Kaiser Permanente South San Francisco Medical Center

Abstract Background Targeted therapies have transformed treatment for HR+/HER2- metastatic breast cancer (mBC), but optimal use depends on timely biomarker testing and matched therapy selection. This study evaluated national trends in PIK3CA, PTEN, AKT1 and ESR1 biomarker testing and treatment patterns among U.S. patients (pts) in community oncology clinics and examined factors associated with timely biomarker testing. Methods We conducted a retrospective cohort study of adult pts (≥18 years) with HR+/HER2- mBC treated between 01/01/2018 and 01/31/2025, using de-identified, electronic health record-derived data from the United States Flatiron Health Network. Eligible pts received at least one line of therapy at U.S. community oncology practices. Biomarker testing and treatment patterns across the first three lines of therapy (1L-3L) were analyzed descriptively. Logistic regression model evaluated associations between timely testing and baseline demographic, socioeconomic (SES), and clinical characteristics. Timely testing was defined as completing biomarker testing with results available before initiating a line of therapy for which an approved targeted treatment was available. Results Among 6,197 eligible pts who received 1L therapy, 3,550 progressed to 2L and 2,045 to 3L during the study period. Biomarker testing rates increased over time prior to 1L (from 4% in 2018 to 35% in 2024), 2L (from 9% to 69%), and 3L (from 13% to 83%). CDK4/6 inhibitors were the predominant 1L treatment regardless of biomarker status. In 2L and 3L, treatment patterns became more fragmented. Among pts with known PIK3CA mutations, the use of targeted approved therapies was 32% in 2L and 36% in 3L in 2019, compared to 27% and 29% in 2024. Among pts with ESR1+, elacestrant use rose from 22% in 2023 to 29% in 2024 in 2L and remained steady at 26-27% in 3L. In AKT1/PTEN+ pts, capivasertib use was 6% in 2L and 11% in 3L in 2024. Among pts with no test, or with negative or inconclusive biomarker results, 1% in 1L, 9% in 2L and 17% in 3L received Antibody Drug Conjugates in 2024. Treatment choices for dual-mutant (ESR1+ with either PIK3CA, AKT1 or PTEN) pts remained highly variable, with no dominant regimen: 27% received targeted therapies in 2L versus 34% in 3L. Pts were less likely to receive timely biomarker testing if they were older, lived in lower-SES areas, were treated at smaller practices, or had a worse ECOG score. However, timely testing became more common in more recent years. Conclusions Despite the availability of targeted therapies, major gaps persist in both biomarker testing and the uptake of these treatments. In 2024, nearly one-third of pts remained untested before 2L, and only 35% were tested prior to initiating 1L, limiting timely access to newly approved options. Even when actionable mutations were identified, over two-thirds of eligible pts did not receive matched therapies. Timely testing was less common in smaller practices and lower-SES settings, highlighting systemic barriers to precision oncology. To close these gaps, coordinated, equity-focused strategies are needed to improve timely testing and ensure appropriate use of targeted treatments across all pts populations. Study Number: SL46196 and PL-03044. Financial Statement: This study was sponsored by Genentech, Inc., a member of the Roche Group. Citation Format: I. M. Abbass, D. Lebovitch, N. Jain, T. Stricker, S. Nunnery, A. Pregenzer, E. Behan, R. Wang, L. Chen, P. Dhillon, Y. Liu, T. Szado, E. Yu, S. Ogale. Trends and Barriers in Biomarker Testing and Treatment Patterns in HR+/HER2- 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 PS1-12-27.

Prognostic models in oncology have a profound impact on personalized cancer care and patient profiling, but tend to be heterogeneously developed and implemented in narrow patient cohorts. Here, we develop and benchmark multiple machine learning models to predict survival in pan-cancer and 16 single-cancer settings using a de-identified clinico-genomic database of 28,079 US patients with cancer. We identify key predictors of cancer prognosis, including 15 shared across seven or more cancer types, revealing strong consistency in cancer prognostic factors. We demonstrate that pan-cancer models generally outperform or match single-cancer models in predicting survival and risk stratifying patients, especially in smaller cancer cohorts, suggesting a unique transfer learning advantage of pan-cancer models. This work demonstrates the potential of pan-cancer approaches in enhancing the accuracy and applicability of prognostic models in oncology, paving the way for more personalized and effective cancer care strategies.

Severe hypoglycemia is a life-threatening, iatrogenic complication of diabetes medications associated with increased risks of falls, cardiovascular events, cognitive decline, and mortality. To determine whether proactive outreach by a clinical pharmacist applying an evidence-based hypoglycemia-prevention algorithm (Hypoglycemia on a Page) would result in safer prescribing of diabetes regimens among patients with type 2 diabetes (T2D) with hypoglycemia risk. This randomized clinical trial was conducted between July 20, 2023, and January 22, 2024, with follow-up outcomes collected through January 2025. The study included adults with T2D at high risk of hypoglycemia based on a validated hypoglycemia risk tool. The trial was conducted within Kaiser Permanente Northern California, a large, integrated health care delivery system. Patients were randomized 1:1 to either a protocol-driven outreach by a clinical pharmacist (intervention) arm or a usual care (control) arm. The main outcome was the comparison of the proportion of patients who were prescribed safer (less hypoglycemia-prone) diabetes regimens, defined as discontinuation of sulfonylureas and/or rapid-acting or short-acting or mixed insulins, using an intention-to-treat analysis. From an eligible population of 1204 patients, 200 were enrolled into the clinical trial. Among these, 191 patients were in the intention-to-treat cohort (mean [SD] age, 71.3 [11.5] years; 100 females [52.4%]). The 2 study arms were similar at baseline in terms of race and ethnicity, sex, mean (SD) hemoglobin A1c (HbA1c) level (intervention: 8.0 [1.3]; control: 8.3 [1.8]), and number (percentage) of patients receiving insulin (intervention: 82 [85.4%]; control:85 [89.5%]) and sulfonylurea (intervention: 25 [26.0%]; control: 21 [22.1%]). At 6 months, patients in the intervention arm were more likely to be prescribed a safer diabetes regimen than those in the control arm (27 [28.1%] vs 15 [15.8%]; risk difference [RD], 12.3% [95% CI, 0.6% to 24.0%]). Patients in the intervention arm also experienced significantly fewer hypoglycemia-related emergency department or inpatient encounters (0 vs 5 [5.3%]; RD, -5.3% [95% CI, -11.8% to -1.3%]). There was no worsening of HbA1c control in the intervention arm compared with the control arm (47 [61.8%] vs 49 [63.6%] with HbA1c <8%; RD, -1.8% [95% CI, -17.0% to 13.5%]). In this randomized clinical trial, adding proactive, protocol-driven clinical pharmacist outreach into collaborative team-based care improved medication optimization and patient outcomes. This approach provides an evidence-based strategy for reducing the risk of developing severe hypoglycemia in individuals with T2D at high risk, enhancing patient safety, and potentially reducing overall health care cost. ClinicalTrials.gov Identifier: NCT06746714.

BackgroundDelayed HIV diagnosis and treatment may increase the risk of developing dementia later in life. We evaluated whether low CD4 count (<200 cells/µL) prior to first known use of antiretroviral therapy (ART)—a proxy for delayed HIV diagnosis or treatment—was associated with risk of age-associated dementia.MethodsWe conducted a retrospective cohort study (2000–2023) among U.S. adults with HIV aged ≥50 years, all on ART and dementia-free at baseline. The exposure of interest was low pre-ART CD4 count. Dementia diagnoses were identified via electronic health records. The association of low pre-ART CD4 with incident dementia was evaluated using Fine–Gray subdistribution hazard models, accounting for the competing risk of death and adjusting for sociodemographic and clinical confounders. Sub-analyses examined dementia risk among individuals who had low pre-ART CD4 but demonstrated CD4 recovery to ≥500 cells/µL after ART initiation.ResultsAmong 21 354 people with HIV on ART (mean age 54; 87% men; 46% White, 23% Black, 21% Hispanic, 4% Asian), 30% had pre-ART CD4 < 200 cells/µL. Over a mean follow-up of 7 years, 618 were diagnosed with dementia. Low pre-ART CD4 was associated with greater risk of dementia (adjusted hazard ratio [aHR]: 1.33, 95% CI: 1.13–1.57). CD4 recovery with ART attenuated but did not eliminate dementia risk (aHR: 1.17, 95% CI: 0.85–1.60).ConclusionsLow CD4 count prior to ART—reflecting delayed HIV diagnosis or treatment—was associated with higher dementia risk. Continuing assertive HIV screening and prompt ART initiation in the community will be important to support long-term cognitive health in people with HIV.

The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-endoribonuclease and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we describe a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin-RING Ligase (CRL) substrate receptor, VHL. G6374 induces a stable, cooperative interaction between IRE1 and VHL, driving K48-linked ubiquitination on two principal lysine residues in the IRE1-kinase domain and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutagenesis studies reveal a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocks growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide a proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1421:"<h3>Background</h3> Fenebrutinib is a potent, highly selective, noncovalent, reversible Bruton’s tyrosine kinase inhibitor. In the Phase II FENopta study (NCT05119569), participants received Fenebrutinib 200mg orally BID or placebo. Fenebrutinib reduced inflammatory disease activity in RMS and demonstrated CNS penetrance during the 12-week double blind treatment period. Here we present open label extension study results through Week 48, during which all participants received Fenebrutinib 200 mg BID. <h3>Results</h3> 99 participants enrolled in the OLE; and 96 (97%) remain. At OLE week 48, 96% of participants were relapse free (ARR 0.04) and mean T1 Gd+ lesions were 0.015 lesions per scan (n=67), with 99% of participants free of T1Gd+ lesions. T2 lesion volume decreased in both groups during the OLE. Median EDSS change from baseline was 0 for each arm. The most common AEs were UTI (8%), COVID-19 (7%) and pharyngitis (5%). Serious AEs occurred in one participant (1%) as did asymptomatic ALT elevation (1%), which resolved with treatment discontinuation. <h3>Conclusions</h3> 1 year of fenebrutinib treatment resulted in low ARR, stable EDSS and low MRI activity in participants with RMS, with a favourable safety profile. Ongoing Phase III trials will better characterise the effects of fenebrutinib on disease progression across MS phenotypes. sophie.wrigley{at}roche.com ";}