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Because of improvements in the treatment of patients with metastatic breast cancer, the development of brain metastases (BM) has become a major limitation of life expectancy and quality of life for many breast cancer patients. The improvement of management strategies for BM is thus an important clinical challenge, especially among high-risk patients such as human epidermal growth factor receptor 2-positive and triple-negative patients. However, the formation of BM as a multistep process is thus far poorly understood. To grow in the brain, single tumor cells must pass through the tight blood–brain barrier (BBB). The BBB represents an obstacle for circulating tumor cells entering the brain, but it also plays a protective role against immune cell and toxic agents once metastatic cells have colonized the cerebral compartment. Furthermore, animal studies have shown that, after passing the BBB, the tumor cells not only require close contact with endothelial cells but also interact closely with many different brain residential cells. Thus, in addition to a genetic predisposition of the tumor cells, cellular adaptation processes within the new microenvironment may also determine the ability of a tumor cell to metastasize. In this review, we summarize the biology of breast cancer that has spread into the brain and discuss the implications for current and potential future treatment strategies.

Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8–34·4) for the pembrolizumab group and 31·5 months (27·8–34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9–16·3) for the pembrolizumab group and 11·6 months (8·3–13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57–1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3–12·5) for the pembrolizumab group and 10·2 months (7·9–12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69–1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3–11·4) for the pembrolizumab group and 10·8 months (9·1–12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82–1·15]). The most common grade 3–4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. Merck Sharp & Dohme.

The presence of circulating tumor cell (CTC) clusters is associated with disease progression and reduced survival in a variety of cancer types. In breast cancer, preclinical studies showed that inhibitors of the Na + /K + ATPase suppress CTC clusters and block metastasis. Here we conducted a prospective, open-label, proof-of-concept study in women with metastatic breast cancer, where the primary objective was to determine whether treatment with the Na + /K + ATPase inhibitor digoxin could reduce mean CTC cluster size. An analysis of nine patients treated daily with a maintenance digoxin dose (0.7–1.4 ng ml −1 serum level) revealed a mean cluster size reduction of −2.2 cells per cluster upon treatment ( P  = 0.003), meeting the primary endpoint of the study. Mechanistically, transcriptome profiling of CTCs highlighted downregulation of cell–cell adhesion and cell-cycle-related genes upon treatment with digoxin, in line with its cluster-dissolution activity. No treatment-related adverse events occurred. Thus, our data provide a first-in-human proof of principle that digoxin treatment leads to a partial CTC cluster dissolution, encouraging larger follow-up studies with refined Na + /K + ATPase inhibitors and that include clinical outcome endpoints. ClinicalTrials.gov identifier: NCT03928210 . This proof-of-concept phase 1 trial shows that the size of circulating tumor cell clusters (which can promote metastatic spread) can be reduced by treatment with the Na + /K + ATPase inhibitor digoxin in patients with metastatic breast cancer.

The detection of a pathogenic variant in the BRCA1 or BRCA2 gene has medical and psychological consequences for both, affected mutation carriers and their relatives. A two-phase study with explanatory sequential mixed methods design examined the psychological impact of genetic testing and associated family communication processes. Analyzing a survey data of 79 carriers of a BRCA1 or BRCA2 mutation, the majority had general psychological distress independent of cancer diagnosis in the patients’ history. The point prevalence of depression was 16.9%. Contrary to their subjective perception, the respondents’ knowledge about those mutations was moderate. Despite the high rate of information transfer to relatives at risk (100%), their reported uptake of genetic testing was low (45.6%). Communication about the mutation detection was more frequent with female than with male relatives. In-depth focus group interviews revealed significant barriers to accessing genetic counseling including anxiety, uncertainty about the benefits of testing and about the own cancer risk, particularly among males. This study suggests that an adequate knowledge of the genetic background and psychological support is required to reduce emotional distress, to support familial communication and to facilitate genetic testing.

Background The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. Methods Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). Results CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status ( p  = 0.029) of the primary tumor as well as with the prevalence of bone metastases ( p  = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time ( p  < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. Conclusion The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.

L-arginine limits proliferation in highly proliferative tissues. It is a substrate for nitric oxide synthases, arginases; its methylation by protein-L-arginine methyltransferases (PRMTs) leads to asymmetric (ADMA) and symmetric dimethylarginine (SDMA). We measured L-arginine and its metabolites L-ornithine, L-citrulline, ADMA, and SDMA in a prospective cohort of 243 women with primary breast cancer (BC) and their associations with mortality and disease recurrence during 88 (IQR, 82–93) months of follow-up. We quantified these metabolites and expression of genes involved in L-arginine metabolic pathways in MCF-7, BT-474, SK-BR-3, MDA-MB-231, and MDA-MB-468 cells representing ER-positive, HER2-positive, and triple-negative BC compared to MCF-12 A cells. Plasma L-arginine and ADMA concentrations were elevated in 47 patients with recurrent disease and in 34 non-survivors. ADMA was significantly associated with mortality and recurrent disease in Luminal A patients; low L-citrulline was significantly associated with survival in triple-negative BC. In all BC cells except MCF-7, DDAH1 and DDAH2 expression was higher than in MCF-12 A ( DDAH1 : 32–44 fold, DDAH2 : 1.7–4.2 fold; p  < 0.05). By contrast, MCF-7 cells showed low DDAH1 and DDAH2 , but high PRMT4 and PRMT6 expression and high L-arginine content. BT-474 and MDA-MB-468 cells showed high ARG2 expression and high L-ornithine concentrations, and MDA-MB-468 cells had the highest L-citrulline/L-arginine ratio. In conclusion, regulation of L-arginine metabolic pathways shows a complex and differential pattern between BC subtypes. ADMA is a prognostic biomarker in Luminal A patients; its metabolizing enzyme, DDAH, is highly overexpressed in BC cells. Thus, fingerprinting of L-arginine metabolism may offer novel personalized treatment options within BC subtypes.

To evaluate the technical performance and clinical integration of FoundationOne®CDx (F1CDx) for high-grade serous ovarian cancer (HGSOC), focusing on its role in guiding PARP inhibitor (PARPi) therapy recommendations in a tertiary oncology center. We conducted a retrospective analysis of 178 F1CDx tests performed on 168 HGSOC patients with unknown BRCA mutation status between January 2019 and August 2024. Molecular findings, including mutations, homologous recombination deficiency (HRD) status, loss of heterozygosity (LOH) scores, and HRR-related gene alterations, were correlated with tumor board recommendations and decisions for PARPi therapy. Laboratory turnaround time (TAT), assay performance, and integration into clinical workflows were assessed. The F1CDx assay successfully generated comprehensive molecular profiles in 174 samples, with minimal limitations due to computational tumor content or inconclusive HRD readout. mutations were detected in 13.1% of patients, and 39.5% of tumors were HRD-positive (LOH ≥16%). In the internal cohort, 81.8% of patients received PARPi therapy recommendations, all directly informed by F1CDx results. PARPi selection differed by HRD status, with niraparib favored in HR-proficient and olaparib in HRD-positive tumors. The mean laboratory TAT was 8.4 days (standard deviation ±3.8), with 92.2% of tests completed within 14 days. No additional profiling was required for PARPi therapy recommendation, and no incidental findings beyond the scope of HRD testing were detected. Molecular profiling with F1CDx proved to be a technically feasible, clinically impactful, and time-efficient assay, demonstrating its value in supporting molecular-guided PARPi therapy recommendations in the routine care of HGSOC patients.

Purpose The RAS family comprises three proto-oncogenes (H-RAS, K-RAS, and N-RAS) and is among the most widely studied of oncogenes. The present study aimed at investigating the clinical relevance of mRNA levels of the three isoforms in a large group of breast cancer patients with a long-term follow-up. Methods 198 previously untreated patients were enrolled in the study. mRNA levels of K-RAS, H-RAS, and N-RAS were measured using microarray (Affymetrix HG-U133A). Results Elevated H-RAS levels were found significantly more frequently in patients with larger ( p  = 0.021) and ER-positive tumors ( p  = 0.048), while elevated K-RAS levels were associated with nodal positivity ( p  = 0.001) and HER2-positivity ( p  = 0.010). Patients with high N-RAS mRNA levels were more likely to be diagnosed with triple-negativity ( p  < 0.001) and higher grading ( p  = 0.001). Patients with high K-RAS levels were more likely to show an elevated H-RAS ( p  = 0.003). After a median follow-up of 183 months, patients with high N-RAS expression had significantly reduced overall survival (OS) compared with patients with low N-RAS (mean: 146.9 vs. 211.0 months; median 169.3 vs. not reached; p  = 0.009). In patients with non-metastatic disease at the time of tissue sampling, mean disease-free survival (DFS) was 150.1 months for patients with high N-RAS versus 227.7 months with low N-RAS; median DFS was not reached ( p  = 0.004). The expression of H-RAS and K-RAS was not associated with DFS/OS. In the multivariable analysis, distant metastasis, HER2 positivity, and elevated N-RAS mRNA levels independently predicted reduced OS, while nodal status, HER2 status, and N-RAS predicted reduced DFS. Conclusions Elevated N-RAS mRNA levels predict impaired clinical outcome; hypothetically, further exploration of the RAS signaling pathway might enable identifying potential targeted treatment strategies. The association between high N-RAS levels and the most aggressive among breast cancer subtypes, the triple-negative phenotype, for which targeted approaches are still lacking, underlines the need to further investigate the RAS family.

In breast cancer (BC), elevated levels of urokinase-type plasminogen activator (uPA) in tumor tissue have been confirmed as a strong prognostic factor in level-of-evidence-1 studies. The aim of the present study was to evaluate the clinical relevance of uPA levels in serum of metastatic BC patients and to compare uPA with other blood-based biomarkers. 252 patients were enrolled in this prospective, multicentre study. Blood samples were collected before begin of first-line or later-line systemic treatment. Serum uPA was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Using the ROC analysis, the optimal cut-off value (determined by the Youden index) of serum uPA was 2.52 ng/ml. Using this value, 26% of patients had elevated uPA levels. Patients with visceral metastasis and more than one metastatic site were significantly more likely to present with elevated uPA levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in univariate analysis (median OS: 7.5 months [95%-CI 4.5–10.5 months] vs. not reached, p < 0.001; PFS: 4.8 [95%-CI: 3.1–6.5] vs. 9.1 [7.4–10.8] months, p < 0.001). In multivariate analysis, elevated uPA, presence of ≥5 CTCs, elevated RAS p21, higher grading and higher line of therapy were independent predictors of shorter OS, while elevated CTC counts, higher line of therapy and negative estrogen receptor status were independent predictors of shorter PFS. In conclusion, elevated uPA levels independently predict reduced overall survival and improved prognostication in patients with known CTC status. Whether high serum uPA might identify patients most likely to benefit from therapies targeting uPA, remains to be evaluated in future trials.

Background Shared decision-making (SDM) is preferred by many patients in cancer care. However, despite scientific evidence and promotion by health policy makers, SDM implementation in routine health care lags behind. This study aimed to evaluate an empirically and theoretically grounded implementation program for SDM in cancer care. Methods In a stepped wedge design, three departments of a comprehensive cancer center sequentially received the implementation program in a randomized order. It included six components: training for health care professionals (HCPs), individual coaching for physicians, patient activation intervention, patient information material/decision aids, revision of quality management documents, and reflection on multidisciplinary team meetings (MDTMs). Outcome evaluation comprised four measurement waves. The primary endpoint was patient-reported SDM uptake using the 9-item Shared Decision Making Questionnaire. Several secondary implementation outcomes were assessed. A mixed-methods process evaluation was conducted to evaluate reach and fidelity. Data were analyzed using mixed linear models, qualitative content analysis, and descriptive statistics. Results A total of 2,128 patient questionnaires, 559 questionnaires from 408 HCPs, 132 audio recordings of clinical encounters, and 842 case discussions from 66 MDTMs were evaluated. There was no statistically significant improvement in the primary endpoint SDM uptake. Patients in the intervention condition were more likely to experience shared or patient-lead decision-making than in the control condition ( d =0.24). HCPs in the intervention condition reported more knowledge about SDM than in the control condition ( d = 0.50). In MDTMs the quality of psycho-social information was lower in the intervention than in the control condition ( d = − 0.48). Further secondary outcomes did not differ statistically significantly between conditions. All components were implemented in all departments, but reach was limited (e.g., training of 44% of eligible HCPs) and several adaptations occurred (e.g., reduced dose of coaching). Conclusions The process evaluation provides possible explanations for the lack of statistically significant effects in the primary and most of the secondary outcomes. Low reach and adaptations, particularly in dose, may explain the results. Other or more intensive approaches are needed for successful department-wide implementation of SDM in routine cancer care. Further research is needed to understand factors influencing implementation of SDM in cancer care. Trial registration clinicaltrials.gov, NCT03393351 , registered 8 January 2018.