tbuckley/cabot-search huggingface dataset:
The genomic landscape of patients with advanced colorectal adenocarcinoma with <i>PIK3CA</i> mutations using comprehensive cell free tumor DNA next generation sequencing.
Authors: Nilesh Verma, Syed Mohammad Ali Kazmi, Jill Tsai
Journal: Journal of Clinical Oncology (2024)

181 Background: PIK3CA mutations ( PIK3CAm) are highly prevalent in advanced CRC but the prognostic value is unclear. PIK3CAm are associated with advanced stage disease, tumor aggressiveness, resistance to therapy, and a poorer prognosis. In some cases, PIK3CAm co-occur with other genetic alterations leading to complex signaling networks. Understanding these genetics are crucial to devise effective treatments. In this study, evaluated the genomic landscape of PIK3CAm in advanced CRC using cell free tumor DNA (ctDNA) next generation sequencing. Methods: This analysis assessed advanced CRC samples between 2020-2022 from the Guardant360 database using plasma-based ctDNA (~15000 patients, ~17000 samples). PIK3CAm were assessed by patient demographics, MSI-H status, TMB score, and frequency of co-occurring alterations via cbioportal. A sub analysis was collected between 2021-2022 (~8000 samples) to examine the frequency of PIK3CA exon 9 vs. 20 mutations between BRAF V600E and non- V600E BRAF mutations, and separately between KRAS G12C and G13D. Comparisons were analyzed by two-sided Fisher’s exact test. Results: PIK3CAm were detected in ~21% (~3500) of mCRC samples. Of these samples, the median age was 63 years old and the sex distribution was 56% males. MSI-H was reported in 3.3% of samples. PIK3CAm included 25% E545 (Exon 9), 13% E542 (Exon 9), 5% Q546 (Exon 9), and 10% H1047 (Exon 20). PIK3CAm had increased median alterations per sample to PIK3CA not detected (8 vs. 5) and a significant increase in co-occurrence with most genes in the panel. Relevant clinical co-occurrences were APC (73.7% vs. 57.4%), BRAF (19.9% vs. 13.0%), EGFR (34.7% vs. 24.9%), ERBB2 (9.2% vs. 6.0%), and KRAS (62.9% vs. 41.2%). Additionally, PIK3CAm samples had higher median TMB scores (13.4 vs. 9.8 mut/Mb), with &gt;25% of PIK3CAm reporting a TMB score above the 80 th percentile (20.19 mut/Mb). In a sub analysis, there were significantly greater frequencies of PIK3CAm in exon 20 in BRAF V600E samples vs. non-V600E BRAFm samples (p=0.0003) with no significant differences in exon 9 or 20 mutations in KRAS G12C vs. G13D. Conclusions: Our study shows the frequency of PIK3CAm and distribution of exons 9 and 20 are similar to those found previously in the literature by Tan (Xie) et al., 2022. Our results demonstrate PIK3CA having a low frequency of MSI-H co-occurrence, higher TMB scores, and increased co-occurring alterations with notable increased in APC, BRAF, EGFR, ERBB2 and KRAS, which may suggest higher genomic instability. Our findings underscore the clinical significance of PIK3CAm in the context of CRC, emphasizing their role as key drivers of oncogenesis, and supports the development of tailored therapeutic strategies such as combining PIK3CAi with immunotherapy or other targeted therapies.
Association of congestive heart failure (CHF) with incidence rates of enteric infections and gram-negative sepsis (GNS) in patients with hepato-pancreatico-biliary cancers (HPBCs).
Authors: Himil Mahadevia, Karnav Modi, Deepthi Vodnala, Marc Thomas Roth
Journal: Journal of Clinical Oncology (2024)

567 Background: ChronicCHF leads to volume overload and can cause bowel wall edema. This may compromise local immune defense and promote increased translocation of gut bacteria into the blood.HPBCs can cause biliary tract obstruction which is also associated with bacteremia. Additionally, cancer treatments are associated with an increased risk of clostridium difficile infection (CDI), regardless of antibiotic exposure. While associations between cancer and increased infection rates are well-established, we questioned whether concomitant CHF increases this risk further in the HPBC population. We therefore investigated whether concomitant CHF and HPBC influenced CDI, other infectious gastroenteritis (IGE), GNS rates or all-cause-hospital mortality. Methods: A retrospective study was conducted by obtaining patients with HPBC through the application of specific ICD 10 codes from the National Inpatient Sample 2020, a large publicly available database of inpatient hospital stays incorporating data from hospitals across 48 U.S. states. Among this cohort, patients with chronic CHF were further identified by applying all CHF-specific ICD 10 codes. All patients with HPBC were divided into two groups, one with CHF (group A) and the other without CHF (group B). Outcomes were compared between the two groups using multivariate regression analysis (MVRA) adjusting for demographic factors, hospital-specific characteristics like location, bed size, etc., comorbidities including obesity, diabetes, hypertension, prior cardiovascular events, HIV, CKD, OSA, etc., prior coronary intervention/surgery as well as alcohol, smoking or substance use. Results: 211,790 patients were identified with HPBC. 40.55% were female. 18,955 patients (9.95%) were found to have chronic CHF. The incidence of GNS was higher in group A compared to group B in the MVRA (Adjusted (Ad) OR: 1.4, CI 1.07-1.95, p=0.015). However, there was no difference in the incidence rate of CDI between groups A and B (Ad OR: 1.0, CI 0.71-1.50, p=0.86). Similarly, the two groups had no difference in other IGE (Ad OR: 1.0, CI 0.71-1.37, p=0.96). All-cause hospital mortality was slightly higher in group A than group B but failed to reach statistical significance (Ad OR: 1.1, CI: 0.99-1.29, p=0.069). Conclusions: GNS was more common in patients with HPBC who also had comorbid chronic CHF. Future investigations may focus on the effect of increased GNS on outcomes beyond hospitalization, correlation between the severity of CHF and GNS as well as primary site of HPBC and infection risk. Based on this signal-finding analysis, it is postulated that early inter-disciplinary collaboration between oncology and cardio-oncology/cardiology may have special significance in the management of patients with chronic CHF and HPBCs, the latter of which already carries a dismal prognosis.
First-line therapies in a Latino-rich cohort of US patients (pts) with hepatocellular carcinoma (HCC) and Child Pugh B (CPB) cirrhosis.
Authors: Moses Andrew Alfaro, Sukeshi Patel Arora
Journal: Journal of Clinical Oncology (2024)

453 Background: There are limited prospective clinical trials in patients with both HCC and CPB cirrhosis. As the prevalence of HCC and cirrhosis has been rising among Latinos in South Texas, it is crucial to examine the liver dysfunction within this demographic to understand the contributing factors to treatment patterns. Therefore, we conducted a retrospective analysis of 36 patients with both HCC and Child Pugh B (CPB) cirrhosis. Methods: A dataset of 65 patients with HCC and cirrhosis from 2009 – 2019 was used to identify 36 patients with CPB treated at a Latino-Rich NCI-designated Cancer Center. We further segmented patients of Child Pugh Class B by ALBI grades (1-3) to explore variations in demographics, liver dysfunction, and first-line therapies. Results: Median age overall of the cohort is 59 (50-71). Ethnicity: Latino White (83%), Non-Latino White (14%), Black (3%). Etiology: HCV (78 %) EtOH (50%), NASH (19%), and HBV (3%). ALBI Grade: I (6%), II (50%), III (44%). First line treatment in CPB: Sorafenib (86%), Nivolumab (8%), Lenvatinib (6%). Sorafenib was used across all ALBI grades, while Lenvatinib and Nivolumab were given only in ALBI II (Table). Conclusions: Sorafenib was more often given to patients with CPB cirrhosis, in the first line setting; however, more patients were treated with nivolumab or lenvatinib with ALBI II. Further investigation of survival based on ALBI levels and the trajectory of liver function over time in response to different treatment approaches is underway in a larger cohort who has received newer immunotherapy-based regimens. With more agents approved for HCC, prospective clinical trials are needed in CPB and HCC. [Table: see text]
Comparison between different therapeutic sequences in patients affected by metastatic pancreatic ductal adenocarcinoma.
Authors: Andrea Pretta, Riccardo Giampieri, Federico Nichetti, Pina Ziranu, Alessio Lupi, Giusy Moledda, Paola Andena, Cristiano Felicetti, Alessandra Pia D'Agata, Chiara Carlotta Pircher, Claudia Codipietro, Simone Rota, Daiana Rizzo, Giorgia Sanna, Eleonora Lai, Marco Puzzoni, Valeria Pusceddu, Rossana Berardi, Monica Niger, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

674 Background: The first-line treatment of metastatic pancreatic cancer involves different therapeutic regimens, among them, mFOLFIRINOX and gemcitabine-nabpaclitaxel. However, it remains to be clarified which sequence might correlate with better outcomes. The aim of our work was to evaluate which sequence leads to better overall survival in this setting. Methods: We retrospectively collected data from 358 patients affected by stage IV pancreatic ductal adenocarcinoma from 3 different Italian Institutions. Patients received mFOLFIRINOX or gemcitabine plus nabpaclitaxel as first-line chemotherapy, followed by a second-line non-cross-resistant chemotherapy (gemcitabine or fluoropyrimidine-based combinations). Survival distribution was assessed by Kaplan-Meier curves. The primary endpoint was median overall survival. Statistical analysis was performed with MedCalc package. Results: The median age was 66 (± 9), 195 (54,4%) were male and 163 (45,6%) were female. 292 (81,5%) patients start gemcitabine plus nabpaclitaxel as first line treatment, while 66 (18,5%) patients start mFOLFIRINOX first-line therapy. No statistically significant differences in terms of mOS were observed between the two mFOLFIRINOX and gemcitabine-nabpaclitaxel groups: 16 versus 15 months, respectively, p = 0,2). No significant differences were found in terms of mPFS either: 7 versus 8 months, respectively, p = 0,3). Conclusions: The results of our retrospective study showed no statistically significant survival advantage between the sequences starting with mFOLFIRINOX or with gemcitabine-nabpaclitaxel. Further studies will be necessary to establish the effectiveness of new therapeutic schemes to be introduced into clinical practice in order to define a better therapeutic algorithm.
Perceptions of cancer prevention options for Lynch syndrome (LS) in a multi-national convenience sample.
Authors: Michael J. Hall, Sachi Singhal, Nadine Osorio, Juan Pablo Chavez, Emma D. Riggs, Yana Chertock, Mary Beryl Daly
Journal: Journal of Clinical Oncology (2024)

77 Background: LS is among the most common cancer (CA) syndromes affecting 1:280 individuals and portends high lifetime CA risk. Clinical trials are currently evaluating whether frameshift peptide vaccination (FSPVAX) could reduce LS CA risk. FSPVAX enhances immune response to diverse FSP neoantigens in MSI-H tumors and has shown promising results in an MSH2-mutant mouse model and metastatic MSI-H CRC. However, negative public attitudes towards vaccination and evidence suggesting low uptake of ASA chemoprevention (CP) among patients with LS could undermine success of this novel therapy. Here, we benchmark attitudes towards FSPVAX for CA prevention against colonoscopy (COLO) and aspirin or NSAID chemoprevention (CP). Methods: The PREVENTLynchII survey (IRB 20-8014) was distributed electronically to 1) participants in the Fox Chase Cancer Center (FCCC) Risk Registry and 2) members of two online LS support groups. Patients were invited to complete the one-time survey after providing informed consent. Demographic and personal CA history were collected. Attitudes were measured on 9-point scales indicating low vs high agreement with belief statements: e.g. “Colonoscopy is a convenient way to lower my risk of LS-related CA.” Results: Overall 296 participants at FCCC, nationally, and internationally completed the survey. Median age was 52.6 years [23-78], 84% female, and 95% White. Affected genes included MLH1 (20.3%), MSH2/EPCAM (35.5%), MSH6 (28.7%), and PMS2 (15.5%). Use of CP was uncommon (32.1% and 5.1% respectively). Stratified analyses of COLO perceptions by sex, age, and personal history of CA showed no differences. Interestingly, US pts viewed ASA as more convenient than non-US, and with lower risk of side effects (p=0.007), but were no more likely to use or recommend CP. Compared to COLO, FSPVAX was overall viewed as more convenient, but side effect concerns were higher, and perceptions of efficacy were lower (all p&lt;0.001), while compared to CP, FSPVAX was less convenient and fostered greater concerns about side effects, but was viewed as having higher potential preventive efficacy (all p&lt;0.001). FSPVAX perceptions showed high variability: pts &gt;50 (p=0.003) and CA pts (p=0.01) saw FSP as more convenient (p=0.003) than younger and unaffected pts. CA pts reported higher reassurance than unaffected (p=0.04), while those &gt;50 were more likely to participate in an FSPVAX study (p=0.04). US pts perceived more side effect risk of FSPVAX than non-US (p=0.003). Conclusions: Concerns about ASA CP and FSPVAX convenience, side effects, and efficacy are common among US and international patients with LS. [Table: see text]
Disparities in surgical outcomes and survival based on insurance status among patients with fibrolamellar hepatocellular carcinoma: A national perspective.
Authors: Alec Czaplicki, Christopher Reese Bine, Aron Lee, Eric Nielsen, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2024)

440 Background: Fibrolamellar hepatocellular carcinoma (FL-HCC), encompassing 1%-5% of all liver cancers, is a rare, malignant cancer that typically affects patients less than 40 years old. FL-HCC usually affects individuals with healthy livers and initially presents asymptomatically. Prior studies describe the importance of surgery on survival, with a 5-year survival of about 44%-68% with surgery versus 2%-17% without surgery. Disparities in outcomes regarding surgical factors and survival between private insurance, Medicare, Medicaid, and no insurance remain unknown. This study aims to determine differential surgical factors and survival of patients with FL-HCC based on insurance status. Methods: The National Cancer Database was used to identify patients diagnosed with FL-HCC from 2004-2019 using the histology code 8171 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, Chi-Square, ANOVA, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 29 and statistical significance was set at α=0.05. Results: Of the 436 patients included, 241 (55%) had private insurance and 96 (22%) had Medicare. Patients with private insurance had a longer median survival (49 months) than patients with Medicare (18 months; p&lt;.001) and Medicaid (26 months; p&lt;.004);no significant survival difference existed between Medicare, Medicaid, and no insurance (39 months) ( p’s≥.063). After controlling for age, income, tumor size, adjuvant therapy, receiving surgery, and surgical margins of primary site, private insurance was associated with an independent decrease in hazard (HR=.899; p=.004).Patients with private insurance received more surgery (68%) than those with Medicaid (50%), no insurance (48%), and Medicare (32%) ( p’s&lt;.001); grade did not differ amongst insurance types ( p=.069).Furthermore, patients with private insurance had more surgical margins of the primary tumor site without residual tumor (57%) compared to those with Medicaid (40%), no insurance (38%), and Medicare (23%) ( p’s&lt;.001).While patients with Medicare presented with greater co-morbidities, age at diagnosis (67), tumor size (476 mm), positive regional lymph nodes (90), and days between diagnosis and treatment (45), patients with private insurance presented at a younger age (31) with fewer co-morbidities, smaller sized tumors (366 mm), and fewer days between diagnosis and treatment (26) ( p’s&lt;.018). Conclusions: Since patients with private insurance received the most surgery, best surgical margins, and displayed the highest overall survival, while patients with Medicare were diagnosed at the highest age with the largest tumor size and most positive regional lymph nodes, future research should explore ways to alleviate the disparity in factors affecting surgical resections and early diagnoses among insurance statuses.
Rectal cancer disparities in a large, diverse health system in New York.
Authors: Phyu Thin Naing, Vernon Wu, Daniel King
Journal: Journal of Clinical Oncology (2024)

16 Background: The disproportionate burden of colorectal cancer among African American (AA) patients is striking, with 40% increase relative risk of death compared to non-AA White population (Seer Cancer Statistics Review, 2022). NAPRC aims to ensure equitable delivery of evidence-based treatment to ensure optimal outcomes for all patients. Our study investigated whether care delivery outcomes differed for AA patients in our NAPRC cohort of patients, and explored the reasons associated with the disparities. Methods: Rectal cancer patients were identified by pooling 2019 to 2022 data from NAPRC coordinators from 4 regional sites under Northwell Health, spread across a large geographical area in NY: Westchester and Phelps (Northern), Lenox Hill (Western), NSUH/LIJ (Central), and Huntington (Eastern). The primary outcome was time from biopsy (Bx) to treatment (Tx) initiation, where Tx was rectal cancer resection, chemotherapy, or radiotherapy. The secondary outcome was time from tumor board (TB) to first Tx. Social deprivation index (SDI) is a composite measure of 7 demographic characteristics collected in the American Community Survey (ACS) matched with zip codes of patients. SDI and the deprivation severity have a positive and linear correlation. Results: We collected data on 381 patients; 337 had documented race data: 42 AA and 295 non-AA (includes White, Asians and others). AA, compared to non-AA, patients had significantly longer median time from Bx to Tx in Western (66 vs 42 days, p&lt;0.01) and Central (56 vs 41 days, p= 0.03) regions. AA patients also had higher time from TB to Tx in the Western (29 vs 17 days, p=0.01) and Central (26 vs 19 days, p= 0.05) regions, respectively. Longer time to treatment was associated with: AA patients, Medicare patients, and patients requiring social work assistance. SDI is positively correlated with time from Bx to Tx (p&lt;0.01) and time from TB to Tx (p&lt;0.01). Conclusions: There are significant disparities between AA vs Non-AA in both primary and secondary outcomes. These findings highlight the need for further exploration such as interviewing social workers and developing patient surveys to explore why the care disparities in AA population is more significant in certain regions than others. We need to account for race and social barriers in treating cancer patients. Taking a proactive approach by sending social work referrals for all AA patients may be a potential solution for these marginalized patients.
Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors.
Authors: Aparna Raj Parikh, Vedran Radojcic, Myles Clancy, Susan Brouwer, Shaliny Kushwaha, Yifan Huang, Nashat Gabrail
Journal: Journal of Clinical Oncology (2024)

TPS227 Background: Aberrant transcription in cancer can be reversed by targeting critical epigenetic regulators. For example, in acute leukemias driven by increased HOX gene expression, inhibition of the menin-KMT2A interaction by revumenib induced remission in patients with heavily pretreated disease (Issa et al 2023). In solid tumors promoted by the aberrant activation of the Wnt/β-catenin pathway, in vitro data and in vivo studies have shown that small molecule inhibition of the menin-KMT2A interaction restricts growth, with potential therapeutic benefit in colorectal cancer (CRC), castration-resistant prostate cancer, estrogen receptor–positive breast cancer, gastrointestinal stromal tumors, and Ewing sarcoma. To test the therapeutic strategy of inhibiting the menin-KMT2A interaction in solid tumor malignancies, this study (NCT05731947) will evaluate revumenib in patients with CRC and other solid tumors. Revumenib is an oral, potent, selective inhibitor of the menin-KMT2A interaction. Methods: This phase 1/2 study is evaluating revumenib in adults aged ≥18 years with locally recurrent or metastatic CRC who have failed ≥1 prior line of therapy and in patients with other solid tumors who have failed available standard therapies. Inclusion criteria include diagnosis of microsatellite stable/proficient mismatch repair CRC or other solid tumors. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti–epidermal growth factor receptor therapy. The primary phase 1 objectives are to determine the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose of revumenib in patients with CRC and other solid tumors and to assess its antitumor effects. The phase 2 primary objective is to assess the antitumor effects of revumenib by blinded radiographic review. Phase 1 consists of all-comers’ dose escalation (phase 1a), and signal-seeking expansion in CRC (phase 1b). Using a rolling 6 design, the revumenib starting dose will be 163 mg 3 times daily in 28-day cycles. Up to 6 patients will be enrolled in a dose cohort. Dose escalation cohorts may be expanded and used for signal seeking in non-CRC tumor types. Phase 1b in CRC will begin when a potential phase 2 dose has been identified. The disease control rate at 6 cycles and overall response rate will be used to assess antitumor activity and will determine initiation of phase 2. In phase 2, patients with advanced CRC will be randomized 2:1 to revumenib or investigator's choice of 1 of 2 standard-of-care therapies. Patients will be followed for progression-free survival, with response assessments evaluated locally and confirmed by blinded radiographic review. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947 .