Xianling Lianxia formula improves the efficacy of trastuzumab by enhancing NK cell-mediated ADCC in HER2-positive BC.

Trastuzumab has improved survival rates in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), but drug resistance leads to treatment failure. Natural killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC) represents an essential antitumor immune mechanism of trastuzumab. Traditional Chinese medicine (TCM) has been used for centuries to treat diseases because of its capacity to improve immune responses. Xianling Lianxia formula (XLLXF), based on the principle of "strengthening body and eliminating toxin", exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC. Notably, this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC, as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments. Mechanistically, the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2 (SH2) containing protein (CISH) expression, which in turn activates the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 5 (STAT5) pathway. Collectively, these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.

Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study.

Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD. Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer. Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC. Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited. Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center. Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.

Targeting HER2 in breast cancer with brain metastases: a pharmacological point of view with special focus on the permeability of blood-brain barrier to targeted treatments.

Understanding the capability of a drug to penetrate the blood-brain barrier (BBB) is an unmet medical need in patients with positive human epidermal growth factor receptor 2 (HER2 positive) and brain metastases. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. Predicting the BBB permeability of these therapeutic agents is a pharmacological challenge due to the various factors involved in the barrier functions. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

PI3K Mutation Profiles on Exons 9 (E545K and E542K) and 20 (H1047R) in Mexican Patients With HER-2 Overexpressed Breast Cancer and Its Relevance on Clinical-Pathological and Survival Biological Effects.

Background: Trastuzumab resistance is associated with overexpressing the human epidermal growth factor receptor 2 (HER-2), which results from the altered phosphoinositide 3-kinase (PI3K) pathway in breast cancer patients. Objective: We quantified the frequency of PI3K enzyme single and double-point mutations in Mexican patients with HER-2 overexpressing breast cancer and its association with clinical-pathological variables. Methods: We embedded HER-2 breast samples in paraffin from 60 patients, extracted their DNA, and evaluated PI3K mutations in 49 HER-2-positive breast tumors. We focused on mutations for one exon 20 (H1047R) and two exon 9 PI3K (E545K, E542K) hotspots and characterized them as single and double-point mutations. The mean patient follow-up was 86 months. Results: Of 49 patients who tested positive for HER-2 breast cancer, 14.28% showed mutations in PI3K, 71.42% single-point, and 28.56% double-point mutations. We found single-point mutations in H1047R (42.85%) and E545K (28.57%). Only two patients exhibited double-point mutations: one in E542K/E545K and another in H1047R/E545K (14.28% each). Although we observed lower survival in patients with mutations in PI3K, we did not find a significant association between these factors (p = 0.191). However, single and double-point mutations in PI3K were significantly associated with the clinical stages of diagnosis and tumor size (p = 0.027 and p = 0.04, respectively). Conclusion: Single and double-point mutations in PI3K are related to tumor size and advanced clinical-pathological traits in Mexican patients with HER-2 overexpression, and future molecular studies are necessary to understand these findings.

Biomimetic Modification of siRNA/Chemo Drug Nanoassemblies for Targeted Combination Therapy in Breast Cancer.

The development and progression of tumors are characterized by intricate biological processes. Monotherapy not only struggles to achieve effective treatment but also tends to precipitate a series of issues, including multidrug resistance and limited antitumor effect. Consequently, it is imperative to adopt a synergistic multitherapy approach to enhance the efficacy of tumor treatment. The integration of chemotherapy drug with oligonucleotide drug for combinational treatment has shown significant promise in improving tumor therapeutic efficiency. However, the effective in vivo codelivery of oligonucleotide drugs and chemotherapy drugs faces substantial challenges such as poor stability of oligonucleotide drugs during the circulation time, limited tumor accumulation, and uncertain delivery ratios of different payloads. To overcome these obstacles, we have engineered cyclic Arg-Gly-Asp (cRGD)-modified red blood cell membrane (RBCm)-coated multidrug nanocomplexes, which were self-assembled from the Polo-like kinase 1 siRNA (siPlk1) and an irreversible tyrosine kinase inhibitor neratinib targeted to human epidermal growth factor receptor 2 (HER2) overexpressed in breast cancer. Through electrostatic and amphiphilic interactions between the positively charged neratinib and negatively charged siPlk1, we have successfully fabricated uniform multidrug nanoparticles. The cRGD-modified red blood cell membranes coated on the surface of the multidrug nanoparticles could enhance drug stability in circulation and tumor accumulation. This targeted combinational therapy significantly enhanced the antitumor efficiency in HER2-positive breast cancer in vitro and in vivo.

Nodal involvement in patients with small, clinically node-negative HER2-positive breast cancer after staging with FDG-PET/CT and neoadjuvant systemic therapy.

BACKGROUND: Guidelines recommend systemic therapy for stage I HER2+ breast cancer (BC). Neoadjuvant systemic treatment (NAST) allows response-guided adjuvant treatment. However, prior to NAST only clinical nodal staging is available, risking undertreatment if ypN+ is observed. Here, we aim to evaluate the impact of FDG-PET/CT and NAST on nodal disease status in patients with small, node-negative HER2+ BC. METHODS: This retrospective study included patients with small (≤3 cm), clinically node-negative HER2+ BC diagnosed between 2011 and 2023. Primary outcome was the proportion of patients with nodal disease on final pathology after upfront surgery or NAST followed by surgery with or without FDG-PET/CT. Patients received either paclitaxel + trastuzumab (PT) or a more extensive regimen. RESULTS: Of the 370 included patients, 183 underwent FDG-PET/CT, detecting regional or distant metastases in 14 patients (7.7 %). Among 356 patients with cN0 disease, 44.1 % (n = 157/356) had upfront surgery, with only 3 % (5/157) having an FDG-PET/CT. The remaining 55.9 % (199/356) started with NAST, with 82 % (n = 164/199) having an FDG-PET/CT. Among patients treated with NAST, 36 % received PT. Nodal involvement on pathology was seen in 19.1 % (n = 29/152) after upfront surgery without FDG-PET/CT and 6.1 % (10/164) after NAST combined with FDG-PET/CT. After NAST, 58 % had a pCR (PT: 49 %, other: 63 %). Nodal involvement on final pathology was seen in 6.9 % after PT and in 5.5 % after more extensive regimen. CONCLUSIONS: The proportion of patients with ypN + after NAST combined with FDG-PET/CT was only 6.1 %. Neoadjuvant treatment can be a safe treatment strategy for patients with stage I HER2+ BC.

Pyrotinib combined with metronomic etoposide in heavily pretreated HER2-positive metastatic breast cancer: a single-arm, phase II study.

BACKGROUND: Exploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC. METHODS: HER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety. RESULTS: 22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6-10.4 months), and the median OS was 27.0 months (95%CI, 20.9-33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed. CONCLUSION: The combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity. TRIAL REGISTRATION: Registry number: NCT03923179. Registered April 18, 2019.

HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.

Her2 positive metastatic breast cancer treated with low dose lapatinib in a resource-constrained setting in South India: a retrospective audit.

Despite the development of newer anti-Her2 agents, access to these medicines is still restricted with lapatinib being widely used as a second-line agent in Her2-positive metastatic breast cancer. However, lapatinib at approved doses of 1,250 to 1,500 mg/day contributes to a high pill burden and financial toxicity. In a population that has an average national per capita income of only USD 2238.1, lapatinib alone contributes to a financial burden of USD 6153.56 per year (approximately USD 500 per month). A concept of 'value meal' has been suggested - the higher bioavailability of lapatinib with the meal being exploited to reduce its administered dose. This concept was utilised in a resource-constrained tertiary care center in South India and we report the outcomes. In our institution, consecutive patients with Her2 positive metastatic breast cancer from 1 January 2014 to 31 December 2020 who could not afford trastuzumab, lapatinib or any other anti-Her2 agent were offered low-dose lapatinib, 500 mg daily with meal. We conducted a retrospective cohort study of the safety and efficacy of this regimen. Among the 47 patients who received low-dose lapatinib, the majority had de novo metastatic disease (57.4%) and multiple visceral metastases (48.9%). The median number of lines of treatment before lapatinib was one. The disease control rate with lapatinib was 61.7%. The median progression-free survival was 7 months (95% CI: 5.6-8.4 months). The median duration of response was 4.5 months, ranging from 1.3 to 45.8 months. Only eleven patients (23.4%) experienced toxicity, mainly dermatological, with grade 3 in only one (2.1%) and no grade 4 toxicities. Low-dose lapatinib is a regimen that offers an acceptable disease control rate. This strategy requires further exploration, particularly for the benefit of resource-limited areas.

Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trial.

BACKGROUND: The PHILA study suggests that pyrotinib, trastuzumab, and docetaxel significantly improved progression-free survival (PFS) compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2-positive metastatic breast cancer. In this study, we aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and provide further insights for the PHILA trial. METHODS: The in vitro activity of combination treatments was assessed through cell biological and biochemical experiments. The in vivo efficacy was evaluated in cell-derived xenografts, a TUBO tumour model, and one clinical case. Next-generation sequencing was performed on circulating tumour DNA (ctDNA) from patients in the PHILA trial. FINDINGS: The combination of pyrotinib and trastuzumab more effectively inhibited cell growth than pyrotinib or trastuzumab alone in models of HER2-dependent breast cancer. It potentiated membrane HER2 ubiquitination and downregulation, which resulted in a comprehensive blockade of the HER2 signalling pathway. The pyrotinib-altered membrane HER2 levels had no significant effect on trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). We further validated the synergistic mechanisms in TUBO tumours and one clinical case, rather than models of HCC1954 cells harbouring the PIK3CA H1047R mutation. Similarly, in our centre cohort of the PHILA study, patients with genetic alterations in the HER2 signalling cascade had significantly shorter median PFS than individuals with the wild-type pathway. INTERPRETATION: Our findings underscore the robust synergy between pyrotinib and trastuzumab in overcoming HER2 dependency and provide a rationale for pyrotinib, trastuzumab, and docetaxel as one of the optimal choices for patients with untreated HER2-positive metastatic breast cancer, who are dependent on the HER2 signalling cascade. FUNDING: This work was supported by the National Key Research and Development Program of China (2021YFF1201300), the National Natural Science Foundation of China (82172875), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-001), and the Joint Innovative Fund of Beijing Natural Science Foundation and Changping District (L234004).

The MiR-200c/FOXP3 Network: A Promising Biomarker for Predicting Trastuzumab Response in HER2-Positive Breast Cancer.

Purpose: Resistance to Trastuzumab is a significant challenge in the management of HER2-positive Metastatic Breast cancer (HER2-MBC), and a better understanding of the molecular causes of resistance is required to develop more effective treatment plans. While elevated plasma levels of miR-200 and FOXP3 have been linked to breast cancer progression and treatment response, no clinical studies have confirmed these results. Methods: The study involved 40 patients with HER2-positive metastatic breast cancer (HER2-MBC). The expression levels of miR-200c-3p and the FOXP3 gene were assessed in plasma samples at two time points: baseline (BL) and after the consent completion of one cycle of Trastuzumab, utilizing quantitative polymerase chain reaction (qPCR). Clinical response to Trastuzumab was evaluated 12 months post-therapy and correlated with the time to progression (TTP) through Kaplan-Meier analysis. Results: Low plasma expression level of miR-200c-3p was detected before therapy in HER2-MBC, compared to healthy controls, and decreased dramatically in the follow-up sample at disease progression, while increased after one cycle of Trastuzumab therapy in patients who were sensitive to Trastuzumab. At baseline, a low expression level of miR-200c was significantly associated with overexpression of FOXP3, poor prognosis, and shorter time to progression. Conclusions: The findings suggest that miR-200c-3p may be a promising biomarker for predicting the response to Trastuzumab in HER2-MBC patients.

Stable or at least once HER2-low status during neoadjuvant chemotherapy confers survival benefit in patients with breast cancer.

BACKGROUND: Temporal heterogeneity in human epidermal growth factor receptor 2 (HER2) status may be associated with the prognosis of breast cancer. We aimed to clarify the relationship of HER2-low transition during neoadjuvant therapy with survival outcomes under the new classification of HER2 status. METHODS: This retrospective study was conducted based on the prospective database of breast cancer patients treated with neoadjuvant therapy from September 2013 to August 2020. RESULTS: This analysis enrolled 185 patients, including 44 patients with HER2-zero tumours, 93 patients with HER2-low tumours and 48 patients with HER2-positive tumours after neoadjuvant therapy. Nearly, 57.6% of HER2-zero tumours turned into HER2-low tumours after neoadjuvant therapy, while 25.0% of HER2-low patients changed to HER2-zero or HER2-positive tumours. We found that at least once diagnosis as HER2-low breast cancer was related to hormone receptor status (p < .001) and Ki-67 expression (p = .036). Patients ever diagnosed as HER2-low tumours had favourable clinicopathological features (less Ki-67 expression, lower pathological staging, etc.) as well as significantly better locoregional relapse-free survival (LRFS; p = .007) and overall survival (OS; p = .026) compared with those never exhibiting HER2-low expression. Furthermore, the 6-year OS rates were 94.2% (95% confidence interval (CI) 83.1-98.1), 88.7% (74.4-95.2) and 78.1% (65.4-86.6) for patients with stable, once and none HER2-low expression, respectively (adjusted HR, 0.514 [95%CI, 0.294-0.897], p = .019). CONCLUSIONS: Our study first indicated in patients across all expression levels of HER2 that stable or at least once HER2-low status may confer favourable attributes including less malignant biological behaviour and long-term survival benefit for breast cancer receiving neoadjuvant therapy.

Stable or at least once HER2-low status may confer favourable attributes including less malignant biological behaviour and long-term survival benefit for breast cancer receiving neoadjuvant therapy.HER2-low expression was highly instable during disease evolution from primary lesion to residual tumour and was associated with hormone receptor status, which warrants HER2 re-test in residual lesion, especially for patients with HER2-zero disease at initial diagnosis, so as to give a clear picture of not only prognostic significance but also treatment availability.

Long-Term Survival in Human Epidermal Growth Factor Receptor 2-Positive Bone-Only Metastatic Breast Cancer: Trastuzumab, Denosumab, and Potential Synergistic Effects.

Breast cancer is the second most common cancer worldwide. There are four main subtypes of breast cancer, one of which involves positivity for human epidermal growth factor receptor 2 (HER2). Here, we present a case series of unusually long survival in three patients with HER2-positive metastatic breast cancer. All cases involved post-menopausal women with bone-only metastases undergoing treatment with the HER2-targeted therapy trastuzumab and the receptor activator of nuclear factor kappa-Β ligand (RANK-L) inhibitor denosumab. Our three patients survived for 17, 13, and 11 years, respectively, from the time of metastasis. The patients who survived for 17 and 13 years both presented with metastatic disease at diagnosis, while the patient who survived for 11 years with metastatic disease was known to have non-metastatic breast cancer for four years prior. We also report the development of foot fractures from minor trauma, as low as walking, despite a bone density reported as normal in the patient with 17 years of treatment. These unusually long survival times and the unusual location of the fractures are questioned to be secondary to the long duration of treatment with HER2-targeted therapy and RANK-L inhibitor therapy. Our case series is the first to describe the use of trastuzumab and denosumab in HER2-positive metastatic breast cancer. All three reported cases had no clinical or radiographic disease progression at the time of reporting. Furthermore, our case of survival for 17 years represents the longest survival time reported yet, raising the possibility of a synergistic relationship between RANK-L inhibitors and HER2-targeted therapy in the long-term control of HER2-positive metastatic breast cancer. This manuscript discusses evidence from primary studies on HER2 and receptor activator of nuclear factor kappa-Β (RANK) signalling and drug responses and hypothesizes on possible mechanisms of synergism. Given that treatment of HER2-positive breast cancer has historically not involved RANK-L inhibition, this study may outline future areas of research in improving treatment algorithms, especially for bone-only metastatic disease.

A validated UPLC-MS/MS method for quantification of pyrotinib and population pharmacokinetic study of pyrotinib in HER2-positive breast cancer patients.

Objective: Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer. Method: An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 µm), sample separation was accomplished in 5.5 min. Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used. Results: The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1-1,000 ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively: C L / F L / h = 88.8 × e TP / 67.2 × 0.376 , V / F L = 3940 , K A h - 1 = 0.357 F I X E D . No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude. Conclusion: In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions.

Effectiveness of trastuzumab deruxtecan rechallenge in a patient with HER2-positive metastatic breast cancer: a case report.

Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.

Survival prediction and analysis of drug-resistance genes in HER2-positive breast cancer.

Despite the approval of several therapeutic agents for HER2-positive breast cancer, drug resistance remains a significant challenge, hindering the patient's prognosis. Thus, our study aimed to establish a risk model to predict the prognosis of patients and identify key genes regulating drug resistance in HER2-positive breast cancer. Utilizing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), a predictive model was constructed based on 5 drug resistance-related genes, which demonstrated a notable capacity to indicate the survival rates of patients. Besides, through eccDNA and transcriptome sequencing of drug-sensitive and resistant cancer cells, 3 significant DEGs were identified: MED1, MED24, and NMD3. Among them, MED1 showed the most significant elevation in drug-resistance cells, highlighting its crucial role in mediating drug resistance. MED1 may serve as a valuable target for alleviating drug resistance in HER2-positive breast cancer.

Real-world effectiveness and safety of trastuzumab-deruxtecan in Japanese patients with HER2-positive advanced gastric cancer (EN-DEAVOR study).

BACKGROUND: Trastuzumab-deruxtecan (T-DXd) was approved for the treatment of HER2-positive patients with advanced gastric cancer in Japan based on the results of the DESTINY-Gastric01 trial. This study aimed to collect real-world data and evaluate the effectiveness and safety of T-DXd. METHODS: Patients aged ≥ 20 years at the start of T-DXd administration with a histopathologically confirmed diagnosis of HER2-positive unresectable advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma that had worsened after chemotherapy were enrolled in this retrospective cohort study. Key outcomes included T-DXd treatment status, overall survival (OS), real-world progression-free survival (rwPFS), time to treatment failure (TTF), objective response rate and frequency of grade ≥ 3 adverse events (AEs). RESULTS: Of the 312 patients included in the analysis, 75.3% were male, the median (range) age was 70.0 (27.0-89.0) years, 12.2% had an ECOG PS ≥ 2, 43.3% had ascites and the initial T-DXd dose was > 5.4- ≤ 6.4 mg/kg in 78.2% of patients. The median (95% confidence interval) OS, rwPFS and TTF (months) was 8.9 (8.0-11.0), 4.6 (4.0-5.1) and 3.9 (3.4-4.2), respectively. The response rate was 42.9% in patients with a target lesion. In total, 48.4% of patients experienced a grade ≥ 3 AE, 2.6% experienced grade 5 AEs and 60.9% experienced AEs leading to T-DXd dose adjustments (reduction: 36.9%, interruption: 34.0% or discontinuation: 23.7%). No new safety signals were detected. CONCLUSIONS: T-DXd was effective and had a manageable safety profile as a third- or later-line treatment for patients with HER2-positive gastric or GEJ cancer in Japanese clinical practice. CLINICAL TRIAL REGISTRATION: UMIN000049032.

Severe Thrombocytopenia from Trastuzumab and Pertuzumab Combination Therapy in a Patient with HER2-Positive Metastatic Rectal Cancer.

Introduction: In recent years, trastuzumab and pertuzumab have been used in treatment protocols for patients with HER2-positive colorectal cancer. Although severe thrombocytopenia is an uncommon side effect of anti-HER2 antibody therapy, we present the first patient with HER2-positive metastatic rectal cancer who developed significant thrombocytopenia after trastuzumab and pertuzumab administration. Case Presentation: The condition was identified as drug-induced immune thrombocytopenia associated with trastuzumab and pertuzumab. Despite the discontinuation of anti-HER2 treatment and administration of corticosteroids, and in addition to frequent platelet transfusions, a low platelet count persisted. Consequently, we determined that the patient presented with a condition similar to immune thrombocytopenic purpura (ITP) and selected a treatment approach consisting of eltrombopag, a thrombopoietin receptor agonist. Subsequently, the patient's platelet count did not decrease further but rather improved. Conclusion: Although uncommon, anti-HER2 antibodies can cause severe thrombocytopenia. Furthermore, if thrombocytopenia persists after treatment discontinuation and the administration of corticosteroids, exploring treatment options aligned with managing ITP is essential.

Final analysis of the ALTTO trial: adjuvant trastuzumab in sequence or in combination with lapatinib in patients with HER2-positive early breast cancer [BIG 2-06/NCCTG N063D (Alliance)].

BACKGROUND: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial. PATIENTS AND METHODS: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety. RESULTS: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups. CONCLUSIONS: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy.

EGFR-directed antibodies promote HER2 ADC internalization and efficacy.

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody drug conjugate that has remarkable activity in HER2-positive cancers. However, the degree of benefit of T-DXd is not uniform among solid tumors even with high levels of HER2. Despite high HER2 expression, the HER2/T-DXd complex may not always undergo internalization and payload release dependent on the receptor's conformation and context. We hypothesize that epidermal growth factor receptor (EGFR), a dimerization partner of HER2, can modulate HER2 trafficking through endocytic pathways and affect T-DXd uptake. We demonstrate that elevated EGFR expression levels can promote EGFR/HER2 heterodimer formation and suppress T-DXd internalization and efficacy. Knockdown of EGFR expression or pharmacologic stimulation of EGFR endocytosis with EGFR monoclonal antibodies restores T-DXd trafficking and antitumor activity in EGFR-overexpressing cancers in vivo. Our results reveal EGFR overexpression to be a potential mechanism of resistance to T-DXd, which can be overcome by combination therapy strategies targeting EGFR.