Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.

Comparison of breast cancer surrogate subtyping using a closed-system RT-qPCR breast cancer assay and immunohistochemistry on 100 core needle biopsies with matching surgical specimens.

BACKGROUND: Routine clinical management of breast cancer (BC) currently depends on surrogate subtypes according to estrogen- (ER) and progesterone (PR) receptor, Ki-67, and HER2-status. However, there has been growing demand for reduced immunohistochemistry (IHC) turnaround times. The Xpert® Breast Cancer STRAT4* Assay (STRAT4)*, a standardized test for ESR1/PGR/MKi67/ERBB2 mRNA biomarker assessment, takes less than 2 hours. Here, we compared the concordance between the STRAT4 and IHC/SISH, thereby evaluating the effect of method choice on surrogate subtype assessment and adjuvant treatment decisions. METHODS: In total, 100 formalin-fixed paraffin-embedded core needle biopsy (CNB) samples and matching surgical specimens for 98 patients with primary invasive BC were evaluated using the STRAT4 assay. The concordance between STRAT4 and IHC was calculated for individual markers for the CNB and surgical specimens. In addition, we investigated whether changes in surrogate BC subtyping based on the STRAT4 results would change adjuvant treatment recommendations. RESULTS: The overall percent agreement (OPA) between STRAT4 and IHC/SISH ranged between 76 and 99% for the different biomarkers. Concordance for all four biomarkers in the surgical specimens and CNBs was only 66 and 57%, respectively. In total, 74% of surgical specimens were concordant for subtype, regardless of the method used. IHC- and STRAT4-based subtyping for the surgical specimen were shown to be discordant for 25/98 patients and 18/25 patients would theoretically have been recommended a different adjuvant treatment, primarily receiving more chemotherapy and trastuzumab. CONCLUSIONS: A comparison of data from IHC/in situ hybridization and STRAT4 demonstrated that subsequent changes in surrogate subtyping for the surgical specimen may theoretically result in more adjuvant treatment given, primarily with chemotherapy and trastuzumab.

Efficacy and tolerability of metronomic chemotherapy in patients with metastatic breast cancer - an international experience in West Sweden and in the South of Ireland.

INTRODUCTION: Metronomic chemotherapy (MCT) is the continuous administration of low dose chemotherapy. It has significant clinical efficacy with minimal toxicity as compared to conventional chemotherapy regimens. Thus represents an attractive treatment modality in selected patients with advanced breast cancer. METHODS: Patients who received MCT in the form of Capecitabine/Cyclophosphamide for the treatment of advanced breast cancer between May 2014 and October 2018 in Sahlgrenska University Hospital in Sweden and in Cork University Hospital, University Hospital Kerry and the South Infirmary-Victoria University Hospital in Ireland were identified. Medical records were retrospectively reviewed to collect data. All survival analyses were described by Kaplan-Meier curves and analysed with log-rank tests. The primary end-point was time on treatment, used as a surrogate marker for efficacy. RESULTS: 148 patients were identified (84 - Sweden, 64 - Ireland), with a median age of 64.2 (range 31-89). The overall mean time on treatment for all patients in both countries is 9.05 months (range 0.36 - 67.21). In patients with bone only disease the mean time on treatment was 10.1 months (range 0.7 - 67.2), compared to patients with visceral disease of 8.91 months (range 0.36 - 39.77). Treatment was ended in the majority of patients because of progression of disease, representing 108 patients (72.9%). CONCLUSION: This is an observational, retrospective study demonstrating the real world effectiveness of MCT in the treatment of advanced breast cancer. In this cohort of unselected pre-treated patients, the efficacy of MCT was comparable with the survival outcomes of landmark clinical trials.

Synthesis of polycaprolactone-grafted microfibrillated cellulose for use in novel bionanocomposites--influence of the graft length on the mechanical properties.

In the present work, microfibrillated cellulose (MFC) made from bleached sulfite softwood dissolving pulp was utilized to reinforce a poly(ε-caprolactone) (PCL) biopolymer matrix. To improve the dispersibility of the hydrophilic MFC in the nonpolar matrix and the interfacial adhesion in the composite material, we covalently grafted the MFC with PCL via ring-opening polymerization (ROP) of ε-caprolactone (ε-CL). To be able to investigate the effect of the PCL graft length on the mechanical properties of the composite material, we performed ROP to different molecular weights of the grafts. Bionanocomposites containing 0, 3, and 10 wt % MFC were prepared via hot pressing using both unmodified and PCL grafted MFC (MFC-g-PCL) as reinforcement. PCL grafting resulted in improved dispersion of the MFC in a nonpolar solvent and in the PCL matrix. The mechanical testing of the biocomposites showed an improvement in the mechanical properties for the PCL grafted MFC in comparison to ungrafted MFC. It was also shown that there was an impact on the mechanical properties with respect to the PCL graft lengths, and the strongest biocomposites were obtained after reinforcement with MFC grafted with the longest PCL graft length.

Stereological study of neovascularization in temporal arteritis.

OBJECTIVE: As giant cell arteritis (GCA) progresses, newly formed microvessels are one of the main sites of leukocyte-endothelial cell interaction. Our aim was to stereologically map the distribution of microvessels in the temporal arterial wall and to assess their relationship to the degree of inflammation in GCA. METHODS: Inflamed temporal arteries from 21 patients who fulfilled the American College of Rheumatology criteria for GCA were analyzed. Paraffin sections, stained with an antibody directed at vascular endothelium, were analyzed stereologically. The degree of inflammation and the surface of microvascular endothelium per volume (microm2/microm3) were assessed in 4 different layers of the arterial wall. RESULTS: The degree of inflammation and of vascularization was greatest in the adventitia, smaller in the media, and smallest in the intima. A significant positive relationship was observed between the degree of inflammation and the degree of vascularization in the media and in the outer and inner layers of the intima. In 8 biopsies, the microvessels formed a prominent plexus in the intima without apparent connection with microvessels in the adventitia/media, and there were no signs of endothelial budding from the arterial lumen. CONCLUSION: Our results confirm that inflammation is a major determinant in neovascularization in GCA. Some new microvessels are formed by the budding of the adventitial vasa vasorum. The presence of intimal microvascular networks without apparent connection with microvessels in the media might indicate additional influence on neovascularization.