Receptor Human Epidermal Growth Research Articles

Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components.

In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: "Pure" (those without an invasive component), "W/invasive" (those with an invasive component), and "All" (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the "Pure" and "W/invasive" groups. There was no significant difference in ER/PR expression between "Pure" luminal subtypes of DCIS and "W/invasive" cases. We compared the HER2 IHC scores of "0", "1+", and "2+" among LumA and LumB HER2 subtypes and identified no statistically significant differences between "Pure" and "W/invasive" (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

Twenty-five years with HER2 targeted therapy.

The development of trastuzumab is among the most significant cancer drug development projects in the 20th century. Trastuzumab became a gamechanger for the treatment of human epidermal growth receptor 2 (HER2) positive breast cancer, with a significant positive impact on disease recurrence and survival. The development of trastuzumab was the beginning of a new era of cancer drug development, which showed us the importance of understanding the molecular pathophysiology and drug mechanism of action. The drug-diagnostic codevelopment model, in which the drug is developed in parallel with a predictive biomarker assay, has had a significant impact on today's cancer drug development, and we are indebted to trastuzumab when it comes to the clinical enrichment trial design. Trastuzumab is not the only drug developed to target the HER2 protein. Over the past few decades, several new HER2 targeted therapies have been developed, including small-molecule tyrosine kinase inhibitors (TKI), monoclonal antibodies, and antibody-drug conjugates (ADC). In particular, the ADC trastuzumab deruxtecan seems to pave new avenues when it comes to HER2 targeted treatment not only for breast cancer, but also for gastric cancer and non-small cell lung cancer. With the development of trastuzumab as a reference point, this article will provide a brief summary of the efficacy of HER2 targeted therapy, including testing for HER2 positivity, as it has evolved over the past 25 years.

Abstract PO3-04-04: Long term survival of metastatic HER2 positive breast cancer patients with no radiographic evidence of disease (NED) on HER2 antibody therapy

Abstract Introduction A small proportion of women with human epidermal growth receptor 2 (HER2) positive metastatic breast cancer (mBC) achieve “no evidence of disease” (NED) status with HER2 monoclonal antibody therapy. Patients who achieve NED status have excellent long term outcomes with overall (OS) and progression free survival (PFS) rates greater than 95%. Presently there are no reliable biologic or clinical factors which are predictive of NED. It is also unclear in NED patients when it would be safe to discontinue therapy. Therefore, even in HER2+ mBC NED patients, HER2 therapy is often continued indefinitely. In this study, we characterize clinical outcomes in HER2+ mBC patients who achieved NED status and received HER2 antibody therapy for 5+ years. Methods We conducted a retrospective analysis of patients at a U.S. academic medical center. Patients with HER2+ mBC who had received at least 5 years of either trastuzumab or trastuzumab/pertuzumab (from 2014- 2023) were identified for our NED cohort. For a non-NED comparator group, we identified women with stage IV HER2+ mBC from the tumor registry (from 2012-2021). Descriptive statistics were used to describe the demographic information and clinical characteristics. Kaplan-Meier method with log-rank test was used to analyze OS and PFS between both patient cohorts. Results 102 patients were identified that received trastuzumab or trastuzumab/pertuzumab for 5+ years. From this group, 33 patients were identified as NED based on clinical documentation and imaging. From our tumor registry data, there were 58 stage IV HER2+ patients. 34 patients met inclusion criteria for our non-NED cohort. The median follow-up time was 132 (range: 39 - 296) months for the NED cohort and 26 (range: 1-99) months for the non-NED cohort. The average diagnosis age was significantly older for the NED cohort (61 vs. 52 years, P=0.001). No other significant differences with respect to hormone receptor expression, race, or the presence of brain metastases were observed between groups. With respect to HER2 therapy, 61% of NED patients had received trastuzumab alone, and 39% trastuzumab/pertuzumab. By contrast in the non-NED cohort most received trastuzumab/pertuzumab (59%). The median time on HER2 therapy for the NED group was 125 months—70% of patients in the NED cohort were still receiving therapy vs, 12% for the non-NED cohort. As expected, the median OS (NR vs. 25.5 months; P&amp;lt; 0.0001) and PFS (NR vs. 7.9 months; P&amp;lt; 0.0001) were significantly longer in the NED cohort. 5 and 10 year OS rates for the NED cohort were 90.5% (95% confidence interval (CI): 80.8-100%) and 87% (95% CI: 75.9-99.8%), respectively. By contrast, for the non-NED cohort 5 and 10 year OS rates were only 21.3% (95% CI: 11.06-41.1%) and 0% (95% CI: 0-0%), respectively. 5 and 10 year PFS rates were 84.1% (95% CI: 72.2-97.9%) and 76.6% (95% CI: 67.7-93.6%), respectively for the NED cohort, and both were 0% for the non-NED cohort. The presence of brain metastases in the NED cohort was associated with reduced 5 and 10 year OS rates: 60% (95% CI: 29.3-100%) and 40% (95% CI: 13.7-100%), respectively. We observed in the NED cohort was associated with a drop in ejection fraction and clinically significant heart failure in 24% of patients while on HER2 therapy. Conclusions HER2+ mBC patients who achieve NED status have an excellent prognosis with starkly different clinical outcomes compared to HER2+ mBC patients who do not. We observed that 10 year OS rates in HER2+ NED patients was approximately 90%, which did not differ from 5 year OS rates. This suggests that HER2 therapy could be potentially discontinued after 5 years in mBC patients who achieve NED. More studies are needed to develop robust predictive markers for patients likely to achieve NED with HER2 targeted therapy. Citation Format: Alexis Bennett, Zhengyi Chen, James Martin, Naji Mallat, Pingfu Fu, Alberto Montero. Long term survival of metastatic HER2 positive breast cancer patients with no radiographic evidence of disease (NED) on HER2 antibody therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-04.

A single centre, real world experience of T-DM1 in the treatment of HER2-positive metastatic breast cancer patients in India

Background: HER2 (Human Epidermal Growth Receptor 2) positive breast cancer is an aggressive subtype. Treatment for patients with HER2-positive breast cancer has advanced significantly over time with the introduction of targeted therapies like trastuzumab, pertuzumab, lapatinib, trastuzumab emtansine, trastuzumab, deruxtecan, and tucatinib. In a lower-middle-income nation, accessibility is still problematic for any newer therapy. This study aimed to describe the safety and practical effectiveness of the first T-DM1 biosimilar in India for treating patients with HER2-positive mBC. Methodology: This is a retrospective, observational, single-center study of patients with HER2-positive metastatic breast cancer treated with T-DM1 biosimilar. The study involved 16 mBC patients. The primary goal was to assess T-DM1's effectiveness regarding PFS and ORR, with safety and OS as the secondary goals. Results: The ORR was observed to be 81.3%. One (6.29%) of the patients achieved CR, while 3 patients (18.8%) are on stable disease, and 12 patients (75 %) achieved PR. The major adverse events reported among study patients were thrombocytopenia (31.25%) and anemia (31.25%), followed by neutropenia, hyperglycemia, and fatigue in 12.5 % of cases. Grade 3 thrombocytopenia was seen in 2 patients, and grade 3-4 fatigue was observed in 1 patient. Median PFS was nearly six months, and OS data is available for only 25% of patients; the rest continue the therapy. Conclusion: This retrospective observational study offers significant information about the safety and efficacy of T-DM1 biosimilar in treating HER2 positive mBC.

Therapy for Hormone Receptor-Positive, Human Epidermal Growth Receptor 2-Negative Metastatic Breast Cancer Following Treatment Progression via CDK4/6 Inhibitors: A Literature Review.

Endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the first-line standard treatment for most patients with hormone receptor-positive (HR+) and human epidermal growth receptor 2-negative (HER2-) metastatic or advanced breast cancer. However, the majority of tumors response to and eventually develop resistance to CDK4/6is. The mechanisms of resistance are poorly understood, and the optimal postprogression treatment regimens and their sequences continue to evolve in the rapidly changing treatment landscape. In this review, we generally summarize the mechanisms of resistance to CDK4/6is and ET, and describe the findings from clinical trials using small molecule inhibitors, antibody-drug conjugates and immunotherapy, providing insights into how these novel strategies may reverse treatment resistance, and discussing how some have not translated into clinical benefit. Finally, we provide rational treatment strategies based on the current emerging evidence.

Cost-effectiveness of one-year adjuvant trastuzumab therapy in treatment for early-stage breast cancer patients with HER2+ in Vietnam.

In Vietnam, trastuzumab is included in social health insurance's benefits package with a reimbursement rate of 60%, but policymakers have been concerned about its cost-effectiveness. The research aims to evaluate the cost-effectiveness of one-year adjuvant trastuzumab therapy for early-stage breast cancer patients with human epidermal growth receptor 2 (HER2+) from a societal perspective. A Markov model was developed and validated to estimate the lifetime cost and effectiveness (using life year and quality-adjusted life year) of one-year adjuvant trastuzumab therapy compared to chemotherapy (using paclitaxel) alone. Treatment efficacy and transition probabilities were estimated based on published trials (i.e., N9831, NSABP B-31, HERA, and BCIRG 006). Local cost and utility data were employed to capture the Vietnam context. One-way sensitivity analysis, probabilistic sensitivity analysis, threshold, and scenario analysis were also performed. One-year adjuvant trastuzumab therapy combined with chemotherapy compared to chemotherapy alone yielded an additional cost of 888,453,971VND (39,062 US$) with an additional 3.09 LYs and 1.61 QALYs, resulting in an ICER of 287,390,682 VND (12,635 US$) per LY gained, or 519,616,972 VND (22,845 US$) per QALY gained. The ICER exceeds the cost-effective threshold of 1- and 3-time GDP per capita by 6.3 and 2.1 times. The probabilistic sensitivity analysis shows similar results. According to one-way sensitivity analysis, ICERs were driven mainly by transition probabilities and trastuzumab price. One-year adjuvant trastuzumab therapy would be cost-effective at the 3-time GDP per capita threshold if the cost of Herceptin 150mg and 450mg vials were reduced by 56% and 54%, correspondingly. In Vietnam, one-year adjuvant trastuzumab therapy for early-stage breast cancer with HER2+ is not cost-effective. The research provided reliable and updated evidence to support policymakers in revising the health insurance benefit package. The policymakers should consider the options to reduce the cost of trastuzumab (e.g., regarding the use of trastuzumab biosimilars, price negotiation options, and options of optimizing the use of Herceptin vials among concurrent hospitalized breast cancer patients).

Kaiso Expression in Triple Negative Breast Cancer in a Tertiary Hospital in Ghana.

Breast cancer has produced more lost disability-adjusted life years (DALYs) than any other type of cancer. The prevalence of the disease, especially triple negative breast cancer (TNBC) in Africa is on the rise, with poor survival rates. With the great advancements in treatments of breast cancers, that of TNBC is still a challenge due to its narrowed treatment options and poor disease prognosis. This research seeks to explore the expression of kaiso in Ghanaian breast cancer and how they may modulate clinicopathological features, and disease prognosis. A cross-sectional retrospective study was conducted on formalin-fixed paraffin-embedded (FFPE) breast cancer tissues retrieved from the archives of the pathology unit of Komfo Anokye Teaching Hospital (KATH). Immunohistochemistry assessment was performed on haematoxylin and eosin-stained slides selected for tissue microarray construction. Data were analysed using SPSS version 28 and Microsoft excel 2013. 55.3% of the cases tested negative to progesterone receptor (PR), oestrogen receptor (ER), and human epidermal growth receptor 2 (HER2). There were significant associations between menopausal status and molecular subtype (p=0.010), Kaiso expression and histological diagnoses (<0.001) and Kaiso against lymphovascular invasion (0.050). However, there were no significant associations between Kaiso localization and the clinicopathological features although 63.9% of the expression was seen in the nucleus. The study indicates that Kaiso is highly expressed in Ghanaian TNBC and likely associated with worse outcomes in aggressive tumour types.

Abstract B042: Analysis of predictive indicators of invasive breast cancer: Modeling survival rates

Abstract Objective: We aim to investigate indicators of risk for invasive breast cancer (IBC) and to predict and assess the impact of these risk indicators on survival rates in breast cancer (BC) patients who received various therapies. Background: It has been identified that several indicators including BC subtypes, age at diagnosis, history of breast disease, menopausal status, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth receptor (HER2) status, tumor stage, tumor size, among others, can cause genomic alterations and driver mutations in BC, leading to invasive carcinogenesis. To assure improved BC outcomes, we investigate the influence of BC indicators on survival rates in patients receiving hormone therapy, chemotherapy and radiotherapy. Methods: This study uses the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset, which included 31 clinical indicators, m-RNA levels z-score for 331 genes, and mutation in 175 genes for 1904 BC patients. Both bivariate and multivariate associations were examined using logistic regression and Cox proportional hazard models. The multivariate logistic regression analysis is used to determine predictors of IBC. The Cox proportional hazard model was also used to evaluate the magnitude of the impacts of clinical and demographic variables on IBC, as well as the effects of therapy on survival. All analyses for this investigation were carried out using SAS. A p-value &amp;lt; 0.05 was considered statistically significant. Results: We examined 1,043 patients (with the median age 61±13.1 years) from a total of 1904 for this study: 78.8% of patients had breast invasive ductal carcinoma; 87.4% were HER2 negative; 22.8%, 60.7%, and 67.6% received chemotherapy, hormone therapy, and radiotherapy treatments, respectively; 56.9% died but only 34.6% died from the disease; the average overall survival months was 127.3±77.6 months; and the most common age group was "65+ years" (39.4%). Chemotherapy (p=0.0474), neoplasm histologic grade (p=0.0015), Nottingham prognostic index (p&amp;lt;.0001), radiation (p=0.0068), and BReast CAncer gene 1 (BRCA1) (p=0.0251) were all associated with IBC. Overall survival was also correlated to age at diagnosis (p=0.0002), neoplasm histologic grade (p&amp;lt;.0001), lymph nodes (p&amp;lt;.0001), mutation count (p&amp;lt;.0001), Nottingham prognostic index (p&amp;lt;.0001), radiotherapy (p=0005), tumor size (p&amp;lt;.0001), tumor stage (p&amp;lt;.0001), BRCA1 (p=0.250), PTEN (p&amp;lt;.0001), and TP53 (p=0.0248). The overall accuracy of the model for each IBC and survival status was 82.1% and 74.2%, respectively. Conclusion: Our analysis demonstrated the importance of predictive analysis using the logistic regression model and survival analysis using the Cox proportional hazard model in cancer research. Predictive and survival analysis results aided in predicting the invasiveness and survival rate of BC among the study participants. In general, predictive and survival analyses are more accurate and may be used to make more realistic treatment decisions and precision oncology. Citation Format: Olumide Arigbede, Gebre-Egziabhe Kiros. Analysis of predictive indicators of invasive breast cancer: Modeling survival rates [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B042.

Human epidermal growth receptor polymorphisms (HER1-rs11543848 and HER2-rs1136201) exhibited significant association with breast cancer risk in Pashtun population of Khyber Pakhtunkhwa, Pakistan.

Breast cancer is the most common type of cancer in women. The genetic polymorphism in HER (HER1-rs11543848 and HER2-rs1136201) were found to be associated with breast cancer risk in different ethnicities worldwide with inconsistent results. The aim of this research study was to evaluate the association of HER1-rs11543848 and HER2-rs1136201 polymorphisms as a risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. A total of 314 women including 164 breast cancer patients and 150 age and gender-matched healthy controls were enrolled from June 2021 to May 2022. All the samples were subjected to DNA extraction followed by Tetra-ARMS-PCR for genotyping and gel electrophoresis. Our results indicated that HER1-rs11543848 risk allele A (p = 0.0001) and heterozygous genotype GA (p = 0.0001) displayed highly significant association with breast cancer, while the homozygous mutant genotype AA indicated association but nonsignificant results (odds ratio [OR] = 2.637, 95% confidence interval [CI] = 1.2258-5.6756, p = 0.0833). Similarly, the HER2-rs1136201 risk allele G (p = 0.0023), the heterozygous genotype AG (p = 0.0530) and homozygous mutant genotype GG showed significant association (OR = 2.5946, 95% CI = 0.9876-6.8165, p = 0.0530) with breast cancer risk. Both the SNPs presented a higher but nonsignificant risk of breast cancer in postmenopausal women (OR = 2.242, p = 0.08 and OR = 2.009, p = 0.06). However, both the SNPs showed significant association (p < 0.005) with family history, metastasis, stage, luminal B, and TNBC. In conclusion, HER1-rs11543848 and HER2-rs1136201 polymorphisms are significantly associated with the higher risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. These findings advocate for further exploration with larger datasets, offering promising avenues for personalized approaches in breast cancer research and potentially enhancing clinical practices for better risk assessment and targeted management strategies.

Cost-effectiveness analysis of add-on pertuzumab to trastuzumab biosimilar and chemotherapy as neoadjuvant treatment for human epidermal growth receptor 2-positive early breast cancer patients in Singapore

ABSTRACT Objectives The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore. Methods A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties. Results The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained. Conclusions This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.

A sensitive sandwich-type electrochemical immunosensor using nitrogen-doped graphene/metal-organic framework-derived CuMnCoOx and Au/MXene for the detection of breast cancer biomarker

In terms of cancer-related deaths among women, breast cancer (BC) is the most common. Clinically, human epidermal growth receptor 2 (HER2) is one of the most commonly used diagnostic biomarkers for facilitating BC cell proliferation and malignant growth. In this study, a disposable gold electrode (DGE) modified with gold nanoparticle-decorated Ti3C2Tx (Au/MXene) was utilized as a sensing platform to immobilize the capturing antibody (Ab1/Au/MXene). Subsequently, nitrogen-doped graphene (NG) with a metal-organic framework (MOF)-derived copper-manganese-cobalt oxide, tagged as NG/CuMnCoOx, was used as a probe to label the detection antibody (Ab2). A sandwich-type immunosensor (NG/CuMnCoOx/Ab2/HER2-ECD /Ab1/Au/MXene/DGE) was developed to quantify HER2-ECD. NG/CuMnCoOx enhances the conductivity, electrocatalytic active sites, and surface area to immobilize Ab2. In addition, Au/MXene facilitates electron transport and captures more Ab1 on its surface. Under optimal conditions, the resultant immunosensor displayed an excellent linear range of 0.0001 to 50.0 ng. mL−1. The detection limit was 0.757 pg·mL−1 with excellent selectivity, appreciable reproducibility, and high stability. Moreover, the applicability for determining HER2-ECD in human serum samples indicates its ability to monitor tumor markers clinically.

Long-term Survival Among Patients With De Novo Human Epidermal Growth Receptor 2-Positive Metastatic Breast Cancer in Manitoba.

Although metastatic breast cancer (MBC) is considered incurable, human epidermal growth receptor 2 (HER2)-directed therapy has improved outcomes significantly, with some patients experiencing durable responses to treatment. The aim of this study was to identify potential predictors of long-term survival (LTS) among patients with de novo HER2-positive MBC who received HER2-directed treatment. Eligible patients from 2008 to 2018 were identified using the Manitoba Cancer Registry. LTS was defined as survival ≥5 years from the time of diagnosis. Univariate logistic regression models were performed to assess variables of clinical interest and the odds of LTS. Overall survival (OS) was defined as the time from diagnosis of MBC to death of any cause. OS was estimated using the Kaplan-Meier method with log-rank comparative analyses as a univariate analysis. A Cox proportional hazards model was used for OS estimates in a univariate analysis. A total of 62 patients were diagnosed with de novo HER2-positive MBC and received HER2-directed therapy. Eighteen (29%) achieved LTS. The median OS of the whole cohort was 50.2 months (95% CI: 28.6-not reached). Radiographic response to first-line treatment was associated with LTS; complete and partial responses were both associated with higher odds of LTS (odds ratio: 28.33 [95% CI: 2.47-4006.71, P = 0.0043] and odds ratio: 7.80 [95% CI: 0.7317-1072.00, P = 0.0972], respectively). The best radiographic response was associated with improved OS. Radiographic response to first-line HER2-directed therapy is a predictor for LTS in patients with de novo HER2-positive MBC. Larger studies are needed to identify patients who can safely discontinue HER2-targeted therapy.

In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

Breast MRI radiomics and machine learning radiomics-based predictions of response to neoadjuvant chemotherapy - how are they affected by variations in tumour delineation?

Manual delineation of volumes of interest (VOIs) by experts is considered the gold-standard method in radiomics analysis. However, it suffers from inter- and intra-operator variability. A quantitative assessment of the impact of variations in these delineations on the performance of the radiomics predictors is required to develop robust radiomics based prediction models. In this study, we developed radiomics models for the prediction of pathological complete response to neoadjuvant chemotherapy in patients with two different breast cancer subtypes based on contrast-enhanced magnetic resonance imaging acquired prior to treatment (baseline MRI scans). Different mathematical operations such as erosion, smoothing, dilation, randomization, and ellipse fitting were applied to the original VOIs delineated by experts to simulate variations of segmentation masks. The effects of such VOI modifications on various steps of the radiomics workflow, including feature extraction, feature selection, and prediction performance, were evaluated. Using manual tumour VOIs and radiomics features extracted from baseline MRI scans, an AUC of up to 0.96 and 0.89 was achieved for human epidermal growth receptor 2 positive and triple-negative breast cancer, respectively. For smoothing and erosion, VOIs yielded the highest number of robust features and the best prediction performance, while ellipse fitting and dilation lead to the lowest robustness and prediction performance for both breast cancer subtypes. At most 28% of the selected features were similar to manual VOIs when different VOI delineation data were used. Differences in VOI delineation affects different steps of radiomics analysis, and their quantification is therefore important for development of standardized radiomics research.

Evaluation of HER2 Positivity Based on Clinicopathological Findings in HER2 Borderline Tumors in Iranian Patients with Breast Cancer.

Human epidermal growth receptor-2 (HER2) gene amplification is an important predictive and prognostic factor in breast cancer treatment. However, the expression of HER2 determined by immunohistochemistry (IHC) is considered as borderline in some cases, and confirmation of the HER2 status by either fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) is necessary for correct treatment decision-making. Considering the high cost of FISH and CISH, we aimed to investigate whether clinicopathological findings of the tumor could predict the HER2 status. A retrospective study was performed using the data from 584 patients with breast cancer with HER2-borderline disease, confirmed by IHC. Final HER2 status, pathologic tumor size and type, nodal involvement, Ki67 index, presence of estrogen and progesterone receptors (ER, PR), lymphovascular invasion (LVI), and stage were retrieved from the clinical records. One hundred twenty-one (20.7%) patients were HER2-positive according to the FISH or CISH results. Logistic regression analysis showed that the pathologic size was positively associated with HER2 positivity with an odds ratio (OR) of 1.02 (95% CI: 1.01-1.04). In addition, the adjusted OR illustrated a statistically significant association between HER2 positivity and PR negativity (OR= 2.22, 95% CI: 1.29-3.83). In HER2 borderline breast cancer, HER2 positivity significantly increases with tumor size and PR negativity. Further studies are recommended that may find an applicable model to predict the actual status of HER2 in borderline cases.

A Double-blind Randomized Comparative Phase I Study to Assess Biosimilarity and Immunogenicity of "Trastuzumab" (LLC "Mabscale", Russia) and Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland) in Healthy Volunteers

Introduction. Trastuzumab is the first drug based on the monoclonal antibodies’ technology targeted to the neu oncogene expression product discovered in the middle 80-s – human epidermal growth receptor, HER2. After being approved trastuzumab had become the drug of choice for combine therapy of metastatic breast cancer (BC). This therapy had also allowed to improve patients’ 5-year survival rate dramatically, almost up to 90 % in some cases. Despite the fact that more than 10 biosimilars of trastuzumab are now in the pipeline around the world, including Russia, the development and registration of trastuzumab biosimilars still remain relevant.Aim. Aim of the study was to conduct the analytical part of the double-blind randomized comparative clinical trial for trastuzumab pharmacokinetics and safety assessment in healthy volunteers with subsequent biosimilarity evaluation of "Trastuzumab" (LLC "Mabscale", Russia) and Herceptin® (F. Hoffmann-La Roche Ltd., Switzerland).Materials and methods. 92 healthy volunteers, who fulfilled the inclusion/exclusion criteria, were enrolled to the study. Trastuzumab quantitation and anti-trastuzumab antibodies detection was performed using ELISA method with photometric detection. To support the clinical trial two different independent bioanalytical methods were validated.Results and discussion. Trastuzumab quantitation method in human blood serum was validated for selectivity, calibration curve and regression model, sensitivity (LLOQ), accuracy and precision, MRD, dilution linearity and stability. The method for anti-trastuzumab antibodies detection, that was previously described by the authors, was validated for cut-point, selectivity, sensitivity, prozone effect, drug tolerance, precision and stability (short-term and long-term). The validated methods were successfully applied to the study samples assay to perform the analytical part of the comparative study for trastuzumab pharmacokinetics and immunogenicity assessment. The obtained drug concentrations were used for PK-parameters and confidence interval calculations to estimate the biosimilarity of test and reference drug.Conclusion. The study results showed that test and reference drug are biosimilar, and moreover immunogenicity assessment showed no anti-trastuzumab antibodies in any samples of healthy volunteers.

A Review on Biomarkers for Predicting Radioresistance and Role of Natural Radiosensitizers in Triple-Negative Breast Cancer

Breast cancer mortality rate is fifth among all cancer and increasing day by day due to modern lifestyles. Its molecular subtype is classified as per their significant receptor expression, such as estrogen receptor (ER), progesterone receptor (PR) &amp; human epidermal growth receptor 2 (Her2). Triple-negative breast cancer (TNBC) is an aggressive subgroup among breast cancer subtypes and clinically challenging to treat due to loss of all three receptor (ER/PR/Her2) expression. Treatment modalities of TNBC include surgery, chemotherapy, radiotherapy and immunotherapy. Postoperative radiation therapy (RT) improves locoregional control and overall survival in TNBC patients. The powerful ionizing radiation (IR) response to RT is contributed by the inherent radiosensitivity of the tumor, which is influenced by genes associated with the cell cycle, DNA damage repair, apoptosis, etc. This review article narrates the role of biomarkers obtained through data mining and manual curation of published literature to predict radioresistance in patients receiving radiotherapy. Further, the role of natural radiosensitizers in overcoming radioresistance for effectively managing TNBC is also discussed.

HER2-Positive Gastric Cancer: The Role of Immunotherapy and Novel Therapeutic Strategies.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, this being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Treatment Algorithm for Patients With Gastric Adenocarcinoma: Austrian Consensus on Systemic Therapy - An Update.

Over the last decade, therapeutic options for patients with gastric cancer have improved significantly. However, despite these recent advances, mortality is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Immune checkpoint inhibitors as well as targeted treatments such as HER2-directed therapies and antiangiogenic agents contribute to improved patient prognosis. Herein, we present the updated version of an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and adenocarcinoma of the lower gastroesophageal junction, including those with human epidermal growth receptor 2 (HER2) overexpression, microsatellite instability, programmed death-ligand 1 (PD-L1)-positive disease, and claudin 18.2 positivity. The consensus considers the curative setting as well as first-line and later-line systemic treatment options in advanced disease. For HER2-positive disease, HER2 testing is discussed in addition to a review of first-line and later-line therapies. Potential future therapies are also listed, with a focus on targeted [e.g., fibroblast growth factor receptor 2 (FGRF2)-directed] treatments that might provide a further step forward in the management of patients with gastric cancer.

In silico analysis of the different variable domain oriented single-chain variable fragment antibody-antigen complexes

Single-chain variable fragment (scFv) antibodies hold great potential as diagnostic tools and therapeutic agents, especially for tumor cells. Since these applications require their production with improved properties, the design strategy of scFvs is crucial for their active, soluble, and high yield expression with high affinity towards their antigens. The order of VL and VH domains is one of the important parameters that affect the expression and binding affinity properties of scFvs. In addition, the optimum order of VL and VH domains could change for each scFv. In the present study, we used computer simulation tools to evaluate the effect of variable domain orientation on structure, stability, interacting residues of scFvs, and binding free energies of scFv-antigen complexes. We selected anti-HER2 scFv, which is specific for human epidermal growth receptor 2 (HER2) overexpressed in breast cancer, and anti-IL-1β scFv against IL-1β which is an important inflammatory biomarker, as model scFvs. Molecular dynamics simulations of the scFv-antigen complexes for 100 ns resulted in stability and compactness for both scFv constructs. Interaction and binding free energies calculated by the Molecular Mechanics–Poisson–Boltzmann Surface Area (MM-PBSA) approach suggested that the relative binding energies of anti-HER2 scFv-VLVH and anti-HER2 scFv-VHVL constructs had similar binding affinity towards HER2, while a relatively more negative binding free energy obtained between anti-IL-1β scFv-VHVL and IL-1β pointed to a higher binding affinity. The in silico approach and the results obtained here could be applied as a guide for future experimental interaction studies for highly specific scFvs used as biotechnological tools. Communicated by Ramaswamy H. Sarma