tbuckley/cabot-search huggingface dataset:
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study.
Authors: Thierry Andre, Elena Elez, Eric Van Cutsem, Lars Henrik Jensen, Jaafar Bennouna, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Heinz-Josef Lenz, Jose Luis Manzano Mozo, Giampaolo Tortora, Rocio Garcia-Carbonero, Elvis Cela, Yingsi Yang, Ming Lei, Lixian Jin, Sara Lonardi
Journal: Journal of Clinical Oncology (2024)

LBA768 Background: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo ± targeted therapies. NIVO ± IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study. CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO + IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO + IPI vs chemo in the 1L setting. Methods: Pts ≥ 18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. Results: In the 1L setting, 303 pts were randomized to NIVO + IPI (n = 202) or chemo (n = 101); of these pts, 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32]; P &lt; 0.0001) (Table). No new safety signals were identified (Table). Conclusions: NIVO + IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO + IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO + IPI as a standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]
Outcomes and prognostic factors of advanced biliary tract cancers in Saudi Arabia.
Authors: Kanan Alshammari, Reema Alduaiji, Lena Alotaibi, Reema Alqadiri, Laila Alqahtani, Faizah Alotaibi, Turki Al-Fayea, Fouad Sabatin, Ashwaq Alolayan, Mohammad Alkaiyat, Husam Shehata, Joud Al Qahtani, Mohammed Ahmed Algarni
Journal: Journal of Clinical Oncology (2024)

460 Background: Biliary tract cancers which include gallbladder adenocarcinoma, intrahepatic and extrahepatic cholangiocarcinoma are rare, and carry a poor prognosis. There is limited data on biliary tract cancers in the Saudi population. Methods: This single center retrospective study was conducted with data of eligible cases from the last 4 years. Survival, chemotherapy regimens, and variables such as neutrophil to lymphocyte ratio (NLR), and other potential prognostic variables were collected. Results: The study included 155 patients of which 75 had intrahepatic cholangiocarcinoma and 74 had gallbladder adenocarcinoma. The majority were females at 63% of patients. Overweight to obese patients represented 59% of the study cohort. The majority of patients (62%) had an ECOG performance status of 2 and below. Comprehensive genomic profiling was done to 20% of cholangiocarcinoma cases. Elevated CA19-9 tumor marker (&gt; 37 micromol/L) was found in 57% of patients. De novo metastatic disease affected 82% of patients. One third of patients (33%) were not fit for first line chemotherapy, and were given best supportive care. First line chemotherapy of platinum + gemcitabine was given to 53% of fit patients, followed by gemcitabine alone given to 38%, followed by 5-Fluorouracil chemotherapy given to 9% of patients. Very few patients lived for 12 months or more at 16%. There was a significant association between NLR and progression free survival (PFS) with median PFS being 3.5 months in the NLR &gt; 3 group (95% CI 1.2-6 months) versus median PFS of 9.8 months in the NLR &lt; 3 group (95% CI 7.5-12 months, p=0.019). Conclusions: Biliary tract cancers still carry a poor prognosis. NLR ratio of more than 3 was found to predict a low PFS.
Pharmacogenomic study of gemcitabine on the safety and efficacy in patients with metastatic pancreatic cancer (GENESECT study): Analysis of a subpopulation.
Authors: Takashi Yokokawa, Daiki Tsuji, Masahiro Hatori, Kenichi Suzuki, Kazuyoshi Kawakami, Masahiko Nakao, Takuya Yano, Yuichiro Arakawa, Keisuke Matsuo, Yasukata Ohashi, Masato Ozaka, Naoki Sasahira, Yasuhiko Sakata, Yuki Kogure, Shinya Tamaki, Atsushi Wada, Yusuke Taki, Hiroshi Ishii, Kunihiko Itoh, Masakazu Yamaguchi
Journal: Journal of Clinical Oncology (2024)

651 Background: In the GENESECT study, we examined the relationships between gemcitabine (GEM) metabolism-related germline genetic polymorphisms (GPs) and treatment efficacy and safety. However, no significant GPs were found because approximately 70% of the patients were treated with nab-paclitaxel, which has a different metabolic process than GEM. In the present study, a subanalysis including only GEM monotherapy patients was performed. Methods: Of the 159 patients analyzed in the GENESECT study, only the GEM monotherapy patients were selected. The endpoints were the carbohydrate antigen 19-9 (CA19-9) response (reduction ≥50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs from the viewpoint of efficacy, and neutropenia ≥Grade 3 and thrombocytopenia ≥Grade 3 in relation to GPs from the viewpoint of safety. The analyzed genes included those encoding GEM transporters and metabolic enzymes ( SLC29A1, ABCC5, CDA, DCK, RRM1/2), and a tumor cell proliferation enzyme ( COX-2). Statistical analysis included univariate and multivariate logistic regression analyses. The significance level was set to 5%. Results: Data of 50 patients were analyzed. AA genotype in ABCC5 1146A&gt;G (rs7636910) was associated with a significantly higher percentage of CA19-9 responses compared to AG/GG (52.9% vs 21.2%, p = 0.023), and the association remained significant on multivariate analysis (OR: 6.255, p = 0.014). Patients with AA genotype in ABCC5 1146A&gt;G tended to be associated with PFS, but this was not statistically significant (HR: 0.464, p = 0.074). On the other hand, there was no significant association between CA19-9 responses and DCK-1205C&gt;T (rs4694362), TT/CT genotype in DCK-1205C&gt;T was significantly associated with prolonged PFS compared to CC (median, 127 vs 48 days, p = 0.002), and the association remained significant on multivariate analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS, and the presence of second-line chemotherapy was the only relevant factor. In terms of safety, no GPs were significantly associated with either neutropenia or thrombocytopenia. Conclusions: The results suggest that ABCC5 and DCK might be related to the efficacy of treatment with GEM, but further research is needed. Clinical trial information: UMIN000012720 .
Early onset metastatic colorectal cancer: Clinical-prognostic characteristics and correlation to molecular profile.
Authors: Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Paolo Ciracì, Lorenzo Giuliani, Valeria Pusceddu, Maria Caterina De Grandis, Ada Taravella, Marco Puzzoni, Vittoria Matilde Piva, Chiara Boccaccio, Eleonora Lai, Alessandra Anna Anna Prete, Krisida Cerma, Federica Marmorino, Riccardo Giampieri, Sara Lonardi, Chiara Cremolini, Francesca Bergamo, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

195 Background: Despite a reduction of both incidence and mortality of CRC in the elderly population, several studies published in the last decade have shown an increase in the incidence of early-onset CRC (EO-CRC). Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, prognostic, and molecular differences in a large group of patients (pts) with early onset mCRC. Methods: We collected data from 589 metastatic EO-CRC from 4 different Italian Institutions. A historical control group of 316 pts &gt; 50 year old was also included in the analysis. All pts had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment. The main objective of the study was to evaluate clinical outcome in terms of median overall survival for the global population of EO-CRC pts and in different molecular subgroups according to RAS and BRAF status. Results: In the EO-CRC group median age was 44 (±6) and 67 (±11) in the historical control group. M/F ratios were 2:1 and 1:1, respectively. In the overall population mOS was 34,1 in EO-CRC pts vs 42,0 months (mo) (p = 0,0006) in the control group. In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 28,6 vs 36,0 mo in the control group (p = 0,0065). In RAS/BRAF wild type subgroup mOS in EO-CRC pts was 44,1 vs 49 mo (p = 0,13). Finally, in the BRAF V600E mutated subgroup EO-CRC pts showed a 16 mo mOS vs 26 mo (p = 0,04). In the overall population mPFS was 12,0 in EO-CRC pts vs 10,0 mo (p = 0,02) in the control group. Furthermore, the overall response rate (ORR) was 53% in EO-CRC and 69% in LO-CRC. Conclusions: Our work including a large population of EO-CRC pts indicates a general worse prognosis for pts with early onset colorectal cancer compared to late onsets. Interestingly this seems to occur regardless of the molecular status. On the other hand findings in the RAS/BRAF wild type population might also suggest a less unfavourable impact of EO-CRC on prognosis possibly related to anti-EGFR therapy. Subsequent investigations will be needed to further understand the specific clinical and molecular characteristics of this growing group of pts to better define the more appropriate treatment strategy.
Epidemiological characteristics of patients with cholangiocarcinoma with and without ulcerative colitis: A retrospective cohort study.
Authors: Alejandro Nieto Dominguez, Sarah Elizabeth Eichinger, Ayobami Gbenga Olafimihan, Daniel Guifarro Rivera
Journal: Journal of Clinical Oncology (2024)

564 Background: Ulcerative colitis (UC) is correlated with gastrointestinal cancer. While the exact mechanism is unknown, it is thought that a chronic inflammatory state may result in the development of malignancies including cholangiocarcinoma. Patients with UC that develop cholangiocarcinoma usually have a poor prognosis and early detection is key to improve survival. Methods: We used the 2016-2019 National Inpatient Sample (NIS) database, the largest all-payer inpatient care database in the United States, to stratify all patients admitted with a diagnosis of cholangiocarcinoma with and without ulcerative colitis, to further characterize their epidemiological characteristics. Results: There were at total of 46,001 patients with a diagnosis of cholangiocarcinoma studied. Of these patients with cholangiocarcinoma, 401 had concomitant UC (0.87%). Individuals with UC in the database had an increased association with cholangiocarcinoma (OR=7.67, 95% CI 6.96-8.46) compared to those without UC. Patients with cholangiocarcinoma and UC tended to be younger (57.8 vs. 67.9 years old without UC), male (69.51% vs. 53.23% without UC), with private insurance (57.5%) vs. patients without UC who predominately had Medicare (59.46%). Patients with cholangiocarcinoma and UC had on average fewer Charleston Comorbidities (64.63% with 3 comorbidities) vs. patients without UC (74.52% with 3 comorbidities). Of patients with cholangiocarcinoma and UC, 65.85% were Caucasian (vs. 64.85% without UC), 6.1% were Black (vs. 10.09% without UC), 3.66% were Hispanic (vs. 12.37% without), and 24.39% were Asian or Pacific Islander (vs 12.79% without). Conclusions: In the population studied, there was a significant correlation between UC and cholangiocarcinoma. Patients with cholangiocarcinoma and UC tended to be younger with fewer comorbidities than their counterparts without. There were nearly double the percentage of Asian patients with cholangiocarcinoma and UC as compared to Asian patients without UC. Understanding the characteristics of patients with UC who develop cholangiocarcinoma is important as it could inform future best practices in potential screening and early detection of carcinomas in patients with UC. [Table: see text]
Trends in colorectal cancer screening from NHIS survey: Analysis of modalities impact on overall screening.
Authors: Derek W. Ebner, Lila J Finney Rutten, Lesley-Ann Miller-Wilson, Niels Markwat, Vahab Vahdat, A. Burak Ozbay, Paul J. Limburg
Journal: Journal of Clinical Oncology (2024)

67 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality among men and women combined in the United States (US). Although the national screening rate has increased over the years, it remains below the target of 80% recommended by the National Colorectal Cancer Roundtable for improved CRC outcomes. In most recent years, and particularly during COVID-19, screening-eligible individuals preferred at-home, non-invasive screening options over invasive tests such as colonoscopy due to convenience and accessibility. The objective of this study was to understand the CRC screening trends over the last two decades, and the impact of various screening modalities on the overall CRC screening rate. Methods: Using National Health Interview Survey (NHIS) data from 2005 onwards, we examined CRC screening (colonoscopy, mt-sDNA, FIT/FOBT, and sigmoidoscopy) rates among adults aged 50-75 years. A pseudo-time-series cross-sectional (pseudo TSCS) analysis was conducted including random effects Generalized Least Square (GLS) regression model to estimate the relative impact of each modality on the overall increase in CRC rates from 2018 to 2021. Results: Among 50-75 years old individuals, the estimated CRC screening use increased by 32% from 2005 to 2021 (47.7% to 69.9%). Between 2018 to 2021, the rates increased from 64% to 70%, driven largely by increased use of mt-sDNA, a 62.1% increase from 2018 to 2021 (2.5% to 6.6%). During this time period, colonoscopy utilization increased by 4.4% (61.2% to 64.0%), while FOBT/FIT utilization increased by 3.6% (5.3% to 5.5%). A pseudo-TSCS analysis showed that mt-sDNA contributed substantially to the overall CRC screening rate increase during years 2018-2021 (77.3%; p &lt; 0.0001). Conclusions: While CRC screening rates are increasing, they remain below the national goal of 80%. Mt-sDNA as a home-based, non-invasive screening, recommended at a 3-year interval, has been leveraged to improve overall CRC screening rates, particularly to address the screening backlog created during the COVID-19 pandemic. A collaborative approach between healthcare providers and screening-eligible individuals is needed to empower patients with choice for their CRC screening modality to achieve the national goal.
Phase 2 study of trastuzumab deruxtecan as neoadjuvant treatment for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Daisuke Takahari, Akihito Kawazoe, Nozomu Machida, Keiko Minashi, Yukinori Yamagata, Hiroki Hara, Takeshi Omori, Manabu Yamamoto, Hisateru Yasui, Izuma Nakayama, Takanobu Yamada, Masayuki Kano, Takaki Yoshikawa, Masashi Wakabayashi, Yu Komura, Akihiro Sato, Takeshi Kuwata, Motohiro Kojima, Takahiro Kinoshita, Kohei Shitara
Journal: Journal of Clinical Oncology (2024)

309 Background: Currently no HER2 directed therapy is available in the perioperative setting for gastric and gastroesophageal junction (GEJ) cancer. Trastuzumab deruxtecan (T-DXd) received regulatory approval based on the encouraging efficacy demonstrated in the DESTINY-Gastric01 and DESTINY-Gastric02 studies in pretreated patients (pts) with metastatic gastric and GEJ cancer. This multicenter phase 2 study aimed to evaluate the clinical activity and safety of neoadjuvant T-DXd for locally advanced gastric and GEJ cancer. Methods: Eligible pts possessed previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort enrolled pts exhibiting HER2-positivity, defined as IHC 3+ or IHC 2+ with ISH+ by local assessment. An exploratory cohort included patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with serum HER2-ECD exceeded 11.6 ng/ml. Treatment included three cycles of T-DXd administered every 3 weeks, followed by surgery. The primary endpoint was the major pathological response (MPR) rate by central assessment, with an expected rate of 45% and a futility threshold of 20%. The planned sample size in the main cohort was 27 pts with one-sided alpha of 10% and power of 90%, while an additional 10 pts would be enrolled into the exploratory cohort. Pre- and post-treatment samples were subjected to biomarker analyses. Clinical trial identification: NCT05034887. Results: Between November 2021 and November 2022, 27 pts were enrolled into the main cohort from seven Japanese sites. The majority of the pts had IHC3+ (24pts). The primary sites were gastric (16 pts) and GEJ (11 pts). Clinical stages ranged from II/III/IVa: 2/21/4 pts. Of the cohort, 26 pts completed planned 3 courses of T-DXd and one pt discontinued because of toxicity. R0 resection was achieved in 25 pts, with one undergoing R1 resection. The MPR rate as the primary endpoint was 14.8% (80% CI 6.6 % - 27.5 %) which did not surpass the predefined 20%. The pCR rate was 3.7% (95% CI 0.1 % - 19.0 %). There were no new safety signals during T-DXd treatment and during the post-surgery phase. Biomarker analyses remain ongoing. Conclusions: T-DXd monotherapy showed modest single agent activity for locally advanced HER2-positive gastric or GEJ adenocarcinoma in this phase 2 study. An additional cohort combining perioperative T-DXd with capecitabine and durvalumab is planned, to assess whether treatment efficacy and outcomes can be enhanced. Clinical trial information: NCT05034887 .
Impact of next-generation sequencing in biliary tract cancer treatment.
Authors: Priya Goyal, Mahmoud Ouf, Seema Agarwal, Gary Kupfer, Reetu Mukherji, Benjamin Adam Weinberg, Marcus Smith Noel, John Marshall, Aiwu Ruth He
Journal: Journal of Clinical Oncology (2024)

560 Background: Incorporating molecular profiling in BTC treatment has increased. With this study, we aimed to analyze the impact of molecular profiles on the survival of patients with BTC. Methods: This is the retrospective analysis of patients with biopsy-proven biliary tract cancer at our comprehensive cancer center GI oncology clinic from 2018-2022. Only patients with continued care at Lombardi Comprehensive Cancer Center were included in the study. Results: Of 217 patients screened; 160 patients were included in the final analysis. The mean age of the cohort was 63 years, and the majority were females (55%). In the order of frequency, intrahepatic cholangiocarcinoma (77.5%) was the most common type of cancer followed by extrahepatic cholangiocarcinoma (15.6%), and carcinoma of the Gallbladder (6.9%). Molecular profiling was performed in 49.4% of the patients and actionable mutations for FDA approved treatments or clinical trial enrollment were found in 42 patients (26.3%) of the patients. The spectrum of actionable mutations in decreasing order of frequency was KRAS (n=11), FGFR2 (n=9), IDH-1 (n=8), Her-2neu (n=5), BRCA1/2 (n=5), &amp; PD-L1(n=4). Patients who underwent molecular profiling had significantly better survival (43±5 months vs. 25±4, p 0.013). Notably, patients with actionable mutations had even better survival as compared to the rest of the cohort (52±8 months vs. 26±7 months, p 0.019). Conclusions: BTC exhibits diverse genetic alterations. Patients who underwent molecular profiling as a part of the treatment plan had better survival. Identifying actionable mutations was associated with even better survival.
Surveillance of resected metastatic colorectal cancer utilizing circulating DNA.
Authors: Nikolas Naleid, Kevin Zablonski, Hanna Kakish, Melissa Amy Lumish, David L Bajor, J. Eva Selfridge, Madison Conces, AMR MOHAMED, Sakti Chakrabarti, Amit Mahipal
Journal: Journal of Clinical Oncology (2024)

214 Background: There is limited data to guide surveillance in patients with metastatic colorectal cancer (CRC) who have had curative resection using circulating tumor DNA (ctDNA) in addition to labs and imaging studies. Minimal residual disease (MRD) assays utilize circulating tumor DNA (ctDNA) for the purposes of monitoring for early recurrence and predicting therapeutic response. In this study, we aim to investigate the utility of ctDNA monitoring in the setting of resected metastatic CRC. Methods: Patients were identified through retrospective search at a tertiary care and several satellite settings to identify patients with metastatic CRC who had undergone curative resection and later had ctDNA monitoring (using Signatera assay). IRB approval was obtained for the study. We recorded demographic information (sex, race, age at diagnosis), disease characteristics (stage at diagnosis, site of primary cancer, site of metastasis), treatment regimens, clinical outcomes (recurrence, survival) and follow-up data. Our primary outcome was to evaluate the rate of recurrence in patients with metastatic CRC who had curative resection in two different population, ctDNA positive or ctDNA negative, post-surgery. Results: We identified 35 patients with a median age of 55 years (range 31 – 82) at the time of metastatic diagnosis. In this study cohort, 20 (57%) were female; 23 (66%) were white, and 10 (29%) were African American. 22 (63%) patients had left-sided primary tumors and the remaining (47%) had right-sided primary tumors. At the time of presentation, 23 (66%) patients had synchronous metastases and 12 (34%) developed metachronous metastases. ctDNA positivity was reported in 21 (60%) pts post-curative therapy. Median time from curative therapy to ctDNA positivity was 62 days. 22 (63%) pts experienced recurrence of disease post-curative resection. Median time to recurrence after ctDNA test was first positive was 6.6 months. Among 21 patients in ctDNA positive group, 19 (86%) developed recurrences and among 14 ctDNA negative patients, only 3 (21%) developed recurrences (p-value &lt;0.01). Recurrence free survival was significantly shorter in patients who were ctDNA positive post surgery (Median RFS: 7.17 months, 95% CI: 4.4-18.0 months) compared to those who were ctDNA negative (Median RFS: 30.8 months; 95% CI: 12.6-NR) (p-value=0.005). Conclusions: In patients with metastatic CRC who underwent curative resection ctDNA may have utility in predicting disease recurrence at both academic and community sites. Larger studies are needed for validation of ctDNA as an adjunct test for surveillance in broader population.