Interstitial lung disease (ILD) is a common and potentially life-threatening adverse event associated with trastuzumab deruxtecan (T-DXd). In the pivotal T-DXd clinical trials, 10-15% of patients developed ILD, with stringent mitigation strategies aimed at the early detection of low-grade cases. Real-world data are urgently needed to assess ILD incidence and outcomes outside controlled trial settings. This retrospective analysis included 190 patients treated with T-DXd at the Vienna Healthcare Group between August 2020 and December 2023. Among them, 17 (8.9%) developed any-grade ILD, with 8 cases (4.2% of the total cohort; 47.1% of ILD cases) classified as grade ≥3. The median time to ILD onset was 86 days, with a significantly shorter onset for high-grade compared to low-grade ILD (44.5 vs. 119 days, p = 0.01). A pooled real-world analysis (n = 1255, including patients from this study) demonstrated a higher incidence of high-grade ILD in real-world settings compared to phase III trials (2.9% vs. 1.4%, p = 0.014), despite no significant difference in overall ILD incidence (10.4% vs. 11.1%, p = 0.62). However, high-grade ILD rates in the real-world cohort were comparable to those reported in early phase I/II trials (2.9% vs. 3.5%, p = 0.41). These findings suggest a greater risk of high-grade ILD in real-world settings and underscore the need for rigorous patient selection, screening, and management strategies in clinical practice. Furthermore, the shorter onset of high-grade ILD suggests distinct pathophysiological mechanisms that warrant further investigation.

Pathogenic coding variants in BRCA1, BRCA2 and PALB2 confer hereditary breast/ovarian cancer risk, yet these regions comprise less than 10% of the genomic footprint of these genes, leaving most sequence unexplored. We investigated the contribution of non-coding variation to hereditary breast cancer by analyzing intronic variants and 5' upstream regions of BRCA1, BRCA2 and PALB2 in the BEACCON case-control study of over 11,000 participants. Full-gene sequencing showed that 46.3% of cases carried at least one rare non-coding variant. This was associated with a modest increase in breast cancer risk (OR = 1.2, p < 0.0001), most likely reflecting the presence of a small proportion of pathogenic variants within a larger background of predominantly neutral variation. Stronger enrichment was observed for triple-negative disease, particularly for BRCA1 (OR = 1.5, p = 0.0001). Tumor sequencing of 42 high-priority variants identified 11 (26.2%) with wild-type allele loss and high homologous recombination deficiency. Functional CRISPR/Cas9 knock-in assays in MCF10A cells confirmed that two deep intronic variants created aberrant splice sites, disrupted splicing and impacted transcript expression.

This study characterized computed tomography (CT)-derived body composition and tissue morphology in females with non-metastatic breast cancer (BC), both cross-sectionally (n = 56) and longitudinally (n = 38), including comparisons with healthy women and cachexia-prone females with lung cancer. Morphologic changes occurred in the absence of pronounced muscle loss resultant of lean tissue reductions masked by concurrent increases in intra-muscular adipose. Longitudinal analyses suggest divergent phenotypes: non-cachectic patients (63% of BC cohort) demonstrated compositional shifts amid stable muscle quantity, whereas cachectic patients (37%) exhibited wasting of both muscle and adipose quantities alongside remodeling of externally-deposited adipose. Independent of weight, 32 of 38 patients with BC (84%) demonstrated clinically-relevant declines in muscle quantity and/or quality. Findings highlight the discordance between weight loss and underlying tissue dynamics, suggesting that conventional cachexia definitions may under-detect clinically relevant remodeling in early-stage BC. CT-based phenotyping may therefore refine risk stratification to better inform supportive interventions across cancer populations.

Breast cancer stem cells (BCSCs) have been proposed as the cause of resistance to conventional treatments and of breast cancer recurrence and metastasis. This study provides compelling evidence for the role of the transcription factor POU1F1 in the increase of BCSC-like. Using POU1F1-overexpressing and knock-down breast cancer cell lines, as well as immunodeficient mouse models, our data demonstrate that POU1F1 induces a BCSC-like phenotype in breast tumor cells by deregulating markers such as CD24, CD44, CD133, and ALDH. These phenotypic modifications correlate with functional changes, i.e., increased clonogenicity, mammosphere formation, and glycolysis. In addition, we found that a subpopulation of MCF-7 cells with overexpression of POU1F1 and elevated ALDH expression exhibits both a high tumor-initiating capacity and increased resistance to chemotherapy and radiotherapy treatments. Mechanistically, these features are mediated by POU1F1 activation of the IL-6/JAK2/STAT3 pathway and up-regulation of ALDH. Janus kinase inhibitors and monoclonal anti-IL6 receptor antibodies significantly decrease ALDH expression, colony, and mammosphere formation, suggesting possible use of pharmacological inhibitors of the IL-6/JAK2/STAT3 pathway in breast tumors with elevated POU1F1 levels.

While primary invasive lobular carcinoma (ILC) is well characterized, metastatic ILC remains understudied. Within the post-mortem tissue donation programs, UPTIDER (Belgium) and Hope for Others (USA), we first aimed to explore intra-patient heterogeneity of key prognostic and predictive markers (stromal tumor-infiltrating lymphocytes (sTIL), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and KI67). Secondly, we compared detection of the metastases by pathology on autopsy samples versus pre-mortem imaging. In total, 306 metastases from 12 patients were collected at autopsy (median: 27 per patient). Both primary tumors (n = 15) and metastases (n = 232) had low sTIL levels, with a median of 2% (range: 0.67-6.67%) and 0.67% (range: 0-13.33%), respectively. Regression models showed lower ER- and PR-expression in metastases (respectively, n = 265 and n = 64) compared to primary tumors (both p < 0.01). KI67 was significantly higher in metastases (n = 262, p = 0.02). HER2-low metastases were found in all but one patient although in varying proportion of metastases (range: 7.5-100%). Central radiology and pathology review had a median concordance of 78% at organ level (range: 33.33-100%) and 71% at patient level (range: 55.88-85.29%). Our findings suggest that a single metastatic biopsy has great limitations to guide treatment and that more adequate methods are needed to detect and monitor ILC metastases.

The PREoperative therapy and Supportive Care in EarLy and Locally Advanced breast cancers (PreSCella) study, conducted within Singapore's SingHealth network, explored how quality of life (QOL) and supportive care needs change over the course of neoadjuvant therapy (NAT) for breast cancer. Using a longitudinal design, data were collected at three points: before NAT (T1), within two months post-surgery (T2), and at the one-year follow-up (T3). Of 241 patients enrolled, 235 were analysed. Overall QOL improved over time, especially emotional well-being. FACT-B scores rose from 113.3 at T1 to 114.3 at T2 and 120.6 at T3 (T1-T3 change: +7.3 points; 95% CI 4.7-9.8; effect size 0.47). Age-specific assessment tools were used. Women under 40 completed three additional surveys-Body Image Scale (BIS), Dyadic Assessment Scale (DAS), and Female Sexual Function Index (FSFI). They reported mild body image distress (BIS: 6.3 at T1 to 7.2 at T3), stable relationships (DAS: 16.5 to 17.0), but notable declines in sexual function (13% at T1, 75% at T2, 57% at T3). Patients over 65 completed tools like the Attitude Scale and prioritised QOL over survival length. Findings underscore the evolving nature of supportive care needs and the value of age-personalised interventions throughout cancer treatment.

This study examined biomarker alteration prevalence, treatment patterns, and clinical outcomes among patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer to investigate racial differences. Analysis of 2,384 patients from the Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB) (2017-2022) assessed PIK3CA, AKT1, PTEN, ESR1, and BRCA1/2 alterations via NGS testing. Treatment patterns and overall survival were evaluated. In the study population (13% Black, 87% White), Black patients had lower PIK3CA mutation rates (34% vs. 42%, p = 0.03). In first-line treatment, Black patients were less likely to receive CDK4/6 inhibitors (53% vs. 66%, p < 0.01) and more likely to receive chemotherapy (27% vs. 17%, p < 0.01). After adjustment, Black patients had 38% lower odds of receiving first-line CDK4/6 inhibitors and experienced significantly shorter median overall survival (34.1 vs. 42.1 months, p < 0.01). Significant differences exist in biomarker prevalence, treatment access, and survival outcomes in HR+/HER2− metastatic breast cancer by race, highlighting unmet medical needs.

Genome-wide association studies (GWAS) have identified more than 220 loci associated with breast cancer susceptibility, yet identifying effector genes, their modes of action and prioritising therapeutic targets remains a significant challenge. To address this, we performed pooled CRISPR knockout and inhibition screens to identify genes at risk loci that influence cytotoxic T lymphocyte (CTL) killing of MCF7 breast cancer cells in co-culture. These screens uncovered 33 candidate modulating genes, of which we validated six by single gene editing in two cell lines. Deletion of IRF1, ATF7IP, and CASP8 conferred resistance to CTL killing, while disruption of CFLAR, CREBBP and PRMT7 enhanced sensitivity. Analysis of clinical data showed that PRMT7 expression is negatively correlated with CD8+ infiltration and survival in breast cancer patient cohorts. Pharmacological inhibition of PRMT7 sensitized breast cells to CTL killing in vitro, and Prmt7-deficient tumors exhibited reduced growth and increased CD8+ T cell infiltration in immunocompetent mice. Enhanced Prmt7-dependent tumor growth was not observed in immunodeficient mice, implicating Prmt7 in immune evasion. This study underscores the utility of CRISPR screens for high-throughput functional follow-up of GWAS findings and identifies PRMT7 inhibition as a promising therapeutic strategy.

Myeloid cells are highly heterogeneous and play key roles in establishing an immunosuppressive tumor microenvironment (TME), but the mechanisms controlling their differentiation remain unclear. Using orthotopic murine breast cancer models, we investigated how interleukin-1α (IL-1α) influences this process. Deletion of host Il1α resulted in rejection of transplanted tumors. Single-cell RNA sequencing identified CX3CR1⁺ macrophages as the main source of IL-1α in the TME. Il1α deficiency disrupted monocyte-macrophage differentiation, reducing CX3CR1⁺ macrophages and increasing iNOS⁺ macrophages. Myeloid cells from Il1α⁻/⁻ hosts induced lower PD-1 and CTLA-4 expression in co-cultured CD8⁺ T cells than those from wild-type hosts. CellChat analysis showed that IL-1α loss rewired communication between macrophages and other immune cells, particularly affecting M-CSF, TGFβ, and PGE2 signaling. In vitro, the proinflammatory phenotype induced by Il1α deficiency in bone-derived macrophages was reversed by PGE2, indicating a key regulatory axis. Macrophages from Il1α⁻/⁻ tumors exhibited activated immune gene signatures similar to human macrophages. These findings reveal that IL-1α drives an immunosuppressive TME partly through PGE2 signaling, highlighting IL-1α as a potential therapeutic target in breast cancer.