Abidoye, Oluseyi

277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC. Methods: In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents. Results: A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with MET point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7) . HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A and HER2 S310F, which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy. Conclusions: The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.

536 Background: The prognosis of advanced BTC remains poor. Although targeted agents have expanded late-line options, many patients (pts) become ineligible for these therapies after progressing on first-line treatment. Herein, we examined the real-world impact of targeted therapy on survival in advanced BTC. Methods: In this international collaborative study between the Mayo Clinic (US) and the National Cancer Center East (Japan), we included pts with advanced BTC with comprehensive tumor molecular profiling who had received at least 30 days of systemic therapy. Pts were categorized into 3 groups: 1) non-actionable, 2) pts with alterations who received matched targeted therapy at any point during their treatment (matched group), and 3) those with mutations who did not receive matched therapy (unmatched group). OS was calculated from the start date of first-line therapy until death and compared among three subgroups using Cox regression models. Results: Of 932 pts, 366 (39.3%) had an actionable alteration, and 135 of these received matched therapy. 566 (61.7%) did not have an actionable alteration (Table). The most common alterations were somatic BRCA1/2 (N=106, 11.4%), HER2 amplification (N=65, 7%), FGFR2 fusion (N=61, 6.5%), KRAS G12C/D (N=46, 4.9%), and IDH1 (N=38, 4.1%). 78.7% of FGFR2 fusions were found in Caucasian pts, whereas BRCA1/2 (97.5%), HER2 (78.5%), and KRAS G12C/D (67.4%) alterations were more prevalent in Asian pts. The median OS was significantly longer in the matched group (21.4 months; 95% CI 18.4-27.9) compared to the unmatched group (14.6 months; 95% CI 12.8-17.6) and the non-actionable group (17.2 months; 95% CI 15.5-19.0). The 36-month OS rate was 33% in the matched group vs. 7% in the unmatched group (p < 0.0001). After adjusting for age, gender, prior surgical resection, primary tumor location, and country of origin, matched targeted therapy remained a strong independent predictor for improved OS (HR 0.61; 95% CI 0.48-0.79). Conclusions: These real-world findings suggest that matched targeted therapies significantly improve survival in advanced BTC, underscoring the need to incorporate them earlier in the treatment course and address barriers to treatment access. The regional prevalence of actionable alterations should also be considered when developing new targeted therapies. Patient baseline characteristics stratified by actionable alterations and targeted therapy. Non-actionable(N=566) Unmatched group(N=231) Matched group(N=135) Site, n (%) Japan 409 (72%) 166 (72%) 50 (37%) US 157 (28%) 65 (28%) 85 (63%) Age at Dx > 65, n (%) 324 (57%) 122 (53%) 54 (40%) Female, n (%) 235 (42%) 92 (40%) 77 (57%) Primary tumor location (category), n (%) Intrahepatic 217 (43%) 115 (55%) 99 (76%) Extrahepatic 150 (30%) 39 (19%) 17 (13%) Gallbladder 142 (28%) 54 (26%) 14 (11%) Prior surgical resection, n (%) 220 (42%) 74 (34%) 48 (37%)

Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are primarily based on clinicopathological characteristics, which have well-recognized limitations in accurately identifying patients harboring minimal residual disease (MRD), often resulting in unnecessary chemotherapy exposure. Circulating tumor DNA (ctDNA) has emerged as a promising surrogate marker for MRD, offering a more precise approach to identifying patients at risk of recurrence after curative-intent surgery and refining adjuvant chemotherapy decisions. Growing evidence from multiple studies has demonstrated that ctDNA outperforms traditional clinicopathological factors as a marker for MRD. This review synthesizes key studies supporting the role of ctDNA in MRD detection for CRC patients and evaluates clinical trials investigating the application of ctDNA in guiding adjuvant therapy decisions. This emerging strategy holds the potential to transform the adjuvant treatment paradigm in colorectal cancer by optimizing therapeutic precision and minimizing unnecessary treatment.

Abstract Background In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial. Methods The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or &gt;6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS). Results A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG &gt; 6 vs. CGD &gt; 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]. Conclusion Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC.

412 Background: Previously we have reported comparative effectiveness data regarding survival of first line (1L) treatment options in mRCC. However, it is not known how the life-prolonging frontline combinations compare to patient-reported outcomes. Methods: Electronic databases including MEDLINE and EMBASE were searched from each database’s inception through July 1st 2023. Phase III randomized controlled trials (RCTs) assessing 1L immune-checkpoint inhibitor (ICI) combination therapies for mRCC and reporting HrQoL were included. Small sample size adjusted standardized mean differences (SMD; Hedges’ g) with 95% confidence intervals (CI) were computed for global, physical, functional, and emotional QoL. Positive SMD indicated an improvement. A network meta-analysis was conducted to assess the comparative HrQoL across different treatment options. P-scores were computed to assess relative treatment rankings. Results: Of 5770 citations identified, five trials (nine references) were included in this analysis. Patient-reported outcomes have not been reported in the JAVELIN Renal 101 or COSMIC-313 trials yet. Global QoL was significantly improved with cabozantinib-nivolumab (CaboNivo) as compared to Nivo-ipilimumab (SMD 2.74, 95% CI 2.54; 2.93), lenvatinib-pembrolizumab (LenPem; 2.79, 2.53; 3.06), sunitinib (2.87, 2.72; 3.03), Pem-axitinib (PemAxi; 3.09, 2.89; 3.30) and atezolizumab-bevacizumab (AteBev; 3.24, 3.04; 3.45). Global QoL improvement was also observed with NivoIpi compared to sunitinib (0.14, 0.02; 0.25), PemAxi (0.36, 0.18; 0.54) and AteBev (0.51, 0.33; 0.68). Physical QoL improvement were consistent with CaboNivo. Likewise, LenPem significantly improved QoL compared to sunitinib (0.26, 0.04; 0.47), PemAxi (0.38, 0.13; 0.64) and NivoIpi (0.51, 0.27; 0.76). Significant functional QoL benefits were only observed with CaboNivo (0.32, 0.17; 0.48) and NivoIpi (0.19, 0.08; 0.31) compared to sunitinib. No significant mixed treatment comparisons were observed for emotional QoL, however, currently available data suggests that LenPem (rank 1) may potentially improve QoL (Table). Conclusions: CaboNivo and NivoIpi as 1L therapy may offer an improved overall HrQoL compared to other contemporary treatment options in mRCC. [Table: see text]

Abstract Purpose In 2019, the National Comprehensive Cancer Network (NCCN) recommended genetic testing for all patients with pancreatic ductal adenocarcinoma (PDAC). To evaluate the status of implementation of these guidelines in a loco-regional setting, we performed a retrospective, observational study among patients with newly diagnosed PDAC who received oncologic care at Northeast Georgia Medical Center in Georgia. Methods Chart abstraction of patients with newly diagnosed PDAC from January 1, 2020 to December 31, 2021, was performed to include information on genetic testing recommendation and completion, and time from diagnosis to testing. The deidentified dataset was then analyzed using appropriate descriptive and associative statistical testing. Results Of the cohort of 109 patients, 32 (29.4%) completed genetic screening; 16 (14.7%) were screened within 10 days of diagnosis. Among the 77 (70.6%) patients who did not receive genetic screening, 45 (41.3%) were not recommended genetic screening despite treatment intent with standard of care therapy. However, 32 (29.4%) were not recommended genetic screening in conjunction with a desire to pursue palliative care/hospice/or due to terminal illness. Conclusions The study highlighted the gap in implementation of NCCN guideline-directed genetic testing in PDAC patients as only a third underwent testing suggesting the need for systematic processes to facilitate testing. The test was more likely to be completed if done early in the course, especially soon after the diagnosis. Research is needed to explore discussing genetic testing for the large proportion of patients who are terminally ill at diagnosis where genetic screening would potentially benefit the family members.