bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive clinico-molecular profile and efficacy of anti-HER2 therapy for HER2-amplified biliary tract cancer.
Authors: Inoue Kanae , Nakamura Yoshiaki , Caughey Bennett , Zheng-Lin Binbin , Ueno Makoto , Furukawa Masayuki , Kawamoto Yasuyuki , Itoh Shinji , Umemoto Kumiko , Sudo Kentaro , Satoh Taroh , Mizuno Nobumasa , Kajiwara Takeshi , Fujisawa Takao , Bando Hideaki , Yoshino Takayuki , Strickler John H , Bekaii-Saab Tanios S. , Morizane Chigusa , Ikeda Masafumi
Published: January 2024

544

Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.
Artificial intelligence (AI)-powered tumor microenvironment (TME) analysis to identify potential biomarkers for ICIs with or without bevacizumab in hepatocellular carcinoma (HCC).
Authors: Chon Hong Jae , Kim Gwangil , Kang Beodeul , Hong Jung Yong , Kang Haeyoun , Hwang Sohyun , Lee Sung Hwan , Jung Sanghoon , An Chansik , Lee Won Suk , Kim Seulki , Lim Yoojoo , Ali Siraj Mahamed , Ock Chan-Young , Lim Ho Yeong , Kim Chan
Published: January 2024

549

Background: While immunotherapies have been approved for use in HCC patients, there is a need for validated predictive biomarkers that correlate with treatment outcomes. We investigated whether AI-powered spatial analysis of non-cancerous cells within the TME can be potential biomarkers for ICIs with or without bevacizumab in advanced HCC. Methods: Analysis of images of H&E-stained slides was conducted by an AI model, Lunit SCOPE IO in pre-treatment tumor samples of 163 HCC patients treated with atezolizumab plus bevacizumab as first-line ( n=82), or monotherapies of nivolumab or pembrolizumab as ≥ second-line ( n=81) at CHA Bundang Medical Center or Samsung Medical Center. We analyzed the correlation between clinical outcomes after the treatment and AI-powered TME-related variables, including TILs and endothelial cells, within intratumoral or stromal areas. Inflamed immune phenotype (IIP) was defined as cases exhibiting enrichment of intratumoral TILs. Results: Baseline characteristics, including Child-Pugh liver classification, Barcelona Clinic Liver Cancer stage, and hepatitis B virus, were well-balanced between treatment regimens. IIP was predictive of longer progression-free survival (PFS) of nivolumab or pembrolizumab monotherapy (median PFS 4.7 months for IIP vs. 2.2 months for non-IIP; hazard ratio [HR] 0.50; 95% confidence interval [CI] 0.25-0.99; p=0.042), but not PFS of atezolizumab plus bevacizumab (median PFS 6.8 months vs. 6.2 months; HR 0.92; 95% CI 0.50-1.69; p=0.762). PFS of atezolizumab plus bevacizumab was significantly longer in cases harboring intratumoral endothelial cell density in the highest quartile (median PFS 6.7 months for upper 25% vs. 3.9 months for lower 75%; HR 0.51; 95% CI 0.27-0.97; p=0.037), while there was no significant difference in PFS of pembrolizumab or nivolumab monotherapy (median PFS 2.3 months vs. 2.8 months; HR 1.02; 95% CI 0.59-1.77; p=0.935). Conclusions: AI-powered TME analysis shows IIP is predictive of longer PFS with ICI monotherapies, whereas intratumoral endothelial cell density is specifically associated with PFS of atezolizumab plus bevacizumab in advanced HCC. The latter finding may suggest efficacy of combined VEGFRi and ICI activity is dependent on the amount of baseline tumor vasculature.
Real-world analysis of patients with advanced gastrointestinal (GI) cancers harboring inactivating TSC1 and TSC2 alterations using the Foundation Medicine genomic database.
Authors: Deming Dustin A. , Alonzo Palma Norma , Navarro Willis H. , Iyer Gopa , Kwiatkowski David J.
Published: January 2024

558

Background: Genomic profiling of GI tumors can identify potentially actionable genetic alterations, ultimately leading to better outcomes in patients who currently have few treatment options. In exploratory biomarker analyses of patients with perivascular epithelioid cell tumors treated with the mTOR inhibitor nab-sirolimus (AMPECT, NCT02494570), those with inactivating alterations in the tumor suppressor genes TSC1 or TSC2 (critical negative regulators of mTOR activity) had confirmed responses (8/9 patients with inactivating TSC2 alterations and 1/5 patients with inactivating TSC1 alterations). PRECISION 1, a currently enrolling tumor-agnostic study, will evaluate nab-sirolimus in patients with TSC1 or TSC2 alterations. To enumerate the frequency of these alterations in GI cancers, we analyzed data from a real-world genomic database. Methods: Next-generation sequencing (NGS) data from Foundation Medicine’s genomic database of patients with advanced cancer were analyzed using the FoundationInsights web-based platform to identify patients with GI cancers who had inactivating TSC1 or TSC2 alterations (short variants [base substitutions, insertions and deletions], rearrangements, and copy number deletions). Tumor mutational burden (TMB), microsatellite instability status and other mutations were also characterized in this group of patients. Results: As of 29 March 2022, tumor tissue NGS data were available for 5816 patients with GI cancers bearing alterations in TSC1 or TSC2. Of these, 1642 patients had at least one inactivating alteration. The GI tumor types that most frequently expressed inactivating alterations in TSC1 or TSC2 were hepatocellular carcinoma (alterations in 6.5%); colorectal adenocarcinoma (1.7%); gastrointestinal stromal tumors (1.7%); and cholangiocarcinoma (1.6%). Of all 1642 patients, 688 were female, and most (74%) were 51–80 years of age when the sample was obtained. Of patients with inactivating TSC1 and TSC2 alterations, 37.6% were in TSC1 and 62.9% were in TSC2 and included short variants (31.3% and 48.4%), rearrangements (2.7% and 6.6%), and copy number deletions (3.5% and 7.4%), respectively. TMB was low (<6 mutations/megabase) in 58% of patients, and most patients had microsatellite stable (MSS; 71.3%) tumors. Other commonly mutated genes in this cohort were TP53 (62.7%), APC (38.5%) and KRAS (30.4%). Conclusions: TSC1 and/or TSC2 alterations were commonly observed in GI cancers. These cancers were frequently microsatellite stable and of low TMB suggesting that these are actionable alterations that may be candidates for targeted therapy. This hypothesis is being tested in the PRECISION 1 (NCT05103358) trial which is open for enrollment or just-in-time clinical trial sites and available to patients with GI cancers harboring TSC1 or TSC2 alterations.
APC as a high-utility mutational biomarker that may identify subpopulations of patients with mutant RAS/BRAF and right-sided colorectal cancer (CRC) who derive benefit from EGFR inhibitors (EGFRi).
Authors: Thota Ramya , Yeatman Timothy , Gandhi Nishant , Yang Mingli , Schell Michael , Pflieger Lance , Loboda Andrey , Nebozhyn Michael , Elliott Andrew , Xiu Joanne , Sledge George W. , Khushman Moh'd M. , Lou Emil , Goel Sanjay , Pledger Warren Jack
Published: January 2024

56

Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type ( KRASWT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC ( APCMUT) and TP53( TP53MUT) might predict cetuximab sensitivity, particularly in RASWT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53MUT/ APCMUT were associated with improved E-OS compared to TP53MUT alone (hazard ratio [HR]=0.565, p<0.00001), APCMUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APCWT, APCMUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APCMUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p<0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker ( APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. [Table: see text]
Patient factors and survival outcomes of pancreatic signet cell carcinoma: A comprehensive review and analysis.
Authors: Lee Aron , Bine Christopher , Czaplicki Alec , Nielsen Eric , Silberstein Peter T.
Published: January 2024

608

Background: Pancreatic signet cell carcinoma is an aggressive, rare subtype of pancreatic adenocarcinoma that constitutes less than 1% of all pancreatic cancers. This subtype can manifest as solitary cells or a cluster within the background of pancreatitis, often leading to an incorrect diagnosis during biopsies. The rarity and challenges associated with its diagnosis significantly impact its poor prognosis. With an average age of diagnosis of 67.3 years and a median life expectancy of 12.6 months, there exists a lack of information on the disparities that exist in these patients and how patient demographics contribute to differences in survival outcomes. Methods: We used the National Cancer Database to identify patients diagnosed with pancreatic signet ring cell carcinoma (ICD-O-3 histology code 8490) between 2004-2019 (N=1746). Survival was evaluated using Kaplan-Meier curves and log-rank tests. Significance was set at p<0.05. Results: When analyzing insurance status, patients with private insurance had a statistically improved survival outcome (14.3 months) compared to those with Medicare (11.3 months), Medicaid (9.2 months) and without insurance (11.8 months) (p<0.05). Patients with private insurance had fewer positive regional lymph nodes (73), lower grade/differentiation (5.80) and an average tumor size of 444.40 millimeters. Patients treated at academic research programs had a statistically better survival outcome (15.1 months) compared to patients treated at comprehensive community (10.4 months) and integrated network (9.1 months) programs (p<0.001). Surgical treatment had statistically improved survival outcomes compared to non-surgical treatment (p<0.001) with the majority of these procedures being a partial pancreatectomy and duodenectomy with a partial gastrectomy. More patients received surgical intervention at academic research programs (p<0.001), and patients with private insurance predominately attended academic research programs (p<0.001). Conclusions: Factors associated with increased survival outcomes include insurance status, positive regional lymph nodes, grade/differentiation, treatment facility type and surgical intervention. These findings make a valuable contribution to the ongoing research on disparities affecting survival in patients with pancreatic signet cell carcinoma.
Improving timeliness and equity in germline genetic testing for pancreatic ductal adenocarcinoma patients: A comparative analysis and future strategies.
Authors: Zou Xianghui , Sidiqi Baho , Nguyen Cathy , Chen Ellen , Kauff Noah D. , King Daniel
Published: January 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 (c2=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.
Developing cell-free DNA (cfDNA) epigenetic signature (ep-Sig) for early detection of malignant transformation of intraductal papillary mucinous neoplasms (IPMN).
Authors: Manne Ashish , Jogi Soumya , Sara Amir , Sheel Ankur , Jeepalyam Sravan , Esnakula Ashwini K.
Published: January 2024

616

Background: Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers with poor outcomes. Around 20% arise from premalignant lesions (PML) including IPMN. Current guidelines recommend risk stratifying IPMN based on the location, size, and imaging characteristics after first diagnosis, followed by endoscopic ultrasound (EUS) in high-risk populations, and annual or bi-annual imaging. This approach can be improved with cfDNA testing. Traditional mutation testing in cfDNA is not useful secondary to their poor prevalence/detection rates. We propose ep-Sig to improve surveillance and early detection of PDA transformation. Methods: We curated an 11-gene cfDNA ep-Sig from the literature with a proven role in the malignant transformation of IPMN. Evidence suggests that epigenetic changes in every gene of this panel have a role in carcinogenesis in IPMNs. We compared RNA and gene expression of the genes in this ep-Sig between normal (NT) and PDA tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. We used cell-free epigenome atlas (CFEA) database to examine the prevalence of these markers in cfDNA of PDA patients. Results: RNA expression of all the genes from the ep-Sig combined was significantly lower in PDA than NT (0.45, p=3.13e-26). Gene expression was 8/11 genes was lower in PDA tissues than NT (0.44, p=3.13e-26). The other 2 genes were not detected in the tested samples. Prevalence of all the markers in ep-Sig was > 90%. Conclusions: Our proposed ep-Sig has a high prevalence in PDA patients and has reliable preliminary evidence in tissues suggesting its diagnostic value. This study is the first step in developing non-invasive cfDNA testing with the potential to improve the current surveillance strategies for IPMN pending larger prospective studies.
Cardiometabolic risk comorbidities in exocrine pancreatic insufficiency compared to patients with cancer: A single centered observational retrospective cohort study.
Authors: Peeples James , Gore James , Romo Karina G. , Noor Abdullah A. , Uwaifo Gabriel I.
Published: January 2024

642

Background: Exocrine pancreatic insufficiency (EPI) is characterized by inadequate secretion of digestive enzymes. EPI is associated with increased risk for pancreatic cancer as well as increased risk for diabetes and consequently cardiometabolic (CM) risk equivalents. Emerging data suggest patients with cancer also have increased CM risk equivalents. To explore the cardiovascular risk associated with both EPI and cancer, we sought to describe and compare CM comorbidities and surrogates in patients with EPI vs cancer. Methods: A retrospective observational electronic chart analysis was done at Ochsner Health, Louisiana, spanning records from January 2017-2020 comparing two cohorts: patients with EPI (n=677) and patients with Cancer (n=1432). Results: The Cancer cohort was older (65.1 ± 11.9 yrs) than the EPI cohort (54.2 ± 17.6 yrs) (p < 0.05). The Cancer cohort had higher AST levels (63.2 ± 106.2 U/L [nl 8-33 U/L] at start, 84.9 ± 447.3 U/L at end) vs the EPI cohort (50.2 ± 86.9 U/L at start, 65.4 ± 368.9 U/L at end) (p < 0.05). The Cancer cohort also had higher ALT levels (69 ± 111.4 U/L (nl 7-55 U/L) at start, 58.5 ± 141.2 U/L at end) vs the EPI cohort (48.7 ± 79.5 U/L at start, 41.4 ± 100.3 U/L at end) (p < 0.05). No significant differences were seen in Cancer cohort vs EPI cohort for A1c, TG, amylase, lipase, cholesterol, uric acid, tobacco/alcohol use, or blood pressure levels. Within the Cancer cohort, there was an increase in neuropathy (11% at the start vs 26.9% at end [p < 0.05]), CHF (3.63% at the start vs 11.5% at end [p < 0.05]), and HTN prevalence (29.9% at the start vs 66.1% at end [p < 0.05]). Cancer patients also had decreased weight (175.2 ± 46.5 lbs at start, 163.8 ± 43.4 lbs at end [p < 0.05]) and BMI (27.3 ± 6.5 at start, 25.7 ± 6.4 at end [p < 0.05]). Among the general cancer cohort, no statistically different changes were seen in hypoglycemia, DKA, retinopathy, nephropathy, ESRD, dialysis, HLD, NAFLD, OSA, CAD, CVD, PAD, hyperuricemia, or gout prevalence over the period of observation or in comparison to EPI cohort. Conclusions: Patients in the Cancer cohort in this study have some indices of greater CM risk compared to those with EPI. Though older, they had significantly higher AST and ALT levels compared to EPI cohort. Over the 3 years of observation, cancer patients developed a statistically significant increase in neuropathy, CHF, and HTN prevalence, and decrease in weight and BMI. These changes may reflect consequent morbidity related both to natural disease progression and/or effects of cancer treatments such as chemotherapy.
Incorporating stereotactic body radiation therapy for inoperable pancreatic cancer.
Authors: Lukez Alexander , Hasler Jill S. , Reddy Sanjay S. , Dotan Efrat , Astsaturov Igor A. , Lynch Shannon M. , Sorice Kristen A. , Meyer Joshua E.
Published: January 2024

656

Background: The management of inoperable pancreatic cancer (PC) is controversial. We sought to compare local progression (LP) for inoperable PC managed with chemotherapy (CHT) and/or stereotactic body radiation therapy (SBRT). Methods: This single-institution retrospective review analyzed 94 patients diagnosed with locally advanced (LA), medically inoperable, or metastatic PC between 2014 and 2022. Patients received CHT alone, sequential (seq) CHT + SBRT, or SBRT alone. The primary endpoints were LP and intervention due to local progression (ILP) from start of treatment. Obstructive symptoms needing intervention, percutaneous endoscopic gastrostomy tube, gastrojejunostomy, or bleeding needing transfusion were considered ILP. Primary tumor growth on imaging or ILP were defined as LP. Fine-Gray regression models with treatment received considered a time-varying covariate were used to compare ILP and LP between treatment groups where death without LP was treated as a competing risk adjusting for ECOG, stage, age and year of diagnosis. In the subgroup of patients who received SBRT, patients were stratified at the median time between diagnosis and receipt of SBRT, and risk of ILP and LP was compared between the groups using cause-specific cumulative incidence functions. Results: Of 94 patients, 51 had CHT alone, 21 received seq CHT + SBRT, and 22 had SBRT alone. The median year of diagnosis was 2019 (range, 2014 - 2022). The median ECOG was 1 with worse ECOG in SBRT alone and seq CHT + SBRT groups (p = 0.012). There were more LA or metastatic cases in the CHT (78%) and seq CHT + SBRT groups (67%) compared to the SBRT group (23%) [p < 0.001]. The median SBRT dose was 36Gy (range, 25 – 40Gy) in 5 fractions. Rates of LP and ILP were higher for CHT alone (68.6%, 39.2%) compared to seq CHT + SBRT (42.9%, 38.1%) or SBRT alone (18.2%, 4.5%) [p < 0.001; p = 0.004]. Higher rate of ILP associated with an increasing year of diagnosis (HR = 2.03, p < 0.005) and younger age of diagnosis (HR = 0.922, p = 0.011). The median time to SBRT was 116 days. Early (< 116 days) vs late SBRT LP rates differed (ILP: 4.8% vs 30%, LP: 14.3% vs 40%). Cause-specific cumulative incidence functions showed that death without LP favored early vs late SBRT (p = 0.009). Additionally, death without ILP favored early vs late SBRT (p=0.011). Conclusions: LP rates are high among patients with inoperable PC. SBRT for inoperable PC provides reasonable local control. Early SBRT reduces the need for ILP before death compared with late SBRT. Further investigation into the role of SBRT for inoperable PC is necessary. [Table: see text]
A phase II study of maintenance rucaparib in patients with platinum sensitive, advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2: A four year survival update.
Authors: Reiss Kim Anna , O'Hara Mark H. , Teitelbaum Ursina R. , Karasic Thomas Benjamin , Schneider Charles John , Pratz Caroline F. , Nathanson Katherine L. , Vonderheide Robert H. , Domchek Susan M.
Published: January 2024

661

Background: We previously reported the results of a single arm, phase II study of maintenance rucaparib in patients with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2 or PALB2 variants (Reiss et al, JCO, 2021). We now report the five year follow-up of this trial. Methods: Patients with advanced PC and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 were enrolled in this single arm phase II study performed at the Abramson Cancer Center. Patients were required to have received ≥16 weeks of platinum-based treatment without evidence of platinum resistance, which was defined as growing lesions, new lesions or steadily rising tumor markers. Chemotherapy was discontinued and patients received rucaparib 600mg PO BID until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: Of 42 evaluable patients, seven (16.7%) remain progression-free for over four years (5 gBRCA2, 1 sBRCA2, 1 gPALB2) of whom four (9.5%) have been progression-free for five years. Two of these four patients discontinued rucaparib due to adverse events after three and four years of therapy, respectively, without signs or symptoms of progression to date. At the cutoff date, we observe an mPFS 12.9 months, mOS 24.3 months, ORR 41.6% (9 PRs, 6 CRs), noting that three patients converted from partial to complete response since our prior publication. Two patients with ongoing responses succumbed to treatment-related MDS/AML following 2.1 and 4.8 years on study, respectively. Prior to receiving rucaparib, these individuals had received 13 and 10 months of cytotoxic chemotherapy for pancreatic cancer, respectively. Conclusions: Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date. Given the cost and risk of treatment-related leukemia associated with PARP inhibition, this data highlights the need to better understand the highly variable biology of patients with PC and BRCA or PALB2 variants, and raises the possibility of whether a very small, select group may be cured by PARP inhibitors. Clinical trial information: NCT03140670 .
Patient-reported outcomes: The unmet needs of the gastrointestinal cancer community.
Authors: Raymond Martha , Simonetta Margaret-Ann ,   GI Cancers Alliance Membership
Published: January 2024

731

Background: According to the World Health Organization International Agency for Research on Cancer, gastrointestinal (GI) cancers account for 1 in 4 cancer cases and 1 in 3 cancer-related deaths worldwide. An estimated 4.8 million new cases of GI cancers and 3.4 million related deaths occur annually. Understanding the need for increased GI cancer awareness, patient education and support, the GI Cancers Alliance developed a series of engagement activities for the GI cancer community as a needs assessment to identify critical gaps in support services, fragmented education, and disease awareness. Methods: Our 12-month patient-reported outcomes (PRO) research included an online anonymous survey, individual and small group interviews, focus groups, advisory boards, and an interactive workshop at the 2023 American Society of Clinical Oncology annual meeting. 1,122 patients participated during this 12-month PRO research period. Participants reported being diagnosed with one of the following GI cancer primary tumor types: Anus (3%), Appendix (2%), Bile Duct (6%), Colon (19%), Esophagus (7%), Gallbladder (5%), Gastric (14%), GI NET / GI Carcinoid Tumor (3%), Liver (7%), Pancreas (6%), Small Intestine (4%), Rectum (23%), Unknown primary location (1%). Results: Overarching areas of unmet need include: health disparities throughout the care continuum for underserved populations (21%); lack of adequate precision oncology patient education, including biomarker education and testing (19%); the rise of early-age onset (EAO) in GI cancers and the unique needs of the young adult (YA) population (18%); nutritional wellness education (17%); insufficient support for family caregivers and caregiver respite services (16%) scarcity of patient-centered care and adequate patient-clinician communication (11%). Conclusions: Our PRO research underscores the unmet needs and gaps in support services of the GI cancer community. Our global call to action includes partnering with our 100+ member organizations to amplify the patient voice and patient-lived experience, and cross-collaboration with our community of advocates, patients, caregivers, and clinicians. Our shared call to action and continued collaboration provides a greater impact for our GI cancer community to help meet patient needs and eliminate critical gaps in services.
Examining the prevalence of anxiety and depression in surgical oncology patients: Results of a prospective cohort study.
Authors: Li Judy , Khajoueinejad Nazanin , Sarfaty Elad , Yu Allen , Troob Samantha , Buseck Alison , Correa Camilo , Magge Deepa , Sarpel Umut , Cohen Noah A
Published: January 2024

734

Background: Prospective data assessing prevalence of anxiety and depression in a diverse surgical oncology population are currently lacking. Psychological distress may affect patient outcomes in the postoperative setting. The General Anxiety Disorder (GAD) and Patient Health Questionnaire (PHQ9) surveys are validated instruments to assess severity of anxiety and depression, respectively. We aimed to determine the prevalence of anxiety and depression using validated screening tools, and assess associations between anxiety and depression with clinical outcomes in patients presenting to our surgical oncology clinic. Methods: A prospective, surgeon-blinded study was conducted to assess associations of anxiety and depression with postoperative outcomes in patients with histologically proven malignancy who underwent surgical intervention. Preoperatively, the GAD and PHQ9 surveys were administered to evaluate for anxiety and depression, respectively. Frailty level was also assessed using the validated Risk Analysis Index (RAI-C) survey. Postoperative outcomes included rates of ICU admission, 30- and 90-day readmissions, postoperative complications classified by Clavien-Dindo score, and disposition to home versus rehabilitation facilities. Outcomes were compared between different groups as defined by the severity of anxiety and depression. Results: 191 patients met inclusion criteria. The cohort was stratified into three groups by severity of anxiety and depression. Overall, 59 (31%) patients reported at least moderate anxiety as defined by a GAD score ≥5, with 30 (15.7%) patients reporting severe anxiety (GAD score ≥ 10). Similarly, 62 (32%) patients reported at least mild depression as defined by a PHQ9 score ≥5, with 21 (11%) patients experiencing moderate to severe depression (PHQ9 ≥ 10). No difference was detected in length of stay, ICU admission, 30- and 90-day readmission, and postoperative complications. Preoperative frailty, as defined by RAI-C score >21, was also not associated with anxiety or depression. Marital status of single or widowed was found to be significantly associated with mild depression (p=0.027) and moderate to severe depression (p=0.028), respectively. Conclusions: While anxiety and depression were not found to be significantly associated with postoperative outcomes, they are prevalent in surgical oncology patients, affecting approximately one-third of our patient population. The GAD and PHQ9 surveys are validated instruments that can be administered easily to identify surgical oncology patients with psychological distress. Comprehensive evaluation of psychological well-being, in conjunction with a thorough social evaluation, can identify those patients who may benefit from referral to supportive resources.
Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Final analyses from INTRIGUE.
Authors: Zalcberg John Raymond , Jones Robin Lewis , Blay Jean-Yves , George Suzanne , Gelderblom Hans , Schöffski Patrick , von Mehren Margaret , Kang Yoon-Koo , Abdul Razak Albiruni Ryan , Trent Jonathan C. , Attia Steven , Le Cesne Axel , Davis Erika , Achour Haroun , Sherman Matthew L. , Ruiz-Soto Rodrigo , Bauer Sebastian , Heinrich Michael C. ,   on behalf of the INTRIGUE study investigators
Published: January 2024

748

Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]
Comprehensive genomic profiling of squamous cell carcinoma of unknown primary presenting with liver metastases.
Authors: Robinson Hannah Ruth , Davis S. Lindsey , Pavlick Dean C. , Murugesan Karthikeyan , Wong Katy Ann , Lam Elaine T. , Ross Jeffrey S. , Lieu Christopher Hanyoung
Published: January 2024

755

Background: Carcinomas of unknown primary (CUPs) are comprised of metastatic cancers for which a primary tumor of origin cannot be identified despite a full diagnostic workup. They frequently present with liver metastases, which portend a poor prognosis. Strategies employing comprehensive genomic profiling (CGP) to identify targeted treatments for CUPs have shown potential. Despite this, the molecular landscape of squamous cell carcinomas of unknown primary (SCCUPs) remains poorly defined. This study describes the results of CGP testing in patients with SCCUPs identified in the Foundation Medicine, Inc. database, with a focus on those with liver involvement. Methods: Cases of SCCUPs with FoundationOne CDx (F1CDx) assay results were identified based on a reported diagnosis of CUP and the presence of SCC histology. Cases then underwent central pathologist review and were excluded if a known primary site could be determined based on histology and disease location. Cases with liver involvement were selected based on the site of tissue biopsy. Genomic analyses of identified cases were assessed using the FoundationCORE database. Results: Sixty-nine cases of SCCUP presenting with liver involvement were identified. Alterations were observed in 102 of 324 (31.5%) genes evaluated by the F1CDx assay in at least 1 patient. The most frequently altered genes were TP53 (66.7%) , CDKN2A (33.3%) , CDKN2B (23.2%) , KRAS (21.7%; 0% G12C) , PIK3CA (18.8%), NFE2L2 (11.6%), SOX2 (11.6%), M2M2 (10.1%), and MTAP (10.1%). No patients had microsatellite instability-high disease, only 6 (8.7%) patients had a tumor mutational burden (TMB) ≥ 10, and 11 (15.9%) patients had evidence of HPV infection. Among 33 patients with available PDL-1 testing results, 7 (21.2%) had high-positive expression. An additional 374 cases of SCCUP were identified with involvement outside of the liver. Compared to these cases, patients presenting with liver involvement had less genomic alterations per tumor (5.10 vs 6.71, p=0.005), and were less likely to have TMB ≥ 10 (8.7% vs 38.0%; odds ratio [OR] 0.16, p<0.001). KRAS mutations were observed in 21.7% of those presenting with liver metastases compared to 8.3% of other SCCUP patients (OR 3.07, p=0.07). Conclusions: SCCUPs presenting with liver metastases had reduced numbers of genomic alterations and decreased TMB compared to other SCCUPs, suggesting these tumors may be less likely to respond to immunotherapy. Despite this, 36.2% of these patients had at least one alteration that could potentially guide targeted treatment decisions including entry into biomarker-driven clinical trials. Interestingly, there was a trend toward increased KRAS alterations in those with liver metastases. To our knowledge, this is the first report that describes the genomic landscape of SCCUPs presenting with liver metastases.
Real-world analyses of BRAF alterations in patients with non-colorectal gastrointestinal cancers.
Authors: Mahipal Amit , Teslow Emily , Jaeger Ellen B. , Stoppler Melissa Conrad , Jin Zhaohui , MOHAMED AMR , Lumish Melissa Amy , Conces Madison , Chakrabarti Sakti
Published: January 2024

759

Background: BRAF V600E mutations are present in 5-10% of patients with advanced colorectal cancer (CRC) and associated with poor prognosis. Recently, there was tumor agnostic FDA approval of dabrafenib + trametinib for BRAF V600E mutated solid tumors. However, the frequency of BRAF alterations ( BRAF alt), especially non-V600E, in other gastrointestinal (GI) cancers are not well described. This study characterizes BRAF alt in CRC vs other GI cancers (non-CRC). Methods: De-identified records from 51,560 patients diagnosed with GI cancers were retrospectively analyzed from the Tempus database. The molecular landscape including presence of pathogenic/likely pathogenic BRAF alt was evaluated by panel-based tissue DNA, RNA or ctDNA NGS sequencing (Tempus Labs, Inc.). The frequency of BRAF alt, co-mutations, MSI, TMB and MMR were compared between CRC and (non-CRC) by Chi-squared/Fisher’s Exact or Wilcoxon rank-sum tests. False-discovery rate correction was used for multiple testing. Results: BRAF alt were identified in 8.9% of CRC and 2.2% of non-CRC cohort. BRAF alt frequency varied by tumor type with the highest observed in colon (11%), jejunum (9.6%), intrahepatic bile duct (5.3%), rectal (4.5%), and ampulla of vater (4.5%) and lower in esophageal (0.9%) and gastric (1.6%). BRAF alt CRC had higher frequency of females (57% vs 45%, p <0.001) and older age at diagnosis (67 vs 66 yrs, p=0.029) compared to non-CRC group. Race was also significantly different, with white patients being more predominant in both groups (85% CRC,77% non-CRC). Among the BRAF alt, fusions (12% vs 2.2%, p <0.001) and amplifications (3.1% vs 0.3%, p <0.001) were higher in non-CRC vs CRC (Table). BRAF V600E was most common in all GI tumors, but higher in CRC vs non-CRC (75% vs 27%, q<0.001). Mutations higher in non-CRC vs CRC (q<0.009) included class II (G469A, K601E, BRAF-SND1, and BRAF amplification) and class III (D594N & N581S) BRAF alt. BRAF co-occurring mutations in CRC were TP53 (70%), APC (42%), RNF43 (30%), SMAD4 (22%), and PIK3CA (21%), and in non-CRC: TP53 (52%), CDKN2A (32%), CDKN2B (20%) SMAD4 (17%) and MTAP (16%). Among tissue samples, MSI-H (30% vs 4.%, p <0.001) and TMB-H ≥10 mut/MB (32% vs 6.7%, p <0.001) were more frequent in BRAF alt CRC vs non-CRC. Conclusions: Meaningful differences were found between the groups in terms of demographics, frequency, and type of BRAF alt and co-occurring mutations. In particular, certain BRAF fusions were present in a higher proportion of other GI cancers and could be an important therapeutic target for this patient population.[Table: see text]
Effect of laparoscopy-assisted vs open surgery on 3-year disease-free survival in patients with low rectal cancer: The LASRE randomized clinical trial.
Authors: Chi Pan , Su Xiangqian , Xu Jianmin , Qiu Huizhong , Wang Ziqiang , Kang Liang , Deng Haijun , Chen Weiping , Zhang Qingtong , Du Xiaohui , Yang Chunkang , Guo Yincong , Zhong Ming , Ye Kai , You Jun , Xu Dongbo , Li Xinxiang , Xiong Zhiguo , Tao Kaixiong , Ding Ke-Feng ,   LASRE Trial Investigators
Published: January 2024

8

Background: Laparoscopic surgery has been increasingly used for low rectal cancer due to short-term benefits versus open surgery, but the long-term oncologic outcomes have not been fully established. Methods: This is a multicenter, noninferiority trial. Surgeons who had completed ≥100 laparoscopic TME surgeries from 22 high-volume centers in China participated in this trial. A total of 1070 patients scheduled for curative-intent resection of low rectal cancer (lower margin <5.0 cm dentate line) were randomized at a 2:1 ratio to undergo laparoscopic or open surgery from November 2013 to June 2018.The primary outcome was 3-year DFS; the noninferiority margin was 10% in the modified intent-to-treat population. Secondary outcomes included 3-year overall survival (OS) and locoregional recurrence. Results: The final analysis included 1039 patients (median age: 57 years, 620 men; 685 and 354 in laparoscopic and open groups, respectively). Clinical TNM stage was II/III in 659 patients, and I in the remaining 380 patients. The 3-year DFS rate was 81.4% in the laparoscopic group versus 79.8% in the open group (HR, 0.9 [95% CI, 0.7 to 1.2]; log-rank P = .558). The absolute difference was 1.6% (1-sided 97.5% CI, -3.34% to ∞), not exceeding the noninferiority . The 3-year OS rate was 91.7% in the laparoscopic group versus 93.7% in the open group (95% CI, -5.12% to1.54%, log-rank P = .243). The 3-year locoregional recurrence rate was 3.8% and 2.4%, respectively (95% CI, -1.07% to 3.45%, log-rank P = .209). Results of the per-protocol and as-treated analysis were consistent with the main analysis. Conclusions: Among patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons is not inferior to open surgery concerning 3-year disease-free survival. These results support laparoscopic surgery as a safe, minimally invasive approach for low rectal cancer. Clinical trial information: NCT01899547 .
Nivolumab in patients (pts) with advanced gastrointestinal (GI) cancers with high plasma tumor mutational burden (pTMB): Results from a SCRUM-Japan GOZILA phase II trial.
Authors: Nakamura Yoshiaki , Esaki Taito , Nishina Tomohiro , Komatsu Yoshito , Yuki Satoshi , Shinozaki Eiji , Taniguchi Hiroya , Kato Takeshi , Kato Ken , Nomura Shogo , Ikeno Takashi , Ishiguro Yukiko , Takahashi Koji , Higuchi Tsukiko , Sato Akihiro , Odegaard Justin Iver , Kuwata Takeshi , Matsushima Kouji , Nakatsura Tetsuya , Yoshino Takayuki
Published: January 2024

98

Background: TMB is a biomarker for immune checkpoint inhibitors (ICIs). Analysis of circulating tumor DNA (ctDNA) has the potential to non-invasively identify pts likely to benefit from ICIs by assessing pTMB. We conducted a phase II basket trial as part of the SCRUM-Japan GOZILA umbrella/basket trial to evaluate the efficacy and safety of nivolumab monotherapy in pts with advanced GI cancers with high pTMB. Methods: Eligibility criteria included histologically confirmed unresectable or recurrent GI cancers; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high pTMB identified by Guardant360 CDx, a 74-gene ctDNA assay. Pts received intravenous nivolumab monotherapy of 360 mg every 3 weeks until progressive disease. The primary endpoint was objective response rate (ORR) per investigator assessment. The pTMB score was calculated by adjustment of mutation count by tumor fraction, and initial pTMB thresholds were determined based on previously reported ORR for ICI treatment for each GI cancer in the cohort. The cohort 2 proceeded only for esophageal cancer, and an ultra-high TMB cohort was created to include pts in the top 2% for pTMB scores. Results: Fifty-one pts with high pTMB in the cohort 1/2 (n=32) and the ultra-high TMB cohort (n=19) were enrolled. The median duration of follow-up was 7.5 months (range, 0.9–51.3). Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) was observed in 1 pt in cohort 1/2 and 2 in ultra-high TMB cohort. The ORR was 12.5% and 21.1%, with median duration of response of 14.0 months and not reached, respectively. In an exploratory analysis of the overall population, pts with esophageal cancer had the highest ORR of 33.3% (4/12), followed by pancreatic (1/6, 16.7%) and colorectal cancer (3/27, 11.1%). Of 2 pts with proficient MMR/non-MSI-H colorectal cancer who had a response, 1 had a POLE mutation. Pts with response tended to have higher pTMB score (median, 26 vs. 8). dMMR/MSI-H (HR=0.16; 95% CI, 0.02–1.18), PD-L1 CPS ≥1 (HR=0.55; 95% CI, 0.29–1.01), and absence of liver metastasis (HR=0.36; 95% CI, 1.48–5.14) were significantly associated with longer progression-free survival. Treatment-related grade 3–4 adverse events occurred in 3 pts (9%) in the cohort 1/2 and 3 (16%) in the ultra-high TMB cohort, with no treatment death in either cohort. Conclusions: Nivolumab demonstrated antitumor activity in pretreated pts with advanced GI cancer and high pTMB. These results suggest that the use of pTMB potentially identify patients who may benefit from ICI treatment. Clinical trial information: UMIN000033182 .