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Advanced hepatocellular carcinoma (HCC) is responsive to immune checkpoint inhibitors, but there are currently no known biomarkers to predict treatment benefit. Blood TMB (bTMB) estimation via circulating tumor DNA (ctDNA) profiling can provide a convenient means to estimate HCC TMB. Here we provide the first landscape of bTMB in advanced HCC using a commercially available next-generation sequencing assay, show that it is approximately three times as high as matched tissue TMB, and show that bTMB correlates with NAFLD cirrhosis etiology and the presence of genomic alterations in HTERT and TP53. These results lay the foundation for subsequent studies evaluating bTMB as an immune therapy predictive biomarker in HCC.

Background For HR+ MBC, ESR1 point mutations (ESR1-MUT) are a common mechanism of acquired resistance to aromatase inhibition (AI); ESR1 fusions (ESR1-FUS) are rare and promote intrinsic resistance to ER-targeting drugs. Retrospective analyses of CDK4/6i trials suggest ESR1-MUT does not cause CDK4/6i resistance, but whether CDK4/6i is effective for ESR1-MUT, or for ESR1-FUS, in the real-world setting is unknown. Methods Real-world evidence was sourced from the GuardantInform database of commercial payer claims and ctDNA tests from 170,000+ individuals. Patients with MBC who started CDK4/6i within 30 days of ctDNA testing were categorized as ESR1-MUT vs. ESR1-WT and analyzed for time-to-next-treatment (TTNT). Separately, cases with ESR1-FUS detected by tissue RNA-Seq were extracted from a clinicopathologic database at an academic cancer center. Results There was no significant difference in TTNT on CDK4/6i for ESR1-MUT vs. ESR1-WT. As expected, ESR1-MUT had shorter overall survival (OS), even after adjustment for age, CDK4/6i drug, and prior treatment (HR 0.58 (0.42-0.82), p=0.002, multivariable Cox). Endocrine partner analysis was limited by lack of clinical annotation to 27% of cases: AI was given to 55% of ESR1-WT and 25% of ESR1-MUT; fulvestrant was given to 39% of ESR1-WT and 68% of ESR1-MUT. Additional stratified analyses will be presented. In the clinicopathologic database, we identified 4 ESR1-FUS cases, and all received CDK4/6i. Progression-free survival durations on CDK4/6i were 4, 10, 11, and 33+ months. Conclusions Using real-world evidence, we demonstrate that CDK4/6i is effective in both ESR1-MUT and ESR1-WT HR+ MBC, supporting the use of CDK4/6i in this setting. CDK4/6i may be additionally beneficial for patients with ESR1-FUS. Future directions include expanding the ESR1-FUS cohort and deciphering the heterogeneity of CDK4/6i responses in this patient population. ESR1-WT ESR1-MUT p-value n=612 n=145 TTNT, median days (95% CI) 99 (85-121) 102 (85-152) 0.84 (log-rank) OS, median years (95% CI) 5.1 (4.5-NA) 2.2 (2.0-NA) Citation Format: Jamie O. Brett, Caroline M. Weipert, Lauren L. Ritterhouse, Nicole Zhang, Junhua Yu, Lianne Y. Ryan, Laura M. Spring, Miguel N. Rivera, Jochen K. Lennerz, Dora Dias-Santagata, Leif W. Ellisen, Aditya Bardia, Seth A. Wander. CDK4/6 inhibition (CDK4/6i) is effective in the real-world setting for hormone receptor-positive metastatic breast cancer (HR+ MBC) with ESR1 mutations and fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5248.

PURPOSE Cancer of unknown primary (CUP) is a metastatic disease with unidentifiable primary tumor. Somatic alterations can be assessed noninvasively via liquid biopsies interrogating cell-free DNA (cfDNA). METHODS We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes). RESULTS Overall, 1,739 patients (90%) had ≥ 1 cfDNA alteration. We then explored alteration actionability (per the levels of evidence from the OncoKB database); 825 patients (47.4% of 1,739) had level 1, level 2, or resistance/R1 alterations. Among 40 clinically annotated patients with CUP who had cfDNA evaluated, higher degrees of matching treatment to alterations (Matching Score > 50% v ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 v 2.5 months; P = .002), overall survival (13.4 v 5.7 months; P = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% v 25%; P = .003). CONCLUSION In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes.

Purpose: To evaluate the psychosocial impact of semi-annual dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) screening in women at high-risk for breast cancer. Background: For women with BRCA1 and BRCA2 mutations and/or a personal or family history of breast cancer, annual breast MRI has shown improved sensitivity and cancer detection compared to mammography. However, MRI's heightened sensitivity may lead to increased: false positives requiring additional follow-up biopsy/imaging; iatrogenic risk; and psychosocial distress, which all may negatively impact women's overall health-related quality of life. Methods: Between 2004 and 2016, we assembled a prospective cohort of high-risk women undergoing semi-annual DCE-MRI and annual mammography. We reviewed a subset of this group. Participants completed psychosocial assessments at baseline and 6-month visits using the following measures: coping (MBSS); state/trait anxiety (STAI-S/T); depression (BDI-II); risk perception; and mental health (SF-36). Participants were classified according to Monitor or Blunter coping style. Mixed-effects logistic regressions models examined effects of demographics on psychosocial changes over time. Results: 295 women were recruited to the study; 44% of the study participants had pathogenic mutations in BRCA1 or BRCA2 genes. 232 of 295 enrolled participants (78.6%) completed psychosocial assessments. For the total population: median age 44y (range: 21-73), 71% ≥college/post-graduate education; 84% Caucasian; 8% African American; 2% Latino; 99% with health insurance; 72% annual income of >$60,000. One third of women had a personal cancer history. Participants were evenly split between baseline Monitoring and Blunting coping style (49% and 51%, respectively). No significant differences were found between demographics (age, race, income, mutation, cancer type, cancer history) or psychosocial factors (baseline trait anxiety (p =0.64), depression (p =0.65), SF36 global health (p=0.66). After adjusting for education, race, cancer history and coping, women with ≥$60,000 income had lower trait anxiety (p Conclusion: Semi-annual DCE-MRI did not cause a significantly elevated state anxiety or depression, nor was there a significant decline in mental health over time for groups regardless of cancer history and genetic mutation status. Coping style may have an impact on psychosocial outcomes for those undergoing heightened surveillance over time. Citation Format: Amico AL, Fang R, Raoul A, Wroblewski K, Nielsen S, Weipert C, Abe H, Sheth D, Romero I, Kulkarni K, Schacht D, Patrick-Miller L, Verp M, Bradbury AR, Hlubocky F, Olopade OI. Psychosocial impact of a multi-modality surveillance program for women at high-risk for breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-04.

Comprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a two to five-fold relative risk of cancer. Two such genes included on many comprehensive cancer panels are the DNA repair genes ATM and CHEK2, best known for moderately increased risk of breast cancer development. However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized. We convened a large, multidisciplinary, cross-sectional panel of GCRA clinicians to review challenging, peer-submitted cases of patients identified with ATM or CHEK2 variants. This paper summarizes the inter-professional case discussion and recommendations generated during the session, the level of concordance with respect to recommendations between the academic and community clinician participants for each case, and potential barriers to implementing recommended care in various practice settings.

Next-generation sequencing (NGS)–based targeted gene capture panels are used to profile hematopoietic malignancies to guide prognostication and treatment decisions. Because these panels include genes associated with hereditary hematopoietic malignancies (HHMs), we hypothesized that these panels could identify pathogenic germ line variants in malignant cells, thereby identifying patients at risk for HHMs. In total, pathogenic or likely pathogenic variants in ANKRD26 , CEBPA , DDX41 , ETV6 , GATA2 , RUNX1 , or TP53 were identified in 74 (21%) of 360 patients. Germ line tissue was available for 24 patients with 25 pathogenic or likely pathogenic variants with variant allele frequencies >0.4. Six (24%) of these 25 variants were of germ line origin. Three DDX41 variants, 2 GATA2 variants, and a TP53 variant previously implicated in Li-Fraumeni syndrome were of germ line origin. No likely pathogenic/pathogenic germ line variants possessed variant allele frequencies DDX41 and GATA2 are especially likely to be of germ line origin. Thus, tumor-based panels may augment, but should not replace, comprehensive germ line–based testing and counseling.

The amount of information produced by genomic sequencing is vast, technically complicated, and can be difficult to interpret. Appropriately tailoring genomic information for non-geneticists is an essential next step in the clinical use of genomic sequencing. To initiate development of a framework for genomic results communication, we conducted eighteen qualitative interviews with oncologists who had referred adult cancer patients to a matched tumor-normal tissue genomic sequencing study. In our qualitative analysis, we found varied levels of clinician knowledge relating to sequencing technology, the scope of the tumor genomic sequencing study, and incidental germline findings. Clinicians expressed a perceived need for more genetics education. Additionally, they had a variety of suggestions for improving results reports and possible resources to aid in results interpretation. Most clinicians felt genetic counselors were needed when incidental germline findings were identified. Our research suggests that more consistent genetics education is imperative in ensuring the proper utilization of genomic sequencing in cancer care. Clinician suggestions for results interpretation resources and results report modifications could be used to improve communication. Clinicians' perceived need to involve genetic counselors when incidental germline findings were found suggests genetic specialists could play a critical role in ensuring patients receive appropriate follow-up.

BACKGROUND: When parents of newborns are presented with the hypothetical possibility of obtaining genomic sequencing (GS) for their newborn infants immediately after birth, they express substantial interest. This study examined associations between expressed interest in GS and demographic and psychosocial variables some months after birth. METHODS: A total of 1096 parents were enrolled in a study on GS of newborns shortly after the birth of their infants, before discharge from the postpartum floor. Of these parents, 663 (60.5%) completed a follow-up survey 2 to 28 months later that queried their interest in GS for their infant and whether they received worrisome health information during pregnancy, labor, and delivery. They were also administered the Parenting Stress Index. Multivariate logistic regression was used to examine factors associated with interest in GS of newborns. RESULTS: Of parents, 76.1% indicated at least some interest in GS. A 10-point increase on the Parenting Stress Index was associated with an increase in the odds of having some interest in GS (odds ratio: 1.15; 95% confidence interval: 1.01–1.32). Age, gender, race, ethnicity, marital status, education, anxiety, and whether this was the first biological child were not significantly associated with interest in GS. Receiving worrisome health information was associated with greater interest in GS but this did not reach significance (odds ratio: 1.42; 95% confidence interval: 0.95–2.12). CONCLUSIONS: This hypothetical survey study suggests that previous experiences leading to worrisome health information and parenting stress need to be considered when GS is offered. Additional research, currently underway, is exploring factors associated with real-life parental choices around whether to obtain GS of their newborns.

Background: Acquired ESR1 mutations (ESR1MUT) are common resistance mechanisms in estrogen receptor positive (ER+) aBC following aromatase inhibitor (AI) therapy. ESR1MUT can be identified using plasma-based cfDNA testing in patients with progressive aBC and may be cleared (i.e. become undetectable) following response to effective therapeutic interventions. Optimal treatment for ESR1MUTaBC has not been established. We retrospectively examined the impact of various treatments on ESR1MUT detection among patients with aBC undergoing serial cfDNA testing. Methods: The deidentified Guardant Health database was queried for patients with aBC (stage IIIB/IV) with multiple cfDNA samples, at least one of which had an ESR1MUT detected (patients tested between March 2014-March 2019 using a 54-73 gene cfDNA next-generation sequencing panel, Guardant360™). Consecutive sample pairs were identified in which the first sample had ≥1 ESR1MUT and subsequent treatment could be determined from the test request form. For patients receiving combination therapy, each therapy was counted individually (e.g. a patient receiving a CDK4/6 inhibitor and an AI would be counted once for each). Each sample pair was classified as to whether any ESR1MUT persisted in the subsequent cfDNA sample. Additionally, the change in ESR1 variant allele fraction (αVAF) between the first and subsequent sample was calculated for each ESR1MUT identified. We considered ESR1MUT that had lower VAF on the subsequent sample (e.g. a negative αVAF) as evidence of a therapeutic response against ESR1MUT for the purpose of this study. The proportion of sample pairs in which the ESR1MUT was cleared, as well as the proportion of any ESR1MUT with decreased VAF was compared by treatment type using Fisher’s exact test. Results: A total of 262 ESR1 mutations were found in 167 unique sample pairs from 124 aBC patients. The median time between sample collection for each pair was 17 weeks (range: 0.7 - 133 weeks). ESR1MUT were cleared in a minority (30/167, 18%) of sample pairs with an overall minimal change in observed VAF (median αVAF of -0.01). A negative ESR1MUT VAF was observed for more than half of all ESR1MUT in patients receiving certain endocrine therapies, including fulvestrant, tamoxifen, and goserelin, and non-endocrine therapies, including chemotherapy, anti-HER2, and CDK4/6 inhibitors, suggesting these agents may still have some efficacy against ESR1MUT (Table 1). The proportion of sample pairs with ESR1MUT clearance was not significantly different for those on endocrine therapy versus those not on endocrine therapy (16% vs 19%). Similarly, there was no significant difference between these groups when examining the proportion of ESR1MUT with decreased VAF (50% vs 50%). Conclusions: In this exploratory analysis of serial cfDNA testing of ESR1MUTin aBC, some variation was observed in the efficacy of commonly used therapies as measured by the proportion of sample pairs with clearance of ESR1MUT and by the proportion of all ESR1MUT with a decreased VAF. We believe these data may be useful in guiding future analysis into optimal therapy for patients with ESR1MUTaBC. Notably, none of the therapies stood out as having promising efficacy against a large proportion of ESR1MUT subclones suggesting that additional therapeutic options may be needed to effectively target and provide long-term disease control of ESR1MUT aBC. Table 1. Temporal changes in ESR1MUT in cfDNA by therapy in aBCTreatmentNo. Sample PairsESR1MUT ClearedNo. ESR1MUTESR1MUT with VAF DecreaseMedian αVAFAI2520%3842%0.09SERD (Fulvestrant)3312%4553%-0.03Estrogen Receptor Agonist (Tamoxifen)30%667%-0.18GnRH Agonist (Goserelin)813%1464%-0.09Chemotherapy8319%13052%-0.09Anti-HER2229%2752%-0.02Everolimus2512%3749%0.05CDK4/6 Inhibitor3119%4953%-0.05Immune Checkpoint520%838%0.02Any Endocrine Therapy6316%9250%-0.01No Endocrine Therapy10419%17050%-0.01OVERALL16718%26250%-0.01 Citation Format: Caroline M. Weipert, Thereasa A. Rich, Rebecca J. Nagy, Sarah Croessmann, Ben H. Park, Joyce O'Shaughnessy, Mohammad Nezami, Massimo Cristofanilli, Aditya Bardia, Richard B. Lanman. Cell-free DNA (cfDNA) analysis of ESR1-mutant advanced breast cancer (aBC): Impact of subsequent therapy on mutation persistence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-06.

Purpose The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). Methods We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. Results Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). Conclusion A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.