HER2-targeted therapies in cancer: a systematic review.

Abnormal alterations in human epidermal growth factor receptor 2 (HER2, neu, and erbB2) are associated with the development of many tumors. It is currently a crucial treatment for multiple cancers. Advanced in molecular biology and further exploration of the HER2-mediated pathway have promoted the development of medicine design and combination drug regimens. An increasing number of HER2-targeted drugs including specific monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs) have been approved by the U.S. Food and Drug Administration. The emergence of ADCs, has significantly transformed the treatment landscape for various tumors, such as breast, gastric, and bladder cancer. Classic monoclonal antibodies and novel TKIs have not only demonstrated remarkable efficacy, but also expanded their indications, with ADCs in particular exhibiting profound clinical applications. Moreover the concept of low HER2 expression signifies a breakthrough in HER2-targeted therapy, indicating that an increasing number of tumors and patients will benefit from this approach. This article, provides a comprehensive review of the underlying mechanism of action, representative drugs, corresponding clinical trials, recent advancements, and future research directions pertaining to HER2-targeted therapy.

Cost-Effectiveness Analysis of Adjuvant Endocrine Therapy With Ovarian Suppression in Premenopausal Patients With Hormone Receptor-Positive Early Breast Cancer in China.

PURPOSE: Endocrine therapy combined with ovarian function suppression (OFS) is recommended in intermediate- or high-risk patients among premenopausal women with hormone receptor-positive early breast cancer. However, in China, the cost-effectiveness of this strategy compared with endocrine therapy alone is unclear. This study aimed to evaluate the long-term cost-effectiveness of tamoxifen (TAM), TAM+OFS, and exemestane plus OFS (EXE+OFS). METHODS: On the basis of prognostic data from the Suppression of Ovarian Function Trial (SOFT), cost data from the Hospital Information System of the West China Hospital of Sichuan University, and health utility values from the published literature, a Markov model was established. The incremental cost-effectiveness ratio (ICER) was used to compare the treatment strategies. RESULTS: In a 25-year simulation of adjuvant therapy in Chinese women with early breast cancer, the total costs of TAM, TAM+OFS, and EXE+OFS were $7821, $9318, and $9445, respectively. The quality-adjusted life-years (QALYs) were 11.615, 11.896, and 11.734 years, respectively. Compared with TAM, the ICERs of TAM+OFS and EXE+OFS were $5,327.4021/QALY and $13,647.0588/QALY, respectively. The ICERs of TAM+OFS and EXE+OFS were below the threshold of $32,517/QALY. The reliability and stability of the simulation results were verified using Monte Carlo simulation and sensitivity analysis. CONCLUSION: In the context of limited resources in China, TAM+OFS and EXE+OFS are cost-effective options compared with TAM.

CDK4/6 inhibitors for primary endocrine resistant HR-positive/HER2-negative metastatic breast cancer: a case report.

Background: We report a case of hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer with multiple liver metastases who achieved good clinical benefit across cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy. Prior to this, the patient underwent neoadjuvant therapy and surgery as well as adjuvant endocrine therapy. We present and discuss three important treatment decision nodes associated with it. Case Description: A 60-year-old woman was diagnosed with invasive ductal carcinoma of the left breast (cT4bN2M0, stage IIIB, Luminal B HER2-negative type) at the West China Hospital of Sichuan University in 2020, and received neoadjuvant chemotherapy and modified radical mastectomy of the left breast from 2020 to 2021. Postoperative radiotherapy was performed in the left chest wall and left upper and lower clavicular region. Adjuvant therapy is anastrozole endocrine therapy. Multiple liver metastases developed in 2022. The pathological molecular typing of liver metastases was confirmed to be consistent with the primary lesion. In the context of primary endocrine resistance, the first-line treatment of choice was fulvestrant in combination with a targeted CDK4/6 inhibitor (abemaciclib). This combination regimen made the liver metastases visibly shrunk, leading to partial response (PR) and has achieved a progression-free survival of 12 months. And there were no serious drug-related adverse events during first-line treatment. Conclusions: CDK4/6 inhibitor is a promising antineoplastic agent for HR positive, HER2 negative breast cancer patients. With the development of research, the application scope of CDK4/6 inhibitors is gradually expanding, and the precision treatment of breast cancer requires more rational drug selection and combination.

Efficacy and safety of tucidinostat in patients with advanced hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: real-world insights.

Background: Tucidinostat, which is a subtype-selective histone deacetylase inhibitor, has been approved in China for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, existing evidence mainly stemmed from randomized controlled trials, and might have limitations in representing the complexities of clinical practice and diverse patient populations. Therefore, there is a need to explore the efficacy and optimal therapeutic modality for tucidinostat in real-world clinical settings. Methods: The objective of this real-world study was to analyze the clinical data of 47 patients with HR+/HER2- ABC who received tucidinostat treatment at West China Hospital, Sichuan University, between August 2020 and May 2023. The primary outcomes were progression-free survival (PFS) and clinical benefit rate [CBR; defined as partial response (PR) and stable disease (SD) for ≥6 months on clinical evaluation]. Results: A total of 47 patients were included, and the median follow-up time was 18.20 months. The median line of tucidinostat therapy was 3 (range, 1-9). In all, 52.17% patients were treated with tucidinostat plus fulvestrant, while 38.30% were treated with tucidinostat plus aromatase inhibitors. Notably, 10.64% of the patients with rapidly progressing visceral metastases received tucidinostat plus endocrine therapy as maintenance treatment after achieving disease control with chemotherapy. The median PFS was 4.43 months [95% confidence interval (CI), 2.77-10.53], and the median overall survival was 19.57 months (95% CI, 12.83-not reached). The 6-month CBR for the overall population was 41.86%. Patients undergoing maintenance therapy demonstrated a significantly longer PFS than did those who did not receive it as maintenance therapy (14.13 vs. 3.93 months; P=0.01). Univariate Cox regression analysis showed that use of tucidinostat in lines 1-2, use of tucidinostat plus fulvestrant, presence of one metastatic site, and lack of brain metastasis were favorable factors for PFS. Thrombocytopenia was the most frequently reported adverse event, with an incidence rate of 31.91% at all grades and 14.89% at grade ≥3. Four (8.51%) patients discontinued the treatment. Conclusions: For patients with HR+/HER2- ABC, tucidinostat combination therapy offers certain survival benefits with controllable safety. Furthermore, compared with non-maintenance therapy, maintenance therapy after chemotherapy may have promising efficacy.

Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

PI3K/AKT/mTOR-Targeted Therapy for Breast Cancer.

Phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) (PAM) pathways play important roles in breast tumorigenesis and confer worse prognosis in breast cancer patients. The inhibitors targeting three key nodes of these pathways, PI3K, AKT and mTOR, are continuously developed. For breast cancer patients to truly benefit from PAM pathway inhibitors, it is necessary to clarify the frequency and mechanism of abnormal alterations in the PAM pathway in different breast cancer subtypes, and further explore reliable biomarkers to identify the appropriate population for precision therapy. Some PI3K and mTOR inhibitors have been approved by regulatory authorities for the treatment of specific breast cancer patient populations, and many new-generation PI3K/mTOR inhibitors and AKT isoform inhibitors have also been shown to have good prospects for cancer therapy. This review summarizes the changes in the PAM signaling pathway in different subtypes of breast cancer, and the latest research progress about the biomarkers and clinical application of PAM-targeted inhibitors.

Comparison of dyslipidemia incidence in Chinese early-stage breast cancer patients following different endocrine therapies: A population-based cohort study.

Background: There is lack of large-scale real-world research evidence showing the impact of endocrine therapy on blood lipids in Chinese breast cancer patients, especially those with premenopausal breast cancer. Based on a large breast cancer cohort at West China Hospital, we aimed to compare the risk of dyslipidemia between premenopausal and postmenopausal women based on the endocrine therapy used. Methods: A total of 1,883 early-stage breast cancer (EBC) patients who received endocrine monotherapy [selective estrogen receptor modulator (SERM) and aromatase inhibitor (AI), with or without ovarian function suppression] with normal blood lipid levels at baseline were retrospectively included between October 2008 and April 2017. Dyslipidemia was defined as an abnormality in cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein, and total cholesterol (TC) levels. The risk accumulation function was used to calculate the incidence of dyslipidemia in order to assess the absolute risk, while the multivariate Cox regression model was used to calculate the relative risk of dyslipidemia between the groups. Results: Patients with EBC were followed up for 60 months to monitor their blood lipid levels. The accumulated 5-year incidence of dyslipidemia in postmenopausal patients was higher than that in premenopausal patients (adjusted HR [95% confidence interval], 1.25 [1.01-1.56], 41.7% vs. 31.2%, p = 0.045). In premenopausal patients, the risk of abnormal TC was significantly higher in the OFS+AI group compared with that in the SERM group (adjusted HR [95% CI], 6.24 [3.19-12.20], p < 0.001, 5-year abnormal rates: 21.5% vs. 2.4%), and that of abnormal LDL-C level also increased (adjusted HR [95% CI], 10.54 [3.86-28.77], p < 0.001, 5-year abnormal rates: 11.1% vs. 0.9%). In postmenopausal patients, the risk of abnormal TC or LDL-C levels showed a similar trend in the AI and SERM groups. Conclusions: In addition to postmenopausal patients, dyslipidemia is also common in premenopausal Chinese patients with EBC who received endocrine therapy. Irrespective of menopausal status, AI treatment increases the risk of TC/LDL-C dyslipidemia than SERM treatment.

Detection of Phytoestrogen Metabolites in Breastfed Infants' Urine and the Corresponding Breast Milk by Liquid Chromatography-Tandem Mass Spectrometry.

To date, there has been limited information on phytoestrogen (PE) exposure and metabolism in breastfed infants. In the present work, 50 sample pairs of Chinese breastfed infants' urine and the corresponding breast milk were collected. The contents of the relevant PE metabolites in the biosamples were detected via liquid chromatography-tandem mass spectrometry. The correlations between the PE metabolite contents in breastfed infants' urine and those in the corresponding breast milk were analyzed. The average concentrations of total PE metabolites in breast milk and urine were 0.27 and 0.23 nmol/mL, respectively. Genistein and enterolactone levels in the infant urine were positively correlated with their concentrations in the corresponding breast milk samples, which implies that urine excretion can be utilized as a noninvasive parameter for precise genistein and enterolactone intake assessment. Additionally, the efficiency of PE urine excretion showed significant differences across infants with different ages, genders, and durations of pregnancy.