Citations

Abstract Background: Clinical benefit with PARP inhibitors (PARPi) has been demonstrated in patients (pts) with HER2-negative (HER2−) metastatic breast cancer (mBC) and germline or tumor mutations in BRCA1 or BRCA2 (g/tBRCAm). Understanding real-world PARPi use and its impact on clinical outcomes may improve the treatment of pts with BRCAm HER2− mBC. Methods: This retrospective study captured data from US pts aged ≥18 years diagnosed with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified electronic health record-derived Flatiron Health Research Database. PARPi use and outcomes were described by tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), g/tBRCA status, disease stage at diagnosis (de novo or recurrent), line of therapy (LoT), and prior treatments. Real-world overall survival (rwOS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 848 pts with gBRCAm mBC, 352 (42%) received PARPi (Table), with consistent PARPi initiation rates of 42%-48% from 2018-2022. PARPi was initiated in 223/566 (39%) pts with gBRCAm HR+/HER2− mBC, 125/275 (45%) pts with gBRCAm mTNBC, and 4/7 (57%) pts with unknown tumor subtype. Among 304 pts with gBRCAm who had received ≥3 LoT by the end of follow-up, 93/225 (41%) pts with HR+/HER2− mBC and 18/78 (23%) pts with mTNBC received PARPi in the third LoT or later (3L+); 50/103 (49%) pts with de novo mBC and 54/184 (29%) pts with recurrent mBC received PARPi in 3L+. PARPi was also initiated in 13/231 (6%) pts with gBRCA variants of uncertain significance (VUS) and 176/662 (27%) pts with tBRCAm and non-gBRCAm/unknown gBRCAm status. Among 539/1573 (34%) pts with g/tBRCAm who received PARPi, 167 had not received prior chemotherapy in any setting; 40 of these pts (39 with HR+/HER2− mBC and 1 with mTNBC) received PARPi in 3L+. With a median follow-up of 17.0 months from initiation of 1L therapy, median rwOS was numerically longer among pts with gBRCAm who received PARPi versus pts who did not (HR+/HER2− mBC: 39.3 months [95% CI: 35.5-46.8], n=208 vs 24.2 months [95% CI: 21.4-33.0], n=259; mTNBC: 27.6 months [95% CI: 18.0-41.7], n=119 vs 16.9 months [95% CI: 14.5-31.9], n=81). Among pts with tBRCAm who were negative for gBRCAm, median rwOS was numerically longer in pts who received PARPi versus pts who did not. Conclusions: Pts with HR+/HER2− mBC had slightly lower rates of PARPi use, and received PARPi later, than pts with mTNBC. Although improved efficacy with PARPi use in earlier LoT has been demonstrated, many pts first received PARPi in 3L+, suggesting unmet potential to ensure timely testing and optimize treatment. Although immortal time bias and other factors should be considered, rwOS was numerically longer in pts with BRCAm HR+/HER2− mBC and with BRCAm mTNBC who initiated PARPi versus pts who did not. Further research into PARPi use and survival trends in pts with BRCAm and/or other actionable biomarkers in mBC is needed. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world PARP inhibitor use and clinical outcomes in US patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-08.

Abstract Background: International guidelines recommend that all patients (pts) with metastatic breast cancer (mBC) are offered testing for germline BRCA1/BRCA2 mutations (gBRCAm) and other biomarkers to aid treatment decisions. This retrospective study describes real-world testing patterns for germline/tumor (g/t)BRCAm and other biomarkers among US pts with HER2-negative [HER2−] mBC. Methods: Data were captured from US pts aged ≥18 years with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified, electronic health record-derived Flatiron Health Research Database. Demographics, clinical characteristics, and testing patterns for g/tBRCAm and other actionable biomarkers were examined. Testing rates, test timing, and biomarker status were described across subgroups defined by demographics (including age, race, and ethnicity), tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), and disease stage at mBC diagnosis (recurrent/de novo). Results: The BRCA testing rate among pts with mBC increased from 2018 (48%) to 2023 (62%); the overall testing rate was 19,820/34,379 (58%): 5880 pts (17%) received a gBRCA test only, 7285 (21%) received a tBRCA test only, and 6655 (19%) received both gBRCA and tBRCA tests. BRCA testing rates were numerically lower in pts with HR+/HER2− mBC (56%) versus mTNBC (68%), and in pts aged >65 years (HR+/HER2− mBC, 48%; mTNBC, 62%) versus ≤65 years (HR+/HER2− mBC, 64%; mTNBC, 74%; Table). The proportion of pts who received a test before initiation of first-line (1L) therapy was lower among pts with HR+/HER2− mBC than with mTNBC (recurrent, 60% vs 81%; de novo, 37% vs 57%). Among tested pts, 1067/15,168 (7%) with HR+/HER2− mBC and 494/4539 (11%) with mTNBC had a positive result for g/tBRCAm; 365/1067 (34%) pts with g/tBRCAm HR+/HER2− mBC and 138/494 (28%) pts with g/tBRCAm mTNBC were aged >65 years. Among 528 pts with gBRCAm HR+/HER2− mBC, co-mutations in PIK3CA, ESR1, PTEN, and AKT1 were identified in 48 (9%), 38 (7%), 20 (4%), and 3 (<1%) pts, respectively. Among pts diagnosed with gBRCAm HR+/HER2− mBC in 2020-2023 (median follow-up: 15 months), 175/371 (47%) did not receive a test for PIK3CA mutations at any time, and 48/97 (49%) pts diagnosed in 2023 (median follow-up: 6 months) did not receive a test for ESR1 mutations. In 2021-2023, 72/256 (28%) pts with g/tBRCAm mTNBC had tumors with programmed cell death-ligand 1 (PD-L1) combined positive score ≥10; 88 (34%) pts did not receive a PD-L1 test. Conclusions: Although BRCA testing rates increased from 2018 to 2023, 38% of US pts diagnosed with HER2− mBC in 2023 did not receive any BRCA test. BRCA testing rates were low among pts with HR+/HER2− mBC and/or aged >65 years, suggesting that many g/tBRCAm remained undetected. Wider and timelier testing for germline and tumor biomarkers is warranted to identify pts who are eligible for targeted therapies. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world biomarker testing patterns in US patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-08.

PURPOSE Testing for germline BRCA1 and/or BRCA2 mutations (gBRCAm) is recommended for patients with human epidermal growth factor receptor 2–negative (HER2–) breast cancer (BC) to guide treatment selection with poly (ADP-ribose) polymerase inhibitors (PARPis). However, real-world data on germline BRCA1 and/or BRCA2 (gBRCA) testing and PARPi treatment patterns in metastatic BC (mBC) are limited. METHODS Deidentified patient data from adults diagnosed with HER2– mBC between 2014 and 2022 were captured from electronic health records in the US Flatiron Health database. gBRCA testing patterns and prevalence were examined by tumor subtype (hormone receptor–positive [HR+]/triple-negative) and disease stage at diagnosis. Demographic and clinical characteristics were described by receipt of gBRCA testing and PARPi. PARPi treatment patterns were assessed, and real-word overall survival (OS) was estimated in patients with gBRCAm diagnosed with mBC after January 1, 2018. RESULTS Of the 15,006 total patients, 4,654 (31.0%) received a gBRCA test. gBRCA testing rates mostly increased from 2014 to 2022 and were lower in patients with HR+ than triple-negative tumors. Of the patients who underwent gBRCA testing, 337 (7.2%) had gBRCAm. From 2018 to 2022, PARPi was initiated in 94 (45.6%) of 206 patients with gBRCAm. With a median follow-up of 22.8 months across patients with available first-line treatment start dates, real-world OS was numerically longer among 94 patients with gBRCAm who received PARPi (32.3 months [95% CI, 22.7 to 47.4]) than among 99 patients who did not (21.9 months [95% CI, 18.4 to not reached]). CONCLUSION Although gBRCA testing increased over time, testing and PARPi utilization rates remained suboptimal in potentially eligible patients with HER2– mBC. Exploratory analysis showed numerically longer OS in patients who received PARPi. Wider and timelier gBRCA testing is warranted to inform potentially optimal treatment decisions.

e12502 Background: In March 2022, the United States Food and Drug Administration approved olaparib as adjuvant treatment (tx) for patients with germline BRCA1/2 pathogenic or likely pathogenic variants and HER2-negative eBC at high risk of recurrence who have been treated with neo-adjuvant or adjuvant chemotherapy. Approval was based on results from the OlympiA trial which demonstrated a significant increase in invasive-disease free survival [hazard ratio, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001] and overall survival [hazard ratio, 0.68; 99% CI, 0.47-0.97; P=0.009] with olaparib vs placebo. To date, there has been limited real-world data for eBC on olaparib utilization patterns and characteristics of olaparib users. Methods: This retrospective analysis using closed claims from KHM included adult pts with HER2-negative eBC receiving first olaparib prescription (index date) from March 11, 2022 to Nov 30, 2023. Continuous medical and pharmacy enrollment of ≥12 months pre-index and ≥30 days post-index was required. Pt characteristics were summarized descriptively, and Kaplan-Meier (KM) analysis was conducted for time-to-event utilization outcomes. Outcomes were evaluated for pts overall and stratified by hormone receptor (HR) status and race/ethnicity. Non-persistence was defined as minimum of 2 consecutive missed prescription fills. Medication possession ratio (MPR) was calculated as the sum of days of olaparib supply, divided by the total number of days from olaparib initiation to the last claim plus days of olaparib supply in the last claim. Results: We identified 176 pts with HER2-negative eBC who received olaparib. Median age was 44 years, and the majority (66.5%) had commercial insurance. KM-calculated median persistence on olaparib was 11 months (95% CI: 9.2-12.2); overall, adherence measured by MPR ≥80% was 74.2% by month 6 of olaparib use; adherence is higher among Caucasian than non-Caucasian pts (Table). While the majority of HR+/HER2- pts (77.9%, N=53/68) took olaparib concurrently with other (88.7% hormonal) adjuvant tx, most TNBC pts (70.4%, N=76/108) received olaparib alone. Among TNBC pts who took olaparib concurrently with other adjuvant tx (N=32/108), 81.3% received olaparib combined with immunotherapy. Conclusions: Our study provides evidence of favorable persistence and adherence to adjuvant olaparib in a real-world setting and data on utilization of olaparib concurrently with other tx. Recent approvals of other adjuvant tx for HER2- high-risk eBC warrants further research on the efficacy of olaparib used alone, versus olaparib combined or sequenced with other treatments. Olaparib MPR ≥80% by follow-up time points between Caucasians and non-Caucasians. Cohorts 30 days 60 days 180 days 365 days Caucasians (N=70) 92.5% 71.7% 80.6% 90.9% Non-Caucasians(N=55) 88.7% 66.7% 70.0% 50.0%

AbstractBackgroundTau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo.MethodAD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration.ResultsTau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance.ConclusionThis study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.

Abstract This study reports the first pig-to-human lung xenotransplantation using a six gene-edited pig lung. A left lung from a gene-edited Chinese Bama Xiang pig was transplanted into a 39-year-old brain-dead human recipient. The xenograft maintained viability and functionality for 216 hours without signs of hyperacute rejection. Postoperatively, severe edema resembling primary graft dysfunction (PGD) was observed, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9 under the current immunosuppressive regimen. This pioneering study suggests that genetically modified pig lungs could potentially be used for future clinical applications in xenotransplantation.

1113 Background: Testing for BRCA1/BRCA2 mutations (BRCAm) aids systemic treatment decisions for patients (pts) with metastatic breast cancer (mBC). This retrospective study explored real-world germline/tumor (g/t) BRCA testing patterns and PARP inhibitor (PARPi) use in US pts with mBC. Methods: Data from pts ≥18 years old diagnosed with HER2-negative mBC from 2014–2022 were captured in the nationwide Flatiron Health electronic health record-derived deidentified database. Patterns and timing of prospective or incidental BRCA testing were compared across mBC subtypes (hormone receptor-positive [HR+ mBC]/triple-negative mBC [mTNBC]) and disease stage (recurrent/ de novo). BRCAm prevalence was compared by testing modality and mBC subtype. PARPi initiation was assessed in pts with mBC diagnosed from 2018 onwards and a positive BRCAm test result. Clinical characteristics were compared by receipt of a BRCA test, testing modality, and PARPi initiation. Real-world overall survival (OS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 15,006 pts (including 12,349 with HR+ mBC; 1998 with mTNBC), 8178 (54.5%) did not receive any type of BRCA test, 4654 (31.0%) received a gBRCA test, 3075 (20.5%) received a tumor tissue DNA (ttDNA) test, and 1418 (9.4%) received a circulating tumor DNA (ctDNA) test. BRCA testing prevalence was numerically higher in pts with mTNBC (n=1164; 58.3%) than in pts with HR+ mBC (n=5323; 43.1%). As expected, testing prevalence was higher with ttDNA than with ctDNA (mTNBC: n=569 [28.5%] vs n=137 [6.9%]; HR+ mBC: n=2339 [18.9%] vs n=1224 [9.9%]). Over 93% of pts (recurrent and de novo) who received a tBRCA test were tested after an mBC diagnosis, and >1/3 were tested after first-line therapy, with median times from diagnosis to a ttDNA and ctDNA test of 127 and 431 days, respectively. Both gBRCA and tBRCA testing rates increased from 2014–2022, and testing occurred earlier in pts with recurrent than de novo disease. Among pts with tBRCAm, 66.0% had HR+ mBC, and 25.6% had mTNBC. BRCA1 mutations were more common in mTNBC (59.0%) than in HR+ mBC (22.9%) tumors. Of 219 pts with tBRCAm tumors who were diagnosed with mBC from 2018 onwards, PARPi was initiated in 39/74 (52.7%) pts with gBRCAm, 15/71 (21.1%) pts who were gBRCAm-negative, and 19/74 (25.7%) pts with gBRCAm status unknown. Among pts with g or tBRCAm and available OS data, median OS was numerically longer in pts who received PARPi (32.3 months [95% CI: 24.2, 47.4], n=128) versus pts who did not (29.0 months [95% CI: 21.9, 31.9], n=204; median follow-up time 23.2 months). Conclusions: While NCCN guidelines recommend gBRCA testing for all pts with mBC, more than half of pts with HER2-negative mBC (56.9% of pts with HR+ mBC) did not receive any BRCA test. Among pts with tBRCAm, ~2/3 had HR+ disease. Despite the potential benefits of PARPi for pts with BRCAm mBC, utilization remained low from 2018–2022.

Abstract Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC–alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.

Abstract Background: PARP inhibitors (PARPi) have demonstrated progression-free survival benefits vs. chemotherapy in patients (pts) with metastatic breast cancer (mBC) and germline BRCA mutations (gBRCAm). NCCN guidelines recommend that all pts with mBC are offered gBRCAm testing to aid in systemic treatment decisions with PARPi. Understanding real-world gBRCAm testing patterns and PARPi use would be beneficial for improving clinical outcomes of pts with gBRCAm mBC. Methods: This retrospective cohort study identified pts ≥ 18 years old with HER2-negative mBC, diagnosed from 2014 to 2022 (US Flatiron Electronic Health Record database). gBRCAm testing patterns in mBC over time were examined by BC subtype (hormone receptor-positive [HR+] or triple-negative breast cancer [TNBC]) and disease stage at diagnosis [de novo or recurrent]). Timing of gBRCAm testing and subsequent initiation of first-line or later PARPi in pts with gBRCAm HR+ and TNBC mBC was assessed in pts diagnosed after 2018 when PARPi were approved in mBC. Prevalence of gBRCAm was calculated overall and by mBC subtype. Demographic and clinical characteristics were described by gBRCAm testing and PARPi initiation (yes/no). Real-world overall survival (OS) by PARPi use since mBC diagnosis was estimated using the Kaplan-Meier method and a log-rank test. Results: Of 15,006 total pts, 4654 (31.0%) had a gBRCAm test. Compared with pts who were not tested, gBRCAm-tested pts were younger at initial mBC diagnosis (median age: 53.5 vs. 62.0 years), had a shorter median disease-free interval before mBC diagnosis (821 vs. 959 days), and were less likely to have de novo mBC (28.0% vs. 31.2%). gBRCAm testing prevalence was 6.1% in the HR+ group (n=11,945) and 8.9% in the TNBC group (n=2430). gBRCAm testing rates mostly increased from 2014 to 2022 and were lowest in HR+ tumor subtypes; &lt; 2/3 of all pts had a gBRCAm test from 2020 onwards (Table). Most pts with recurrent mBC (HR+: 68.3%; TNBC: 76.1%) were gBRCAm tested before diagnosis, whereas pts with de novo mBC were tested at a later timepoint ( &gt; 60 days after mBC diagnosis – HR+: 48.3%; TNBC: 38.4%). Of all pts with gBRCAm diagnosed from 2018 onwards (n=187), 44.4% initiated PARPi. A higher proportion of pts with gBRCAm in the TNBC group initiated PARPi (52.9%) than in the HR+ group (42.4%). Pts with gBRCAm in the TNBC group received PARPi earlier than pts with gBRCAm in the HR+ group (mean days from mBC diagnosis to first PARPi use: 173 and 411 days, respectively). Fewer pts with de novo mBC (35.7%) initiated PARPi than pts with recurrent mBC (50.8%). With a median follow-up of 15.3 months, pts with gBRCAm initiated on PARPi had numerically longer median OS (32.3 months [95% CI: 24.2–47.4]) than PARPi non-initiators (21.4 months [95% CI:18.4–43.5]). OS results should be regarded with caution due to the small sample size (n=187). Conclusions: Despite NCCN guideline gBRCAm-testing recommendations, &lt; 2/3 of pts with HER2-negative mBC in our study were gBRCAm tested from 2020 onwards. gBRCAm testing was lower in pts with HR+ disease and was performed at a later timepoint for pts with de novo disease. Wider and timelier implementation of gBRCAm testing to identify pts that could benefit from PARPi is warranted. Fewer pts with gBRCAm who had HR+ tumors or de novo disease received PARPi than pts with TNBC. Our data suggest that pts who initiated PARPi had numerically longer OS than PARPi non-initiators; further research into OS trends and PARPi use in gBRCAm mBC would be of interest. Editorial acknowledgment: Medical writing assistance was provided by Leigh-Ann Booth, Ph.D. from BOLDSCIENCE Inc., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US Legal entity responsible for the study: AstraZeneca. Funding: This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US, who are codeveloping olaparib. Table. gBRCAm testing rates over time in pts with HER2-negative mBC HER2-negative mBC is defined as IHC 0, or 1-positive, or IHC2-positive/ISH-negative. *Olaparib approved in mBC; †Olaparib approved in eBC. eBC, early breast cancer; gBRCAm, germline breast cancer gene mutation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; pt, patient; TNBC, triple-negative breast cancer. Citation Format: Siddhartha Yadav, Sam Hillman, Linlin Luo, Weiyan Li, Jagadeswara Earla, Xiaoqing Xu. BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-02.

Abstract Introduction: Identifying dysregulated gene expression in ovarian cancers has been limited by a deficit of available normal tissues. Here, we generated the largest set of high-grade serous ovarian cancer (HGSOC) tumors with normal precursor tissues for transcriptome analyses to identify lncRNA expression patterns, provide insight into their cellular contexts and functions, and assess their relevance to HGSOC pathogenesis and genetic susceptibility. Methods: We performed RNA sequencing on 220 primary HGSOCs and 116 benign epithelia (micro-dissected fallopian tube, ovarian surface, and inclusion cyst epithelia), and combined samples with 428 HGSOCs from TCGA, 60 HGSOCs from a prior study, and 180 bulk ovary tissues from GTEx. Reads were processed with a uniform bioinformatic and quality control pipeline, combined and batch corrected. Normalized TPM expression values were compared using the Wilcoxon rank sum test with &gt;2-fold change and FDR &lt;1% considered statistically significant. We computed weighted gene co-expression networks for each tissue type and tested for enrichment of differentially expressed genes (DEGs) and gene ontologies within co-expression modules. Results: Transcriptomes included 27,700 expressed genes (8,202 lncRNAs) across 706 HGSOCs, 180 bulk ovary, and 88 ovarian epithelia tissues. Most genes were expressed in all tissues, though 5% each showed HGSOC- or normal tissue-specific expression which comprised ≥50% lncRNA. Comparing HGSOCs to normal tissues identified 11,804 DEGs with 4,522 lncRNAs (DElncRNA) of which ~50% were tissue-specific. DEGs included MUC16 and multiple GWAS/TWAS implicated susceptibility genes including RAD51, BRIP1, BNC2, TIPARP-AS1, PRC1, KANSL1, ANKLE1, CHMP4C, ESRP2, and CCNE1. The most highly expressed DElncRNA in HGSOC were upregulated RMRP (P=1.4 × 10−39), SNHG1 (P=3.0 × 10−27), and HAGLR (P=2.0 × 10−24) at the HOXD risk locus. Lower proportions of lncRNA were seen in the HGSOC co-expression modules compared to those in normal tissues and less (3% vs. 15%) HGSOC modules were considered strongly lncRNA regulated (&gt;50% lncRNA in module). Tissue-specific DElncRNA tended toward upregulation in HGSOC compared to ovarian epithelia with enriched modules associated with cell cycle regulation (P=1.5 × 10−38); and toward downregulation in HGSOC compared to bulk ovary with enriched modules associated with chemokine signaling/response (P=1.7 × 10−113). Conclusions: The lower proportion of lncRNA involved in HGSOC co-expression networks indicates a marked loss of regulation by lncRNA. Preliminary interrogation of HGSOC-dysregulated lncRNA expression revealed tissue-specific differences that highlight unique biological pathways in precursor epithelia and the ovarian microenvironment that contribute to HGSOC pathogenesis. Our results provide additional support for previously nominated risk genes. eQTL analysis has recently been completed and integration with GWAS are underway to elucidate lncRNA and lncRNA-regulated susceptibility genes and will be presented at the conference. Citation Format: Brett M. Reid, Ann Chen, Zhihua Chen, Florian A. Karreth, Peter Kanetsky, Jennifer B. Permuth, Ozlen Saglam, Jamie K. Teer, Xiaoqing Yu, Simon Gayther, Ellen Goode, Paul Pharoah, Thomas A. Sellers, Kate Lawrenson, Jonathan Tyrer. Patterns of lncRNA-regulated gene expression in high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A004.