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The management of human epidermal growth factor receptor (HER2)–positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2‐targeted therapies for the treatment of early‐stage and/or advanced‐stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2‐positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2‐positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de‐escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2‐positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2‐positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2‐positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2‐positive BC going forward.

Background The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored. Methods This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH). Results A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p  = 0.022) and OS (HR 0.28, p  = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p  < 0.001) and OS (HR 0.27, p  = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p  = 0.004) and potentially for OS (HR 0.64, p  = 0.054), along with HER2 copy number (PFS HR 0.85, p  = 0.004; OS HR 0.84, p  = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories. Conclusions This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.

Background Brain metastases (BrM) incidence is 25% to 50% in women with advanced human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Radiation and surgery are currently the main local treatment approaches for central nervous system (CNS) metastases. Systemic anti‐HER2 therapy following a diagnosis of BrM improves outcomes. Previous preclinical data has helped elucidate HER2 brain trophism, the blood‐brain/blood‐tumor barrier(s), and the brain tumor microenvironment, all of which can lead to development of novel therapeutic options. Recent findings Several anti‐HER2 agents are currently available and reviewed here, some of which have recently shown promising effects in BrM patients, specifically. New strategies driven by and focusing on brain metastasis‐specific genomics, immunotherapy, and preventive strategies have shown promising results and are under development. Conclusions The field of HER2+ breast cancer, particularly for BrM, continues to evolve as new therapeutic strategies show promising results in recent clinical trials. Increasing inclusion of patients with BrM in clinical studies, and a focus on assessing their outcomes both intracranially and extracranially, is changing the landscape for patients with HER2+ CNS metastases by demonstrating the ability of newer agents to improve outcomes.

Background The variability in responses to neoadjuvant treatment with anti-HER2 antibodies prompts to personalized clinical management and the development of innovative treatment strategies. Tumor-infiltrating Natural Killer (TI-NK) cells can predict the efficacy of HER2-targeted antibodies independently from clinicopathological factors in primary HER2-positive breast cancer patients. Understanding the mechanism/s underlying this association would contribute to optimizing patient stratification and provide the rationale for combinatorial approaches with immunotherapy. Methods We sought to uncover processes enriched in NK cell-infiltrated tumors as compared to NK cell-desert tumors by microarray analysis. Findings were validated in clinical trial-derived transcriptomic data. In vitro and in vivo preclinical models were used for mechanistic studies. Findings were analysed in clinical samples (tumor and serum) from breast cancer patients. Results NK cell-infiltrated tumors were enriched in CCL5/IFNG-CXCL9/10 transcripts. In multivariate logistic regression analysis, IFNG levels underlie the association between TI-NK cells and pathological complete response to neoadjuvant treatment with trastuzumab. Mechanistically, the production of IFN-ɣ by CD16 +  NK cells triggered the secretion of CXCL9/10 from cancer cells. This effect was associated to tumor growth control and the conversion of CD16 into CD16 - CD103 +  NK cells in humanized in vivo models. In human breast tumors, the CD16 and CD103 markers identified lineage-related NK cell subpopulations capable of producing CCL5 and IFN-ɣ, which correlated with tissue-resident CD8 +  T cells. Finally, an early increase in serum CCL5/CXCL9 levels identified patients with NK cell-rich tumors showing good responses to anti-HER2 antibody-based neoadjuvant treatment. Conclusions This study identifies specialized NK cell subsets as the source of IFN-ɣ influencing the clinical efficacy of anti-HER2 antibodies. It also reveals the potential of serum CCL5/CXCL9 as biomarkers for identifying patients with NK cell-rich tumors and favorable responses to anti-HER2 antibody-based neoadjuvant treatment.

Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1. Methods Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay. Results T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7. Conclusion T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer.

Opinion statement The therapeutic landscape for HER2-positive metastatic breast cancer has exploded in the last two decades following the initial advent of trastuzumab, a monoclonal antibody. While the first line treatment has remained a combination of dual HER2 blockade with taxane chemotherapy, we now have several exciting options in the second line and beyond. The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer. Given the excellent outcomes of these drugs, clinical trials are now evaluating the role of ADCs in the front-line setting in previously untreated patients. In addition, there are also clinical trials evaluating the role of other targets in patients with HER2-positive cancers, including PI3KCA mutations, PD-L1 and CDK4/6. Given the predilection for brain metastases in this population, there is enthusiasm to identify the optimal combination of effective treatments. Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments.

HER2-positive metastatic breast cancer (MBC) represents a challenging subtype of breast cancer, characterized by aggressive disease and poor clinical outcomes. Trastuzumab emtansine (TDM1), an antibody–drug conjugate combining trastuzumab and emtansine, has demonstrated efficacy in clinical trials as a second-line treatment for patients progressing after prior therapies. This study aims to provide real-world evidence on the efficacy and safety of TDM1 in HER2-positive MBC patients. A retrospective analysis was conducted on 70 HER2-positive MBC patients treated with TDM1 at our centre between January 2020 and December 2022. Clinical characteristics, progression-free survival (PFS), overall survival (OS), response rates, and toxicity were evaluated using hospital records. PFS and OS were calculated using Kaplan–Meier methods, and survival curves were compared with log-rank tests. The median age of patients was 47 years, with a majority presenting with advanced disease and prior treatment lines. The median PFS was 6.1 months (95% CI, 4.5–7.6), and the median OS was 14.4 months (95% CI, 10.2–18.0). The objective response rate was 75.7%, with 12.8% achieving a complete response and 62.8% a partial response. PFS was significantly longer in hormone receptor-positive patients compared to hormone receptor-negative patients (8.1 vs. 4.1 months, p = 0.035). Toxicity was manageable, with grade 3–4 adverse events including elevated transaminases (8.5%), thrombocytopenia (5.7%), and anemia (4.2%). The efficacy of TDM1 in this real-world cohort aligns with clinical trial data, though PFS and OS were somewhat lower compared to trials, likely due to the inclusion of patients with more extensive disease and prior treatments. Notably, TDM1 demonstrated activity against CNS metastases and a manageable safety profile, with higher incidence of hepatic and hematologic toxicities. Our study supports the use of TDM1 as a viable option for treating HER2-positive MBC in routine clinical practice, confirming its effectiveness and safety profile observed in clinical trials.

Aptamers are oligonucleotide or peptide molecules that bind to a target molecule with high affinity and specificity. The present study aimed to evaluate the target specificity and applicability for in vivo molecular imaging of an aptamer labeled with a radioisotope. The human epidermal growth factor receptor 2 (HER2/ErbB2) aptamer was radiolabeled with .sup.18 F-fluoride. HER2-positive tumor cell uptake of the aptamer was evaluated in comparison to negative controls by flow cytometry and confocal microscopy. Using .sup.18 F-labeled HER2-specific aptamer positron emission tomography (PET), in vivo molecular images of BT474 tumor-bearing mice were taken at 60, 90 and 120 minutes after injection. In flow cytometric analysis, HER2 aptamer showed strong binding to HER2-positive BT474 cells, while binding to HER2-negative MDA-MB231 cells was quite low. Likewise, in confocal microscopic images, the aptamer was bound to HER2-positive breast cancer cells, with minimal binding to HER2-negative cells. In vivo PET molecular imaging of BT474 tumor-bearing mice revealed significant higher uptake of the .sup.18 F-labeled HER2 specific aptamer into the tumor compared to the that of HER2-negative cell tumor(p = 0.033). HER2 aptamer was able to preferentially bind to HER2-positive breast cancer cells both in vitro and in vivo, by recognizing HER2 structure on the surface of these cells. The .sup.18 F-labeled aptamer enabled appropriate visualization of HER2 expression by human breast cancer cells. The results suggest that a radiolabeled HER2 aptamer could potentially be applied in the development of treatment strategies or in targeted therapy against HER2-positive breast cancer cells.

Objectives The aim of this study is to investigate the added value of diffusion-weighted imaging (DWI) to dynamic-contrast enhanced (DCE)-MRI to identify a pathological complete response (pCR) in patients with HER2-positive breast cancer and radiological complete response (rCR). Materials and methods This is a single-center observational study of 102 patients with stage I-III HER2-positive breast cancer and real-world documented rCR on DCE-MRI. Patients were treated between 2015 and 2019. Both 1.5 T/3.0 T single-shot diffusion-weighted echo-planar sequence were used. Post neoadjuvant systemic treatment (NST) diffusion-weighted images were reviewed by two readers for visual evaluation and ADCmean. Discordant cases were resolved in a consensus meeting. pCR of the breast (ypT0/is) was used to calculate the negative predictive value (NPV). Breast pCR-percentages were tested with Fisher’s exact test. ADCmean and ∆ADCmean(%) for patients with and without pCR were compared using a Mann-Whitney U-test. Results The NPV for DWI added to DCE is 86% compared to 87% for DCE alone in hormone receptor (HR)-/HER2-positive and 67% compared to 64% in HR-positive/HER2-positive breast cancer. Twenty-seven of 39 non-rCR DWI cases were false positives. In HR-positive/HER2-positive breast cancer the NPV for DCE MRI differs between MRI field strength (1.5 T: 50% vs. 3 T: 81% [ p  = 0.02]). ADCmean at baseline, post-NST, and ∆ADCmean were similar between patients with and without pCR. Conclusion DWI has no clinically relevant effect on the NPV of DCE alone to identify a pCR in early HER2-positive breast cancer. The added value of DWI in HR-positive/HER2-positive breast cancer should be further investigated taken MRI field strength into account. Clinical relevance statement The residual signal on DWI after neoadjuvant systemic therapy in cases with early HER2-positive breast cancer and no residual pathologic enhancement on DCE-MRI breast should not (yet) be considered in assessing a complete radiologic response. Key Points Radiologic complete response is associated with a pathologic complete response (pCR) in HER2+ breast cancer but further improvement is warranted. No relevant increase in negative predictive value was observed when DWI was added to DCE. Residual signal on DW-images without pathologic enhancement on DCE-MRI, does not indicate a lower chance of pCR.

Background Enhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells is associated with intracellular redox imbalance that impacts cellular viability. To restore redox homeostasis cancer cells evolve to activate redox protective mechanisms. This differential activation of redox defense pathways compared to normal cells provides a therapeutic window for novel targeted therapies in cancer. Although heme metabolism emerges as a crucial regulator of redox homeostasis and iron metabolism in cancer cells with frequent alteration in breast cancer, it remains largely unexplored, and no targeted translational approaches have been developed. Heme-regulated redox homeostasis is coordinately maintained through biosynthetic and degradation pathways. As a byproduct of TCA cycle, cytotoxic heme is initially derivatized by heme oxygenases and progressively metabolized to the potent antioxidant bilirubin by two non-redundant biliverdin reductases, BLVRA and BLVRB. BLVRB overexpression has been observed in breast cancers, although its function in breast cancer pathogenesis remains unknown. Methods CRISPR/Cas9 deletion of BLVRB in multiple breast cancer cell lines demonstrated its profound effect on intracellular redox state and cell proliferation in vitro and in xenograft models. Integrated proteomic, metabolomic, and lipidomic studies identified and validated BLVRB–mediated adaptive metabolic responses required for breast cancer cell cytoprotection. Results We have established BLVRB as a requisite component of the pro-survival redox defense mechanism in breast cancer cells. Targeted deletion of BLVRB induces reductive stress, leading to alterations in endoplasmic reticulum proteostasis and lipid composition. These defects impact plasma membrane functionality and endosomal recycling of multiple oncogenic receptors, such as HER2 and transferrin receptors. Conclusions These data collectively identify BLVRB as a novel metabolic target in breast cancer, distinct from other redox-regulating pathways. This study, along with our recent progress in developing novel specific BLVRB inhibitors, offers a unique translational opportunity for targeted therapies in personalized breast cancer medicine.