anti-HER2 Therapy Research Articles

Targeting BRD4 with BET inhibition synergizes with anti-HER2 therapy and overcomes resistance in HER2-amplified uterine serous cancer

Targeting BRD4 with BET inhibition synergizes with anti-HER2 therapy and overcomes resistance in HER2-amplified uterine serous cancer

Clinical validated risk prediction model for development of heart failure after contemporary breast cancer treatment

Abstract Background Patients receiving breast cancer (BC) treatment are at risk for heart failure and cardiomyopathy (HF/CM). European Society of Cardiology (ESC) cardio-oncology guidelines recommend baseline cardiovascular (CV) assessment, however, there is limited data about cardiotoxicity risk specific to patients with BC. Our aim was to develop and validate model for prediction of HF/CM in women receiving contemporary treatment for invasive early-stage BC. Methods We assembled a cohort women diagnosed with Stage I-III BC from 2008-2020 and followed through 2021 in a large health care plan. Women age >80, with history of HF/CM, and women who received both anthracyclines and trastuzumab were excluded, leaving N=26,044 for analysis. Study cohort was randomly split into derivation (60%) and validation (40%) datasets. Elastic-net penalized Cox proportional hazard model was created using the derivation dataset to select risk factors and to calculate the panelized coefficient which defined the HF/CM risk score. Risk score system was assessed by Hosmer-Lemeshow goodness-of-fit test and area under the ROC curve (AUC). Event rates of <5% constituted low risk; 5-14% moderate; and >15% high risk category. Incident HF/CM events were examined using Kaplan-Meier approach in derivation and validation datasets. Results HF/CM risk score had high discrimination ability and sufficiently good model of fit regarding HF/CM events (P value=0.163 and 0.667 from Hosmer–Lemeshow test;AUC 0.751 and 0.764, in derivation and validation sets, respectively). There were 10% of women in the high risk; 30% in moderate; and 60% in low-risk group. Variables associated with the higher HF/CM risk score included age, receipt of anthracycline-based chemotherapy or anti-HER2 therapy, presence of hypertension, diabetes, or history of other CV conditions at baseline. The score pattern showed major effect of age, with anthracycline and anti-HER2 therapy increasing the risk across all age groups (Figure 1). Kaplan-Meier analysis of incident HF/CM over 14 years after BC diagnosis showed significantly lower number of HF/CM events in low risk compared to moderate and high-risk score groups (p<0.0001, Figure 2). Conclusion Our robust risk prediction model for HF/CM among women with early-stage BC provides a new tool to identify women at higher CV risk and inform cardiac function monitoring during and after BC treatment. Our findings may guide further validation studies and build evidence for the cardiotoxicity risk stratification in patients with BC.Risk Score for HF/CM by Age/ChemoTxK-M curves of freedom from HF/CM

Targeting the Renin-angiotensin-aldosterone System (RAAS) for Cardiovascular Protection and Enhanced Oncological Outcomes: Review.

The renin-angiotensin-aldosterone system (RAAS) is a crucial regulator of the cardiovascular system and a target for widely used therapeutic drugs. Dysregulation of RAAS, implicated in prevalent diseases like hypertension and heart failure, has recently gained attention in oncological contexts due to its role in tumor biology and cardiovascular toxicities (CVTs). Thus, RAAS inhibitors (RAASi) may be used as potential supplementary therapies in cancer treatment and CVT prevention. Oncological treatments have evolved significantly, impacting patient survival and safety profiles. However, they pose cardiovascular risks, necessitating strategies for mitigating adverse effects. The main drug classes used in oncology include anthracyclines, anti-HER2 therapies, immune checkpoint inhibitors (ICIs), and vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSPI). While effective against cancer, these drugs induce varying CVTs. RAASi adjunctive therapy shows promise in enhancing clinical outcomes and protecting the cardiovascular system. Understanding RAAS involvement in cancer and CVT can inform personalized treatment approaches and improve patient care.

Navigating the HER2 Frontier: Advancing Gastrointestinal Adenocarcinoma Diagnosis through Updated NCCN Guidelines

Abstract Introduction/Objective HER2-status is routinely tested in breast and upper-gastrointestinal (GI) cancers. Studies have shown the importance of anti-HER2 therapy with HER2 being a negative predictive marker in advanced colorectal cancer (CRC). Thus, recent NCCN-guidelines recommend screening for HER2-status in such cases. To increase compliance with the NCCN recommendations, we performed a quality assurance project to screen for HER2 status by immunohistochemistry (IHC) in GI adenocarcinomas. Methods/Case Report We conducted a validation of HER2 IHC for GI adenocarcinomas. Surgical pathologists were informed via email discussing the criteria and significance of HER2 IHC in GI adenocarcinomas. A total of 50 GI adenocarcinoma cases were evaluated in our surgical-pathology service, from June to December 2023. Pathologists were periodically reminded, either through email or in-person meetings, to ensure HER2 IHC assessment, especially for cases initially missed. Results (if a Case Study enter NA) Out of 50 GI adenocarcinomas, HER2 IHC was performed on 27 out of 50 cases (54%) without any reminder. The pathologists were reminded to perform HER2 IHC on the remaining 23 cases, resulting in the IHC performance on an additional 22 cases, giving a yield of 98%. Of 49 cases, HER2 was negative in 46 cases and was positive (3+) in one case, and equivocal (2+) in two cases. Subsequent HER2 FISH analysis of equivocal cases showed HER2 amplification in one case. Thus, HER2 expression/amplification was present in 2 out of 50 cases (4%) including one case each in upper and lower GI tracts. Conclusion While we have long recognized importance of HER2 Status in upper GI adenocarcinomas, it’s now clear that understanding HER2 status is crucial in CRC too. New evidence highlights how anti-HER2 therapy can make a difference, especially for advanced cases. By screening for HER2 early, clinicians can enroll such patients in appropriate clinical trials and also guide them on the appropriate treatment options, offering hope and targeted care.

De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer.

Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.

8028 Targeted Therapy-Induced ER And HER2 Chromatin Binding: A Novel Driver Of Poor Response To Treatment In Triple Positive Breast Cancer

Abstract Disclosure: S. Tam: None. M.D. McCoy: None. S. Bahnassy: None. R.B. Riggins: None. Triple positive breast cancer (TPBC) is a unique variant of breast cancer characterized by co-expression of two oncogenic drivers, estrogen receptor alpha (ER) and human epidermal growth factor receptor 2 (HER2). Both drivers promote tumor progression and serve as targets for effective small molecule and monoclonal antibody (mAb) therapies. Previous studies showed that the co-expression of ER reduces the efficacy of anti-HER2 targeted therapy in TPBC, and vice versa. ER is a well-established nuclear receptor and transcription factor. HER2 mainly functions as a transmembrane receptor, activating cytosolic pro-tumorigenic signaling pathways. However, less-studied nuclear HER2 is involved in the transcriptional regulation of several genes, leading to increased BC cell growth and survival. In this study, we investigate the subcellular localization and transcriptional regulatory functions of ER and HER2 in the unique context of TPBC, using cell fractionation, immunofluorescence, chromatin immunoprecipitation (ChIP)-qPCR, and integrated analysis of ER ChIP-seq/RNA-seq data. We hypothesize that crosstalk between ER and HER2 in the nucleus may, in part, underlie poor response to targeted therapy. At baseline, ER has strong nuclear localization in TPBC cells, BT474 and MDA-MB-361, but is predominantly cytosolic in ER+ MCF7 cells. Activated, phospho-HER2 is also localized to the nucleus of TPBC and HER2+ SkBr3 cells at baseline. Treatment with the anti-HER2 mAb combination of trastuzumab and pertuzumab (TP) induces ER binding to specific ER binding sites (ERBSs) in the enhancers or promoters of PGR, TFF1, and FOXC1 in BT474, but this is not observed in MCF7 or SkBr3 cells. Unlike TP, which increases HER2 nuclear localization but not ERBS recruitment, fulvestrant (a selective ER degrader) induces HER2 binding at the same ERBSs in BT474, but not MCF7 or SkBr3 cells. Collectively, these results suggest that the inhibition of either ER or HER2 can promote chromatin binding of the other at ERBSs. Integration of ER ChIP-seq peaks and differentially expressed genes from RNA-seq of BT474 cells treated with E2 vs control following short-term estrogen deprivation shows the ER cistrome is enriched for genes associated with RNA binding, RNA processing, and ribosome biogenesis. Interestingly, nuclear HER2 is reported to increase BC cell growth by activating transcription of ribosomal RNA genes. By contrast, the ER cistrome in MCF7 cells is enriched for genes associated with cell cycle regulation. In summary, anti-HER2 therapy induces recruitment of ER to well-established ERBSs, while anti-ER treatment causes recruitment of HER2 to these same sites in TPBC. Ongoing and future work leverages HER2 cistrome data to further define nuclear HER2/ER functional interactions, at the level of transcriptional regulation, that may contribute to poor treatment outcomes in TPBC. Presentation: 6/2/2024

8028 Targeted Therapy-Induced ER and HER2 Chromatin Binding: a Novel Driver of Poor Response to Treatment in Triple Positive Breast Cancer

Abstract Disclosure: S. Tam: None. M.D. McCoy: None. S. Bahnassy: None. R.B. Riggins: None. Triple positive breast cancer (TPBC) is a unique variant of breast cancer characterized by co-expression of two oncogenic drivers, estrogen receptor alpha (ER) and human epidermal growth factor receptor 2 (HER2). Both drivers promote tumor progression and serve as targets for effective small molecule and monoclonal antibody (mAb) therapies. Previous studies showed that the co-expression of ER reduces the efficacy of anti-HER2 targeted therapy in TPBC, and vice versa. ER is a well-established nuclear receptor and transcription factor. HER2 mainly functions as a transmembrane receptor, activating cytosolic pro-tumorigenic signaling pathways. However, less-studied nuclear HER2 is involved in the transcriptional regulation of several genes, leading to increased BC cell growth and survival. In this study, we investigate the subcellular localization and transcriptional regulatory functions of ER and HER2 in the unique context of TPBC, using cell fractionation, immunofluorescence, chromatin immunoprecipitation (ChIP)-qPCR, and integrated analysis of ER ChIP-seq/RNA-seq data. We hypothesize that crosstalk between ER and HER2 in the nucleus may, in part, underlie poor response to targeted therapy. At baseline, ER has strong nuclear localization in TPBC cells, BT474 and MDA-MB-361, but is predominantly cytosolic in ER+ MCF7 cells. Activated, phospho-HER2 is also localized to the nucleus of TPBC and HER2+ SkBr3 cells at baseline. Treatment with the anti-HER2 mAb combination of trastuzumab and pertuzumab (TP) induces ER binding to specific ER binding sites (ERBSs) in the enhancers or promoters of PGR, TFF1, and FOXC1 in BT474, but this is not observed in MCF7 or SkBr3 cells. Unlike TP, which increases HER2 nuclear localization but not ERBS recruitment, fulvestrant (a selective ER degrader) induces HER2 binding at the same ERBSs in BT474, but not MCF7 or SkBr3 cells. Collectively, these results suggest that the inhibition of either ER or HER2 can promote chromatin binding of the other at ERBSs. Integration of ER ChIP-seq peaks and differentially expressed genes from RNA-seq of BT474 cells treated with E2 vs control following short-term estrogen deprivation shows the ER cistrome is enriched for genes associated with RNA binding, RNA processing, and ribosome biogenesis. Interestingly, nuclear HER2 is reported to increase BC cell growth by activating transcription of ribosomal RNA genes. By contrast, the ER cistrome in MCF7 cells is enriched for genes associated with cell cycle regulation. In summary, anti-HER2 therapy induces recruitment of ER to well-established ERBSs, while anti-ER treatment causes recruitment of HER2 to these same sites in TPBC. Ongoing and future work leverages HER2 cistrome data to further define nuclear HER2/ER functional interactions, at the level of transcriptional regulation, that may contribute to poor treatment outcomes in TPBC. Presentation: 6/2/2024

Evaluation of Treatment and Recurrence-Free Survival in Patients with Early HER2-Positive Breast Cancer: Real-Life Data Comparing Public and Private Healthcare

Abstract Introduction The present study was designed to compare the treatment provided in private and public health care facilities for women positive for early breast cancer of the human epidermal growth factor receptor 2 (HER2) subtype, who received anti-HER2 therapy in neoadjuvant or adjuvant settings, with an evaluation of the recurrence-free survival (RFS) and pathological complete response (pCR) rates. Materials and Methods The current is a retrospective study carried out at the Instituto Brasileiro de Controle do Cancer (IBCC Oncologia), in the city of São Paulo, Brazil. We included patients treated between 2015 and 2020. Results The study included 472 medical records of early HER2-positive breast cancer patients treated in the public and private health care systems who received neoadjuvant or adjuvant treatments. The pathological complete response (pCR) was related to a lower recurrence rate and a longer recurrence-free survival (RFS). The results showed no statistically significant difference between the public and private health care systems in terms of RFS. Discussion Although the public health care patients were diagnosed with more advanced diseases than the private health care patients, both presented similar survival rates. In spite of the small number of patients evaluated, the dual HER2 blockade did not improve the clinical outcomes. These findings should be confirmed through studies with a larger number of patients and a longer follow-up period.

Use of cardiac biomarkers to improve initiation of cardioprotective therapy in patients with breast cancer receiving cardiotoxic chemotherapy in a multidisciplinary cancer center.

344 Background: Treatment for breast cancer commonly includes anthracyclines and anti-Her2 directed therapy, both of which carry a known cardiovascular risk. In high-risk patients, ESMO guidelines recommend consideration of cardiac biomarker (hs-cardiac troponin) testing for patients undergoing potentially cardiotoxic chemotherapy. Prophylactic use of cardioprotective medications such as angiotensin converting enzyme (ACE) inhibitors, angiotensin renin blockers (ARBs) or beta-blockers (BBs) can be considered to reduce development of cardiotoxicity. We aimed to identify the rates of cardiac biomarker testing performed and rates of abnormalities in patients considered to be high risk for cardiovascular disease undergoing breast cancer treatment with potentially cardiotoxic medication in hope of improving prevention efforts. Methods: We performed a retrospective chart review of patients with breast cancer treated with either anthracycline or anti-Her2 based therapy at our ambulatory cancer center from 2020 to 2023. Pre-treatment cardiovascular risk score was determined based on initial cardiac assessment at time of consultation with cardio-oncology. Completion of troponin biomarker testing and initiation of cardioprotective medication therapy was assessed. Patients who were not established with cardio-oncology or not on active cardiotoxic chemotherapy were excluded. Results: A total of 172 patients (66 on anthracycline based therapy and 106 on anti-HER2 therapy) were assessed. The average age of all patients was 57 years. 47 patients were assessed as high risk for cardiovascular disease. Of these high-risk patients, troponin was checked in 42 of 47 (89.4%) and found to be elevated in 23 of 42 (55%). Rate of troponin elevation was statistically significant for high risk patients compared to all other patients (p<0.05). Cardioprotective medications were utilized in 28 of the 47 patients considered to be high risk (59.6%). Conclusions: In patients with breast cancer who require treatment with a potentially cardiotoxic medication, a clinical risk assessment with cardiology can be utilized to select those who may benefit from additional cardiac biomarker monitoring and potential earlier initiation of cardioprotective therapy. This single center study reveals that the use of clinical assessment of high vs low/medium risk allows us to predict patients with increased risk of cardiotoxicity. Our population had cardiac biomarkers checked in nearly all high-risk patients and troponin was elevated 55% of the time. Further study is needed to investigate if biomarker directed initiation of cardio-protective therapy could reduce cardio-toxicity.

Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer.

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.

Tumor-infiltrating immune cell profiles and changes associate with additional trastuzumab in preoperative chemotherapy for patients with HER2-positive gastric cancer

BackgroundHER2(+) gastric cancer (GC) can benefit from trastuzumab. However, the impact of additional trastuzumab in preoperative treatment on immune cells remains largely unknown.MethodsIn cohort I, immune cells were detected by immunohistochemistry in 1321 patients. Then 88 HER2(+) patients received preoperative therapy were collected as cohort II. Immune cell profiles and changes were analyzed in paired pre- and post-operative specimens using multiple immunohistochemistry staining.ResultsIn the treatment-naive GC patients (n = 1002), CD3+ and CD8+ T cell infiltration was significantly lower in the HER2(+) GC patients together with higher FoxP3+ T cells compared with HER2(−). However, FoxP3+ T and CD20+ B cell infiltration was significantly higher in HER2(+) GC after neoadjuvant chemotherapy (n = 319). The trastuzumab-exposed group had higher CD8+ T and lower FoxP3+ T cell infiltration and CD8+ T cell was even more significant in responders. Additionally, tertiary lymphoid structure (TLS) density increased in invasion margin of residual tumors. Patients with lower TLS in the tumor core or lower FoxP3+ T cells had better overall survival in the trastuzumab-exposed group.ConclusionAddition of trastuzumab modulates the immune microenvironment, suggesting the potential mechanism of the favorable outcome of anti-HER2 therapy and providing a theoretical rationale for the combinational immunotherapy in resectable HER2(+) GC patients.

The Role of Predictive and Prognostic Biomarkers in Lower Female Genital Tract Pathology: PD-L1, MMR, HER2, p16, p53, and Beyond.

Biomarkers play a crucial role in the diagnosis, treatment planning, and prognosis of premalignant and malignant lesions and are increasingly used in neoplasia of the lower female genital tract (LFGT) including the cervix, vagina, and vulva. This review will discuss key biomarkers routinely used in LFGT pathology, including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR), and tumor mutational burden (TMB) testing, which are FDA-approved companion diagnostics for anti-PD-1 checkpoint inhibitors. Recent developments in HER2 testing as a marker for anti-HER2 therapies, and prognostic biomarkers such as p53 in HPV-independent vulvar intraepithelial lesions and carcinomas, are also reviewed.

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.

Clinicopathological Factors Predicting Pathological Complete Response to Neoadjuvant Anti-HER2 Therapy in HER2-Positive Breast Cancer

Plain Language SummaryNeoadjuvant treatment is the standard approach for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Especially, pathologic response is an important prognostic factor and the adjuvant treatment is dependent on the response. Therefore, predicting the response is important for modulating the treatment sequence, especially in the initial stage of treatment decision. Therefore, we aimed to identify factors that can predict the effectiveness of neoadjuvant chemotherapy, and our results suggest that factors such as tumor size, grade, hormone receptor, and HER2 status should be considered in the treatment of breast cancer.

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

Transparent precision: Explainable AI empowered breast cancer recommendations for personalized treatment

<p>Breast cancer stands as a prevalent global concern, prompting extensive research into its origins and personalized treatment through Artificial Intelligence (AI)-driven precision medicine. However, AI's black box nature hinders result acceptance. This study delves into Explainable AI (XAI) integration for breast cancer precision medicine recommendations. Transparent AI models, fuelled by patient data, enable personalized treatment recommendations. Techniques like feature analysis and decision trees enhance transparency, fostering trust between medical practitioners and patients. This harmonizes AI's potential with the imperative for clear medical decisions, propelling breast cancer care within the precision medicine era. This research work is dedicated to leveraging clinical and genomic data from samples of metastatic breast cancer. The primary aim is to develop a machine learning (ML) model capable of predicting optimal treatment approaches, including but not limited to hormonal therapy, chemotherapy, and anti-HER2 therapy. The objective is to enhance treatment selection by harnessing advanced computational techniques and comprehensive data analysis. A decision tree model developed here for the prediction of suitable personalized treatment for breast cancer patients achieves 99.87% overall prediction accuracy. Thus, the use of XAI in healthcare will build trust in doctors as well as patients.</p>

Predictors of pathological complete response to neoadjuvant treatment in invasive breast cancer with different human epidermal growth factor receptor 2 (HER2) subcategories.

Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive anti-HER2 treatment, a noteworthy correlation between pathological complete response (pCR) and longer survival has been observed. The rate of pCR varies with the tumor's degree of HER2 protein expression. The aim of this study was to assess the correlations between clinicopathological characteristics, magnetic resonance imaging (MRI) parameters, and pCR in breast cancer with different HER2 subcategories. A total of 281 invasive breast cancer patients diagnosed with HER2-positivity were included. HER2-positive translated to immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)(+). All enrolled patients underwent baseline MRI examination and received neoadjuvant chemotherapy, dual anti-HER2 therapy, and subsequent therapeutic surgery from January 2021 to May 2022. A logistic regression model was used to evaluate the effects of covariates on pCR. Compared to the IHC 2+/FISH(+) group, patients with IHC 3+ tumors had a higher pCR rate (58.1% vs. 26.7%, P<0.001), clinical stage (58.6% vs. 40%, P=0.038), apparent diffusion coefficient (ADC) value (0.96 vs. 0.88 mm2/s, P=0.004), and were more likely to be estrogen receptor (ER) negative (55.9% vs. 31.1%, P=0.002) and progesterone receptor (PR) negative (72.5% vs. 46.7%, P=0.001). In both groups, univariate analysis showed that the pCR group more often had ER-negative and PR-negative status than the non-pCR group (P<0.001). The final multivariable analysis showed that ER-negativity was associated with pCR in the IHC 2+/FISH(+) group (P=0.004). ER-negativity and the longest diameter were two independent predictors of pCR in the IHC 3+ group (P<0.001 for ER, P=0.026 for longest diameter). The IHC 3+ group had a higher pCR rate than the IHC 2+/FISH(+) group. Along with clinicopathological characteristics, MRI parameters were supplemental predictors of pCR, particularly in IHC 3+ patients.

The prognostic significance of circulating tumor cell enumeration and HER2 expression by a novel automated microfluidic system in metastatic breast cancer

BackgroundThe prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®.MethodsCTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system.ResultsThe capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1–55 CTCs, median = 6), < 8 CTCs in 45 (69.2%) and ≥ 8 CTCs in 20 (30.8%) patients at baseline. The patients with < 8 CTCs had longer PFS than ≥ 8 CTCs (median, 7 vs. 4.4 months, p = 0.028). CTC enumeration was found to be an independent prognostic factor in our cohort. Moreover, we found a weak concordance between tissue HER2 (tHER2) status and the corresponding CTCs (k = 0.16, p = 0.266). The patients with tHER2 positive and cHER2 negative had better PFS compared with patients with both tHER2 and cHER2 positive (median, 8.2 vs. 3.3 months, p = 0.022).ConclusionsThis clinical study shows the prognosis value of a new threshold of CTC number and meanwhile the guidance value of cHER2 status in anti-HER2 therapy.

Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data

The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P < 0.05). These findings not only highlight the significance of multi-modal data analysis in enhancing treatment evaluation and personalized medicine for HER2-positive gastric cancer, but also the potential and clinical value of our model.

The Impact of Chemotherapy on Arterial Stiffness and Ventricular-Arterial Coupling in Women with Breast Cancer.

The cardiac toxicity of chemotherapy for breast cancer is not uncommon and has been associated with elevated morbidity and mortality. In the present study, we assessed the impact of chemotherapy on cardiovascular function by assessing the cardio-ankle vascular index (CAVI), global longitudinal strain (GLS) and ventricular-arterial coupling (VAC: CAVI/GLS ratio) in chemotherapy-treated women. This prospective study enrolled 78 women with breast cancer who were receiving anthracycline-based chemotherapy +/- anti-HER2 therapy (trastuzumab +/- pertuzumab). Forty-one age-matched healthy women served as controls. We comparatively evaluated left ventricular ejection fraction (LVEF), CAVI, GLS and VAC, between the chemotherapy and control groups. We also assessed their changes over time (baseline, 3-month and 6-month time point) and their independent association with the incidence of cancer therapy-related cardiovascular dysfunction (CTRCD) in the chemotherapy group. In comparison to healthy controls, women receiving chemotherapy presented with significantly higher GLS (from -21.02 ± 2.09% to -19.01 ± 2.81%, p < 0.001) and VAC (-0.36 ± 0.06 to -0.41 ± 0.11, p < 0.001). The presence of CTRCD was associated with a further increase in GLS and CAVI and a significant decline in LVEF and VAC compared to CTRCD-free women (p < 0.001). Baseline, CAVI, GLS and VAC were independently associated with CTRCD development during follow-up. Women with breast cancer undergoing chemotherapy displayed abnormal levels of CAVI, VAC and GLS, compared to healthy individuals. Those effects on VAC and CAVI were more exaggerated among women with CTRCD, implicating their potential use to refine screening and therapeutic strategies for this specific population.