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As the field of translational ‘omics has progressed, refined classifiers at both genomic and proteomic levels have emerged to decipher the heterogeneity of breast cancer in a clinically-applicable way. The integration of ‘omics knowledge at the DNA, RNA and protein levels is further expanding biologic understanding of breast cancer and opportunities for customized treatment, a particularly pressing need in clinically triple negative tumors. For this group of aggressive breast cancers, work from multiple groups has now validated at least four major biologically and clinically distinct omics-based subtypes. While to date most clinical trial designs have considered triple negative breast cancers as a single group, with an expanding arsenal of targeted therapies applicable to distinct biological pathways, survival benefits may be best realized by designing and analyzing clinical trials in the context of major molecular subtypes. While RNA-based classifiers are the most developed, proteomic classifiers proposed for triple negative breast cancer based on new technologies have the potential to more directly identify the most clinically-relevant biomarkers and therapeutic targets. Phospho-proteomic data further identify targetable signalling pathways in a unique subtype-specific manner. Single cell profiling of the tumor microenvironment represents a promising way to allow a better characterization of the heterogeneity of triple negative breast cancer which could be integrated in a spatially resolved context to build an ecosystem-based patient classification. Multi-omic data further allows in silico analysis of genetic and pharmacologic screens to map therapeutic vulnerabilities in a subtype-specific context. This review describes current knowledge about molecular subtyping of triple negative breast cancer, recent advances in omics-based genomics and proteomics diagnostics addressing the diversity of this disease, key advances made through single cell analysis approaches, and developments in treatments including targeted therapeutics being tested in major clinical trials.

Despite advances in genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens with extended clinical outcomes are widely available. Here, we perform comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, from patients diagnosed in 2008-2013 (n = 178) and 1986-1992 (n = 122) with linked clinical outcomes. These two cohorts are analyzed separately, and we quantify 4214 proteins across all 300 samples. Within the aggressive PAM50-classified basal-like cases, proteomic profiling reveals two groups with one having characteristic immune hot expression features and highly favorable survival. Her2-Enriched cases separate into heterogeneous groups differing by extracellular matrix, lipid metabolism, and immune-response features. Within 88 triple-negative breast cancers, four proteomic clusters display features of basal-immune hot, basal-immune cold, mesenchymal, and luminal with disparate survival outcomes. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification. Protein level information enables the identification of potential biomarkers and therapeutic targets for breast cancer. Here, the authors perform proteomic analysis of 2 cohorts of breast cancer surgical specimens and identify distinct subtypes, immune features and survival outcomes.

Despite advances in our understanding of the underlying molecular drivers of sarcomas, few treatments are available with proven benefit for advanced metastatic sarcomas. Immunotherapy has value in this setting for some types of cancers, but sarcomas, with their multiplicity of rare types, have not been characterized in detail for their expression of targetable immune biomarkers. This study provides the most systematic evaluation to date of tumor-infiltrating lymphocytes and immune checkpoint biomarker expression in sarcomas. We examined by morphology and immunohistochemistry 1072 sarcoma specimens representing 22 types, in addition to 236 benign bone and soft-tissue tumors. Genomically-complex sarcoma types—those driven by mutations and/or copy-number alterations—had much higher numbers of tumor-infiltrating lymphocytes than translocation-associated sarcomas. Prior exposure to radiotherapy was associated with increased immune infiltrates. Higher lymphocytic infiltration was associated with better overall survival among the non-translocation-associated sarcomas. Expression of PD-1 and CD56 were associated with worse overall survival. LAG-3 and TIM-3, two emerging immune checkpoints, were frequently expressed in most sarcoma types. Indeed, most cases positive for PD-(L)1 coexpressed one or both of these novel biomarkers, providing a potential rationale in support for trials targeting LAG-3 and/or TIM-3 in conjunction with PD-1 inhibition.

Synovial sarcoma is an aggressive soft-tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by polycomb repressive complex activity. Because KDM2B brings polycomb repressive complex to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacological inhibition with cytidine analogs 5-aza-2'-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.

Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy that is characterised by a pathognomonic t(X;18)(p11.2;q11.2) translocation, which produces the fusion oncogene named SS18::SSX . Despite recent advancements in our understanding of synovial sarcoma biology, the cell-of-origin remains undefined. A mesenchymal stromal cell (MSC) specific CreERT2 line was employed to express SS18::SSX in fibroblasts and related cell types, resulting in 100% penetrant synovial sarcoma development in mice, with a median latency period of 16.2 ± 2.8 weeks. Murine tumours exhibited high concordance with human synovial sarcoma subtypes at the histological and molecular levels. Genetic refinement of the cell-of-origin revealed that synovial sarcomas derive from a rare Hic1 + Pdgfra + Lgr5 + fibroblastic population. Furthermore, comparative transcriptomic analysis revealed the acquisition of a transformed phenotype initiated by the loss of a mature fibroblastic profile and subsequent unmasking of an epigenetically embedded embryonic MSC program. Adult and embryonic MSCs exhibited overlapping H2AK119ub and H3K4me3/H3K27me3 (bivalent) histone marks, while SS18::SSX-mediated transformation culminated in the widespread loss of H3K27me3 at these genes and their consequent transcription. Collectively, these studies define a rare MSC context, conducive for SS18::SSX-mediated transformation, and demonstrate that SyS tumorigenesis involves the induction and maintenance of an embryonic-like MSC phenotype. The cellular origin of soft-tissue cancers, such as synovial sarcoma (SyS), is unknown. Here, expression of the oncoprotein, SS18::SSX, in fibroblasts was sufficient to produce human-like SyS tumours, thereby identifying a cell of origin for SyS.

Synovial sarcoma is a cancer driven by a fusion oncoprotein, SS18::SSX, that links SS18, a subunit of BAF-family chromatin remodeling complexes, to the carboxy terminus of SSX, which avidly binds nucleosomes with the histone post-translational modification H2AK119ub. Here, we show in mice that SS18::SSX expression redistributes non-canonical GBAF complexes broadly to promoters and distal enhancers marked by H2AK119ub, which causes developmental loci to lose H3K27me3 and become transcriptionally active. Canonical BAF containing SS18::SSX abandons its typical binding sites, is largely absent from H2AK119ub-marked sites, and instead distributes narrowly to transcription start sites with PBAF. Disruption of Arid1a or Arid1b (both CBAF-specific) retains synovial sarcoma character, while Smarcb1 (PBAF- and CBAF-specific) or Pbrm1 (PBAF-specific) disruption does not, although all accelerate SS18::SSX-driven tumorigenesis in mice. Thus, the synovial sarcomagenesis mechanism involves SS18::SSX reprogramming transcription positively through GBAF redistribution to activate polycomb-targeted developmental genes, and negatively by loss of normal CBAF localization and function. Synovial sarcoma (SyS) is a cancer driven by a fusion oncoprotein, SS18::SSX, but the mechanism underlying the oncoprotein-mediated tumorigenesis remains unclear. Here, the authors employ transgenic mouse models and multi-omics to show how SS18:SSX modifies the activity and recruitment of BAF-family chromatin remodeling complexes to drive SyS tumorigenesis.

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition.

Background The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Methods Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). Results In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P  < 0.001 for disease-free survival (DFS), P  = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS ( P interaction  = 0.003 unadjusted, P  = 0.001 adjusted) and OS ( P interaction  = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes. Conclusion The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.

New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1.

Purpose Previous studies indicate that breast cancer molecular subtypes differ with respect to their dependency on autophagy, but our knowledge of the differential expression and prognostic significance of autophagy-related biomarkers in breast cancer is limited. Methods Immunohistochemistry (IHC) was performed on tissue microarrays from a large population of 3992 breast cancer patients divided into training and validation cohorts. Consensus staining scores were used to evaluate the expression levels of autophagy proteins LC3B, ATG4B, and GABARAP and determine the associations with clinicopathological variables and molecular biomarkers. Survival analyses were performed using the Kaplan–Meier function and Cox proportional hazards regression models. Results We found subtype-specific expression differences for ATG4B, with its expression lowest in basal-like breast cancer and highest in Luminal A, but there were no significant associations with patient prognosis. LC3B and GABARAP levels were highest in basal-like breast cancers, and high levels were associated with worse outcomes across all subtypes (DSS; GABARAP: HR 1.43, LC3B puncta: HR 1.43). High ATG4B levels were associated with ER, PR, and BCL2 positivity, while high LC3B and GABARAP levels were associated with ER, PR, and BCL2 negativity, as well as EGFR, HER2, HER3, CA-IX, PD-L1 positivity, and high Ki67 index ( p  < 0.05 for all associations). Exploratory multi-marker analysis indicated that the combination of ATG4B and GABARAP with LC3B could be useful for further stratifying patient outcomes. Conclusions ATG4B levels varied across breast cancer subtypes but did not show prognostic significance. High LC3B expression and high GABARAP expression were both associated with poor prognosis and with clinicopathological characteristics of aggressive disease phenotypes in all breast cancer subtypes.