Citations

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Background Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. Methods We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. Results We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). Conclusion Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs ( NCT04940299 , NCT03999749 ).

Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.

10520 Background: PATHFINDER (NCT04241796) was a prospective, interventional return of results study that enrolled 6,662 participants (pts) from 7 US institutions to assess clinical implementation of a blood-based multi-cancer early detection (MCED) test. Test results for those with a cancer signal detected also included a cancer signal origin prediction designed to help guide diagnostic evaluations. We analyzed whether the diagnostic evaluations in PATHFINDER were appropriately directed by cancer signal origin predictions, assessed the residual risk of cancer after negative initial evaluation, and examined the role of whole-body imaging (WBI, defined as PET/CT or CT chest/abdomen/pelvis) in diagnostic evaluation. Methods: Analysis included pts with a cancer signal detected result from the two different versions of an MCED test evaluated in PATHFINDER. Prespecified criteria blinded to study results were used to define expected diagnostic evaluations by cancer signal origin prediction. These criteria were then used to judge concordance between cancer signal origin predictions and the diagnostic evaluation actually performed. Definitive cancer or no cancer diagnosis (cancer status at end of study [EOS]) was assessed at 12 months after enrollment (EOS). Results: 39 pts had cancer signal detected results by both test versions. Diagnostic evaluations were consistent with cancer signal origin in 30/39 (77%) cases. Diagnostic resolution was achieved in 32/39 (82%) pts after initial evaluation, while 7/39 (18%) required additional workup. 25 of the 32 (78%) pts who achieved diagnostic resolution after initial evaluation had a cancer signal origin-guided workup. Additional evaluation of the 7 pts not achieving initial diagnostic resolution was based on persistent clinical suspicion of cancer due to prior cancer history (n = 1) or abnormal/equivocal findings on initial evaluation (n = 6). Additional workup led to diagnostic resolution in all 7 cases (3 with cancer and 4 with no cancer confirmed at EOS). WBI was ordered in 27 cases, of whom 9 had a prior cancer history, 10 had non-localizing cancer signal origin (hematologic or indeterminate), and 1 had both. WBI was equivocal or had no impact on diagnostic resolution in 8/27 (30%) cases. Conclusions: Most cases resulted in diagnostic resolution after cancer signal origin-directed diagnostic workup. In pts with a cancer history and negative initial evaluations, and those with equivocal initial evaluations, there was still a risk of cancer, suggesting the need for additional evaluation. WBI was used mostly in those with a cancer history or non-localizing cancer signal origins, and had no impact on diagnosis in almost one-third of pts. Clinical trial information: NCT04241796 .

3082 Background: CLDN6, a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies and has little to no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6. Methods: TORL123-001 (NCT05103683) is an ongoing, 2-part, first in human study to characterize the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 monotherapy in participants with advanced solid tumors. Serum pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered as a 30-minute IV infusion once every 3 weeks in 21-day cycles. During Part 1 (Dose Escalation), cohorts of 1 to 6 participants are evaluated at each dose level according to an accelerated titration design. In Part 2 (Dose Expansion), several cohorts of patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6-expressing cancers using a CLDN6 IHC companion diagnostic. Results: As of 01FEB2023, 22 patients with ovarian (n=18), testicular (n=3), and endometrial (n=1) cancers were enrolled and treated across 8 dose levels ranging from 0.2 to 2.4 mg/kg IV every 3 weeks. 95% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=5), Gr1 peripheral neuropathy (n=4), and Gr1 nausea (n=3). No DLTs have been reported and no dose reductions have been required. Preliminary PK data demonstrate sustained exposure of TORL-1-23 ADC over the 21 day dosing interval and low levels of serum MMAE indicating low off-target MMAE exposure outside of tumor. Partial responses (PR) were observed in 4/17 efficacy evaluable participants with CLDN6+ disease (3 ovarian, 1 testicular). Dose escalation is ongoing and updated results will be presented. Conclusions: TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with heavily-pretreated CLDN6-expressing ovarian and testicular cancers. Doses above the historic MTD for MMAE containing ADCs may be explored given the safety/tolerability and PK data observed up to 2.4 mg/kg. Dose finding is ongoing to identify the MTD and optimal doses for subsequent development. Clinical trial information: NCT05103683 .

Abstract Background: Prostate cancer is the second leading cause of cancer-related death in men in the United States and is dependent on androgens and androgen receptor (AR) activation. Androgen deprivation therapy (ADT) is the mainstay treatment, but it as well as next-generation treatments eventually fail. Disease then progresses as castration-resistant prostate cancer (CRPC), which is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) catalyzes the rate-limiting step for potent androgen synthesis from adrenal-derived precursors, thereby stimulating CRPC. HSD3B1, which encodes for 3βHSD1, has a common missense-encoding germline variation that enhances conversion from adrenal DHEA to potent androgens. Clinical studies demonstrate that this “adrenal-permissive” HSD3B1 genotype confers more rapid progression on ADT, and recent studies show that overall survival is shorter in patients with the adrenal-permissive genotype who are treated with ADT + enzalutamide. The Etk/BMX kinase may be involved in the development and progression of CRPC. We sought to determine whether phosphorylation of 3βHSD1 is required for its activation and that the necessary kinase could be a potential target. Methods: In prostate cancer lines, mouse xenograft models, and fresh patient prostatectomy tissues, mass spectrometry and HPLC were used to identify steroid metabolites. Genetic and pharmacological methods were used to identify inhibition of BMX-mediated 3βHSD1 phosphorylation in CRPC. Results: BMX inhibition suppressed castration-resistant prostate cancer through targeting 3βHSD1 phosphorylation. 3βHSD1 transcription level and enzyme activity were induced in enzalutamide-resistant prostate cancer cell lines. 3βHSD1 and SF-1 transcription levels were positively correlated in prostate adenocarcinoma (TCGA database). BMX inhibition by zanubrutinib suppressed enzalutamide resistance induced 3βHSD1 enzyme activity. Conclusions: BMX promotes CRPC by regulating 3βHSD1 phosphorylation. BMX inhibition has potential as a new therapy to optimize CRPC treatment. Citation Format: Xiuxiu Li, Michael Berk, Christopher Goins, Mohammad Alyamani, Yoon-Mi Chung, Chenyao Wang, Monaben Patel, Nityam Rathi, Ziqi Zhu, Belinda Willard, Shaun Stauffer, Eric Klein, Nima Sharifi. BMX inhibition reverses HSD3B1-driven resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A026.

Background: Alcohol-associated hepatitis (AH) is among the deadliest liver diseases, but its incidence is poorly defined. The aim of our study was to define the incidence of AH meeting the National Institute on Alcohol Abuse and Alcoholism criteria and to identify risk factors for AH. Methods: We conducted a retrospective cohort study using the Rochester epidemiology project database on adult patients hospitalized with AH between January 1, 2000 and December 31, 2018. Patients were screened using ICD-9 codes and then included if they met the National Institute on Alcohol Abuse and Alcoholism criteria on manual chart review. Baseline demographics, comorbidities, access to care, liver-related complications, and outcomes were obtained. The HOUsing-based index of SocioEconomic status index was used to measure socioeconomic status. Incidence rates were calculated in cases per 100,000 person-years of follow-up. Results: Among 204 patients, the cumulative AH incidence was 6.8 per 100,000 person-years. Between 2000–2004 and 2015–2018, AH incidence among males increased from 8.4 to 14.7 per 100,000 py, whereas AH incidence among females increased by 7-fold from 0.8 to 5.9 per 100,000 py. Such increases among females were accompanied by increases in comorbid depression and anxiety. The proportion of patients with AH in the lower socioeconomic status quartiles increased from 62.9% between 2000 and 2004 to 73.3% between 2015 and 2019. Conclusions: The incidence of AH is increasing rapidly, especially among females and individuals of lower socioeconomic status. There are areas of unmet need in preventative measures and treatments for comorbid psychiatric disorders in patients at high risk of AH.

Introduction: Nitrogen dioxide (NO 2 ) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO 2 levels in childhood asthma in a mixed rural-urban setting of North America. Methods: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota. Indoor and outdoor NO 2 concentrations were measured using passive air samples over 2 weeks in winter and 2 weeks in summer. We assessed seasonal variation in NO 2 levels in urban and rural residential areas and the association with asthma control status collected from participants’ asthma diaries during the study period. Results: Outdoor NO 2 levels were lower (median: 2.4 parts per billion (ppb) in summer, 3.9 ppb in winter) than the Environmental Protection Agency (EPA) annual standard (53 ppb). In winter, a higher level of outdoor NO 2 was significantly associated with urban residential living area ( P = .014) and lower socioeconomic status (SES) ( P = .027). For both seasons, indoor NO 2 was significantly higher ( P < .05) in rural versus urban areas and in homes with gas versus electric stoves ( P < .05). Asthma control status was not associated with level of indoor or outdoor NO 2 in this cohort. Conclusions: NO 2 levels were low in this mixed rural-urban community and not associated with asthma control status in this small feasibility study. Further research with a larger sample size is warranted for defining a lower threshold of NO 2 concentration with health effect on asthma in mixed rural-urban settings.

Abstract Introduction A new three-piece inflatable penile prosthesis was introduced in 2019. The Rigicon Infla10® has been implanted in 26 centers by 103 physicians. Clinical investigation for FDA approval in United States will begin in late 2022. Objective We report initial survival from explantation and revision rates for infection, mechanical failure and medical problems. Data was obtained from analysis of Patient Information Forms (PIFs) submitted to the manufacturer. Patient information data was omitted prior to analysis. Methods 319 patients implanted from 1/06/2019 to 12/31/2021 were followed to analyze device durability from revision/removal and rates of reoperation for infection, mechanical failure or medical reason. Results Mean follow-up was 21.2 months with a range of 5-36 months. Mean age was 58.5. 4.38% required removal/revision. Mechanical failure was 2.5%. There were no infections reported and only two (0.6%) medical problems (component out of place). One Peyronie's patient required revision for inadequate straightening (0.03% Three patients (0.9%) requested device removal for dissatisfaction. A total of 95.6% of Rigicon Infla10® was free from explant or revision 13 months from the original implant date. Kaplan Meier analysis revealed cumulative survival of the device at 12, 24 and 36 months was 95.6%, 94.7% and 95.7% until surgical invention. Conclusions While this is a retrospective study derived from volunteered Patient Information Forms, we believe the vast majority of the early Rigicon Infla10® performed prior to 1/2022 were included in the analysis. Early results show initial durability from re-operation equivalent to contemporary, devices. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Rigicon, Boston Scientific, Coloplast.