Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability.

Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

Cutaneous Adverse Reactions and Survival Outcomes of Advanced Melanoma Treated with Immune Checkpoint Inhibitors in an Academic Medical Centre in Singapore.

Programmed cell death-1 (PD1) inhibitors, a form of immune checkpoint inhibitor, are efficacious for metastatic melanoma but are associated with cutaneous adverse reactions (CARs). Studies in Europe and North America showed that CARs are associated with an increased overall survival. However, studies from Asia showed mixed results. There is a paucity of data regarding the efficacy of PD1 inhibitors and the effect of CARs on overall survival from Southeast Asia. A retrospective study of patients in the National Cancer Centre Singapore who were diagnosed with melanoma between 2015 and 2020 was conducted. Patients were included in the study if they had stage IV melanoma (advanced melanoma). Sixty-two patients were included in the study. The median age was 62.5 years and acral melanoma was the commonest subtype. Forty-three patients received PD1 inhibitors. Comparing patients who did not receive PD1 inhibitors to patients who received PD1 inhibitors, the former had a median overall survival of 6 months (95% CI: 5.07, 6.93), whereas the latter had a median overall survival of 21 months (95% CI: 13.33, 28.67; p < 0.001) (Hazard ratio 0.32; 95% CI: 0.16, 0.63; p = 0.001). Amongst patients who received PD1 inhibitors, patients who developed CARs had a greater median overall survival of 33 months (95% CI: 17.27, 48.73) compared to 15 months (95% CI: 9.20, 20.80; p = 0.013) for patients who did not (HR 0.29; 95% CI: 0.098, 0.834; p = 0.022). This study provides insight into the outcomes of metastatic melanoma in Singapore, and adds to the body of evidence supporting the use of PD1 inhibitors in Asians.

Molecular and immune pathobiology of human angiosarcoma.

Angiosarcoma is a rare endothelial-derived malignancy that is extremely diverse in anatomy, aetiology, molecular and immune characteristics. While novel therapeutic approaches incorporating targeted agents and immunotherapy have yielded significant improvements in patient outcomes across several cancers, their impact on angiosarcoma remains modest. Contributed by its heterogeneous nature, there is currently a lack of novel drug targets in this disease entity and no reliable biomarkers that predict response to conventional treatment. This review aims to examine the molecular and immune landscape of angiosarcoma in association with its aetiology, anatomical sites, prognosis and therapeutic options. We summarise current efforts to characterise angiosarcoma subtypes based on molecular and immune profiling. Finally, we highlight promising technologies such as single-cell spatial "omics" that may further our understanding of angiosarcoma and propose strategies that can be similarly applied for the study of other rare cancers.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma.

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

Whole genome sequencing of HER2-positive metastatic extramammary Paget's disease: a case report.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape. METHODS: Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed. RESULTS: Notable copy number gains (log2FC > 0.9) on chromosomes 7 and 8 were detected (n = 81), with 92.6% of these unique genes specifically located on chromosome 8. Prominent cancer-associated genes include ZNF703, HOOK3, DDHD2, LSM1, NSD3, ADAM9, BRF2, KAT6A and FGFR1. Interestingly, ERBB2 gene did not exhibit high copy number gain (log2FC = 0.4) although 90% of tumor cells stained HER2-positive. Enrichment in pathways associated with transforming growth factor-beta (TGFß) (FDR = 0.0376, Enrichment Ratio = 8.12) and fibroblast growth factor receptor (FGFR1) signaling (FDR = 0.0082, Enrichment Ratio = 2.3) was detected. Amplicon structure analysis revealed that this was a simple-linear amplification event. CONCLUSION: Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

Unmet Needs in the First-Line Treatment of Diffuse Large B-cell Lymphoma: Expert Recommendations From the Asia-Pacific Region With a Focus on the Challenging Subtypes.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for around 30-60% of all cases. The management of DLBCL in Asia has several unmet needs due to the diversity of the population, the heterogeneity of local clinical guidelines for DLBCL and the wide disparity in resources and healthcare systems across different regions. Rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) is widely recognized as the standard first-line treatment for DLBCL; however, alternative regimens are required to improve patient outcomes in challenging subtypes, such as patients with high International Prognostic Index scores, old/frail patients, and patients with double-hit and double-expressor DLBCL or concurrent central nervous system disease. This review article draws from the expertise of practicing hematologists/oncologists in the region, with the aim of integrating data from current scientific evidence to address the unmet needs and unique socioeconomic challenges faced by challenging high risk patient groups in the Asia-Pacific region.

4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.

Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.

Novel clinical risk stratification and treatment strategies in relapsed/refractory peripheral T-cell lymphoma.

Peripheral T cell lymphoma (PTCL) represents a group of heterogeneous hematological malignancies, which are notoriously challenging to treat and outcomes are typically poor. Over the past two decades, clinical prognostic indices for patient risk stratification have evolved, while several targeted agents are now available to complement combination chemotherapy in the frontline setting or as a salvage strategy. With further understanding of the molecular pathobiology of PTCL, several innovative approaches incorporating immunomodulatory agents, epigenetic therapies, oncogenic kinase inhibitors and immunotherapeutics have come to the forefront. In this review, we provide a comprehensive overview of the progress in developing clinical prognostic indices for PTCL and describe the broad therapeutic landscape, emphasizing novel targetable pathways that have entered early phase clinical studies.

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Special Issue "Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance".

Since the launch of this Special Issue entitled "Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance", the field of cancer immunotherapy has continued to witness rapid growth in the development of novel agents, improvements in our understanding of mechanisms of response and resistance, and the maturation of emerging technologies such as artificial intelligence, machine learning, single-cell sequencing and spatial profiling [...].

Biodiversity Medicine: New Horizon and New Opportunity for Cancer.

SUMMARY: Accessibility to standard of care remains a challenge to patients in low- and middle-income countries (LMIC), hampering efforts to alleviate the burden of cancer and to improve overall health outcomes. In response to this pressing global health care issue, we propose here a new strategy to create affordable, easily accessible, and effective therapeutic solutions to address this inequity in cancer treatment: the use of science-based biodiversity medicine as an alternative to modern drug therapy, in which we will leverage and combine high-throughput omics technologies with artificial intelligence, to study local biodiversity, their potential anticancer properties, and short- and long-term clinical response and outcomes.

Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches.

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

Single-cell landscape of idiopathic multicentric Castleman disease in identical twins.

ABSTRACT: Idiopathic multicentric Castleman disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within the affected lymphoid organs and the host circulation using multiomic high-dimensional profiling. Using spatial enhanced resolution omics sequencing (Stereo-seq) transcriptomic profiling, we performed unsupervised spatially constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. After a cell segmentation approach, interleukin 6 (IL-6) pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10× Chromium). Furthermore, single-cell sequencing of peripheral blood mononuclear cells revealed an "inflammatory" peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model.

Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer.

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.

Recent updates on central nervous system prophylaxis in patients with high-risk diffuse large B-cell lymphoma.

The use of central nervous system (CNS) prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Although uncommon, CNS relapses are invariably fatal in this otherwise curable disease. Accurate identification of patients at risk and the optimal approach to CNS prophylaxis therefore remains an area of unmet need. The existing literature, largely retrospective in nature, provides mixed conclusions regarding the efficacy of CNS prophylaxis. The utility of CNS prophylaxis has itself been challenged. In this review, we dissect the issues which render the value of CNS prophylaxis uncertain. We first compare international clinical guidelines for CNS prophylaxis. We then interrogate the factors that should be used to identify high-risk patients accurately. We also explore how clinical patterns of CNS relapse have changed in the pre-rituximab and rituximab era. We then discuss the efficacy of CNS-directed approaches, intensification of systemic treatment and other novel approaches in CNS prophylaxis. Improved diagnostics for early detection of CNS relapses and newer therapeutics for CNS prophylaxis are areas of active investigation. In an area where prospective, randomized studies are impracticable and lacking, guidance for the use of CNS prophylaxis will depend on rigorous statistical review of retrospective data.

Tumor-Infiltrating Mast Cells in Angiosarcoma Correlate With Immuno-Oncology Pathways and Adverse Clinical Outcomes.

Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.

Establishment and characterization of a patient-derived solitary fibrous tumor/hemangiopericytoma cell line model.

Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma harboring NAB2-STAT6 gene fusions. Mechanistic studies and therapeutic development on SFT/HPC are impeded by scarcity and lack of system models. In this study, we established and characterized a novel SFT/HPC patient-derived cell line (PDC), SFT-S1, and screened for potential drug candidates that could be repurposed for the treatment of SFT/HPC. Immunohistochemistry profiles of the PDC was consistent with the patient's tumor sample (CD99+/CD34+/desmin-). RNA sequencing, followed by Sanger sequencing confirmed the pathognomonic NAB2exon3-STAT6exon18 fusion in both the PDC and the original tumor. Transcriptomic data showed strong enrichment for oncogenic pathways (epithelial-mesenchymal transition, FGF, EGR1 and TGFß signaling pathways) in the tumor. Whole genome sequencing identified potentially pathogenic somatic variants such as MAGEA10 and ABCA2. Among a panel of 14 targeted agents screened, dasatinib was identified to be the most potent small molecule inhibitor against the PDC (IC50, 473 nM), followed by osimertinib (IC50, 730 nM) and sunitinib (IC50, 1765 nM). Methylation profiling of the tumor suggests that this specific variant of SFT/HPC could lead to genome-wide hypomethylation. In conclusion, we established a novel PDC model of SFT/HPC with comprehensive characterization of its genomic, epigenomic and transcriptomic landscape, which can facilitate future preclinical studies of SFT/HPC, such as in vitro drug screening and in vivo drug testing.

Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies.

OBJECTIVES: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. DESIGN: Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. RESULTS: We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. CONCLUSION: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

A Systematic Review and Meta-Analysis of Mapping Biopsy for Primary Extramammary Paget's Disease in Reducing Recurrence Following Surgical Excision.

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.

Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations.

Background: Recently, HER2-negative breast cancers have been reclassified by protein expression into 'HER2-low' and 'HER2-zero' subgroups, but the consideration of HER2-low breast cancer as a distinct biological subtype with differing prognoses remains controversial. By contrast, non-neutral ERBB2 copy number alteration (CNA) status is associated with inferior survival outcomes compared to ERBB2 CNA-neutral breast cancer, providing an alternative approach to classification. Methods: Here, we investigated the molecular landscape of non-metastatic HER2-negative BCs in relation to ERBB2 CNA status to elucidate biological differences. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) TCGA-BRCA datasets (n = 1875) were analyzed. Results: Nearly two-fifths of the cohort harbored ERBB2 CNAs (39.4%), which were significantly enriched within hormone receptor-negative (56.1%) than within hormone receptor-positive BCs (35.5%; p < 0.0001). Globally, CNAs across the genome were significantly higher in ERBB2 non-neutral compared to neutral cohorts (p < 0.0001). Notably, genetic aberrations on chromosome 17 - BRCA1, NF1, TP53, MAP2K4, and NCOR1 - were widespread in the ERBB2 non-neutral cases. While chromosome 17q arm-level alterations were largely in tandem with ERBB2 CNA status, arm-level loss in chromosome 17p was prevalent regardless of ERBB2 gain, amplification, or loss. Differential gene expression analysis demonstrated that pathways involved in the cell cycle, proteasome, and DNA replication were upregulated in ERBB2 non-neutral cases. Conclusion: Classification of HER2-negative BCs according to ERBB2 CNA status reveals differences in the genomic landscape. The implications of concurrent aberrations in other genes on chromosome 17 merit further research in ERBB2 non-neutral BCs.