SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer

Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)-positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer. Patritumab deruxtecan (HER3-DXd) is a promising therapy for breast cancer, targeting HER3. Here, the authors analyse the genomic factors that affect the response to HER3-DXd in patients with early-stage HER2-negative breast cancer as part of the SOLTI-1805 TOT-HER3 clinical trial and report outcomes for Part B of the trial using lower HER3-DXd dose in patients with HER2-negative breast cancer

Seasonal patterns of vertical flux in the northwestern Barents Sea under Atlantic Water influence and sea-ice decline

The northern Barents Sea is a productive Arctic inflow shelf with a seasonal ice cover and as such, a location with an efficient downward export of particulate organic matter through the biological carbon pump. The region is under strong influence of Atlantification and sea-ice decline, resulting in a longer open water and summer period. In order to understand how these processes influence the biological carbon pump, it is important to identify the seasonal and spatial dynamics of downward vertical flux of particulate organic matter. In 2019 and 2021, shortterm sediment traps were deployed between 30 and 200 m depth along a latitudinal transect in the northwestern Barents Sea during March, May, August and December. Vertical flux of particulate organic carbon, δ13C and δ15N values, Chl-a, protists and fecal pellets were assessed. We identified a clear seasonal pattern, with highest vertical flux in May and August (178 ± 202 and 159 ± 79 mg C m− 2 d− 1 , respectively). Fluxes in December and March were − 2 d− 1 . May was characterized by diatom- and Chl a-rich fluxes and high spatial variability, while fluxes in August had a higher contribution of fecal pellets and small flagellates, and were spatially more homogenous. Standing stocks of suspended particulate organic matter were highest in August, suggesting a more efficient retention system in late summer. The strong latitudinal sea-ice gradient and the influence of Atlantic Water probably led to the high spatial variability of vertical flux in spring, due to their influence on primary productivity. We conclude that the efficiency of the biological carbon pump in a prolonged open-water period depends on the reworking of small, slow sinking material into efficiently sinking fecal pellets or aggregates, and the occurrence of mixing