UNASSIGNED: Cardiotoxicity (CTX) induced by adjuvant chemotherapy is a significant factor that impacts the prognosis and quality of life in breast cancer (BC) patients. In this study, we aimed to investigate the changes in epicardial adipose tissue (EAT) before and after treatment in BC patients who received anthracyclines adjuvant chemotherapy protocol (AC-T) and anthracyclines combined with trastuzumabadjuvant chemotherapy protocol (AC-TH). Additionally, we assessed whether there were any differences in the changes in EAT between the two groups of patients. Our objective was to examine the effects of anthracyclines and trastuzumab on EAT and determine the potential role of EAT changes on CTX.
UNASSIGNED: We reviewed female BC patients who were treated with adjuvant chemotherapy protocols of AC-T and AC-TH, all of whom underwent baseline (T0) and follow-up (T1) chest computed tomography (CT) and echocardiography. A cohort of healthy women, matched in age, underwent two chest CTs. EAT was quantified on chest CT using semi-automated software. CTX was defined as a > 10% reduction in left ventricular ejection fraction (LVEF) from baseline, with an absolute value of < 53%.
UNASSIGNED: A total of 41 BC patients were included in the study, with 23 patients in the AC-T group and 18 patients in the AC-TH group. Additionally, 22 healthy females were included as the normal group. None of the BC patients developed CTX after chemotherapy. The age did not differ significantly between the normal group and the AC-T group (p = 0.341) or the AC-TH group (p = 0.853). Similarly, the body mass index (BMI) of the normal group was comparable to that of the AC-T group (p = 0.377, 0.346) and the AC-TH group (p = 0.148, 0.119) before and after chemotherapy. The EAT volume index (mL/kg/ m 2 ) was significantly higher in both the AC-T group (5.11 ± 1.85 vs. 4.34 ± 1.55, p < 0.001) and the AC-TH group (4.53 ± 1.61 vs. 3.48 ± 1.62, p < 0.001) at T1 compared with T0. In addition, both the AC-T group (-72.95 ± 5.01 vs. -71.22 ± 3.91, p = 0.005) and the AC-TH group (-72.55 ± 5.27 vs. -68.20 ± 5.98, p < 0.001) exhibited a significant decrease in EAT radiodensity (HU) at T1 compared to T0. However, there was no significant difference observed in the normal group. At T0, no difference was seen in EAT volume index (4.34 ± 1.55 vs. 3.48 ± 1.62, p = 0.090) and radiodensity (-71.22 ± 3.91 vs. -68.20 ± 5.98, p = 0.059) between the AC-T and AC-TH groups. Similarly, at T1, there was still no significant difference observed in the EAT volume index (-5.11 ± 1.85 vs. 4.53 ± 1.61, p = 0.308) and radiodensity (-72.95 ± 5.00 vs. -72.54 ± 5.27, p = 0.802) between the two groups.
UNASSIGNED: BC patients who underwent AC-T and AC-TH adjuvant chemotherapy protocols demonstrated a significant rise in the volume index of EAT, along with a substantial reduction in its radiodensity post-chemotherapy. These findings indicate that alterations in EAT could potentially aid in identifying cardiac complications caused by chemotherapeutic agents and remind clinicians to focus on changes in EAT after adjuvant chemotherapy in BC patients to prevent the practical occurrence of CTX.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H2Mab-250/H2CasMab-2. In flow cytometry and immunohistochemistry, H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG1 version of H2Mab-250 (H2Mab-250-hG1) possesses compatible in vivo antitumor effects against breast cancer xenografts to trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H2Mab-250-hG1 and trastuzumab. Both H2Mab-250-hG1 and trastuzumab showed ADCC activity against HER2-overexpressed Chinese hamster ovary -K1 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed where trastuzumab showed a more significant ADCC effect compared to H2Mab-250-hG1. Importantly, H2Mab-250-hG1 exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in the mouse IgG2a types of both H2Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H2Mab-250-hG1 and trastuzumab, and indicate a future direction for the clinical development of H2Mab-250-hG1 against HER2-positive tumors.

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

UNASSIGNED: Serous endometrial cancers (ECs) are an aggressive histotype of ECs which are disproportionately responsible for 40% of cancer-specific mortality rates despite constituting only 5-10% of all uterine cancers in incidence. In recent times, it has become increasingly evident that about 20-40% of uterine serous cancers (USCs) have molecular alterations in ERBB2 pathway with human epidermal growth factor receptor 2 (HER2/neu) amplification or overexpression. We summarise the evidence on genetic and molecular alterations in HER2/neu pathway in USC with a focus on testing criteria, targeting agents and resistance mechanisms.
UNASSIGNED: We conducted a database search of PubMed/Medline up to 28th February 2023 for articles published in the English language using pre-defined search terms. One hundred and seventy-one relevant articles were subsequently reviewed for eligibility and inclusion in the review.
UNASSIGNED: The Cancer Genome Atlas (TCGA) classification is a significant development in the molecular profiling of ECs with a positive impact on the treatment of these tumors including USCs. Testing criteria for HER2/neu in USC with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has evolved in more than a decade with progress made towards EC specific testing guidelines. The findings of a recent phase III study have led to the development of practice changing guidelines towards improving patient outcomes.
UNASSIGNED: Molecular aberration in the HER2/neu pathway contributes to the aggressive behaviour of USC. Considering the clinical benefit conferred by HER2/neu targeted therapy, HER2/neu testing is recommended for all cases of serous EC in advanced and recurrent settings. Trastuzumab in combination with platinum and taxanes based chemotherapy is the recommended treatment option for patients with advanced or recurrent serous cancers who test positive to HER2/neu. Clinical trials on targeted therapy are ongoing and future research should focus on selection of patients who will derive the most benefit from such therapy.

UNASSIGNED: Gastric cancer remains a challenging malignancy with a high global mortality rate. Recent advances in targeted therapy and immunotherapy have shown promise in improving patient outcomes. This paper reviews the impact of incorporating targeted agents such as trastuzumab and immunotherapeutic agents like pembrolizumab into standard chemotherapy regimens for gastric cancer treatment.
UNASSIGNED: A comprehensive analysis was conducted on pivotal clinical trials, including KEYNOTE-590, KEYNOTE-811, and ToGA, focusing on their methodologies, patient populations, treatment regimens, and outcome measures. The review also explored emerging research avenues in precision medicine, particularly genomic sequencing and biomarker identification.
UNASSIGNED: To assess the efficacy and survival benefits of adding trastuzumab and pembrolizumab to standard chemotherapy in the treatment of gastric cancer and to outline future directions in gastric cancer research.
UNASSIGNED: Including trastuzumab and pembrolizumab in treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive and PD-L1-expressing gastric cancers significantly improved progression-free and overall survival rates compared to chemotherapy alone. These findings highlight the potential of personalized therapy in enhancing treatment outcomes. Furthermore, ongoing research into the gastric cancer microenvironment and the role of the microbiome suggests novel targets for future therapeutic interventions.
UNASSIGNED: The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in gastric cancer treatment, moving towards more personalized and effective regimens.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

Breast cancer has an average 10-year relative survival reaching 84%. This favorable survival is due, in part, to the introduction of biomarker-guided therapies. We estimated the population-level effect of the introduction of two adjuvant therapies-tamoxifen and trastuzumab-on recurrence using the trend-in-trend pharmacoepidemiologic study design.
We ascertained data on women diagnosed with nonmetastatic breast cancer who were registered in the Danish Breast Cancer Group clinical database. We used the trend-in-trend design to estimate the population-level effect of the introduction of (1) tamoxifen for postmenopausal women with estrogen receptor (ER)-positive breast cancer in 1982, (2) tamoxifen for premenopausal women diagnosed with ER-positive breast cancer in 1999, and (3) trastuzumab for women <60 years diagnosed with human epidermal growth factor receptor 2-positive breast cancer in 2007.
For the population-level effect of the introduction of tamoxifen among premenopausal women diagnosed with ER-positive breast cancer in 1999, the risk of recurrence decreased by nearly one-half (OR = 0.52), consistent with evidence from clinical trials; however, the estimate was imprecise (95% confidence interval [CI] = 0.25, 1.85). We observed an imprecise association between tamoxifen use and recurrence from the time it was introduced in 1982 (OR = 1.24 95% CI = 0.46, 5.11), inconsistent with prior knowledge from clinical trials. For the introduction of trastuzumab in 2007, the estimate was also consistent with trial evidence, though imprecise (OR = 0.51; 95% CI = 0.21, 22.4).
We demonstrated how novel pharmacoepidemiologic analytic designs can be used to evaluate the routine clinical care and effectiveness of therapeutic advancements in a population-based setting while considering some limitations of the approach.

Breast cancer (BC) is the prevailing malignancy among women, with HER2 overexpression observed in 20-30 % of all BC, thereby serving as a prognostic indicator for unfavorable outcomes in affected individuals. There is a necessity to establish innovative treatment protocols to expand the therapeutic alternatives accessible for managing HER2-positive BC. In this study, we report a case of HER2-positive BC that was managed in our department using a combination of three targeted drugs (Trastuzumab, Pertuzumab and Pyrotinib) along with chemotherapy. The treatment resulted in a pathological complete response (pCR) and was observed to be well-tolerated, without any significant adverse reactions. Hence, the combination of Pyrotinib and Dual HER2 blockade treatment shows promise as a neoadjuvant therapy for locally advanced HER2-positive BC to achieve a pCR in surgery. Nevertheless, this conclusion necessitates additional validation via meticulously designed clinical research investigations encompassing larger patient populations.

Biosimilars offer the potential for cost savings and expanded access to biologic products; however, there are concerns regarding the rate of biosimilar uptake. We assessed the relationship between biosimilar and originator pricing, coverage, and market share by describing four case studies that fall into two categories: (1) sole preferred coverage strategy (ie, aim is to have originator product preferred; biosimilar(s) non-preferred), defined as steep average sales price (ASP) reductions for originator products (decline in net prices by at least 50% following the introduction of biosimilar competition by 2022) and (2) non-sole preferred coverage strategy (ie, aim is to have originator product preferred alongside biosimilar products), defined as moderate ASP reductions for originator products with (net prices did not decline by at least 50% of its pre-biosimilar competition value). We found that originators with sole preferred coverage strategies maintained formulary preference and market share relative to originators with non-sole preferred coverage strategies. Regardless of strategy, the market-weighted ASP for all four product families (originator and biosimilars) declined significantly in the years following the introduction of biosimilars, suggesting that biosimilar uptake alone may not be a complete measure of whether the biosimilar market is facilitating competition and lowering prices.

UNASSIGNED: Studies highlighted the bidirectional crosstalk between the HER family members in breast cancer as resistance mechanism to anti-HER agents. Cross-signaling between HER2/EGFR and ER/IGF1R could play role in the development of resistance to therapeutics hence stimulating cell growth. To overcome this resistance, combined therapies targeting both pathways simultaneously have been proposed as an effective strategy. The involvement of miRNAs in resistance of targeted therapies like trastuzumab was demonstrated in recent studies. Hence the regulation of miRNAs in resistance state could reverse the cell behaviour to drugs. Previously we found that overexpression of miR-770-5p downregulated AKT and ERK expression through HER2 signaling and potentiated the effect of trastuzumab. In this study we examined the impact of miR-770-5p on trastuzumab resistance.
UNASSIGNED: Cells were treated with tamoxifen or trastuzumab to examine their role in bidirectional crosstalk. The molecule mechanism of miR-770-5p on HER2/EGFR/IGF1R bidirectional crosstalk was explored by western blot. The expression of miR-770-5p in trastuzumab resistant cells was examined by q-PCR. To investigate the effect of miR-770-5p on cancer cell proliferation in trastuzumab resistance state, resistant cells were analyzed by iCELLigence real-time cell analyzer.
UNASSIGNED: miR-770-5p expression was significantly downregulated in trastuzumab-resistant BT-474 and SK-BR-3 cells. Overexpression of miR-770-5p sensitized the resistant cells to trastuzumab, as evidenced by reduced cell proliferation and increased cell viability. Additionally, in resistant cells, increased expression and activation of EGFR and IGF1R were observed. However, miR-770-5p overexpression resulted in decreased phosphorylation of AKT and ERK, indicating its suppressive role in EGFR/HER2 signaling. Furthermore, miR-770-5p downregulated the expression of IGF1R and mTOR, suggesting its involvement in regulating the escape signaling mediated by IGF1R in resistance.
UNASSIGNED: In conclusion, our findings demonstrate the critical role of miR-770-5p in regulating bidirectional crosstalk and overcoming trastuzumab resistance in breast cancer cells. These results highlight the potential of miR-770-5p as a therapeutic target to improve the efficacy of targeted therapies and address resistance mechanisms in breast cancer.