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Patients with brain metastases (BrMs) from esophageal cancer have poor prognosis, the incidence of which is expected to rise due to improved survival from the primary tumor and increased neuroimaging. We aimed to identify patient and esophageal cancer characteristics associated with longer survival in patients with BrMs and, secondly, to compare the prognosis of patients with HER2 overexpression. We retrospectively reviewed patients with BrMs from esophageal cancer at a single institution from 2008–2021. We collected patient demographics, primary tumor and BrM characteristics, and treatment. Our primary outcome was median survival from the time of BrM. The median age at primary diagnosis was 66.5 years and 86% were male. Of the 49 patients, 71% had adenocarcinoma, 20% squamous cell carcinoma and 8% other. In this group, 71% of patients presented with stage III or IV disease, including 16% with synchronous primary metastatis and BrM. The median time to BrM was 10.1 months (interquartile range 1.7–22.8) and the median survival from BrM was 8.4 months (95% CI 4.8–16.8 months). On multivariable analysis, treatment with stereotactic radiosurgery (hazard ratio [HR] = 0.19; P = 0.04), surgical resection (HR 0.24; P = 0.03), and immunotherapy (HR 0.19; P = 0.04) were associated with increased survival while Karnofsky Performance Status (KPS) ≤70 (HR = 13.2; P < 0.001) was associated with decreased survival. HER2 overexpression was found in 22% of patients, but we noted no survival difference (5.2 months HER2+ vs. 9.8 months HER2neg; P = 0.95). The median survival from esophageal-to-brain metastasis was 8.4 months. Patients with a single lesion, KPS score >70, and treatment with surgical resection was correlated with improved survival. Further, HER2+ patients had distinct patient and BrM characteristics. [ABSTRACT FROM AUTHOR]

Targeted cancer therapy is a promising alternative to the currently established cancer treatments, aiming to selectively kill cancer cells while sparing healthy tissues. Hereby, molecular targeting agents, such as monoclonal antibodies, are used to bind to cancer cell surface markers specifically. Although these agents have shown great clinical success, limitations still remain such as low tumor penetration and off-target effects. To overcome this limitation, novel fusion proteins comprised of the two proteins ADAPT6 and Horseradish Peroxidase (HRP) were engineered. Cancer cell targeting is hereby enabled by the small scaffold protein ADAPT6, engineered to specifically bind to human epidermal growth factor receptor 2 (HER2), a cell surface marker overexpressed in various cancer types, while the enzyme HRP oxidizes the nontoxic prodrug indole-3-acetic acid (IAA) which leads to the formation of free radicals and thereby to cytotoxic effects on cancer cells. The high affinity to HER2, as well as the enzymatic activity of HRP, were still present for the ADAPT6-HRP fusion proteins. Further, in vitro cytotoxicity assay using HER2-positive SKOV-3 cells revealed a clear advantage of the fusion proteins over free HRP by association of the fusion proteins directly to the cancer cells and therefore sustained cell killing. This novel strategy of combining ADAPT6 and HRP represents a promising approach and a viable alternative to antibody conjugation for targeted cancer therapy. [Display omitted] • A novel fusion protein for targeted cancer therapeutics is presented. • The fusion protein combines high affinity to HER2 with enzymatic activity. • The therapeutic protein is easily produced in the bacterial host E. coli. • Efficient cancer cell killing through tumor cell-specific binding and activity has been demonstrated. [ABSTRACT FROM AUTHOR]

Oesophago-gastric cancers (OGCs) are amongst the most commonly diagnosed malignancies worldwide and are associated with high disease-related mortality. Predictive biomarkers are molecules that can be objectively measured and used to indicate a likely response to therapeutic intervention, thus facilitating individualised cancer therapy. However, there remains variation in uptake and implementation of biomarker testing across the UK. We conducted a modified Delphi study to formulate consensus recommendations for best-practice biomarker testing of OGC in the UK. We employed two rounds of online questionnaires followed by a virtual consensus meeting. Biomarkers for discussion included HER2, MSI/MMR, and PD-L1. Topics comprised the overall biomarker pathway, pre-analytical, analytical, and post-analytical considerations, including challenges in current practice. Twenty-six and eighteen participants completed the first and second round Delphi questionnaire, respectively, with an even split of pathologists and oncologists from across the UK. There was consensus (>80% agreement) across several topics, including the requirements for standardisation of the pathway, which must include coordination throughout the tissue journey, requirements for a quality-assured process to ensure accuracy and validity of testing, plus the need for clear, detailed information on the pathology report to support treatment decisions. There was consensus amongst oncologists regarding reflex testing of all biomarkers depending on histology; however, concerns over capacity in relation to workload and availability of pathologists were evident among the pathologists. Overall, participants were in the opinion that reflex testing improves the speed of treatment decisions and improves patient care. The recommendations reflect best-practices and should be implemented to support rapid multidisciplinary team decision-making within oesophago-gastric cancer. Results reflect the need for standardisation and demonstrate the challenges faced in clinical practice by those requesting and testing biomarkers for oesophago-gastric cancer, suggesting significant concerns relating to pathologist capacity. • Recommendations for a biomarker pathway for oesophago-gastric cancer were formulated. • Coordination from biopsy request to communication of results are required. • Sufficient capacity and funding should be in place to accommodate reflex testing. [ABSTRACT FROM AUTHOR]

Biological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets. A study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test. The study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS. BRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC. [ABSTRACT FROM AUTHOR]

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer. [ABSTRACT FROM AUTHOR]

While several studies reported epidermal growth factor receptor (EGFR) expression in salivary gland cancer (SGC), results varied due to a lack of unified definition of EGFR positivity. In this study, we assessed the EGFR expression level using both EGFR positive score and cumulative EGFR score in the patients with SGC. Between January 2010 and April 2021, 102 patients with SGC who underwent surgical resection were reviewed retrospectively by immunohistochemistry. The membrane staining intensity was scored as follows: no staining (0), weak staining (1+), intermediate staining (2+), and strong staining (3+). The cumulative EGFR score was determined on a continuous scale of 0–300 using the formula:1 × (1+: percentage of weakly stained cells) + 2 × (2+: percentage of moderately stained cells) + 3 × (3+: percentage of strongly stained cells). EGFR expression in SGC varied widely even among the same as well as different histopathological types. The average EGFR positive scores were 46.0 %, 55.7 %, 51.6 %, 1.0 %, 26.8 %, 50 %, and 76.8 % for mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (AcCC), adenocarcinoma NOS (ACNOS), carcinoma ex pleomorphic adenoma (CAexPA), and squamous cell carcinoma (SqCC), respectively. The average cumulative EGFR scores were 82, 91, 80, 1, 52, 93, and 185 for MEC, SDC, AdCC, AcCC, ACNOS, CAexPA, and SqCC, respectively. EGFR positive scores and cumulative EGFR scores in SGCs varied among the various histological types, and even in the same histological type. These scores may predict the clinical outcome of SGC treated with EGFR-targeting therapies, such as head and neck photoimmunotherapy, and need to be evaluated in future studies. [ABSTRACT FROM AUTHOR]

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes. [Display omitted] • We have designed enzyme-activated liposomes targeted at HER2-positive cancers. • The liposomes are readily internalized by HER2-positive cancer cells. • In the presence of enzymes expressed by tumors, the liposomes release their cargo. • These liposomes have superior in vivo efficacy compared to control liposomes. • Our liposomes are promising as a treatment for HER2-positive cancer. [ABSTRACT FROM AUTHOR]

A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD. [Display omitted] [ABSTRACT FROM AUTHOR]

In colorectal cancer (CRC), HER2 targeting is a promising treatment and immune infiltrate is an important area of research and strategy. Data regarding HER2 status and immune infiltrate are lacking. The aim of this study was to compare the immune infiltrate between HER2 amplified and non-amplified categories in proficient MisMatchRepair (pMMR)/microsatellite stable (MSS) CRC. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization were performed in a retrospective series of 654 CRC. Lymphocyte infiltrate was analysed by anti-CD3, CD8 and CD4 IHC and evaluated digitally using QuPath software. Among the 654 CRC, we first observed a decreased CD3+ and CD8+ infiltrate between HER2 amplified (all IHC 3+ except one 2+) and non-amplified HER2 2+ IHC CRC (p = 0.059 and 0.072 respectively). A supplementary analysis of 258 pMMR/MSS CRC from the previous cohort, displaying all the IHC scores (0, 1+, 2+, 3+), showed a lower CD3+ infiltrate between HER2 amplified versus HER2 0 (p = 0.002), 1+ (p = 0.088) and non-amplified 2+ (p = 0.081) IHC cases. Our original findings suggest that in pMMR/MSS CRC, the immune infiltrate is reduced in HER2 amplified versus other HER2 categories. These data might be useful for future strategies combining anti-HER2 treatments and immune checkpoint inhibitors and need to be confirmed in larger CRC cohorts. [ABSTRACT FROM AUTHOR]

This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2 (HER2)-low early breast cancer (BC) and HER2-IHC0 BC. Patients diagnosed with HER2-negative BC (N = 999) at our institution between January 2011 and December 2015 formed our study population. Clinicopathological characteristics, association between estrogen receptor (ER) expression and HER2-low, and evolution of HER2 immunohistochemical (IHC) score were assessed. Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes (5-year follow-up) between the HER2-IHC0 and HER2-low groups. HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor (PgR) positivity than HER2-IHC0 BC group (P < 0.001). The rate of HER2-low status increased with increasing ER expression levels (Mantel-Haenszel χ2 test, P < 0.001, Pearson's R = 0.159, P < 0.001). Survival analysis revealed a significantly longer overall survival (OS) in HER2-low BC group than in HER2- IHC0 group (P = 0.007) in the whole cohort and the hormone receptor (HR)-negative group. There were no significant differences between the two groups in terms of disease-free survival (DFS). The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%. HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles. [ABSTRACT FROM AUTHOR]

Bispecific antibody‒drug conjugates (BsADCs) represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates (ADCs) and bispecific antibodies (BsAbs). Positioned as the next-generation ADC approach, BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs, particularly pertaining to issues such as poor internalization, off-target toxicity, and drug resistance. Presently, ten BsADCs are undergoing clinical trials, and initial findings underscore the imperative for ongoing refinement. This review initially delves into specific design considerations for BsADCs, encompassing target selection, antibody formats, and the linker–payload complex. Subsequent sections delineate the extant progress and challenges encountered by BsADCs, illustrated through pertinent case studies. The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs. Nevertheless, the symbiotic interplay among BsAb, linker, and payload necessitates further optimizations and coordination beyond a simplistic "1 + 1" to effectively surmount the extant challenges facing the BsADC domain. In comparison to traditional ADCs, bispecific antibody drug conjugates present distinct design considerations and properties as the next-generation ADCs. [Display omitted] [ABSTRACT FROM AUTHOR]

Precise targeting is a major prerequisite for effective cancer therapy because it ensures a sufficient therapeutic dosage in tumors while minimizing off-target side effects. Herein, we report a live-macrophage-based therapeutic system for high-efficiency tumor therapy. As a proof of concept, anti-human epidermal growth factor receptor-2 (HER2) affibodies were genetically engineered onto the extracellular membrane of macrophages (AE-Mφ), which further internalized doxorubicin (DOX)-loaded poly(lactic- co -glycolic acid) nanoparticles (NPs) to produce a macrophage-based therapeutic system armed with anti-HER2 affibodies. NPs(DOX)@AE-Mφ were able to target HER2+ cancer cells and specifically elicit affibody-mediated cell therapy. Most importantly, the superior HER2 + -targeting capability of NPs(DOX)@AE-Mφ greatly guaranteed high accumulation at the tumor site for improved chemotherapy, which acted synergistically with cell therapy to significantly enhance anti-tumor efficacy. This study suggests that NPs(DOX)@AE-Mφ could be utilized as an innovative 'living targeted drug' platform for combining both macrophage-mediated cell therapy and targeted chemotherapy for the individualized treatment of solid tumors. Ning et al. present a live-macrophage-based therapeutic system as a novel dosage form for high-efficiency tumor therapy. Anti-human epidermal growth factor receptor-2 (HER2) affibodies were genetically engineered on the extracellular membrane of macrophages (AE-Mφ), which further internalized doxorubicin (DOX)-loaded poly (lactic- co -glycolic acid) nanoparticles (NPs) to produce as an innovative "living targeted drug" platform of delivery science and technology for combining both macrophage-mediated cell therapy and targeted chemotherapy for individualized treatment of solid tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are a rapidly expanding class of anticancer therapeutics, with 14 ADCs already approved worldwide. We developed unique linker technologies for the bioconjugation of drug molecules with controlled-release applications. We synthesized cathepsin-cleavable ADCs using a dimeric prodrug system based on a self-immolative dendritic scaffold, resulting in a high drug-antibody ratio (DAR) with the potential to reach 16 payloads due to its dendritic structure, increased stability in the circulation and efficient release profile of a highly cytotoxic payload at the targeted site. Using our novel cleavable linker technologies, we conjugated the anti-human epidermal growth factor receptor 2 (anti-HER2) antibody, trastuzumab, with topoisomerase I inhibitors, exatecan or belotecan. The newly synthesized ADCs were tested in vitro on mammary carcinoma cells overexpressing human HER2, demonstrating a substantial inhibitory effect on the proliferation of HER2-positive cells. Importantly, a single dose of our trastuzumab-based ADCs administered in vivo to mice bearing HER2-positive tumors, showed a dose-dependent inhibition of tumor growth and survival benefit, with the most potent antitumor effects observed at 10 mg/kg, which resulted in complete tumor regression and survival of 100% of the mice. Overall, our novel dendritic technologies using the protease-cleavable Val-Cit linker present an opportunity for the development of highly selective and potent controlled-released therapeutic payloads. This strategy could potentially lead to the development of novel and effective ADC technologies for patients diagnosed with HER2-positive cancers. Moreover, our proposed ADC linker technology can be implemented in additional medical conditions such as other malignancies as well as autoimmune diseases that overexpress targets, other than HER2. [Display omitted] • A single dose of our dendritic Trastuzumab-exatecan led to a complete response in vivo in a HER2+ breast cancer model • A novel, unprecedented dendritic linker payload system for ADCs releasing 2 payloads per 1 enzymatic cleavage • Flexible Chemistry allows attachment of different payloads as well as hydrophobicity modifications • Conjugation at Fc position Q295 creates a favorable PK profile in vitro and in vivo • Model system with Exatecan spotlights the potential of this construct for future applications [ABSTRACT FROM AUTHOR]

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic- co -glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications. [Display omitted] • The first targeted PLGA for chemo&photothermal therapy (targosomes) is reported. • HER2-specificity of targosomes results in excellent bioimaging capabilities. • Chemo&photothermal therapy via targosomes is promising for cancer treatment. [ABSTRACT FROM AUTHOR]

The standard of care for advanced urothelial carcinoma includes platinum chemotherapy and immunotherapy. Antibody-drug conjugates (ADCs), originally developed for hematologic malignancies, involve potent cytotoxic agents linked to antibodies that recognize tumor-specific antigens; this rational drug design allows for more on-target efficacy, while mitigating systemic toxicity. Herein, we review the emerging landscape of ADCs in urothelial carcinoma. The anti-Nectin-4 ADC enfortumab vedotin has demonstrated efficacy in prospective studies in patients with advanced urothelial carcinoma in several settings either alone or in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also shown efficacy in single-armed studies. Both conjugates have full or accelerated approval from the Food and Drug Administration. Common adverse events include rash and neuropathy for enfortumab vedotin and myelosuppression and diarrhea for sacituzumab govitecan. Several anti-human epidermal growth factor receptor 2 ADCs are in clinical trials, and in localized bladder cancer, the anti-epithelial cell adhesion molecule ADC oportuzumab monatox is being studied in patients refractory to intravesical bacillus calmette-guerin therapy. Antibody-drug conjugates for urothelial carcinoma are approved and emerging as therapies for patients with advanced urothelial carcinoma, filling a prior void for treatment of progressive disease. Ongoing studies are also evaluating these agents in the neoadjuvant and adjuvant settings. [ABSTRACT FROM AUTHOR]

HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer. We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant. 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75–2.30, p = 0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR = 4.03, 95% CI: 2.15–7.56, p < 0.001), T staging category (T2/T3 vs. T1: OR = 3.44, 95% CI: 1.96–6.04, p < 0.001), progesterone receptor (PR ≥ 20% vs. <20%: OR = 0.44, 95% CI: 0.23–0.83, p = 0.01), nodal staging category (N+ vs. N0: OR = 3.8, 95% CI: 1.89–7.62, p < 0.001) and histological grade (grade 2 vs. 1: OR = 2.41, 95% CI: 1.01–5.73, p = 0.04; grade 3 vs 1: OR = 5.40, 95%CI: 1.98–14.60, p = 0.001). In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67 ≥ 20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50. • HER2-low is not associated with a high-risk PAM50 compared to HER2-zero. • High-risk PAM50 correlates to high-risk clinical and pathological tumor characteristics. • HER2-low has a predictive role in advanced BC, although its prognostic value is controversial. • HER2-low does not seem to be a distinct biological subtype in early breast cancer. [ABSTRACT FROM AUTHOR]

The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer. • Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (n = 765). • HER2DX pCR score was found to be significantly associated with pCR in all patients. • HER2DX identify patients who benefit more from dual HER2 blockade. • HER2DX identify patients who benefit more from multi-agent chemotherapy over single taxane. • HER2DX risk score identify patients with lower risk of recurrence irrespective of pCR status. [ABSTRACT FROM AUTHOR]

Ratiometric electrochemical biosensors have attracted the attention of researchers due to their ability to self-calibrate, which can improve accuracy of the detection. We constructed a radiometric electrochemical aptasensor based on functionalized bimetallic Zn–Co-MOF@ferrocene (Fc) and Fe–Co-MOF@methylene blue (MB) composites with high specific surface area, high electrical conductivity and strong adsorption properties to detect human epidermal growth factor receptor 2 (HER2). In this paper, we synthesized bimetallic Zn–Co-MOF@Fc by in situ electrochemical synthesis and bimetallic Fe–Co-MOF, and the MB signal was wrapped in Fe–Co-MOF, making it immune to the interference of the external environment. In addition, bimetallic MOFs can also immobilize aptamer on their surfaces through adsorption. Therefore, we used Zn–Co-MOF@Fc/aptamer as the capture probe for HER2 and Fe–Co-MOF@MB as the signal labeling probe to jointly construct the radiometric electrochemical aptasensor. By calculating the ratio of signal peaks, simple, fast and accurate detection of HER2 is achieved. The linear range of the sensor is 0.75–250 pg/mL, and the detection limit is 0.37 pg/mL. It provides a new idea for the detection of breast cancer tumor biomarkers. • A ratiometric electrochemical aptasensor based on bimetallic Zn–Co-MOF and Fe–Co-MOF was constructed to detect HER2. • We synthesized bimetallic Zn–Co-MOF@Fc in situ by electrochemical deposition. • Bimetallic Fe–Co-MOF realizes one-step encapsulation of MB, which avoids external interference. • A lower detection limit of 0.37 pg/mL was obtained with good selectivity and accuracy. [ABSTRACT FROM AUTHOR]

This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer. The dose-finding part enroled patients (2–<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m2/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1–<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response. Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (−81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14–38). Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion. • 12% of 536 paediatric patients screened had ≥2 potential ErbB-activation markers. • 56 paediatric patients with ErbB-dysregulated tumours received afatinib. • MTD in children was 18 mg/m²/d; PK and safety were equivalent to adults. • Objective response observed in one patient (>3 years), with a CLIP2::EGFR fusion. • EGFR gene fusion or driver mutations are rare in paediatric cancer but are sensitive to afatinib. [ABSTRACT FROM AUTHOR]

MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAF mut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/ BRAF wt or HER2‒/MSS/ BRAF mut/ RAS mut). Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128). Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAF mut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAF mut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/ BRAF wt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. ClinicalTrials.gov: NCT02291289. • Biomarker-driven maintenance therapy after induction treatment in metastatic colorectal cancer (mCRC) is feasible. • Maintenance vemurafenib/cetuximab/5-FU/LV in BRAF mut mCRC merits further study. • Emergent mitogen-activated protein kinase genomic alterations in BRAF mut mCRC may offer actionable targets. • New strategies to increase microsatellite stable mCRC susceptibility to immunotherapy are required. [ABSTRACT FROM AUTHOR]

A subgroup of patients with HER2-positive metastatic gastric and gastroesophageal junction cancers shows long-term response under trastuzumab maintenance monotherapy. Obviously, HER2 status alone is not able to identify these patients. We performed this study to identify potential new prognostic biomarkers for this long-term responding patient group. Tumour samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospectively collected from multiple centres. Patients were divided into long-term responding (n = 7) or short-term responding group (n = 12) according to progression-free survival (PFS≥12 months vs. PFS < 12 months). Next-generation sequencing and microarray-based gene expression analysis were performed along with HER2 and PD-L1 immunohistochemistry. Long-term responding patients had significantly higher PD-L1 combined positive scores (CPS) and CPS correlated with longer progression-free survival. PD-L1 positivity (CPS ≥ 1) was further associated with an increased CD4+ memory T-cell score. The ERBB2 copy number as well as the tumour mutational burden could not discriminate between short-term and long-term responding patients. Genetic alterations and coamplifications in HER2 pathway associated genes such as EGFR , which were connected to trastuzumab resistance, were present in 10% of the patients and equally distributed between the groups. The study highlights the clinical relevance of PD-L1 testing also in the context of trastuzumab treatment and offers a biological rational by demonstrating elevated CD4+ memory T-cells scores in the PD-L1-positive group. • Identify potential new prognostic biomarkers for trastuzumab long-term response. • Retrospective study of HER2-positive gastric cancer patients treated with trastuzumab. • Biomarker analysis using immunohistochemistry, NGS and gene-expression analysis. • PD-L1 expression has clinical relevance for HER2-positive gastric cancer. • PD-L1 positivity was associated with higher CD4+ memory T-cell scores. [ABSTRACT FROM AUTHOR]

Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. Z HER2 -ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of Z HER2 -ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting Z Taq -ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of Z HER2 -ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequently diagnosed cancer among women worldwide, and histopathology is the gold standard in diagnosing the disease. Hematoxylin and Eosin (HE) staining, routinely employed to observe the overall tissue structure, is an affordable and commonly practiced cancer diagnosis. In contrast, Immunohistochemistry (IHC), which detects the increased presence of particular antigens linked to the mutation, can require multiple tests to conduct and is relatively costly. Generally, in computer-aided diagnosis, the conventional methods rely on a single network to extract features. However, these methods have significant limitations and fail to generalize. In this study, we propose an automated novel weighted average algorithm called HER2-ETNET, which ensembles the chosen three pre-trained deep learning models, DenseNet 201, GoogLeNet, and ResNet-50, to classify breast histopathology HE images into multi-class Human Epidermal Growth Factor Receptor-2 (HER2) status (HER2-0+, HER2-1+, HER2-2+, HER2-3+). The proposed method has the potential to bypass the IHC laboratory test. In this study, we form a weight matrix by fusing together, the scores of False Positive Rate (FPR) and False Negative Rate (FNR) of both training and validation sets, and the computed weights are assigned to the three base learners. This is in contrast to the previous works, in which the weights were generally assigned empirically to the chosen deep learning models, which might be erroneous. The proposed approach is evaluated on the unseen test set, and it achieves accuracy, precision, recall and AUC of 97.44%, 97.32%, 97.39%, and 99.75% respectively. The proposed framework outperforms all the existing methods on the same dataset and is proven to be the reliable method in detecting the HER2 status (HER2-0+, HER2-1+, HER2-2+, HER2-3+) from HE images. This also proves that, HE stained images contain adequate information for efficiently detecting the HER2 status in breast cancer. [ABSTRACT FROM AUTHOR]

Prolonged cold ischemia time (CIT) and neoadjuvant chemotherapy (NACT) can each independently impact the expression of breast cancer-related biomarkers, but their combined effects are not well studied. Herein, we assessed whether prolonged CIT has a higher modulatory effect on post-NACT biomarker expression in breast cancer specimens than in otherwise similar but non-NACT specimens. Our study cohort included 334 biopsy/resection breast cancer specimen pairs in which immunohistochemistry (IHC for estrogen receptor [ER], progesterone receptor [PR], HER2) and HER2 FISH had been performed on both specimens. These included 209 pairs with a post-NACT resection (NACT[+]), and 125 pairs unassociated with NACT (NACT[-]). Each group was subclassified into prolonged CIT (>1 hr; CITp) and non-prolonged CIT (≤1 hr, CITnp). NACT[+]/CITp (n = 125) and NACT[-]/CITp (n = 84) subgroups showed no statistically significant differences regarding the frequency of biopsy-to-resection change in the final result [i.e. positive versus negative] for any of the 4 biomarkers. Similarly, the NACT[+]/CITp and NACT[+]/CITnp subgroups showed no significant differences regarding the percentage of cases with any biopsy-to-resection change in final result for ER, HER2 (IHC) and HER2 (FISH). For PR, a biopsy-to-resection change in status was more commonly observed in CITnp (44.1 %) as compared to the CITp (19.2 %) subgroup (p = 0.02). In summary, we found no conclusive evidence that prolonged CIT has a more significant modulatory effect on biomarker expression in post-NACT breast cancer resection specimens than their otherwise comparable (i.e. NACT[-], CITp) counterparts regarding the final test result, which suggests that post-NACT specimens do not require more stringent CIT-related handling requirements than NACT[-] specimens. [ABSTRACT FROM AUTHOR]

This study presents an innovative approach based on electrochemiluminescence resonance energy transfer (ECL-RET) through the introduction of a new pattern donor-acceptor couple. The donor of self-enhanced Ce(III, IV)-MOF@Ru is created by immobilizing Ru(bpy) 3 2+ on Ce-based metal-organic frameworks (Ce(III, IV)-MOF). The acceptor of CuO@PDA@AuNPs is the CuO nanospheres polydopamine (PDA) framework grafted with gold nanoparticles (AuNPs). An ultrasensitive detection of human epidermal growth factor receptor-2 (HER2) was achieved through the development of a quenched ECL immunosensor. Ce(III, IV)-MOF, a unique 3D infinite extension framework, was recognized for its excellent nanostructure and remarkable capacity to greatly activate tripropylamine (TPrA) and generate abundant radicals. Fortunately, it was simultaneously utilized as a highly effective coreactant accelerator and encapsulation agent, thereby facilitating the immobilization of Ru(bpy) 3 2+ and the generation of radicals for creating a self-enhanced emitter of Ce(III, IV)-MOF@Ru. Consequently, by effectively reducing the distance of electron transmission and minimizing the loss of energy, Ce(III, IV)-MOF@Ru achieved a significantly high efficiency in ECL. More importantly, CuO@PDA@AuNPs was prepared as a perfect quenching agent. The ultraviolet-visible (UV–vis) spectra of CuO@PDA@AuNPs exhibited partial overlap with ECL spectra of Ce(III, IV)-MOF@Ru, thus efficiently initiating the ECL-RET interaction between the donor and acceptor. With the purpose of demonstrating the superiority of newly obtained self-enhanced nanoemitter and donor-acceptor couple, an ECL immunoassay was proposed for the analysis of HER2 with range of 0.2 fg/mL ∼ 10 ng/mL and the limit of detection of 0.067 fg/mL. Therefore, this method supplies convenient and significant strategy for the clinical analysis. [Display omitted] • The electrochemiluminescence resonance energy transfer was by introduction of a new pattern donor-acceptor couple. • The donor of self-enhanced Ce(III, IV)-MOF@Ru was created by immobilizing Ru(bpy) 3 2+ on the Ce(III, IV)-MOF. • The acceptor of CuO@PDA@AuNPs was achieved through the CuO nanospheres PDA framework grafted with AuNPs. • The research obtained sensitive ECL detection with the range of 0.2 fg/mL ∼ 10 ng/mL and LOD of 0.067 fg/mL. [ABSTRACT FROM AUTHOR]

Increasing life expectancy increases breast cancer (BC) rates in elderly, where better health allows for improved tolerance of treatments. We assessed trends in BC incidence of tumor subtypes for women with focus on the elderly. Changes in BC incidence in women by age from 2012 to 2021 were assessed using data from the Nordic countries. We calculated the incidence of BC subtypes by age group using data from the Danish Breast Cancer Group (DBCG) database. We used generalized linear models assuming a Poisson distribution. In the Nordic countries, 205 305 women were diagnosed with BC between 2012 and 2021. In Denmark, 50 858 BC patients were diagnosed between 2012 and 2022, identified with tumor characteristics. Incidence of BC among women aged 80+ increased significantly across the Nordic Countries, with 1.24 % per year (95 % CI: 0.07 %: 2.41 %). In Denmark, in the 80+ group, the ER+/HER2- subtype had the highest increase, with 1.98 % per year (95 % CI: 1.10 %: 2.87 %). Across the Nordic countries, incidence of BC in women aged 80+ increased. In Denmark, rising incidence of BC is driven by the ER+/HER2- subtype in the 80+ group, which has the best prognosis and gentle treatments. More elderly BC patients will require treatment and follow-up in the future. [Display omitted] • We assessed trends in the incidence of breast cancer subtypes. • In elderly the incidence of breast cancer increased across the Nordic countries. • The increase was driven by the ER+/HER2- subtype with the best prognosis. • The more aggressive ER-/HER2- subtype was stable. • More elderly breast cancer patients will require treatment in the future. [ABSTRACT FROM AUTHOR]

• We included 18 studies with 786 HER2-positive BC patients with CNS disease. • Overall and IC responses were higher than 60% in patients with BMs. • The 12-month IC PFS was 64.7% for patients with BMs. • Patients with LMD had an IC-ORR of 59.4% and an IC-CBR of 94.1% Trastuzumab deruxtecan (T-DXd) has shown promising activity in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and central nervous system (CNS) involvement. In this updated meta -analysis, we explore the effectiveness of T-DXd in a large subset of patients with HER2-positive BC and CNS disease. A systematic search was made on September 16th, 2024, for studies investigating T-DXd in the scenario of HER2-positive BC and brain metastases (BMs) and/or leptomeningeal disease (LMD). We used random effects models for all statistical analyses. We included 18 studies with 786 HER2-positive BC patients with CNS involvement (16 studies with 750 BMs patients and three studies with 36 LMD patients). We observed high overall antitumor responses (objective response rate [ORR], 60.4 %; disease control rate [DCR], 94.4 %; and clinical benefit rate [CBR], 79.3 %) and a 12-month PFS of 64.7 % and OS of 82.7 %. Intracranial ORR, DCR, and CBR were seen in 62.2 %, 88.6 %, and 68.6 % of patients, respectively, and 67.4 % achieved intracranial PFS at 12 months. Both stable and active BMs subgroups derived similar benefit from T-DXd. Better intracranial responses were seen for 33 patients with untreated BMs compared to 56 patients with previously treated or progressing lesions (odds ratio 3.82, 95 % confidence interval 1.3–10.8, p = 0.01). For the LMD group, T-DXd elicited intracranial ORR and CBR in 59.4 % and 94.1 % of patients, respectively. This updated meta -analysis continues to support the overall and intracranial activity of T-DXd in patients with HER2-positive BC and CNS involvement, including those with LMD. [ABSTRACT FROM AUTHOR]

: To develop a novel MRI-based vector radiomic approach to predict breast cancer (BC) human epidermal growth factor receptor 2 (HER2) status (zero, low, and positive; task 1) and its changes after neoadjuvant therapy (NAT) (positive-to-positive, positive-to-negative, and positive-to-pathologic complete response; task 2). : Both dynamic contrast-enhanced (DCE) MRI data and multi- b -value (MBV) diffusion-weighted imaging (DWI) data were acquired in BC patients at two centers. Vector-radiomic and conventional-radiomic features were extracted from both DCE-MRI and MBV-DWI. After feature selection, the following models were built using the retained features and logistic regression: vector model, conventional model, and combined model that integrates the vector-radiomic and conventional-radiomic features. The models' performances were quantified by the area under the receiver-operating characteristic curve (AUC). The training/external test set (center 1/2) included 483/361 women. For task 1, the vector model (AUCs=0.73 ∼ 0.86) was superior to (p <.05) the conventional model (AUCs=0.68 ∼ 0.81), and the addition of vector-radiomic features to conventional-radiomic features yielded an incremental predictive value (AUCs=0.80 ∼ 0.90, p <. 05). For task 2, the combined MBV-DWI model (AUCs=0.85 ∼ 0.89) performed better than (p <. 05) the conventional MBV-DWI model (AUCs=0.73 ∼ 0.82). In addition, for the combined DCE-MRI model and the combined MBV-DWI model, the former (AUCs=0.85 ∼ 0.90) outperformed (p <. 05) the latter (AUCs=0.80 ∼ 0.85) in task 1, whereas the latter (AUCs=0.85 ∼ 0.89) outperformed (p <. 05) the former (AUCs=0.76 ∼ 0.81) in task 2. The above results are true for the training and external test sets. MRI-based vector radiomics may predict BC HER2 status and its changes after NAT and provide significant incremental prediction over and above conventional radiomics. [Display omitted] • Vector radiomics outperformed conventional radiomics in predicting HER2 status. • The addition of vector RFs to conventional RFs yielded incremental predictive values. • DCE-MRI outperformed MBV-DWI in predicting HER2 status. • MBV-DWI outperformed DCE-MRI in predicting the changes in HER2 status after NAT. [ABSTRACT FROM AUTHOR]

Breast cancer has become the most prevalent malignant tumor worldwide and remains one of the leading causes of cancer-related mortality among women globally. The prognosis for patients with metastatic breast cancer remains poor, necessitating the exploration of novel therapeutic strategies to improve survival rates. In the era of precision medicine, antibody-drug conjugates (ADCs) have gained significant attention as a targeted therapeutic strategy in breast cancer treatment. ADCs, a relatively new treatment for breast cancer, deliver cytotoxic drugs (payloads), directly into the tumor space, turning chemotherapy into a targeted agent, which enables patients to experience significant improvements with manageable drug toxicity. For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. Recent clinical studies have demonstrated that the benefits of ADC therapies extend beyond HER2-positive breast cancer toinclude hormone receptor (HR)-positive breast cancer, triple-negative breast cancer (TNBC), and HER2-low expressing breast cancer. Notably, the DESTINY-Breast series of studies, particularly focusing on T-Dxd, encompass neoadjuvant, adjuvant, and multiple lines of therapy for advanced breast cancer. This marks the advent of a comprehensive ADC era in breast cancer treatment. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment. • ADCs are transforming breast cancer (BC) treatment with unprecedented precision. • ADCs are expanding the therapeutic potential to HER2-low, ultra-low, and negative BC. • ADCs are poised to become a standard of care across various stages of BC. • Personalized ADC treatment strategies represent the future of BC therapy. • A Combination strategy and novel payload are essential to overcoming drug resistance. [ABSTRACT FROM AUTHOR]

Targeting low levels of human receptor epidermal growth factor 2 (HER2) expression has reshaped the treatment paradigm for half of the patients with advanced breast cancer. HER2-low is currently defined as a HER2 immunohistochemical expression of 1+ or 2+ without amplification by in-situ hybridization. Until recently, HER2-targeted agents were ineffective in treating patients with HER2-low disease. In this narrative review, we summarize the current management of HER2-low breast cancer. We highlight the findings of the DESTINY-Breast 04 phase 3 trial, which confirmed the efficacy of trastuzumab-deruxtecan (T-DXd) for the treatment of patients with advanced, pretreated HER2-low breast cancer. We also discuss how to implement this new treatment option in treatment algorithms of hormone receptor (HR)-positive and triple-negative tumors, as well as how to optimally manage selected toxicities of T-DXd. T-DXd is currently the standard of care for patients with advanced, pretreated, HER2-low breast cancer. Based on the design of the DESTINY-Breast04 trial, the current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer. Up to 10–15% of the patients receiving T-DXd are expected to develop interstitial lung disease, which in 1–2% of the cases can be fatal. Adequate monitoring and prompt management are required to minimize the impact of ILD and to safely implement T-DXd in clinical practice. • HER2-low is defined as a HER2 immunohistochemical expression of 1+ or 2+ without amplification by in-situ hybridization. • HER2-low is not a distinct breast cancer subtype, but rather a target for potent, novel HER2-directed agents. • Trastuzumab-deruxtecan (TDX-d) is approved for the treatment of pretreated, advanced HER2-low breast cancer. • Education about the risk of interstitial lung disease and cardiac toxicity is needed prior to the initiation of TDX-d. [ABSTRACT FROM AUTHOR]

T2 gallbladder cancer (GBC) is the only stage showing a survival benefit after complete surgical resection, but recurrence rates remain high. Although human epidermal growth factor receptor 2 (HER2) has emerged as a therapeutic target, its role in T2 GBC remains unclear. This study investigated the status and prognostic impact of HER2 expression on T2 GBC. HER2 expression and amplification were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively, in 90 patients with T2 GBC who underwent radical cholecystectomy. We evaluated HER2 status according to the breast and gastric cancer guidelines and analyzed the effect of relevant prognostic factors on survival. HER2 positive status was observed in 11.11% (10/90) and 8.89% (8/90) of cases based on gastric and breast cancer guidelines, respectively. Poor differentiation and a higher level of perineural invasion were independent prognostic factors of disease-free survival (DFS). Old age, male sex, presence of lymph node metastasis, poor differentiation, high levels of perineural invasion, and HER2 positivity based on breast cancer guidelines were identified as independent prognostic factors of overall survival (OS). Patients with HER2-positive T2 GBC according to breast cancer guidelines had worse OS. HER2 positivity based on breast- but not gastric-cancer guidelines was associated with poorer survival. These results provide a criterion for the evaluation of HER2 and a rationale for therapeutic strategies targeting HER2 in T2 GBC. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV) X protein (HBX), a viral macromolecule, plays a vital role in the development of HBV-related hepatocellular carcinoma (HCC). Increased expression of HER2 is linked to HBV infection, and HBX is responsible for HER2 upregulation in HCC. Nevertheless, the underlying molecular mechanisms are not yet fully understood. In the study, we discovered that HBX promoted HER2 expression to facilitate the sensitization of the insulin signaling pathway and enhance the growth and migration of HCC cells. Mechanistically, the viral protein enhanced the stability of HER2 by preventing its ubiquitination-mediated proteasomal degradation through LASP1, which could bind to HER2. Furthermore, increased SUMOylation of LASP1 contributed to the upregulation of HER2 and the interaction of LASP1 with HER2. In addition, RANBP2 and RANGAP1 were found to interact with LASP1 and promote SUMOylation of LASP1 to upregulate HER2 expression in HBX-associated hepatoma cells. In summary, our work provides a novel insight into hepatocarcinogenesis mediated by HBX and estimates the detailed mechanisms related to the increase in HER2 regulated by the viral protein, which might help provide a theoretical basis for identifying novel targets for HBV-positive HCC treatment. • HBX promotes HER2 expression to facilitate the activation of the insulin signal pathway and enhance the growth and migration of HCC cells. • HBX mediates the expression of HER2 protein via LASP1, which binds to HER2 in hepatoma cells. • HBX enhances the stability of HER2 by preventing its ubiquitination-mediated proteasomal degradation through LASP1 in HCC cells. • The increased SUMOylation of LASP1 contributes to the upregulation of HER2 and the interaction of LASP1 with HER2 in HBX-related HCC cells. • RANBP2 and RANGAP1 interact with LASP1 and promote the SUMOylation of LASP1 to upregulate HER2 in HBX-positive HCC cells. [ABSTRACT FROM AUTHOR]

Advances in the development of anti-HER2 monoclonal antibodies (mAbs) represent one of the most significant milestones in the treatment of HER2+ breast cancer patients. However, HER2+ metastatic breast cancer (MBC) patients display resistance towards first-generation anti-HER2 mAbs or antibody-drug conjugate (ADC) treatment. In recent years, new generation of anti-HER2 mAb and ADC including margetuximab and trastuzumab deruxtecan (T-DXd), respectively, have been approved for the treatment of previously treated HER2+ MBC patients. The successes of margetuximab and T-DXd have renewed the interest in the research and development of anti-HER2 immunotherapies for both HER2+ and HER2-low breast cancer patients. In this review, we focus on these two immunotherapeutics in terms of their mechanisms of action, preclinical findings and clinical trials leading to their approval, as well as the mechanisms of resistance to conventional anti-HER2 immunotherapies (i.e. trastuzumab, pertuzumab and T-DM1). In the future, combination of either margetuximab or T-DXd with small molecule inhibitors such as tyrosine kinase inhibitors that elicit anticancer immunogenicity may further enhance the efficacy of margetuximab or T-DXd in the treatment of HER2+ MBC patients. [Display omitted] • Inhibited binding to HER2 and immunosuppressive microenvironment cause resistance to earlier generation of anti-HER2 mAbs. • The second generation anti-HER2 monoclonal antibody margetuximab enhances binding with FcR on NK cells for cancer killing. • The novel antibody-drug conjugate T-DXd displays clinical efficacy in HER2-low breast cancer patients. • Combination of margetuximab or T-DXd with inhibitors that elicit anticancer immunogenicity mayenhance their efficacy. [ABSTRACT FROM AUTHOR]

To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT). Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed. We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717). Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy. • There is less known about the efficacy of trastuzumab alone, although it avoids toxicity, especially in older patients. • It is currently unknown whether adjuvant trastuzumab therapy alone can offer a benefit over no adjuvant therapy. • Here, for the first time, we added an implication to this issue with propensity-adjustment analysis in a prospective study. • We found that trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab. • Although trastuzumab plus chemotherapy remains a standard of care, trastuzumab can be considered for selected older patients. [ABSTRACT FROM AUTHOR]

The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer. • HER2 targeting ADCs have changed the treatment landscape of metastatic HER2+ BC. • The third generation HER2 targeting ADC, T-DXd, is effective against HER2-low/ultralow BC. • The validation of new techniques to refine the definition of HER2 expression is required. • Ongoing translational research aims to evaluate the mechanisms of action and resistance to this new generation of ADC's. • Current clinical trials aim to evaluate treatment combinations and new HER2-tagreting ADCs. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed. HER2-targeted therapies have significantly improved outcomes for patients with ABC Ideal sequencing of regimens is key to maximize treatment benefits New HER2-targeted agents are used at earlier stages in BC treatment Clinical evidence for treatment of special populations with ABC is lacking Approved drugs are not accessible in all countries [ABSTRACT FROM AUTHOR]

Based on recent evidence derived from clinical trials and translational research, breast cancer pathology has witnessed a rapid increase in the utilization of predictive markers, companion diagnostics and molecular testing for tailored management of patients with breast cancer. New diagnostic entities with specific molecular phenotypes have also been included in the classification of breast cancer. Genomic assays including Oncotype DX®21-gene Recurrence Score (RS), Prosigna and EndoPredict are currently used in routine practice to guide adjuvant/neoadjuvant therapy. The analysis of established biomarkers such as ER and PR immunohistochemistry has been updated to recognize new categories with different clinical behaviour and significance, such as the ER low expressors and HER2 low carcinomas. PD-L1 testing and PIK3CA mutation have been introduced for advanced TNBC and recurrent ER positive breast cancer respectively. This review provides an update on the rapidly evolving field of predictive & prognostic markers, companion diagnostics, molecular and genomic testing of breast cancer. [ABSTRACT FROM AUTHOR]

HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7). Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic. • Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with breast cancer. • Consider an actionable role for BRCA mutations in HER2-positive disease. • Combinations of PARPi plus anti-HER2 therapies are warranted in this setting. [ABSTRACT FROM AUTHOR]

The upregulation of programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor 2 (HER2) may play a role in gastric adenocarcinoma (GAC). To study PD-L1 and HER-2 expression and prognosis in GAC. PD-L1 and HER2 expression was determined in tumor tissues of 75 patients with GAC. The correlations between PD-L1, HER2 expression, and clinicopathological factors were analyzed. The positive expression rate for PD-L1 was 57.3% (43/75) and the HER2 over-expression rate was 17.3% (13/75). PD-L1 expression negatively correlated with the grade of GAC differentiation (r =-0.26, P<0.05). Approximately 85% of HER2-positive GACs were found to be PD-L1-positive and PD-L1 expression positively correlated with HER2 overexpression. The TNM stage and combined HER2 and PD-L1 expression were independent prognostic factors affecting the survival of patients with GAC. The median overall survival and recurrence-free survival of groups I (HER2 overexpression and PD-L1 positive), II (HER2 overexpression and PD-L1 negative), III (No HER2 overexpression and PD-L1 positive) and IV (No HER2 overexpression and PD-L1 negative) were (47 (17–77), 15 (0–44), 81 (62–101), and 78 (60–98) months, respectively. PD-L1 expression is upregulated in more than half of patients with GAC. Anti-PD-L1 treatment combined with anti-HER2 therapy may benefit patients with locally advanced GAC with HER2 overexpression. [ABSTRACT FROM AUTHOR]

The tumor suppressor fragile histidine triad (FHIT) is frequently lost in non-small cell lung cancer (NSCLC). We previously showed that a down-regulation of FHIT causes an up-regulation of the activity of HER2 associated to an epithelial-mesenchymal transition (EMT) and that lung tumor cells harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to decipher the FHIT-regulated HER2 signaling pathway in NSCLC. Transcriptomic analysis of tumor cells isolated from NSCLC revealed the endocytic receptor low density lipoprotein receptor-related protein 1 (LRP1), a central regulator of membrane trafficking and cell signaling, as a potential player of this signaling. In a cohort of 80 NSCLC assessed by immunohistochemistry, we found a significant association between a low FHIT expression and a high pHER2 and LRP1 expression by tumor cells. Experiments of FHIT silencing showed that FHIT regulated LRP1 expression both at the mRNA and protein levels in lung cell lines. Analyzing the relationship between LRP1 and HER2, we observed that an anti-HER2 targeted therapy reversed LRP1 overexpression induced by FHIT silencing whereas LRP1 silencing did not affect HER2 activity. Studying the functional role of LRP1, we showed that cell proliferation and invasion induced by FHIT silencing were LRP1-dependent. In addition, we found that the induction of vimentin upon FHIT inactivation was counteracted by LRP1 silencing. These results suggest that LRP1 acts downstream of HER2 to induce EMT and tumor progression following FHIT loss. Dual targeting of HER2 and LRP1 might represent a therapeutic strategy to more efficiently inhibit HER2 signaling in FHIT-negative NSCLC. • LRP1 high expression is correlated to a FHITlow/pHER2high phenotype in NSCLC. • LRP1 expression is regulated by FHIT. • LRP1 acts downstream of HER2 upon FHIT loss. • FHIT-mediated regulation of EMT involves LRP1. • HER2/LRP1 dual targeting might be efficient in FHIT-negative NSCLC. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer among females with Li-Fraumeni syndrome (LFS), but available data on LFS-related BC characteristics are derived from small retrospective cohorts. Prior work has demonstrated a high proportion of HER2-positive BCs, but our understanding of how HER2-positive LFS BCs respond to anti-HER2 treatments is limited. BCs diagnosed in patients with germline TP53 variants between 2002–2022 were assembled from three institutions. Hormone receptor (HR) and HER2 expression were retrieved from pathology records. Pathologic complete response (pCR) was defined as ypT0/is ypN0. A total of 264 BCs were identified among 232 patients with LFS: 211 (79.9 %) were invasive carcinomas, of which 106 were HER2-positive. Among HER2-positive BCs, most tumors co-expressed HRs (72.6 %) and were more frequent among those diagnosed at younger age (p < 0.001). Mastectomy was the preferred surgical approach among women with nonmetastatic cancers (77.8 %) and most received anti-HER2 targeted therapy (74.7 %). Among 38 patients receiving neoadjuvant therapy with available post-treatment pathology reports, 27 (71.1 %) achieved pCR: 18/26 (69.2 %) among HR-positive and 7/10 (70.0 %) HR-negative. The rate of pCR was 84.6 % among patients treated with an anthracycline-free regimen (all received trastuzumab). Among classifiable HER2-negative BCs (n = 77), 31 (40.3 %) were HER2-low and 46 (59.7 %) HER2-zero. Among females with LFS and BC, HER2-positive subtype was associated with younger age at diagnosis and a predominant HR-positivity. Favorable pCR rates were observed among those receiving neoadjuvant HER2-directed therapies, for both HR-positive and negative tumors. These data may inform the counseling and care of patients with LFS. • Our study examined treatment of HER2-positive breast cancer in Li-Fraumeni syndrome. • HER2-positive subtype was associated with younger age at diagnosis. • Remarkable pCR rates (over 70 %) were observed in HER2-positive cancers. • Favorable results were observed in patient treated with anthracycline-free regimens. [ABSTRACT FROM AUTHOR]

Assessing the molecular profiles of bladder cancer (BC) from patients with locally advanced or metastatic disease provides valuable insights, such as identification of invasive markers, to guide personalized treatment. Currently, most molecular profiling of BC is based on highly invasive biopsy or transurethral tumor resection. Liquid biopsy takes advantage of less-invasive procedures to longitudinally profile disease. Circulating tumor cells (CTCs) isolated from blood are one of the key analytes of liquid biopsy. In this study, we developed a protein and mRNA co-analysis workflow for BC CTCs utilizing the graphene oxide (GO) microfluidic chip. The GO chip was conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from 1 mL of blood drawn from BC patients. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent-based whole transcriptome sequencing, respectively. Elevated CTC counts were significantly associated with patient disease status at the time of blood draw. We found a count greater than 2.5 CTCs per mL was associated with shorter overall survival. The invasive markers EGFR, HER2, CD31, and ADAM15 were detected in CTC subpopulations. Whole transcriptome sequencing showed distinct RNA expression profiles from patients with or without tumor burden at the time of blood draw. In patients with advanced metastatic disease, we found significant upregulation of metastasis-related and chemotherapy-resistant genes. This methodology demonstrates the capability of GO chip-based assays to identify tumor-related RNA signatures, highlighting the prognostic potential of CTCs in metastatic BC patients. [ABSTRACT FROM AUTHOR]