Usón, Pedro Luiz Serrano

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

4079 Background: Cell-free circulating tumor DNA (ctDNA) holds significant promise and is being used for clinical decision making in multiple tumors. This study aimed to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment. Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS). Results: The median age of patients was 67 y/o (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancer. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 14 (21%) patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 7 (10.4%) patients were treated on a clinical trial with gemcitabine and cisplatin plus additional targeted agents (CX4945 or PEGPH20). TP53, KRAS, APC, FGFR2 and IDH1 were the genes with highest frequency as dominant clone. The median dominant clone allele frequency (DCAF) was 3% (0-97%). DCAF >3% was associated with statistically significant worse PFS (median PFS: 4.05 vs. 7.70 months, p=0.046) and OS (median OS: 10.8 vs. 18.8 months, p=0.056). Each 1% increase in DCAF is associated with a hazard ratio of 26.21 in OS when adjusting for subtypes, age, treatment type, and CA19-9 [Table]. Conclusions: Patients with metastatic BTC with DCAF > 3% at diagnosis have worse PFS and OS compared to patients with low ctDNA when treated with upfront platinum-based chemotherapy.[Table: see text]

Abstract The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are burgeoning as first-line treatment therapeutic modalities in HCC.

PURPOSE To present a summary of the recommendations for the treatment and follow-up for the biochemical recurrence of castration-resistant prostate cancer (PCa) as acquired through a questionnaire administered at the Prostate Cancer Consensus Conference for Developing Countries. METHODS A total of 27 questions were identified as relating to this topic. Responses from the clinician were tallied and are presented in percentage format. Topics included the use of imaging in staging, treatment recommendations across different patient scenarios of life expectancy and prostate-specific antigen (PSA) doubling time, and follow-up for nonmetastatic castration-resistant PCa. RESULTS A consensus agreed that in optimal conditions, positron emission tomography-computed tomography with prostate-specific membrane antigen would be used although in limited resource situations the combined use of CT of the abdomen and pelvic (or pelvic MRI), a bone scan, and a CT of the thorax or chest x-ray was recommended. In cases when PSA levels double in < 10 months, more than 90% of clinicians agreed on the use of apalutamide or enzalutamide, regardless of life expectancy. With a doubling time of more than 10 months, > 54% of experts recommended no treatment independent of life expectancy. More than half of the experts, regardless of resources, recommended follow-up with a physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms. CONCLUSION The voting results and recommendations presented in this document can be used by physicians to support management for biochemical recurrence of castration-resistant PCa in areas of limited resources. Individual clinical decision making should be supported by available data.

Abstract Purpose Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. Materials and Methods From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. Results All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. Conclusion Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. Implications for Practice Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

Purpose of review To review new treatment and advances in biliary tract cancer (BTC). Recent findings In the prespecified per-protocol analysis of the randomized phase III trial BILCAP, adjuvant capecitabine offers overall survival (OS) benefit when compared with observation with statistical significance. In the first-line setting in metastatic BTC, gemcitabine and S-1 had noninferior OS compared with gemcitabine and cisplatin. In a separate phase III study, the triplet of gemcitabine, cisplatin and S-1 (GCS) had superior OS compared with standard gemcitabine and cisplatin. The regimen of modified FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen can be considered a potential standard option in the second-line setting for patients who failed first-line therapy with gemcitabine-based regimens. Trials in genomically selected patients indicate activity of fibroblast growth factor receptor inhibitors, mutant isocitrate dehydrogenase inhibitors and immune checkpoint inhibitors. Summary Capecitabine is a new option for adjuvant treatment in resected BTC. In the metastatic setting, gemcitabine and S-1 or GCS are new options for first-line therapy and modified FOLFOX regimen should be considered as a potential new empirical standard of care in genomically agnostic patients requiring second-line therapy. Future randomized trials will evaluate the role of targeted agents and immunotherapy in advanced BTC, both in monotherapy and in combination.