Human Epidermal Growth Factor Research Articles

A Novel HER2 Protein Identification Methodology in Breast Cancer Cells Using Raman Spectroscopy and Raman Imaging: An Analytical Validation Study.

Conventional assays such as immunohistochemistry (IHC) and in situ hybridization (ISH) used in clinical procedures for quantification of the human epidermal growth factor receptor-2 (HER2) status in breast cancer have many limitations. In the current study, we have used HER2 expression in a broad range of breast cancer phenotypes to explore the potential utility of a novel immunodetection technique using Raman spectroscopy and Raman imaging combined with artificial intelligence models. The correlations between the Raman method and conventional HER2 testing methodologies (IHC and ISH) have been tested. Raman measurements showed a strong linear correlation (p = 0.05, R2=0,9816) with IHC analysis in the studied breast cell lines: MCF-10A, MCF-7, MDA-MB-231, HTB-30 (SK-BR-3), and AU-565 represent normal, nontumorigenic epithelial cells, triple-positive breast carcinoma, and triple-negative breast cancer cell lines. Analytic testing of Raman spectroscopy and Raman imaging demonstrated that this method may offer advantages over the currently used diagnostic methodologies.

Altered glycosylation in cancer: molecular functions and therapeutic potential

AbstractGlycosylation, a key mode of protein modification in living organisms, is critical in regulating various biological functions by influencing protein folding, transportation, and localization. Changes in glycosylation patterns are a significant feature of cancer, are associated with a range of pathological activities in cancer‐related processes, and serve as critical biomarkers providing new targets for cancer diagnosis and treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) for breast cancer, alpha‐fetoprotein (AFP) for liver cancer, carcinoembryonic antigen (CEA) for colon cancer, and prostate‐specific antigen (PSA) for prostate cancer are all tumor biomarkers approved for clinical use. Here, we introduce the diversity of glycosylation structures and newly discovered glycosylation substrate—glycosylated RNA (glycoRNA). This article focuses primarily on tumor metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, and cellular senescence to illustrate the role of glycosylation in cancer. Additionally, we summarize the clinical applications of protein glycosylation in cancer diagnostics, treatment, and multidrug resistance. We envision a promising future for the clinical applications of protein glycosylation.

Analysis of Clinicopathological Characteristics and Factors Affecting the Prognosis of Patients With Resectable Sarcomatoid Carcinoma of the Bladder

To investigate the clinicopathological characteristics and the factors affecting the prognosis of patients with resectable sarcomatoid carcinoma of the bladder (SCB). A retrospective analysis was conducted with the clinical data of patients with resectable SCB treated at the Second Hospital of Tianjin Medical University between September 2008 and December 2023. The patients were divided into two groups, a bladder-preserving surgery (BPS) group and a radical cystectomy (RC) group, according to the specific surgical approach used for each patient. Kaplan-Meier survival curves were used to evaluate overall survival (OS) in both groups, and Cox regression models were employed to identify risk factors affecting survival. A total of 77 patients with resectable SCB were included. Among them, 35 patients (45.5%) underwent BPS, while 42 patients (54.5%) underwent RC. Ki-67 expression≥30% was observed in 91.7% of the patients. A total of 92.2% of the patients was tested positive for cytokeratin (CK) and 98.1% for vimentin. In addition, 62.5% and 37.5% of patients had the human epidermal growth factor receptor 2 (Her-2) scores of 0 and 1+, respectively. The median follow-up time was 23.2 months (ranging from 0.4 to 164.7 months). The 1-year, 3-year, and 5-year survival rates for the BPS group and the RC group were as follows, 76.2% vs. 84.9%, 46.7% vs. 61.1%, and 35.6% vs. 43.2%, respectively. Multivariate Cox regression analysis revealed that in the RC group, age≥75 years old (hazard ratio [HR]=3.836, 95% confidence interval [CI]: 1.168-12.595, P=0.027), tumor multiplicity (HR=3.439, 95% CI: 1.235-9.574, P=0.018), and lack of adjuvant therapy (HR=3.164, 95% CI: 1.015-9.862, P=0.047) were independent risk factors affecting survival. In the BPS group, female sex was identified as an independent risk factor for survival (HR=3.601, 95% CI: 1.200-10.804, P=0.022). Ki-67, CK, and vimentin are significantly overexpressed in SCB patients, while Her-2 is either unexpressed or expressed at low levels. In the RC group, tumor multiplicity, age ≥75 years, and lack of postoperative adjuvant therapy are independent risk factors for overall survival. Female sex is an independent risk factor affecting prognosis in the BPS group.

Analytical and Clinical Validation of the Oncomine Dx Target Test to Assess HER2 Mutation Status in Tumor Tissue Samples From Patients With Non–Small Cell Lung Cancer Treated With Trastuzumab Deruxtecan in the DESTINY-Lung01 and DESTINY-Lung02 Studies

Context.— Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)–targeted therapy, has demonstrated durable anticancer activity in patients with advanced, metastatic HER2 (also known as ERBB2)–mutant (HER2m) non–small cell lung cancer (NSCLC) who have limited treatment options and poor prognosis. Objective.— To analytically validate and assess the clinical utility of the Oncomine Dx Target (ODxT) Test as a companion diagnostic to identify patients with HER2m NSCLC. Design.— Tumor samples from patients in DESTINY-Lung01 and DESTINY-Lung02 were retrospectively analyzed alongside commercially procured samples using the ODxT test and compared to the assays used for screening in these clinical trials. Results.— Positive percent agreement (PPA) and negative percent agreement (NPA) between the ODxT Test and TruSight Tumor 170 assay when testing DESTINY-Lung01 and commercially procured samples met prespecified thresholds (PPA and NPA ≥90%) for analytical accuracy (100% and 99.1%). The ODxT Test results were highly concordant with clinical trial assays (CTAs) used in DESTINY-Lung01 (PPA and NPA, 98.0% and 100%) and DESTINY-Lung02 (PPA and NPA, 96.7% and 100%) to identify activating HER2 mutations in tumor samples. Confirmed objective response rates were similar between patients with HER2m tumors identified by the ODxT Test and by CTAs in DESTINY-Lung01 (58.3% and 54.9%) and DESTINY-Lung02 (53.6% and 53.8%). Response duration was 12.0 and 9.3 months for patients identified by the ODxT Test and CTAs, respectively, in DESTINY-Lung01. Conclusions.— The ODxT Test detected HER2 mutations in NSCLC with high analytical and clinical accuracy and identified HER2m populations with response rates similar to populations identified by CTAs, supporting clinical utility of the ODxT Test to inform treatment decisions for HER2m NSCLC.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Expression of Ki-67 in Invasive Breast Carcinoma and Its Correlation With Different Clinicopathological Features.

Introduction Worldwide, breast cancer is still the most common cancer that affects women. Breastcancer prognosis is based on a number of clinical and pathological indicators. Further features are needed to predict early metastasis andprognosis of patients with breast carcinoma, as the current pathological characteristics, such as tumor differentiation, vascular infiltration, and TNM (tumor, node, and metastasis) staging, cannot fully describe the early metastatic biological behavior in breast carcinoma. High Ki-67 expression is seen to be associated with worse survival in cancer patients. Hence, this study was conducted to study the utility of Ki-67as a prognostic marker in invasive breast carcinoma and its association with known clinicopathological factors. Methodology The study was a hospital-based cross-sectional study carried out in the Histopathology Section of the Department of Pathology, Shri BM Patil Medical CollegeHospital and Research Centre, Bijapur Lingayat District Education (BLDE) (Deemed to be University), Vijayapura. The study was conducted between September 1, 2022, and April 30, 2024. The study population consisted of 55 cases of mastectomy specimens of primary breast cancer admitted to our hospital. Data regarding the patient's age, tumor size, histological type, histological grade, lymph node status, and vascular invasion were noted from medical records. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2/neu (HER2/neu) proto-oncogene, and Ki-67 markers was performed according to standard protocol. The relationship of Ki-67with these clinicopathological parameters was analyzed statistically. Results In the current study, high-grade Ki-67 nuclear positivity was seen in 30 cases out of 55 cases, and low-grade Ki-67 was seen in the remaining 25 cases. The association of Ki-67 with tumor size and histological grade showed statistical significancewith a p-value of less than 0.05 and 0.001, respectively. However, no statistical significance was seen with lymph node status, vascular invasion, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2/neu (HER2/neu)proto-oncogene status with p-values greater than 0.05. Conclusion The expression of Ki-67 was statistically significant with histological grading and tumor size in our study. Immunohistochemical determination of the Ki-67 proliferation index should be performed in routine cases of breast cancerto obtain clinically useful information on tumor aggressiveness as reflected in their proliferative rate. Hence, Ki-67 can be used as a predictive and prognostic marker in managing breast cancer patients.

PEARL: A Phase Ib/II Biomarker Study of Adding Radiation Therapy to Pembrolizumab Before Neoadjuvant Chemotherapy in Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

PURPOSE To assess safety and immune biomarkers after preoperative radiation therapy (RT) and anti-PD1 therapy in breast cancer. MATERIALS AND METHODS A phase I/IIb trial of pembrolizumab with RT was conducted in patients with triple-negative breast cancer (TNBC) and hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer. All received pembrolizumab followed by a second cycle + RT (anti-PD1/RT) of 24 Gy/three daily fractions delivered to the breast tumor and then neoadjuvant chemotherapy (NAC). Blood and tumor biopsies were obtained at baseline, after anti-PD1, and after anti–PD-RT. Coprimary end points were safety and change in tumor-infiltrating lymphocytes (TILs). Secondary end points were pathologic complete response (pCR), residual cancer burden (RCB) rates, and event-free survival (EFS). RESULTS Sixty-six patients with stage I-III breast cancer (54 TNBC, 12 HR+/HER2–) were enrolled. The median follow-up was 32 months. Safety end point was met. Incidence of grade ≥3 toxicities was 41%. The pCR rate was 59.2%, 33.3%, and 54.5% for the TNBC, HR+/HER2–, and entire cohort, respectively. A total of 77.8% of TNBC and 41.6% of HR+/HER2– had a near pCR (RCB 0-1). The 3-year EFS was 80%. In the entire cohort, PD-L1 expression increased after anti-PD1 (median Combined Positive Score [CPS], 7.49-23.20; 95% CI, –41.88 to –6.30; P = .044) and anti-PD1/RT (median CPS, 7.49-23.41; 95% CI, –41.88 to –6.30; P = .009), compared with baseline. In TNBC, adding RT to anti-PD1 significantly decreased TILs (28.9%-17.1%; 95% CI, 2.46 to 21.09; P = .014). Baseline TILs correlated with PD-L1 expression and TNF-a. CONCLUSION Preoperative RT with pembrolizumab is safe and results in high pCR rates and 3-year EFS, despite the lack of pembrolizumab during NAC. PD-L1 and TILs may be predictive biomarkers for preoperative anti-PD1/RT response. Reduction in TILs after adding RT to anti-PD1 highlights the importance of treatment sequencing.

The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study

BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399–1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. ConclusionsWe found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.

Explainable breast cancer molecular expression prediction using multi-task deep-learning based on 3D whole breast ultrasound

ObjectivesTo noninvasively estimate three breast cancer biomarkers, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) and enhance performance and interpretability via multi-task deep learning.MethodsThe study included 388 breast cancer patients who received the 3D whole breast ultrasound system (3DWBUS) examinations at Xijing Hospital between October 2020 and September 2021. Two predictive models, a single-task and a multi-task, were developed; the former predicts biomarker expression, while the latter combines tumor segmentation with biomarker prediction to enhance interpretability. Performance evaluation included individual and overall prediction metrics, and Delong’s test was used for performance comparison. The models’ attention regions were visualized using Grad-CAM + + technology.ResultsAll patients were randomly split into a training set (n = 240, 62%), a validation set (n = 60, 15%), and a test set (n = 88, 23%). In the individual evaluation of ER, PR, and HER2 expression prediction, the single-task and multi-task models achieved respective AUCs of 0.809 and 0.735 for ER, 0.688 and 0.767 for PR, and 0.626 and 0.697 for HER2, as observed in the test set. In the overall evaluation, the multi-task model demonstrated superior performance in the test set, achieving a higher macro AUC of 0.733, in contrast to 0.708 for the single-task model. The Grad-CAM + + method revealed that the multi-task model exhibited a stronger focus on diseased tissue areas, improving the interpretability of how the model worked.ConclusionBoth models demonstrated impressive performance, with the multi-task model excelling in accuracy and offering improved interpretability on noninvasive 3DWBUS images using Grad-CAM + + technology.Critical relevance statementThe multi-task deep learning model exhibits effective prediction for breast cancer biomarkers, offering direct biomarker identification and improved clinical interpretability, potentially boosting the efficiency of targeted drug screening.Key PointsTumoral biomarkers are paramount for determining breast cancer treatment.The multi-task model can improve prediction performance, and improve interpretability in clinical practice.The 3D whole breast ultrasound system-based deep learning models excelled in predicting breast cancer biomarkers.Graphical

The Correlation between Immunohistochemistry and In Situ Hybridization for the Assessment of Human Epidermal Growth Factor Receptor 2 (HER-2) Status in Breast Cancer in Buddhasothorn Hospital

The Correlation between Immunohistochemistry and In Situ Hybridization for the Assessment of Human Epidermal Growth Factor Receptor 2 (HER-2) Status in Breast Cancer in Buddhasothorn Hospital

Ultrasound-based radiomics nomogram for predicting HER2-low expression breast cancer.

Accurate preoperative identification of Human epidermal growth factor receptor 2 (HER2) low expression breast cancer (BC) is critical for clinical decision-making. Our aim was to use machine learning methods to develop and validate an ultrasound-based radiomics nomogram for predicting HER2-low expression in BC. In this retrospective study, 222 patients (108 HER2-0 expression and 114 HER2-low expression) with BC were included. The enrolled patients were randomly divided into a training cohort and a test cohort with a ratio of 8:2. The tumor region of interest was manually delineated from ultrasound image, and radiomics features were subsequently extracted. The features underwent dimension reduction using the least absolute shrinkage and selection operator (LASSO) algorithm, and rad-score were calculated. Five machine learning algorithms were applied for training, and the algorithm demonstrating the best performance was selected to construct a radiomics (USR) model. Clinical risk factors were integrated with rad-score to construct the prediction model, and a nomogram was plotted. The performance of the nomogram was assessed using receiver operating characteristic curve and decision curve analysis. A total of 480 radiomics features were extracted, out of which 11 were screened out. The majority of the extracted features were wavelet features. Subsequently, the USR model was established, and rad-scores were computed. The nomogram, incorporating rad-score, tumor shape, border, and microcalcification, achieved the best performance in both the training cohort (AUC 0.89; 95%CI 0.836-0.936) and the test cohort (AUC 0.84; 95%CI 0.722-0.958), outperforming both the USR model and clinical model. The calibration curves showed satisfactory consistency, and DCA confirmed the clinical utility of the nomogram. The nomogram model based on ultrasound radiomics exhibited high prediction value for HER2-low BC.

Racial Differences in Breast Cancer Survival Between Black and White Women According to Tumor Subtype: A Systematic Review and Meta-Analysis.

Despite effective early-detection approaches and innovative treatments, Black women in the United States have higher breast cancer mortality rates compared with White women. The purpose of this systematic review and meta-analysis is to determine the extent of disparities in breast cancer survival between Black and White women according to tumor subtype. A comprehensive database search was performed for full-text, English-language articles published from January 1, 2000, to December 31, 2022. Included studies compared survival between Black and White female patients with breast cancer within subtypes defined by hormone receptor and human epidermal growth factor receptor 2 (HER2)/neu (HER2; now known as ERBB2) status. Random-effects models were used to combine study-specific results and generate pooled relative risks (RRs) and 95% CIs for breast cancer-specific or overall survival (OS). A protocol for this review was registered in PROSPERO (CRD42021268212). Eighteen studies including 228,885 (34,262 Black; 182,466 White) patients with breast cancer were identified. Compared with White women, Black women had a higher risk of breast cancer death for all tumor subtypes. The summary risk of breast cancer death was 50% higher among hormone receptor-positive HER2-negative [HER2-] tumors (RR, 1.50 [95% CI, 1.30 to 1.72]), 34% higher for hormone receptor+/HER2+ (RR, 1.34 [95% CI, 1.10 to 1.64]), 20% higher for hormone receptor-negative (-)/HER2+ (RR, 1.29 [95% CI, 1.00 to 1.43]), and 17% higher among individuals with hormone receptor-/HER2- tumors (hazard ratio, 1.17; 95% CI, 1.10 to 1.25). Black women also had poorer OS than White women for all subtypes. These results suggest there are both subtype-specific and subtype-independent mechanisms that contribute to disparities in breast cancer survival between Black and White women, which require multilevel interventions to address and achieve health equity.

Tackling triple negative breast cancer with HDAC inhibitors: 6 is the isoform!

Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by the lack in the expression of estrogen and progesterone receptors, and human epidermal growth factor receptors 2. TNBC stands out among other breast cancers subtypes for its high aggressiveness and invasiveness, and for the limited therapeutic options available, which justify the poor survival rates registered for this breast cancer subtype. Compelling new evidence pointed out the role of epigenetic modifications in cancer, prompting tumor cell uncontrolled proliferation, epithelial-to-mesenchymal transition, and metastatic events. In this review we showcase the latest evidence supporting the involvement of histone deacetylase 6 (HDAC6) in cancer pathways strictly related to TNBC subtype, also tracking the latest advancements in the identification of novel HDAC6 inhibitors which showed efficacy in TNBC models, offering insights into the potential of targeting this key epigenetic player as an innovative therapeutic option for the treatment of TNBC.

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.

Cryoablation Without Excision for Early-Stage Breast Cancer: ICE3 Trial 5-Year Follow-Up on Ipsilateral Breast Tumor Recurrence

BackgroundThe ICE3 trial evaluated the safety and efficacy of cryoablation in women aged ≥60 years with low-risk, early-stage breast cancers, aiming to provide a non-operative treatment option and avoid potential surgical risks. This study presents 5-year follow-up trial results.MethodsThe ICE3 trial is an Institutional Review Board-approved, prospective, multicentered, non-randomized trial including women ≥ 60 years of age with unifocal, ultrasound visible, invasive ductal carcinoma ≤ 1.5 cm in size, histologic grade 1–2, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. The primary study endpoint of 5-year ipsilateral breast tumor recurrence (IBTR) was evaluated based on Kaplan–Meier estimates.ResultsOverall, 194 patients meeting eligibility received successful cryoablation treatment per protocol and were included for analysis. The mean age was 74.9 years (55–94) with a mean tumor size of 7.4 mm transverse (2.8–14.0 mm) and 8.1 mm sagittal (2.5–14.9 mm). With a mean follow-up period of 54.16 months, the IBTR rate at 5 years was 4.3% and breast cancer survival was 96.7%. Of the 124 patients who received endocrine therapy only, the IBTR was 3.7%. No serious device-related adverse events were reported. Minor (88.2%) and moderate (9.6%) adverse events were mild in severity and resolved without residual effects. Quality-of-life score demonstrated statistically significant improvement (p < 0.001) in distress at 6 months as compared with baseline.ConclusionsBreast cryoablation presents a promising alternative to surgery in selected patients, offering the benefits of a minimally invasive procedure with minimal risks. Further studies are encouraged to confirm cryoablation as a viable alternative to surgical excision low-risk patients.

Neutrophil-to-lymphocyte ratio at the end of treatment with CDK4/6 inhibitors is an independent prognostic factor for ER-positive HER2-negative advanced breast cancer.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), at the end of treatment (EOT) with CDK4/6 inhibitors abemaciclib and palbociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer. We included 67 patients treated with fulvestrant plus abemaciclib or palbociclib. Overall survival (OS) since the EOT with CDK/4/6 inhibitors was compared in relation to the levels of ALC and NLR. The cut-off values of ALC and NLR were set at 1000/μL and 3, respectively. Patients with a high ALC at EOT showed significantly longer OS than those with a low ALC (p = 0.0358). Moreover, patients with a low NLR at EOT showed significantly longer OS than those with a high NLR at EOT (p = 0.0044). Looking at the changes of ALC and NLR between baseline and the EOT, patients with a high ALC both at baseline and at the EOT showed significantly longer OS than others (p = 0.0201). Similarly, patients with a low NLR both at baseline and at the EOT showed significantly longer OS after EOT than others (p = 0.0136). Multivariable analysis revealed that the NLR at EOT (low vs. high) and changes in NLR (low at baseline to low at EOT vs. others) were significant and independent prognostic factors for OS after EOT (p = 0.0337, p = 0.0039, respectively). NLR at EOT with CDK4/6 inhibitors is a significant and independent prognostic marker for patients with ER-positive HER2-negative advanced breast cancer.

Prevalence and impact of metabolic associated fatty liver disease in non-metastatic breast cancer women at initial diagnosis: a cross-sectional study in China.

The epidemiologic data of metabolic associated fatty liver disease (MAFLD) in breast cancer (BC) patients remains limited. We aimed to investigate the prevalence and clinicopathological characteristics of hepatic steatosis (HS) and MAFLD in Chinese BC women at initial diagnosis. 3217 non-metastatic primary BC women with MAFLD evaluation indexes at initial diagnosis and 32,170 age-matched (in a 1:10 ratio) contemporaneous health check-up women were enrolled. The prevalence of HS (21.5% vs. 19.7%, p = 0.013) and MAFLD (20.8% vs. 18.6%, p = 0.002) were significantly higher in BC women than in health check-ups, respectively. Meanwhile, the prevalence of HS/MAFLD among elderly BC women (≥ 60years) was significantly higher than the health check-ups (38.7%/37.6% vs 31.9%/30.8%), respectively. In BC women with HS/MAFLD, the prevalence of overweight/obesity was up to 85.7%/88.6%, dyslipidemia and elevated blood pressure were 63.2%/63.7% and 59.7%/61.7%, respectively. No statistical significance of the expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER-2) and Ki67 were found between BC women with HS/MAFLD and BC women without HS/MAFLD. After adjustment, BC women with HS showed significantly higher risk of lymph node metastasis than BC women without HS. Subjects with HS/MAFLD had higher risks of overweight/obesity, dyslipidemia, elevated blood pressure, hyperuricemia, and elevated enzymes than those without HS/MAFLD. Compared with health check-ups, BC patients have higher prevalence of HS/MAFLD. HS/MAFLD coexist with high prevalence of metabolic complications, and the risk of lymph node metastasis was significantly higher in BC women with HS than in BC women without HS.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial.

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

Prognostic and Predictive Roles of HER2 Status in Non-Breast and Non-Gastroesophageal Carcinomas.

The oncogene ERBB2, also known as HER2 or c-ERB2, is located on chromosome 17 (q12). It encodes a tyrosine kinase receptor, the human epidermal growth factor receptor 2 (HER2), involved in neoplastic proliferation, tumor angiogenesis, and invasiveness. Over the past years, the introduction of various anti-HER2 therapies has significantly improved outcomes for patients with HER2-positive breast and gastroesophageal carcinomas. More recently, the introduction of a new antibody-drug conjugate, that is trastuzumab deruxtecan, expanded the therapeutic options to low-HER2 breast and gastroesophageal tumors. HER2 protein overexpression is investigated using immunohistochemistry, gene amplification using fluorescence in situ hybridization, and gene mutation using next-generation sequencing. This review evaluated the predictive and prognostic role of HER2 status in various types of epithelial malignant cancers beyond breast and gastroesophageal cancers. We critically analyzed the key published studies, focusing on utilized scoring systems and assays used, and analyzed clinical parameters and therapeutic approaches. Although the evidence about prognostic and predictive roles of HER2 in carcinomas other than breast and gastroesophageal has been widely increasing over the last decade, it still remains investigational, revealing a tumor site-related prognostic and predictive value of the different types of HER2 alterations. However, standardized and validated scoring system assays have not been well-established for many organs.