Rachna T. Shroff's research while affiliated with The University of Arizona and other places

4116 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis despite systemic chemotherapy. Until recently, gemcitabine (G) and cisplatin (C) was a standard first-line systemic therapy with overall response rates (ORR) of 26% and 18.7%, median progression-free survival (PFS) of 8.0 and 5.7 months (mo), and median overall survival (OS) of 11.7 mo and 11.5 mo in the phase (Ph) 3 ABC-02 and TOPAZ-1 trials, respectively. CPI-613/Devimistat (D) is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle, preferentially within the mitochondria of cancer cells augmenting chemotherapeutic cytotoxicity. Methods: This investigator-initiated, multi-institutional Ph 1b/2 trial across 10 sites in the US investigated the combination of G 1000 mg/m ² , C 25 mg/m ² and D (dose levels: (-1) 500, (1) 1000, (2) 1500 and (3) 2000 mg/m ² ) (GCD) on days 1 and 8 every 21 days in pts with previously untreated advanced BTC. The recommended Ph 2 dose (RP2D) from the Ph1 b portion was 2000 mg/m ² (n=20 pts; TiTE-CRM methodology). The primary endpoint of the Ph 2 portion (n=48-58 pts; 2:1 randomization with Bayesian control arm) was to determine the best ORR in the GCD arm with an alternative hypothesis of 38% (null of 21.1% with 80% power and two-sided alpha of 0.05). GC arm efficacy estimates were to be compared to the null hypothesis to confirm reasonable comparison. Secondary endpoints included evaluation of median PFS and OS, and safety. Exploratory objectives include targeted exome/ transcriptomic analysis of tissue, and metabolomic analysis of plasma (pre-, on- and post-treatment). Clinical trial information: NCT04203160. Results: 75 pts were enrolled (20 Ph1b GCD, 37 Ph 2 GCD arm and 18 Ph 2 GC arm) between Jun 2020 to Mar 2023; median age 67 years (range 33-84), ECOG PS 0/1 (36/35), women (49%), Caucasian (88%), intrahepatic/hilar/distal cholangiocarcinoma and gallbladder (48/9/4/7), and metastatic/locally advanced stage (52/17). For the Ph 2 primary endpoint of ORR, 63 pts were evaluable (GCD at RP2D + GC with follow-up scans or clinical progression). ORR in the GCD was 15/50 (30%; 95% CI 17.9-44.6). ORR in GC arm was 6/13 (46.2%; 95% CI 19.2-74.9) and not different than historical estimate/null hypothesis. In the intention-to-treat analysis (n=75), median PFS and OS of pts treated with GCD (n=57) and GC arms (n=18) were 8.7 mo (95% CI 6.3-12.6) and 8.6 mo (4.0-NE), and 16.3 mo (11.3-21.5) and 22.2 mo (6.5-NE), respectively. Conclusions: The combination of GCD did not meet the primary endpoint of increased ORR. GCD was well tolerated, however, and demonstrated encouraging PFS and especially OS as compared to historical estimates in this Ph 1b/2 trial. Targeted exome/ transcriptome and plasma metabolome analyses are ongoing. Clinical trial information: NCT04203160 .

4107 Background: Aberrant Wnt/β-catenin activation has been implicated in tumor formation and progression in BTC. CTNNB1 is a key transcriptional co-activator in Wnt signaling. The impact of CTNNB1 alterations on outcomes in intrahepatic (IHCC) vs extrahepatic (EHCC) vs gallbladder (GB) tumors and patterns of gene co-expression is unclear. We examined the molecular correlates and predictive and prognostic significance of CTNNB1 expression in a real-world cohort of pts with BTC. Methods: 7450 BTC tumors were analyzed using Next Generation Sequencing (NextSeq), Whole Exome and Whole Transcriptome Sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPM) expression was considered high expressors (Q4), bottom quartile was considered low expressors (Q1) within each subtype. Real-world overall survival (OS) data was obtained from insurance claims. Hazard ratio (HR) was calculated using Cox proportional hazards model, P values were calculated using log-rank test. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: The cohort was comprised of 61% IHCC, 14% EHCC, 23% GB, 2% NOS. CTNNB1 mutations are rare in BTC (1.3%). Pts with CTNNB1-wt tumors had significantly better OS vs CTNNB1-mt (13.6 vs 10.2 mo, HR 0.74, p=0.008). This association remained significant in IHCC (13.2 vs 4.5 mo, HR 0.64, p=0.031) but not EHCC (18.0 vs 11.8 mo, HR 0.87, p=0.64) or GB (12.9 vs 11.0 mo, HR 0.75, p=0.071). CTNNB1-mt tumors were more frequently TP53-mt (63% vs 41%), ERBB2-mt (9% vs 2%) and ATM-mt (9% vs 3%). CTNNB1-wt tumors were more likely BAP-mt (9% vs 0%) and IDH1-mt (10% vs 0%) (all q<0.05). CTNNB1-mt tumors had higher median CTNNB1 expression vs wt (154.9 vs 113.4, q<0.009). Pts with CTNNB1 Q1 expression had significantly better OS vs Q4 (14.5 vs 12.4 mo, HR 0.88, p=0.007). This association held in IHCC (15.0 vs 10.6 mo, HR 0.77, p<0.00001) but not EHCC (17.5 vs 19.9 mo, HR 1.05, p=0.70) or GB (12.4 vs 12.8 mo, HR 1.05, p=0.63). CTNNB1 Q4 expressing tumors were more likely to be TP53-mt (55% vs 34%), PIK3CA-mt (9% vs 5%), KRAS-mt (23% vs 12%) and less likely IDH1-mt (4% vs 14%) compared to Q1 (all q<0.05). CTNNB1 Q4 pts had higher ARID1A, CTLA4, LAG3, HIF1A, TGFB1/2/3, EPHB4, EPHA2, VEGFA expression (FC: 2.1-4.2, all q<0.05) and higher T-cell inflamed score vs Q1. There was a trend towards improved OS in pts with IHCC CTNNB1 Q1 tumors receiving gemcitabine or fluorouracil (17.5 vs 15.0 mo, HR 0.86, p=0.064); no difference in outcomes by CTNNB1 expression in pts receiving immunotherapy. Conclusions: CTNNB1 mutations and mRNA expression levels impact survival in BTC, especially IHCC, and may be associated with benefit from chemotherapy. CTNBB1 alterations are associated with immunogenic, DNA repair and angiogenic pathways and may help identify novel therapeutic strategies for BTC.

4106 Background: The WNT/beta catenin (CTNNB1) pathway plays an integral role in the development of HCC. CTNNB1 has been implicated in HCC progression, metastasis, and drug resistance. We examined associations between CTNNB1 mutations and mRNA expression and clinical outcomes in a real-world cohort of patients with HCC. Methods: 1652 HCC tumors were tested at Caris Life Sciences (Phoenix, AZ) and analyzed with Whole Transcriptome Sequencing (WTS; Illumina Novaseq), Whole Exome Sequencing (NovaSeq,WES) and NextGen DNA sequencing (NextSeq, 592 genes). mRNA expression (transcripts per million) was further stratified into top (Q4) and bottom quartiles (Q1). Kaplan Meier estimates were calculated for overall survival (OS) in the molecularly defined cohorts and estimated from time of tissue collection to last contact. Significance was determined to be p <0.05. Chi-square and Mann-Whitney tests determined molecular differences between subgroups and adjusted for multiple comparisons (q<0.05). Results: Pathogenic CTNNB1 mutations were present in 32% of HCC and mutation status was not associated with CTNNB1 expression level. Pts whose tumors had lower CTNNB1 expression had significantly improved OS, 17.9 vs 12.4 months, Q1 vs Q4, HR 0.72, CI: 0.58-0.89 p=0.002. This association remained significant in patients who received first-line IO (Q1 vs Q4: OS 16.7 vs 10.6 mo, HR 0.54, CI: 0.32-0.94, p=0.025) or TKI (Q1 vs Q4: OS 27.1 vs 17.6 mo, HR 0.60, CI: 0.38-0.94, p=0.025). Low CTNNB1-expressing tumors (Q1) had more frequent ARID1A mutations (15% vs 8%); less frequent TP53 mutations (31% vs 42%); lower VEGFA, EPHB4, EPHA2, HIF1A, TGFB1/2/3 expression, lower MAPK activation and lower T-cell inflamed scores vs Q4 tumors (all q < 0.05). All tumors were MSS. CTNNB1 mutation status (MT vs WT) did not impact survival (OS 17.6 vs 15.3 mo, CTNNB1-MT vs CTNNB1-WT, HR 1.05, CI: 0.91-1.20, p=0.55). Similarly, CTNNB1 mutation status (MT vs WT) did not impact OS in pts treated with IO (19.8 vs 19.6 mo, HR 0.99, p=0.94) or TKI (23.0 vs 22.0 mo, HR 0.86, p=0.33). Conclusions: CTNNB1 mRNA expression, but not CTNNB1 mutation status, is associated with survival in HCC. Patients whose tumors had lower CTNNB1 expression appeared to derive more benefit from immune checkpoint inhibitors and TKI therapy in first line. CTNNB1 expression is associated with DNA repair, immune, neuronal and angiogenic pathways which may pave the way for potential therapeutic opportunities. Further studies are needed to prospectively evaluate CTNNB1 as a biomarker for treatment selection in HCC.

9009 Background: Gender disparities exist in medicine, including academic and medical society leadership, journal editorial boards, and research teams. Women are also underrepresented in clinical trial leadership and authorship, with one study reporting fewer than 10% female corresponding authors for randomized clinical trials in GI Oncology, GU oncology, and Hematology. Clinical trial leadership, subsequent podium presentations and authorship have downstream effects on promotion, reputation, and funding opportunities. We examined the gender of speakers in scientific sessions at the ASCO Annual Meeting (AM) and Gastrointestinal Symposium (ASCO GI) from 2019-2023. Methods: We examined speaker gender, role (session chair, abstract presenter, abstract discussant), speaker region (Asia, Europe, N. America), and presentation topic (colorectal cancer or non-colorectal cancer) for the ASCO AM GI scientific sessions and ASCO GI from 2019-2023. For the ASCO AM, we included GI oral abstracts and plenary sessions; for ASCO GI we included oral and rapid abstracts. Self-identified gender was not available; therefore, gender was assigned by physical appearance via ASCO video or institutional websites. Statistical analyses were performed using the two-proportions z-test with a p value <0.05 considered statistically significant. Results: 208 scientific abstracts were reviewed across both meetings over 5 years. There was a statistically significant difference in the % of men vs. women as abstract presenters (77% vs 23%, p <0.001). This did not differ when looking at ASCO and ASCO GI separately (ASCO 76% vs 24%, ASCO GI 78% vs 22%, p <0.001 for both) and was observed across all 5 years. Similarly, there was a predominance of men as abstract presenters regardless of speaker region (Asia 93%, Europe 74%, N. America 67%, p<0.001 for all) and presentation topic (CRC 76% vs 24%, non-CRC 78% vs. 22%; p <0.001 for both). The percent of men as repeat presenters for scientific abstracts was statistically higher than women (84% vs 16%, p <0.001). Importantly, there was no difference in men vs. women in the invited chair/discussant roles (51% vs 49%, p = 0.89). Conclusions: Our analysis of 5 years of scientific sessions for ASCO and ASCO GI shows a stark difference in the proportion of men vs women as abstract presenters regardless of presentation topic, region of presenter, and meeting year. Our data highlight the need for all trial sponsors to be more intentional in the selection of principal investigators and lead authors as these opportunities are critical to the promotion of women in GI Oncology and to diversifying approaches to clinical trial design and access. Our data is limited by how gender was assigned (i.e., not self-reported). Lastly, we commend ASCO on their efforts to ensure gender equity among the roles that are within their control, and we advocate for them to consider opportunities for self-identification of gender in their membership directory.