CDK4/6 Inhibitor Efficacy in ESR1-Mutant Metastatic Breast Cancer.

BACKGROUND: In estrogen receptor-positive metastatic breast cancer, ESR1 mutations (ESR1m) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact ESR1 alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific ESR1 allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1m metastatic breast cancer and associated clinical factors. METHODS: ESR1m were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1m or non-ESR1-mutant (non-ESR1m) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment. RESULTS: One hundred forty-five patients with ESR1m and 612 with non-ESR1m metastatic breast cancer were analyzed. ESR1m and non-ESR1m tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of ESR1 status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1m had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant. CONCLUSIONS: These data suggest ESR1 variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1m metastatic breast cancer.

ERBB2 (HER2) amplifications and co-occurring KRAS alterations in the circulating cell-free DNA of pancreatic ductal adenocarcinoma patients and response to HER2 inhibition.

Purpose: Despite accumulating data regarding the genomic landscape of pancreatic ductal adenocarcinoma (PDAC), olaparib is the only biomarker-driven FDA-approved targeted therapy with a PDAC-specific approval. Treating ERBB2(HER2)-amplified PDAC with anti-HER2 therapy has been reported with mixed results. Most pancreatic adenocarcinomas have KRAS alterations, which have been shown to be a marker of resistance to HER2-targeted therapies in other malignancies, though the impact of these alterations in pancreatic cancer is unknown. We describe two cases of ERBB2-amplified pancreatic cancer patients treated with anti-HER2 therapy and provide data on the frequency of ERBB2 amplifications and KRAS alterations identified by clinical circulating cell-free DNA testing. Methods: De-identified molecular test results for all patients with pancreatic cancer who received clinical cell-free circulating DNA analysis (Guardant360) between 06/2014 and 01/2018 were analyzed. Cell-free circulating DNA analysis included next-generation sequencing of up to 73 genes, including select small insertion/deletions, copy number amplifications, and fusions. Results: Of 1,791 patients with pancreatic adenocarcinoma, 36 (2.0%) had an ERBB2 amplification, 26 (72.2%) of whom had a KRAS alteration. Treatment data were available for seven patients. Two were treated with anti-HER2 therapy after their cell-free circulating DNA result, with both benefiting from therapy, including one with a durable response to trastuzumab and no KRAS alteration detected until progression. Conclusion: Our case series illustrates that certain patients with ERBB2-amplified pancreatic adenocarcinoma may respond to anti-HER2 therapy and gain several months of prolonged survival. Our data suggests KRAS mutations as a possible mechanism of primary and acquired resistance to anti-HER2 therapy in pancreatic cancer. Additional studies are needed to clarify the role of KRAS in resistance to anti-HER2 therapy.

Pan-Cancer Prevalence of Microsatellite Instability-High (MSI-H) Identified by Circulating Tumor DNA and Associated Real-World Clinical Outcomes.

PURPOSE: Immune checkpoint inhibitors are approved for advanced solid tumors with microsatellite instability-high (MSI-H). Although several technologies can assess MSI-H status, detection and outcomes with circulating tumor DNA (ctDNA)-detected MSI-H are lacking. As such, we examined pan-cancer MSI-H prevalence across 21 cancers and outcomes after ctDNA-detected MSI-H. METHODS: Patients with advanced cancer who had ctDNA testing (Guardant360) from October 1, 2018, to June 30, 2022, were retrospectively assessed for prevalence. GuardantINFORM, which includes anonymized genomic and structured payer claims data, was queried to assess outcomes. Patients who initiated new treatment within 90 days of MSI-H detection were sorted into immunotherapy included in treatment (IO) or no immunotherapy included (non-IO) groups. Real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed in months as proxies of progression-free survival (PFS); real-world overall survival (rwOS) was assessed in months. Cox regression tests analyzed differences. Colorectal cancer, non-small-cell lung cancer (NSCLC), prostate cancer, gastroesophageal cancer, and uterine cancer (UC) were assessed independently; all other cancers were grouped. RESULTS: In total, 1.4% of 171,881 patients had MSI-H detected. Of 770 patients with outcomes available, rwTTD and rwTTNT were significantly longer for patients who received IO compared with non-IO for all cancers (P ≤ .05; hazard ratio [HR] range, 0.31-0.52 and 0.25-0.54, respectively) except NSCLC. rwOS had limited follow-up for all cohorts except UC (IO 39 v non-IO 23 months; HR, 0.18; P = .004); however, there was a consistent trend toward prolonged OS in IO-treated patients. CONCLUSION: These data support use of a well-validated ctDNA assay to detect MSI-H across solid tumors and suggest prolonged PFS in patients treated with IO-containing regimens after detection. Tumor-agnostic, ctDNA-based MSI testing may be reliable for rapid decision making.

Detection of microsatellite instability high (MSI-H) status by targeted plasma-based genotyping in metastatic breast cancer.

We evaluate microsatellite instability-high (MSI-H) status with cell-free DNA (cfDNA) in metastatic breast cancer (MBC) and the association with clinico-genomic characteristics. Patients with MSI-H in cfDNA (Guardant360®, 74 gene next-generation sequencing (NGS) with MBC are identified. We conduct a retrospective review. The median number of alterations and a median maximum mutant allelic fraction (MAF) in MSI-H and non-MSI-H cohorts are compared with Mann-Whitney U-test. Of 6718 patients with breast cancer with ≥1 plasma NGS alteration, 42 (0.63%) have MSI-H. A median number of genomic alterations per sample is 11 in MSI-H vs. 3 in non-MSI-H (Mann-Whitney U-test p < 0.0001) and the median maximum MAF is 16.8% in MSI-H vs. 2.6% in non-MSI-H (Mann-Whitney U-test p < 0.0001). The co-existing genomic landscape is heterogeneous. The median response duration for seven patients receiving immunotherapy is 92 days (range 29-273 days). CfDNA can identify MSI-H in MBC. Research is needed to validate immunotherapy usage in cfDNA-detected MSI-H MBC.

Interventional pulmonology use of cell-free DNA assay for metastatic non-small cell lung cancer: the UC Davis experience.

BACKGROUND: Interventional pulmonologists (IPs) are often the first specialist to see patients with suspected metastatic non-small cell lung cancer (mNSCLC). Consequently, they are potentially ideally positioned to expedite the identification of actionable molecular mutations by ordering blood-based cell-free DNA (cfDNA), prior to or upon tissue diagnosis of mNSCLC. METHODS: Retrospective review of cfDNA ordered by IP as part of a routine clinical practice. Patients were categorized into two groups based on when cfDNA was ordered by IP: (1) IP suspected mNSCLC prior to histologic confirmation or (2) IP diagnosed mNSCLC based on histologic confirmation of NSCLC. RESULTS: Twenty patients were identified. Twelve of 13 in group 1 were confirmed to have mNSCLC by oncology and 1 had stage IIIA. Seven of 7 in group 2 were confirmed to have mNSCLC by oncology. Fifteen of 20 also had next-generation tissue molecular testing. Thirteen of 20 (65%) had targetable alterations. Seven of 13 (54%) were identified on cfDNA and tissue, 5/13 (38%) on cfDNA only, and 1/13 (8%) on tissue alone. Tissue results were available a medium of 24 days after, and cfDNA results a medium of 4 days prior to, the patients' first oncology visit. CONCLUSIONS: IP appears to be able identify patients who have mNSCLC and for whom testing for molecular mutations is appropriate even prior to tissue confirmation of NSCLC. A strategy whereby IP employ blood-based cfDNA testing in suspected and tissue confirmed mNSCLC could potentially provide medical oncologists with more timely information on actionable mutations than tissue-based testing first, potentially expediting patient treatment.

Prevalence of ARID1A Mutations in Cell-Free Circulating Tumor DNA in a Cohort of 71,301 Patients and Association with Driver Co-Alterations.

ARID1A abnormalities disturb transcriptional processes regulated by chromatin remodeling and correlate with immunotherapy responsiveness. We report the first blood-based cell-free DNA (cfDNA) next-generation sequencing (NGS) ARID1A analysis. From November 2016 through August 2019, 71,301 patients with advanced solid tumors underwent clinical blood-derived cfDNA testing. Of these patients, 62,851 (88%) had ≥1 cfDNA alteration, and 3137 (of the 62,851) (5%) had ≥1 deleterious ARID1A alteration (a frequency similar to the ~6% generally reported in tissue NGS), suggesting this non-invasive test's value in interrogating ARID1A. ARID1A cfDNA alterations were most frequent in endometrial cancer, 21.3% of patients; bladder cancer, 12.9%; gastric cancer, 11%; cholangiocarcinoma, 10.9%; and hepatocellular carcinoma, 10.6%. Blood samples with a functional ARID1A abnormality had more alterations/sample (median, 6 versus 4; p < 0.0001) and more frequent co-alterations in ≥1 gene in key oncogenic pathways: signal transduction, RAS/RAF/MAPK, PI3K/Akt/mTor, and the cell cycle. Taken together, our data suggest that liquid (blood) biopsies identify ARID1A alterations at a frequency similar to that found in primary tumor material. Furthermore, co-alterations in key pathways, some of which are pharmacologically tractable, occurred more frequently in samples with functional (deleterious) ARID1A alterations than in those without such aberrations, which may inform therapeutic strategies.

Profile and Predictors of Blood Tumor Mutational Burden in Advanced Hepatocellular Carcinoma.

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.

Therapeutic Actionability of Circulating Cell-Free DNA Alterations in Carcinoma of Unknown Primary.

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.

Complementary Role of Circulating Tumor DNA Assessment and Tissue Genomic Profiling in Metastatic Renal Cell Carcinoma.

PURPOSE: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study, we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC. EXPERIMENTAL DESIGN: Results of 839 patients with mRCC who had ctDNA assessment with a Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed. RESULTS: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. Mutations identified in tissue (34.7%; 42/121) were also identified via ctDNA, whereas 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays. CONCLUSIONS: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.

Erlotinib and Onalespib Lactate Focused on EGFR Exon 20 Insertion Non-Small Cell Lung Cancer (NSCLC): A California Cancer Consortium Phase I/II Trial (NCI 9878).

BACKGROUND: Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC. PATIENTS AND METHODS: Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. RESULTS: Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m2 intravenously on days 1, 8, and 15 every 28 days. CONCLUSION: Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).

Novel Genomic Differences in Cell-Free Circulating DNA Profiles of Young- Versus Older-Onset Colorectal Cancer.

We present the first analysis examining molecular alterations detected utilizing a clinically available cell-free circulating tumor DNA (cfDNA) assay in a cohort of patients with advanced colorectal cancer (aCRC) diagnosed <50 versus ≥50 years of age. Patient characteristics and mutation frequencies were compared using cfDNA tests from 5873 patients. Patients <50 had more sequence alterations in APC, CTNNB1, and SMAD4, as well as a higher frequency of focal BRAF and ERBB2(HER2) amplifications. Our study adds further evidence suggesting that young- versus older-onset CRC may have distinct molecular underpinnings, with prognostic and therapeutic implications.

Duration of Targeted Therapy in Patients With Advanced Non-small-cell Lung Cancer Identified by Circulating Tumor DNA Analysis.

BACKGROUND: Outcomes of therapy targeting molecular driver alterations detected in advanced non-small-cell lung (NSCLC) using circulating tumor DNA (ctDNA) have not been widely reported in patients who are targeted therapy-naive. PATIENTS AND METHODS: We performed a multicenter retrospective review of patients with unresectable stage IIIB to IV NSCLC who received matched therapy after a targetable driver alteration was identified using a commercial ctDNA assay through usual clinical care. Eligible patients must not have received targeted therapy prior to ctDNA testing (prior chemotherapy or immunotherapy was permitted). Kaplan-Meier analysis was used to estimate the median duration of targeted therapy. Patients still on targeted therapy were censored at last follow-up. RESULTS: Seventy-six patients met inclusion criteria. The median age of diagnosis of NSCLC was 64.5 years (range, 31-87 years), 67% were female, 74% were never-smokers, and 97% had adenocarcinoma histology. Twenty-one (28%) patients received systemic treatment prior to targeted therapy, including chemotherapy (n = 17), immunotherapy (n = 5), and/or a biologic (n = 4). Thirty-three (43%) patients remain on targeted therapy at the time of data analysis. The median time on targeted therapy was similar to what has been reported for tissue-detected oncogenic driver mutations in the targeted therapy-naive setting. CONCLUSIONS: Patients with ctDNA-detected drivers had durable time on targeted therapy. These treatment outcomes data compliment previous studies that have shown enhanced targetable biomarker discovery rates and high tissue concordance of ctDNA testing when incorporated at initial diagnosis of NSCLC. Identification of NSCLC driver mutations using well-validated ctDNA assays can be used for clinical decision-making and targeted therapy assignment.

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.

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.

Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk.

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 2 to fivefold 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.

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.

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 <0.4. This study demonstrates that NGS-based prognostic panels may identify individuals at risk for HHMs despite not being designed for this purpose. Furthermore, variants known to cause Li-Fraumeni syndrome as well as known pathogenic variants in genes such as 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.

Physician Experiences and Understanding of Genomic Sequencing in Oncology.

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.

Psychosocial Factors Influencing Parental Interest in Genomic Sequencing of Newborns.

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.