95% CI 8.7 to 10.3) and progression-free survival (PFS) 3.5 months (3.2 to 3.6). RAS mutation was detected in 54.2% patients. KRAS G12 mutation was found in 117 patients (29.1%), KRAS G13 in 19 (4.7%), other RAS mutation in 25 (6.2%), non-specified RAS mutation in 57 (14.2%), and BRAF mutation in 14 (4.8%). No difference in OS in RAS wildtype (wt) vs mutated group (P=.50) was observed. OS in the defined groups was found: wtRAS group (9.1 months), KRAS G12 (9.1 m), KRAS G13 (5.6 m), and other RAS mutations (10.6 m, P=.180). Patients with KRAS G13 had worse OS vs all other patients (P=.029; HR 1.97), vs wt (P=.02; HR 2.08), vs other mutated (P=0.067; HR 1.75), vs KRAS G12 mutated patients (P=.069; HR 1.75). Patients with KRAS G12 had no OS difference vs other groups of patients. In KRAS G12 group we found that specific gene variants have different OS (for G12C, 7 patients, OS was 6.0 months; for G12D, 41 patients, 9.0 m; for G12V, 45 patients, 10.5 m; for G12S, 7 patients, 16.1 m; for G12A, 11 patients, 7.6; other G12 variants, 5 patients, 10.0 months, P=.028). BRAF mutation was associated with worse OS (6.6 vs 9.1 months, P=.02, HR 2.46). Conclusions: We did not confirm the negative predictive value of KRAS G12 mutation in patients treated with T/T, however, OS depends on the specific G12 mutation. In contrast, patients with KRAS G13 mutation had worse survival.
PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Thomas Seufferlein, Antonio Cubillo Gracian, Marc Kueng
Journal: Journal of Clinical Oncology (2024)

TPS718 Background: TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is noninvasive, locoregional, and is delivered via a portable electric field generator and skin-placed arrays. TTFields therapy has low risk of systemic toxicity and is approved for glioblastoma (and grade 4 glioma in Europe), and pleural mesothelioma. In vitro, TTFields (150 kHz) application decreased pancreatic cancer cell proliferation and clonogenicity; in vivo, TTFields concomitant with chemotherapy (chemo) had greater antitumor effect than chemo alone in orthotopic pancreatic tumors. Co-application of TTFields with immune checkpoint inhibitors (ICIs) significantly decreased tumor volume, increased tumor infiltration and IFN-γ production, and did not impede ICI-induced effector memory T-cell production versus in vivo controls. The pilot (phase 2) PANOVA clinical study (NCT01971281) showed safety and feasibility with TTFields therapy plus NabP and GEM in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The randomized, pivotal (phase 3) PANOVA-3 clinical study (NCT03377491), evaluating TTFields therapy with GEM and NabP in LAPC, is ongoing. Methods: PANOVA-4 (pilot, single-arm clinical study) assesses the safety and efficacy of TTFields therapy (NovoTTF-200T device) concomitant with atezolizumab, GEM, and NabP as 1L treatment for mPDAC. Eligible patients (pts) are ≥18 years of age and have a new mPDAC diagnosis, measurable abdominal disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no prior systemic PDAC therapy. Atezolizumab (1680 mg, IV infusion) is given before chemo on day 1 of each 28-d cycle, with NabP (125 mg/m 2 IV) and GEM (1000 mg/m 2 IV) given on days 1, 8, and 15. TTFields therapy (150 kHz) is delivered for ≥18 h/d until disease progression per RECIST v1.1 or loss of clinical benefit. Clinical follow-up occurs every 4 weeks (q4w) with CT scans q8w. Survival is assessed every 3 mo post last on-site visit. The primary endpoint is disease control rate (DCR). Secondary endpoints include overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate, PFS at 6 mo, duration of response, and safety. 76 pts are required to achieve 80% power (1-sided α level 0.05) to detect a 63% DCR vs historical 48% DCR in pts with mPDAC receiving 1L GEM and NabP. Clinical trial information: EUCTR2022-003157-55 .
Association of circulating tumor DNA (ctDNA) molecular disease (MRD) detection with lymph node metastasis after local excision of pathological T1 colorectal cancer: First results from DENEB, a CIRCULATE-Japan GALAXY substudy.
Authors: Masaaki Miyo, Takeshi Kato, Yoshiaki Nakamura, Saori Mishima, Hideaki Bando, Hiroki Yukami, Koji Ando, Jun Watanabe, Naoya Akazawa, Mitsuru Yokota, Yoshinori Kagawa, Adham A Jurdi, Minetta C. Liu, Koji Oba, Hiroya Taniguchi, Daisuke Kotani, Eiji Oki, Ichiro Takemasa, Masaki Mori, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2024)

23 Background: Patients with pathological T1 (pT1) colorectal cancer (CRC) at high risk for lymph node metastasis (LNM) after complete local resection are recommended to receive additional intestinal resection along with lymph node dissection. However, the existing pathological criteria for risk stratification of LNM are inadequate, such that ~90% of patients without LNM are exposed to potentially unnecessary treatment. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective substudy within the GALAXY observational study, to explore the ability of predicting LNM using circulating tumor DNA (ctDNA) detection compared to the standard pathological criteria. Methods: This study included patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk-stratification criteria for LNM. The additional surgery was indicated for patients meeting any of the following criteria: (1) depth of submucosal invasion (&gt;1000µm); (2) lymphovascular invasion; (3) poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous carcinoma; and (4) high-grade tumor budding (BD2/3) at the site of deepest invasion according to the Japanese guideline. ctDNA was analyzed from plasma samples collected within 4 weeks before the additional intestinal resection using a personalized, tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay). The study assessed the diagnostic concordance rate between ctDNA detection and the occurrence of LNM. Results: Of 208 CRC patients enrolled between July 2021 and May 2023 in DENEB, 166 patients met the inclusion criteria. Of these, 22 (13.3%) were ultimately diagnosed with pStage III due to the presence of LNM in additional intestinal resection. Among the 166 patients, 6 patients tested ctDNA-positive; all 6 had LNM, yielding a positive predictive value of 100.0%. On the other hand, 160 patients had ctDNA-negative results, 144 of whom did not have LNM, resulting in a negative predictive value of 90.0%. The overall diagnostic concordance rate for ctDNA in detecting LNM was 90.4% (95% confidence interval, 84.8% to 94.4%). All 6 patients with a ctDNA-positive result and LNM had left-sided colorectal cancer and a tumor diameter greater than 13 mm. Conclusions: This analysis showed that ctDNA testing has the potential to improve risk stratification of LNM in patients with pT1 CRC who underwent complete local resection. Clinical trial information: UMIN000039205 .
Identification of MAPK and mTOR pathway alterations in HER2-amplified colorectal cancer.
Authors: Svea Cheng, Cyndi Gonzalez, Morgan Ferrell, Richard Giza, Masood Pasha Syed, Tara Magge, Riyue Bao, Aatur D. Singhi, Anwaar Saeed, Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2024)

185 Background: Human epidermal growth factor receptor 2 (HER2) amplification is now a highly actionable alteration for patients with colorectal cancer (CRC) with distinct combination therapies. Recent studies have shown that oncogenic KRAS, BRAF, and PIK3CA mutations, may serve as biomarkers of response to HER-directed treatments such as Trastuzumab and Tucatinib/Pertuzumab. In this study, we investigated the incidence of MAP kinase and mTOR pathway alternations in patients with HER2-amplified CRC. Methods: The cBioPortal for Cancer Genomics was utilized to obtain data and graphics on HER2 amplification in CRC. cBioPortal was queried to select 21 published studies that contain CRC specimens (assessed April 2023). Clinical, specimen, copy number alteration (CNA), and somatic mutation data of each study were downloaded and aggregated across all studies, followed by filtering, standardization, and harmonization to generate ~30 analysis-ready fields encompassing demographic variables, HER2 amplification, and KRAS/NRAS/PIK3CA/BRAF mutations. Results: Among a pool of 4822 CRC patients with known gender, 44.4% (2139) were female and 55.6% (2683) were male. The incidence of HER2 amplification in the overall cohort was 2.6% (123/4822) and was noted to be higher in males (3.1%, 82/2683) than in females (1.9%, 41/2139). The incidence of HER2 amplification was highest in Asian CRC patients (3.9%, 9/228), followed by Black CRC patients (3.0%, 9/298), and then Caucasian CRC patients (2.7%, 57/2118). Rates of HER2 amplification were similar in the colon and the rectum at 2.6% (61/2360 and 26/1015, respectively). After analyzing rates of concurrent MAPK and mTOR pathway mutations in patients with HER2-amplified CRC, KRAS mutations were noted to be the most common mutation in HER2-amplified colon cancer (27.9%, 17/61), but were less common in HER2-amplified rectal cancer (7.7%, 2/26). PIK3CA mutations were also common, with an incidence of 13.1% (8/61) in HER2-amplified colon cancer and 7.7% (2/26) in HER2-amplified rectal cancer. NRAS mutations occurred at comparable, low rates in HER2-amplified colon and rectal cancer, at 3.3% (2/61) and 3.8% (1/26) respectively. No BRAF mutations were reported in either disease group. Conclusions: In this study, we identified that MAPK and mTOR pathway alterations are relatively common among patients with HER2-amplified CRC. These somatic events appear to be more common in HER2-amplified colon cancer than rectal cancer. Next generation based molecular profiling is recommended to identify potential resistance mechanisms before initiation of HER2-directed therapy.