Citations

Abstract Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Abstract Introduction: Acquired ESR1 mutations (mutESR1) after long-term endocrine therapy drive treatment resistance, metastasis, and poor prognosis for patients (pts) with ER+/HER2- metastatic breast cancer (mBC). Lasofoxifene (LAS), a selective estrogen receptor modulator, alone or with a CDK4/6 inhibitor (CDK4/6i) reduced tumor growth better than fulvestrant (Fulv) in mutESR1 BC xenograft models. ELAINE 1 is a randomized trial of LAS vs Fulv in pts with mutESR1 and prior progression on aromatase inhibitor and CDK4/6i. Preliminary results (ESMO 2022) showed that LAS prolonged median progression-free survival (mPFS) compared with Fulv with a favorable safety profile. Here, we report changes in ESR1 ctDNA mutant allele frequency (MAF) from baseline to 8 wks and their associations with clinical benefit (CB) and mPFS. Methods: ELAINE 1 pts were randomized to oral LAS 5 mg daily or IM Fulv 500 mg on days 1, 15, and 29, then every 4 wks, until disease progression or severe toxicity. ctDNA mutESR1 mutations (baseline and 8 wks) were assessed using the Sysmex Inostics OncoBeam or SafeSeq assays—which detect mutESR1 at low allele fractions. MAF changes from baseline to wk 8 were characterized as decreased (decrease in ESR1 MAF or fully cleared), increased (increase in MAF), or equivocal (polyclonal patients [>1 mutESR1] with some increasing and decreasing MAF trends); correlations with PFS and CB were explored. Efficacy measures included objective response rate (ORR), PFS, and CB at 24 wks (CB defined as response or stable disease ≥24 wks). Results: 103 pts received LAS (n=52) or Fulv (n=51). Most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal. Of the 61 pts with evaluable baseline and wk 8 ctDNA, LAS decreased mutESR1 MAF in 29/35 pts (83% [11 complete clearance]) while Fulv decreased mutESR1 MAF in 16/26 pts (61.5% [6 complete clearance]) (Table). mPFS with LAS was 8 and 4 mos for pts with decreased/cleared MAF and increased MAF, respectively, and with Fulv was 4.5 and 2.8 mos, respectively (Table). LAS decreased the common mutESR1 variants more frequently than Fulv (median relative change -87.1% vs -14.7%). In pts with decreased MAF, CB was observed in 16/29 LAS pts (55%) and 4/16 Fulv pts (25%). The predictiveness of ESR1 MAF clearance for CB was also explored. Of 11 pts with ESR1 MAF clearance taking LAS, 10 achieved CB, yielding a positive predictive value (PPV) of 90.9%. In contrast, 2/6 pts with ESR1 MAF clearance taking Fulv had CB for a PPV of 33.3%. Sensitivity for predicting CB based on direction of ESR1 MAF change was 94% with LAS and 80% with Fulv. In pts with Y537S MAF (n=33), LAS decreased Y537S in 13/15 (87%), with a median relative MAF decrease of 89%. In marked contrast, Fulv increased Y537S MAF in 11/18 pts (61%), corresponding to an MAF relative increase of 82%. LAS and Fulv resulted in complete clearance of Y537S MAF in 33% and 6% of pts, respectively. Conclusion: Our data demonstrate that LAS more effectively decreased or cleared mutESR1 than Fulv. Further, mutESR1 clearance was associated with prolonged PFS and more CB in LAS but not Fulv pts, suggesting that LAS results in robust mutESR1 target engagement. Taken together, our data suggest mutESR1 as a potential liquid biomarker for predicting response to LAS in mutESR1, endocrine-resistant mBC pts. Table. Change from baseline to week 8 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; PFS, progression-free survival. Citation Format: Matthew P. Goetz, Einav Gal-Yam, Daniel Stover, Sarah L. Sammons, Stephanie L. Graff, Grace Wang, Massimo Cristofanilli, Gary Riordan, Hillary S. Sloane, Dominic Carroll, Paul V. Plourde, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-04.

Heterozygous loss-of-function (LOF) mutations in PIK3R1 (encoding phosphatidylinositol 3-kinase [PI3K] regulatory subunits) cause activated PI3Kδ syndrome 2 (APDS2), which has a similar clinical profile to APDS1, caused by heterozygous gain-of-function (GOF) mutations in PIK3CD (encoding the PI3K p110δ catalytic subunit). While several studies have established how PIK3CD GOF leads to immune dysregulation, less is known about how PIK3R1 LOF mutations alter cellular function. By studying a novel CRISPR/Cas9 mouse model and patients’ immune cells, we determined how PIK3R1 LOF alters cellular function. We observed some overlap in cellular defects in APDS1 and APDS2, including decreased intrinsic B cell class switching and defective Tfh cell function. However, we also identified unique APDS2 phenotypes including defective expansion and affinity maturation of Pik3r1 LOF B cells following immunization, and decreased survival of Pik3r1 LOF pups. Further, we observed clear differences in the way Pik3r1 LOF and Pik3cd GOF altered signaling. Together these results demonstrate crucial differences between these two genetic etiologies.

Adductor spasmodic dysphonia (AdSD) disrupts laryngeal muscle control during speech and, therefore, affects the onset and offset of phonation. In this study, the goal is to use laryngeal high-speed videoendoscopy (HSV) to measure the glottal attack time (GAT) and glottal offset time (GOT) during connected speech for normophonic (vocally normal) and AdSD voices. A monochrome HSV system was used to record readings of six CAPE-V sentences and part of the “Rainbow Passage” from the participants. Three raters visually analyzed the HSV data using a playback software to measure the GAT and GOT. The results show that the GAT was greater in the AdSD group than in the normophonic group; however, the clinical significance of the amount of this difference needs to be studied further. More variability was observed in both GATs and GOTs of the disorder group. Additionally, the GAT and GOT time series were found to be nonstationary for the AdSD group while they were stationary for the normophonic voices. This study shows that the GAT and GOT measures can be potentially used as objective markers to characterize AdSD. The findings will potentially help in the development of standardized measures for voice evaluation and the accurate diagnosis of AdSD.

Background Height-adjusted total kidney volume (htTKV) measured by imaging defined as Mayo Imaging Class (MIC) is a validated prognostic measure for autosomal dominant polycystic kidney disease (ADPKD) in adults to predict and stratify disease progression. However, no stratification tool is currently available in pediatric ADPKD. Because magnetic resonance imaging and computed tomography in children are difficult, we propose a novel 3D ultrasound-based pediatric Leuven Imaging Classification to complement the MIC. Methods A prospective study cohort of 74 patients with genotyped ADPKD (37 female) was followed longitudinally with ultrasound, including 3D ultrasound, and they underwent in total 247 3D ultrasound assessments, with patients' median age (interquartile range [IQR]) at diagnosis of 3 (IQR, 0–9) years and at first 3D ultrasound evaluation of 10 (IQR, 5–14) years. First, data matching was done to the published MIC classification, followed by subsequent optimization of parameters and model type. Results PKD1 was confirmed in 70 patients (95%), PKD2 in three (4%), and glucosidase IIα unit only once (1%). Over these 247 evaluations, the median height was 143 (IQR, 122–166) cm and total kidney volume was 236 (IQR, 144–344) ml, leading to an htTKV of 161 (IQR, 117–208) ml/m. Applying the adult Mayo classification in children younger than 15 years strongly underestimated ADPKD severity, even with correction for height. We therefore optimized the model with our pediatric data and eventually validated it with data of young patients from Mayo Clinic and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease used to establish the MIC. Conclusions We proposed a five-level Leuven Imaging Classification ADPKD pediatric model as a novel classification tool on the basis of patients' age and 3D ultrasound-htTKV for reliable discrimination of childhood ADPKD severity.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org .

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141