The impacts of the Association for Molecular Pathology vs. Myriad Supreme Court decision regarding patenting DNA segments and multi-gene testing on cancer genetic counseling practice have not been well described. We aimed to assess genetic counselors' perceptions of how their genetic testing-related practices for hereditary breast and/or ovarian cancer (HBOC) changed after these events. One-hundred fifty-two genetic counselors from the National Society of Genetic Counselors Cancer Special Interest Group completed an anonymous, online, mixed-methods survey in November 2013. The survey presented four hypothetical patients and asked about changes in testing practice. Across the vignettes, a majority of participants reported specific changes in testing decisions following Association for Molecular Pathology vs. Myriad and availability of multi-gene testing. Ninety-three percent of participants reported changing the types of first- and second-line tests they order for HBOC; the degree of change varied geographically. Qualitative analysis indicated that some counselors have altered the counseling session content, trading depth of information for breadth and spending more time counseling about uncertainty. This study shows that cancer genetic counselors are adapting quickly to genetic testing changes, but with wide variability. Findings suggest future research to elucidate clinicians' and patients' preferences for guidance on the clinical implementation of next-generation sequencing.

747 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths. KRAS is a primary oncogenic driver in the majority of PDAC patients. KRAS wild-type (wt) PDAC (~10%) is a molecularly heterogeneous subgroup that may harbor alternate drivers and targetable alterations. In this study, we sought to characterize the circulating tumor DNA (ctDNA) landscape of alterations in PDAC patients harboring KRAS mutations ( KRAS mut) compared to KRAS wt. Methods: We analyzed ctDNA samples from 2000 patients ( N= 1000 each for KRAS mut and KRAS wt) collected prospectively between 2019-2022 using a 74-83 gene next generation sequencing panel (Guardant360). KRAS mutation not detected was used as a proxy for KRAS wt. To limit bias from low tumor shed, samples were excluded if they did not have maximum variant allele fraction (VAF) > 0.34% and if the only maximum VAF > 0.34% was within putative germline range (40-60%). Statistical analyses were performed using Fisher’s exact test or t-test. Results: No significant gender differences were noted between KRAS wt and KRAS mut patients. Median age was 72yo in KRAS wt and 69yo in KRAS mut patients. Overall, KRAS wt patients had higher frequency of alterations in ATM, BRAF, ERBB2, FGFR2, JAK3, MET and NOTCH1 compared to KRAS mut (all p < 0.05). Meanwhile, KRAS wt patients had lower frequency of alterations in CDKN2A, SMAD4, CDK6, ARID1A, and TP53 compared to KRAS mut (all p < 0.05). The most frequently mutated gene in KRAS wt PDAC was TP53 (46%), followed by ATM (26%) and EGFR (11%). The most common currently targetable alterations identified in KRAS wt patients were ATM (26%), BRCA1/2 (12%), EGFR (11%; 70% mutations, 30% amplifications), FGFR1/2 (9%), BRAF (8%; 91% mutations, 9% amplifications), PIK3CA (7%), MET (7%; 80% mutations, 20% amplifications) and ERBB2 (5.8%; 79% mutations, 21% amplifications) among others. Median tumor mutational burden for KRAS wt patients was higher than KRAS mut (10.0 vs. 7.77 mut/Mb, p = 0.035). There were no significant differences in rates of MSI-H between KRAS wt and KRAS mut patients (1.9% vs. 1.3%, p = 0.37). KRAS wt patients harbored higher number of oncogenic gene fusions compared to KRAS mut (1.6% vs 0.2%, p = 0.0013). The most common fusion partners among KRAS wt patients included FGFR2 (0.4%), BRAF (0.4%), ALK (0.2%), NTRK (0.2%), RET (0.2%), FGFR3 (0.1%) and EGFR (0.1%). Potential germline variants (pathogenic/likely pathogenic) were detected in both KRAS wt and mut patients, most commonly in the DNA-damage repair genes, including ATM (3.5%), BRCA2 (1.8%) and BRCA1 (0.6%). Conclusions: Targetable alterations and oncogenic rearrangements are enriched in KRAS wt PDAC compared to KRAS mut. These analyses provide additional therapeutic options and may improve outcomes for KRAS wt patients, warranting blood-based ctDNA genomic profiling in PDAC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

588 Background: The incidence of gastrointestinal and obesity related cancers, including pancreatic cancer, is increasing in individuals <50 years old. Early-onset pancreatic cancer (EOPC; age<50 years old at diagnosis) is characterized by higher incidence in males, enrichment for KRAS wild-type tumors with targetable genomic alterations (GAs), and improved outcomes compared to average-onset pancreatic cancer (AOPC; age>50 years old at diagnosis). Little is known about the genomic correlates underlying these clinical differences. In this study, we sought to characterize the circulating tumor DNA (ctDNA) landscape in EOPC compared to AOPC. Methods: We analyzed ctDNA samples from a total of 8548 patients (EOPC n=488 [age<30yo n=13, 30-39yo n=87, 40-49yo n=388]; AOPC n=8060) collected prospectively between December 2017 to March 2021 using a 73 gene next generation sequencing panel (Guardant360). Statistical analyses were performed using Fisher’s exact test. Results: Of the 488 EOPC patients, 261 (53%) were male and 227 (47%) were female. Median age was 45yo in EOPC and 69yo in AOPC. Contrary to prior reports from tissue-based sequencing studies, EOPC patients were more likely to harbor KRAS alterations (p≤0.0001), specifically KRAS G12V (p≤0.0072) and KRAS amplifications (p≤0.0001). 1.24% of pancreatic cancer patients harbored KRAS G12C mutations; 0.05% were in EOPC patients. The most common currently-targetable GAs identified in EOPC were PIK3CA (10%), BRCA1/2 (10%), EGFR (9%), BRAF (7%), MET (7%), ATM (7%), FGFR1/2 (7%), CDK6 (5%), and ERBB2 (4%). EOPC patients had higher proportion of targetable GAs in BRCA2 (p≤0.041), MET (p≤0.005), and PIK3CA (p≤0.0023) compared to AOPC. Conversely, AOPC patients had higher proportion of GAs in TP53 (p≤0.0001) and ATM (p≤0.0001). MSI-high and TMB-high were detected in 0.07% and 0.06% of EOPC patients respectively, while 0.6% and 1.7% AOPC patients were MSI-high and TMB-high. Gene fusions were detected in 0.3% pancreatic cancer patients, predominantly in FGFR2 (0.2%) and FGFR3 (0.02%). Potential germline variants were detected in both EOPC and AOPC patients, most commonly in BRCA2 (54%). Females displayed higher proportion of TP53 (p<0.0001), EGFR (p<0.0029), CDKN2A (p<0.0001), BRCA2 (p<0.0336) and ATM (p<0.0001) mutations compared to males. Gender was predictive of the pattern of GAs in EOPC with MET (p≤0.0027) , ARID1A (p≤0.0376) , and BRAF (p≤0.0034) alterations enriched in males, and PIK3CA (p≤0.0017) alterations enriched in females. Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of EOPC. Based on this age and gender-stratified molecular characterization of pancreatic cancer, EOPC is a distinct molecular entity compared to AOPC. Identification of multiple targetable GAs may improve patient outcomes in EOPC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

2561 Background: Some cancers, including breast, ovarian, pancreatic, and prostate cancers, are traditionally considered “cold” tumors, less likely to trigger an immune response and/or respond to immune checkpoint inhibitors (ICIs). However, some patients with these cancer types may benefit from ICIs. Here we investigate if a high blood tumor mutational burden (bTMB-H) may predict benefit to ICIs in such tumor types. Methods: We retrospectively queried the Guardant Health database for patients with advanced breast (n = 8531), ovarian (n = 1106), upper GI/pancreatic (n = 5110), and prostate (n = 7153) cancer who had ctDNA next-generation sequencing (Guardant360, Redwood City, CA) as part of routine clinical care from 2020-2022. Mutation profiles were evaluated for patients with bTMB-H (based on previously reported 80th percentiles for each tumor type, breast ≥15.31mut/Mb, ovarian ≥14.98mut/Mb, pancreatic ≥11.36mut/Mb, prostate ≥13.4mut/Mb) vs those with bTMB below this threshold (bTMB-L). A subset of cases were analyzed in a multi-institutional clinical cohort with a bTMB of ≥10mut/Mb (n = 35). Results: bTMB-H was observed in 9.5% of patients with breast cancer, 5.1% ovarian, 2.0% pancreatic, and 4.4% prostate. Genes more often mutated in patients with pTMB-H vs pTMB-L in each cancer type included TP53 and PIK3CA in breast cancer; TP53 and CHEK2 in ovarian; ATM and CHEK2 in pancreatic; TP53 and AR in prostate (all p values < 0.01). Patients in the clinical cohort (n = 35) had a median age of 74 (range: 40-85) 29/35 White / 4/35 Black, 27 prostate, 1 breast, 3 upper GI. Patients underwent first ctDNA analysis after a median of 3 (range 0-11) lines of therapy. The median bTMB detected was 16.59 mut/Mb (range: 10.02-152.85); six patients (6/35) were MSI-H. Twenty-three patients received ICI after a median of 6 (range: 0-8) lines of therapy, either alone (9, 39%) or in combination with hormonal therapy (5, 22%), chemotherapy (3, 13%) or targeted therapy (6, 26%). The median time to progression on ICI was 5.0 (95% CI, 3.6-6.4) months and median duration of response was 19.8 months (12.1-20.2). The ORR for evaluable patients was 13% and 74% of patients had progressed on therapy at time of data cut-off. Conclusions: "Cold” tumors represent a meaningful portion of patients with advanced cancer in which ICIs are not typically leveraged, and ctDNA was a feasible tool for identifying patients with bTMB-H who achieved durable responses from ICI-based therapy. The efficacy in this clinical cohort of traditionally “cold” tumors approaches other pan-cancer cohorts that include more traditionally immunoresponsive tumor types; further research is warranted to explore predictive value of bTMB, including potential tumor-specific thresholds, for optimizing patient selection for ICIs.

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