HER-2-H

Using a drug conjugated anti-HER2 antibody (trastuzumab emtansine) in a mouse PCa xenograft model delayed metastatic tumor growth, suggesting approaches that target HER2-high cells may be beneficial in treating PCa. We propose that HER2 is deserving of further study in PCa as a target on quiescent cells to prevent recurrence, decrease chemotherapy resistance, or eradicate minimal residual disease.

In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer.

Overall, these results demonstrate that ICG-Herceptide is a promising optical probe for the diagnosis and localization of HER2-overexpressing tumors. Moreover, Herceptide is a novel HER2-targeting peptide and can be further used for developing theranostic agents.

HER2-low tumors were strongly associated with HR status, however, no evidence was found that HER2 status was associated with chemotherapy response and prognosis in NAC patients.

P1/2; N=220 --> 490 | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Apr 2022 --> Jul 2025

HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.

Background: NeoALTTO showed increased pathological complete response (pCR) with paclitaxel combined with dual over single anti-HER2 blockade. The trial included six initial weeks of treatment with lapatinib (L), trastuzumab (T) or their combination (L+T) followed by chemotherapy (CHT)... Biomarkers of early T-cell and monocyte-macrophage activation, as well as HER2 downregulation hold the potential to reliably identify patients likely to achieve a pCR and a favorable prognosis. New effective treatments need to be explored for cases lacking an early GEP response.

In vitro study indicated that induction of DNA damage mimicked TZM-induced lipid peroxidation and cardiomyocyte contractile dysfunction while the ferroptosis inducer erastin mitigated Empagliflozin-offered protection against lipid peroxidation and cardiomyocyte dysfunction (but not DNA damage). Likewise, in vivo and in vitro inhibition of ferroptosis recapitulated Empagliflozin-offered cardioprotection against TZM exposure. Taken together, these data demonstrated that Empagliflozin may be possible candidate drug for TZM cardiotoxicity likely through a DNA damage-ferroptosis-mediated mechanism.

HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer.

P=N/A, N=40, Recruiting, King's College London | Unknown status --> Recruiting | Trial completion date: Jun 2021 --> Jun 2023 | Trial primary completion date: Dec 2020 --> Jun 2023

High expression of Talin2 is associated with lymph node metastasis and HER-2 overexpression in breast cancer patients.Down-regulation of miR-4324 inhibits the proliferation, invasion and migration and induces apoptosis of breast cancer cells, and the inhibitory effect of miR-4324 knockdown on breast cancer cell migration is mediated probably by targeted inhibition of Talin2 expression.

Background: Based on the results of the DESTINY-Breast04 study, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) and the Ventana PATHWAY 4B5 companion diagnostic were recently approved by the US Food and Drug Administrated for the treatment and identification of patients with HER2-low (IHC2+/ISH- or IHC1+) (Modi et al...JAMA Oncol 2022). These data demonstrate pathologists’ ability to achieve an acceptable level of accuracy for identifying HER2 IHC 0 and HER2-low patients even after short-term training; however, additional training techniques and experience are needed to further improve accuracy.

Altogether, our data pinpoint an important biological role of the interconnection between HER2 and ATM. The latter appear to be an independent prognostic biomarker and may serve as targets to develop novel combination therapies to improve the outcome of patients with bladder cancer.

MT-5111 is a 55kD engineered toxin body targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. sHER2 biomarker data is expected for all cohorts with PK correlation and 23µg/kg safety and efficacy data. PK profile of MT-5111, C1D1 values

Background: & Objective Trastuzumab deruxtecan is effective in HER2-positive (IHC3+ or ISH- positive) and HER2-low (IHC1+; IHC2+/ISH-negative) breast cancer...Accurate assessment of HER2 IHC1+ and IHC2+ status was observed to be compromised by Decal STAT and Richard Allan decalcification solutions. Decalcification of bone metastasis samples for HER2-positive and HER2-low status determination may be possible using formic acid, but this would require further validation.

Methods Two-hundred ninty-five patients with HER2-positive breast cancer who received neoadjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) were included in this retrospective analysis. After adjusting other clinicopathologic factors, the high HER2 protein expression was only an independent factor for pCR (adjusted OR 3.85, 95% CI, 1.66-8.91, p=0.002). Conclusions Our results suggest that high expression of HER2 protein assessed by IHC is important in predicting neoadjuvant TCHP response in HER2-positive breast cancer.

This is the first study to report that higher HER2/CEP17 ratio is associated with longer PFS in HER2-positive advanced breast cancer patients treated with palliative first-line DHP. The strength of this study is that we identified prognostic role of ISH even in patients with HER2 IHC 3+. It would be helpful to perform ISH not only in patients whose HER2 IHC is ambiguous, but also in patients with HER2 IHC 3+ to make better prediction of treatment outcome.

In vitro cytotoxicity of RC48 (Disitamab Vedotin), alone or in combination with lemzoparlimab was evaluated in co-culture of human PBMC with tumor cell lines. In vivo activity of RC48 or in-house produced DS8201 analogue in combination with lemzoparlimab were investigated in CDX (HER2 0/1+/3+ by IHC) and PDX (HER2 2+ by IHC) models...Lemzoparlimab potentiated HER2 ADC mediated tumor killing by modulating NK cells and macrophage activity to increase cytotoxicity and phagocytosis. These data support future clinical investigation of lemzoparlimab and HER2 ADC combination in HER2 positive patients, especially those with HER2-low expressing tumors.

Conclusions The combination of allogeneic NK therapy, Herzuma® and paclitaxel showed synergistic anticancer activity in HER2-low breast cancer preclinical model. This combination merits further clinical investigation in HER2-low breast cancer patients.

PD-L1 expression was demonstrated in 3 out of 13 HER-3‑positive patients and 2 out of 2 HER-3‑positive TNBC patients. There was a strong correlation between positive HER-3 and PD-L1 TNBC expression (p = Keywords: breast cancer, HER family, overexpression, HER-3, HER-2, PD-L1, TNBC.

In this perspective, we highlight the need for disaggregated research of BCa among AZN women and advocate for comprehensive, culturally sensitive strategies to address health disparities in this priority population. Improving BCa literacy and awareness, access to care, and equitable recruitment into clinical trials are a few amelioratory goals to consider in the future.

We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.

As CESM is a relatively young imaging technique, a few related works were found; this may be due to the "off-label" modality. In the next few years, the role of CESM in breast cancer diagnostics will be more thoroughly investigated.

Conclusions Varlitinib combined with paclitaxel revealed manageable toxicities and antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy. Updated outcomes for ongoing patients and biomarker analysis will be presented.

The selected biomarkers were not associated with activity and efficacy of P added to T-CT. Conclusions HER2-high CNV assessed by NGS is associated with significantly better ORR, PFS, OS in a pts subgroup from the JACOB trial, independent from treatment arm and especially if combined with HER2 3+.

Clinical trial identification Editorial acknowledgement Legal entity responsible for the study The authors. Conclusions HER2DX predicts endocrine sensitivity and pCR following neoadjuvant T+P+letrozole in pts with early-stage HER2+/HR+ BC. HER2DX could help tailor systemic therapy in this context.

Our results underlined the promising and fundamental role of the oHSV oncolytic activity together with its reawakening of the immune system. The resultant therapy worked like an agnostic vaccination since the immune response was directed against an unknown repertoire of tumor neoantigens and the outcome is the development of a durable immune memory that vaccines the host against the tumor.

The median survival of mice, which were treated by three injections of 16 MBq Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ.

In conclusion, our study provides a comprehensive blueprint of the immune microenvironment of HER2-positive gastric tumors. This analysis highlights the importance of considering the tumor microenvironment when assessing response to immune checkpoint inhibitors.

Thus, the amount of competition from the carrier dose automatically adjusts to expression levels, allowing tailored competition between different patients/metastases. The computational model highlights two dimensionless numbers, the Thiele modulus and a newly defined competition number, to design an optimal HALA antibody carrier dose for any target.

No abstract available

Ibrutinib had limited clinical efficacy in patients with c-MYC and/or HER2 amplified OG cancer. Unexpected gastrointestinal bleeding was observed in 3 out of 8 treated patients which was considered a new safety finding for ibrutinib in this population.

Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure.

Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib...Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib... Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted.

HER2-targeted therapies for HER2-low metastatic BC (mBC) are under investigation (eg, T-DXd in the phase 3 DESTINY-Breast04 study; NCT03734029), but HER2 assays currently used to select patients (pts) for approved anti-HER2 therapies are optimized for high HER2 expression and are not validated for HER2-low detection... Data on HER2-low prevalence in BC is limited. Preliminary data from this study of mBC samples suggest a somewhat higher prevalence estimate (≈63%) than a previous study of primary BC samples (≈50%). Concordance was 82%; ongoing analyses with updated data will clarify the concordance between rescored and historical HER2 slides.

To achieve this, we developed a microfluidic approach combining both CTC capture, identification and HER2-HER3 status quantification by Proximity Ligation Assay (PLA). We first optimized and demonstrated the potential of the on-chip quantification of HER2-HER3 dimerization using cancer cell lines with various levels of HER2 overexpression and validated its clinical potential with a patient's sample treated or not with HER2-targeted therapy.

If it is low-risk eBC with clinically node-negative disease and tumor size <2 cm, upfront surgery is usually advised followed by adjuvant chemotherapy with trastuzumab +/- pertuzumab depending on pathologic LN status...If it is non-pCR after surgery, trastuzumab emtansine (T-DM1) therapy should be considered for 14 cycles because it significantly improved invasive disease-free survival compared to trastuzumab. Extended therapy with neratinib could be considered for patients who have completed 1 year of trastuzumab when it is an ER+HER2+high risk disease...The introduction of new antibody drug conjugate (ADC) such as trastuzumab deruxtecan in metastatic breast cancer is shaking the definition of HER2 positivity as it is showing not only groundbreaking efficacy in HER2 positive BC but also outstanding data even in low HER2 BC (IHC 1 or 2 with ISH negative) which is previously considered HER2 negative disease. According to the results of trials in eBC with trastuzumab deruxtecan, all the aforementioned paradigms of treatments would be affected in near future.