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HER2-Positive Breast Cancer

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of HER2-Positive Breast Cancer. Core disease mechanisms, molecular and cellul...

2026-05-26
Asta MONDO:0006244 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of HER2-Positive Breast Cancer. Core disease mechanisms, molecular and cellul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Resistance and Overcoming Resistance in Breast Cancer

  • Authors: Andrea Luque-Bolivar, E. Pérez-Mora, V. Villegas, Milena Rondón-Lagos
  • Year: 2020
  • Venue: Breast Cancer : Targets and Therapy
  • URL: https://www.semanticscholar.org/paper/8cf9a7b648985175a9f0f35ca0bdc8a2889359a9
  • DOI: 10.2147/BCTT.S270799
  • PMID: 33204149
  • PMCID: 7666993
  • Citations: 108
  • Summary: This review is focused on recent studies on the possible biological and molecular mechanisms involved in both response and resistance to treatment in BC and emerging treatments that seek to overcome resistance and reduce side effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.533) > Cancer is a common disease and represents one of the biggest health problems in the world and a significant global concern. The incidence and mortality rates of breast cancer (BC) have increased in recent years, and BC is currently the leading cause of cancer death in women worldwide. 1 Decision making for the treatment of patients with BC is primarily based on the assessment of clinical and pathological parameters. In particular, the immunohistochemical evaluation of prognostic factors, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are critical for tumor subtype classification and histological grade, which play an important role in determining therapeutic strategies. For example, patients with ER-positive (ER+) tumors receive endocrine therapy, and a small fraction of these patients also receive chemotherapy. Patients with HER2-positive tumors (HER2 enriched or HER2+) are treated with antibodies directed against HER2 or small-molecule inhibitors in combination with chemotherapy. ][4] BC is a heterogeneous and complex disease in which each patient has unique morphological and molecular features, rather than a disease in which only a few genes, proteins, and/or signaling pathways contribute to disease progression in a simple, independent, and autonomous manner. Studies have shown that patients with the same type of BC can show differential responses to treatment, which further indicates the high heterogeneity in this disease. Despite the great technological advances that have enhanced our understanding of human cancers as heterogeneous diseases, current clinicopathological and molecular parameters leave a significant number of patients at risk of over-treatment and side effects. > Currently, drug-resistant BC is treated by selecting other drugs, without understanding the molecular mechanisms involved in the resistance of a given case. Better understanding of the mechanisms involved in the development of resistance might not only reduce the adverse effects of treatment but also lead to the development of new strategies for improving diagnosis and prognosis and achieving a better response to therapy. This review focuses on recent studies on the biological and molecular mechanisms of response and resistance to treatment in BC.

[2] Circulating metabolites serve as diagnostic biomarkers for HER2‐positive breast cancer and have predictive value for trastuzumab therapy outcomes

  • Authors: Changfei Mao, Min Wang, Li Li, Jin-hai Tang
  • Year: 2022
  • Venue: Journal of Clinical Laboratory Analysis
  • URL: https://www.semanticscholar.org/paper/c170d9b1deaced83d0f44f9f270bbfa9a81949e0
  • DOI: 10.1002/jcla.24212
  • PMID: 34994982
  • PMCID: 8842188
  • Citations: 14
  • Influential citations: 1
  • Summary: S serum‐based metabolic biomarkers for diagnosis of HER2‐positive breast cancers and predicts the therapeutic effects of trastuzumab therapy are developed.
  • Evidence snippets:
  • Snippet 1 (score: 0.507) > The overall goal of this study was to delineate the unique serum metabolic biomarkers of HER2-positive breast cancer patients. By using the UPLC-TOF-MS method platform to analyze the serum samples of 20 women with HER2-positive breast cancer and 30 normal women in the control group, we detected a series of significantly changed metabolites that were associated with HER2-positive breast cancer, covering a wide range of metabolic classes. Finally, from archived trastuzumab response data from HER2-positive breast cancer patients, we discovered 2 metabolites and developed a risk score that can predict trastuzumab resistance status. Through comprehensive data interpretation, we acquired a better understanding of the metabolic features in HER2-positive breast cancer and trastuzumab therapy status. > The emergence of omics methods is effectively accelerating predictive, treating and personalized therapeutics. 9 Metabolites more directly reflect and are linked closer to the phenotype of the pathology than genes and proteins. 10 Focusing on metabolite differences and the discovery of characteristic metabolites can be a shortcut and supplement the gene and protein level omics methods, and could also efficiently explain the mechanisms underlying various phenotypic variations. Thus, metabolomics screening is considered to be an effective, money-saving, and noninvasive option. > Each breast cancer subtype has inherent molecular features and metastatic potential, and its natural heterogeneity results in a high degree of difference in prognosis and the clinical response to available drugs, even for patients with a similar diagnosis, histology, and disease stages. 11 Therefore, accurate determination of the molecular subtype of breast cancer is very important for personalized treatment. In fact, there is evidence that compared with patients with mismatched therapies, patients who receive the correct molecularly matched therapy have a higher overall response rate, less treatment failure, and higher survival rates. 12 Clinically, liquid biopsy procedures and subsequent histopathological analysis are usually used to study the molecular and genetic information of cancer cells to diagnose and differentiate breast cancer and classify it into subtypes. 13 is analysis technique is invasive and time-consuming.
  • Snippet 2 (score: 0.474) > its application. 3,4 However, there are no known diagnostic biomarkers to improve the early diagnosis of HER2-positive breast cancer and the clinical utility of trastuzumab therapy. > Cancer-related liquid biopsy biomarkers can demonstrate the occurrence, progression and prognosis of cancers and are of great value for the early diagnosis of cancers, prediction of treatment response, and prognostic monitoring. 5 Metabolomics has emerged as a powerful analytical tool to provide new discoveries, and modern analysis methods are being used to study metabolic biomarkers related to diseases for clinical applications and to detect their abnormal changes in the living body. 6 As active modulators of gene and protein activity, metabolites have been widely adopted to investigate metabolic mechanisms underlying cancer occurrence, to evaluate treatment efficacy and monitor the prognosis to provide new diagnostic ideas and guide the development of better therapeutic strategies. 7 However, to the authors' knowledge, untargeted metabolomic investigation of serum metabolites has not been thoroughly conducted. > In our work, we used ultrahigh-performance liquid time of flight mass spectrometry (UPLC-TOF-MS)-based serum metabolomics and multivariate statistical analysis to investigate the circulating metabolite profiling of HER2-positive breast cancer. L-arginine and arachidonic acid were elevated in trastuzumab-responsive and trastuzumab-resistant HER2-positive breast cancer patients, and increased until reaching their peaks in trastuzumab-resistant HER2positive breast cancer patients. Moreover, an equation for assessing the risk scores based on linear logistic regression models involving L-arginine and arachidonic acid was created, which was beneficial for revealing metabolic changes in HER2-positive breast cancer and enhancing current trastuzumab-based therapy. These unique circulating metabolites in serum not only uncover the molecular characteristics of HER2-positive breast cancer patients but also enable personalized therapy.

[3] Determining the Factors Predicting the Response to Anti-HER2 Therapy in HER2-Positive Breast Cancer Patients

  • Authors: Jinshan You, K. Park, Eun Sook Lee, Y. Kwon, Kyoungsook Kim et al.
  • Year: 2021
  • Venue: Cancer Control : Journal of the Moffitt Cancer Center
  • URL: https://www.semanticscholar.org/paper/41207408a25f78de91d31876a037ff6f63afe2dd
  • DOI: 10.1177/10732748221141672
  • PMID: 36814068
  • PMCID: 9950611
  • Citations: 1
  • Summary: This multigene assay-based study provides insights into breast cancer signaling and possible predictions of therapeutic response to targeted therapies such as trastuzumab.
  • Evidence snippets:
  • Snippet 1 (score: 0.507) > We found that expression changes in 34 genes in several pathways were related to the response to trastuzumabcontaining treatment in HER2-type breast cancer, interfered with adhesion to other cells or tissues (focal adhesion), and regulated ECM-receptor interactions and phagosome action. As a result, the decreased tumor invasiveness and enhanced drug effects might be considered as a potential mechanism for better drug response in the CR group. Of note, functional pathway analysis showed that these pathways affect the HER2 response by interacting with the PI3K pathway and the MAP kinase pathway. As previously reported by Toomey et al and other investigators, high activation of the PI3K pathway is associated with poor response to anti-HER2 therapy in HER2positive breast cancer patients. 12 Neoadjuvant chemotherapy (NAC) is used in the context of locally advanced breast cancer to lower the staging of the tumor, improve operability, and increase the chances of breastconserving surgery. 13,14 Patients receiving NAC share equivalent disease progression and overall survival as patients receiving postoperative chemotherapy alone. 15 Currently, Trastuzumab is a HER2-targeted therapy approved by the United States Food and Drug Administration for HER2positive breast cancer in neoadjuvant, adjuvant, and metastatic settings. Since 2013, Korean health insurance coverage for trastuzumab has expanded to the neoadjuvant setting; hence, the number of patients who can undergo this treatment has increased. Neoadjuvant therapy is administered before surgery, and it is important to predict the treatment response. > Achieving pCR with neoadjuvant anti-HER2 targeted chemotherapy is a crude surrogate for long-term survival of patients with HER2-positive breast cancer. Hou et al demonstrated that HER2 intratumoral heterogeneity is associated with an incomplete response to anti-HER2 neoadjuvant chemotherapy. 16 Our study suggested that genes that are unique to HER2 and related to this HER2 intratumoral heterogeneity are associated with the functional pathways for cell signaling, such as the cell cycle and cell structure. Nahta et al reported that cell signaling pathways were related to a mechanism underlying resistance to HER2-targeted therapy in human breast cancer. 4 This can be in

[4] Immune Effects of Transtuzumab in HER2 Positive Breast Cancer

  • Authors: A. Zgura, L. Galeș, B. Haineala, E. Brătilă, C. Mehedințu et al.
  • Year: 2019
  • Venue: Revista de Chimie
  • URL: https://www.semanticscholar.org/paper/e8a43325891084c3abce704239aacecfc11ae542
  • DOI: 10.37358/rc.19.8.7428
  • Summary: The results of a study that included 22 patients diagnosed with Her2 positive breast cancer undergoing treatment with Transtuzumab are presented, finding that the drug induces antibody-dependant cell-mediated cytotoxicity.
  • Evidence snippets:
  • Snippet 1 (score: 0.505) > Breast cancer is a multifactorial disease in which the key mechanisms of cellular function are implicated, involving molecules of different biochemical classes, functions and types: hormones, growth factors, receptors, signalling pathways, proteases, chromosomal genes, and specific molecules of ribonucleic acids [1][2]. Each of these factors represents a direct therapeutic target, describing a new era in the cancer therapy-molecular biological therapy [3]. > The human epidermal growth factor receptor (EGFR) family comprises four transmembrane receptors, which are involved in the signal transduction pathways regulating cell growth and differentiation: EGFR/HER1, c-erbB2/HER2, HER3, and HER4 [2,3]. Breast cancers overexpressing the human epidermal growth factor receptors, HER1 (EGFR/ c-erbB-1) or HER2 (neu-c-erbB-2), have been associated with disease progression, survival, stage and treatment response [4]. HER2 expression in breast cancer tissue is indicative of an aggressive pathology and it is considered a marker of poor prognosis. > The development of trastuzumab and lapatinib has improved the way for women with HER2-positive disease [5][6]. > The targeted therapy of Trastuzumab represents the standard treatment for breast cancer patients with HER2 positive [7]. There has been increasing evidence that the immune system plays a significant role in the therapeutic effects of HER2-targeted therapy [8].

[5] Construction of a human epidermal growth factor receptor 2-related gene risk model for predicting breast cancer prognosis

  • Authors: Limin Huang, Chunhong Xu, Yining Song, F. Sun, Xuemei Sun et al.
  • Year: 2025
  • Venue: Oncology Letters
  • URL: https://www.semanticscholar.org/paper/10d68928636e88ffc221bc3d48135d918831b1a8
  • DOI: 10.3892/ol.2025.15414
  • PMID: 41383978
  • PMCID: 12690547
  • Summary: It was found that patients in the high-risk group had significantly shorter survival times than those in the low-risk group, and a nomogram, incorporating risk groups and clinicopathological features, demonstrated strong predictive ability and high accuracy.
  • Evidence snippets:
  • Snippet 1 (score: 0.499) > Therefore, in the present study, the molecular mechanisms of the key gene ELOVL2 in HER2-positive breast cancer were preliminarily explored. The results showed that ELOVL2 overexpression inhibited the proliferation of HER2-positive breast cancer cells by inhibiting the PI3K-AKT pathway, suggesting that ELOVL2 is a potential target gene for the treatment of patients with HER2-positive breast cancer, laying the foundation for targeted therapy and improving the clinical adaptability of this model. > However, the current study has several limitations. First, the small sample size may have affected the accuracy of the results. Second, the molecular mechanisms of key genes affecting the prognosis of patients with HER2-positive breast cancer require further exploration. Third, the screened drugs must be validated experimentally. Therefore, future studies should collect additional cases, include a larger number of clinical samples, and conduct relevant clinical studies to provide effective personalized treatment plans or targeted therapies for patients and to improve their prognosis. > In conclusion, a valuable prognostic model that included eight HER2-related genes was developed in the current study. This model could accurately evaluate the survival rate of patients with HER2-positive breast cancer, and provide effective indicators or therapeutic targets for HER2-positive breast cancer. The present findings provide a new direction for the development of novel immunotherapeutic targets and personalized treatment for HER2-positive breast cancer.

[6] Targeted Therapeutic Options and Future Perspectives for HER2-Positive Breast Cancer

  • Authors: A. Ferrando-Díez, E. Felip, A. Pous, Milana Bergamino Sirvén, M. Margelí
  • Year: 2022
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/400fa20871992d6e43674daf76cd66ca0515696a
  • DOI: 10.3390/cancers14143305
  • PMID: 35884366
  • PMCID: 9320771
  • Citations: 36
  • Summary: The milestones that have had an impact on this disease up to their implementation in clinical practice are intended to understand and the role that modulation of the immune response might play in treatment and prognosis is focused on.
  • Evidence snippets:
  • Snippet 1 (score: 0.497) > Simple Summary The development of several antiHuman Epidermal Growth Factor Receptor 2 (HER2) treatments over the last few years has improved the landscape of HER2-positive breast cancer. Despite this, relapse is still the main issue in HER2-positive breast cancer. The reasons for therapeutic failure lie in the heterogeneity of the disease itself, as well as in the drug resistance mechanisms. In this review, we intended to understand the milestones that have had an impact on this disease up to their implementation in clinical practice. In addition, understanding the underlying molecular biology of HER2-positive disease is essential for the optimization and personalization of the different treatment options. For this reason, we focused on two relevant aspects, which are triple-positive disease and the role that modulation of the immune response might play in treatment and prognosis. Abstract Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immun

[7] Partial Response to Pyrotinib Plus Capecitabine in an Advanced Breast Cancer Patient with HER2 Amplification and R157W Mutation After Anti-HER2 Treatment: A Case Report and Literature Review

  • Authors: Yan-chun Qu, Yufeng Liu, Kailin Ding, Yong Li, Xiaoyu Hong et al.
  • Year: 2021
  • Venue: OncoTargets and therapy
  • URL: https://www.semanticscholar.org/paper/f9585f092f5e6fad50f311e227b947fcad414b1d
  • DOI: 10.2147/OTT.S289876
  • PMID: 33688205
  • PMCID: 7936716
  • Citations: 3
  • Summary: The small-molecule pan-HER family irreversible inhibitor pyrotinib combined with capecitabine has shown a promising effect in the treatment of HER2 mutation-induced resistance, but the molecular mechanism and efficacy need to be further verified.
  • Evidence snippets:
  • Snippet 1 (score: 0.495) > apatinib has achieved certain clinical efficacy in metastatic HER2-positive breast cancer treated with trastuzumab, but a significant proportion of patients develop disease progression due to innate or acquired resistance to lapatinib. 24,25 Studies on the molecular mechanisms of trastuzumab and lapatinib resistance 26 found that overexpression of other HER family receptors and their ligands, loss of PTEN leading to activation of the PI3K/Akt/mTOR pathway, PI3KCA mutation, and Akt mutation or amplification were common causes of drug resistance. Drug resistance has become an urgent problem. > The patient developed resistance to lapatinib combined with trastuzumab. The HER2 gene mutation was not detected before the patient received lapatinib plus trastuzumab treatment, while the R157W mutation was found in the disease progression after treatment. Moreover, by comparing the two gene test results (Table 1), only the HER2 mutation was acquired, so it was believed that the HER2 mutation was the main mechanism of drug resistance in this case. In recent years, with the gradual deepening of the understanding of HER2, it is believed that HER2 mutation plays an important role in the incidence, development and resistance of breast cancer. 27,28 The primary HER2 mutation mostly occurred in HER2 negative conditions, while in HER2 positive breast cancer the HER2 mutation mostly occurred after anti-HER2 treatment. Fang et al 6 performed HER2 full-length gene sequencing on the tissues of 198 patients with metastatic breast cancer (MBC) after multiple cycles of treatment and found that the rate of HER2 mutations in patients treated with trastuzumab was as high as 17.7%. Park et al 7 also carried out NGS tests on the tissues of 36 refractory MBC patients after multi-cycle and multi-drug treatment, and found that 5 out of 6 patients with HER2 mutation were HER2 positive and developed drug resistance after receiving anti-HER2 drugs (trastuzumab, lapatinib).

[8] A Decade of Innovation in Breast Cancer (2015–2025): A Comprehensive Review of Clinical Trials, Targeted Therapies and Molecular Perspectives

  • Authors: Klaudia Dynarowicz, D. Bartusik-Aebisher, Sara Czech, A. Kawczyk-Krupka, D. Aebisher
  • Year: 2026
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/00d888cd7d78bd5c497ea7ad83fb06be53f0b6f3
  • DOI: 10.3390/cancers18030361
  • PMID: 41681834
  • PMCID: 12897389
  • Citations: 1
  • Summary: This review summarizes the major progress made between 2015 and 2025 across all main types of breast cancer, including modern hormone therapies, drugs that block key growth pathways, treatments directed at the Human Epidermal Growth Factor Receptor 2 (HER2) protein, immunotherapies, antibody–drug conjugates, as well as emerging and primarily adjunctive photodynamic approaches.
  • Evidence snippets:
  • Snippet 1 (score: 0.491) > Hormone receptor-positive/HER2-negative (HR+/HER2−) breast cancer is the most common biological subtype, accounting for approximately 70% of all cases [28]. Its development and maintenance are closely linked to the activity of the estrogen receptor (ER) and the progesterone receptor (PR), which regulate the expression of numerous genes involved in proliferation, differentiation, and survival of mammary epithelial cells [29]. Activation of ER increases the expression of cyclin D1, initiating the formation of CDK4/6-cyclin D complexes. These complexes subsequently phosphorylate the retinoblastoma (RB) protein, releasing its inhibitory effect on the E2F transcription factor and enabling the G1-S phase transition of the cell cycle [30]. Deregulation of this mechanism results in excessive cellular proliferation and loss of cell-cycle control, representing one of the fundamental pathogenic processes in HR-positive breast cancer [31]. The HR+/HER2−subtype is typically characterized by slower disease progression and a strong dependence on hormonal signaling, which makes it particularly responsive to endocrine therapy. Over time, however, endocrine resistance may emerge, driven by mechanisms such as ESR1 mutations, activation of the PI3K/AKT/mTOR pathway, or other adaptive cellular processes [32,33]. The intricate interplay between hormonal, proliferative, and molecular signaling pathways positions HR+/HER2− breast cancer as a quintessential example of a tumor in which underlying biological processes directly dictate therapeutic responsiveness.

[9] Screening and Identification of Key Biomarkers in Acquired Lapatinib-Resistant Breast Cancer

  • Authors: S. Bao, Yi Chen, Fan Yang, Chunxiao Sun, Mengzhu Yang et al.
  • Year: 2020
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/ce98e91310c373596010ed74698f9a7ae34f3cde
  • DOI: 10.3389/fphar.2020.577150
  • PMID: 33013420
  • PMCID: 7500445
  • Citations: 8
  • Summary: Hub genes are involved in the complex mechanisms underlying AlR in breast cancer and provide favorable support for treatment of ALR in future, according to analysis of seven hub genes.
  • Evidence snippets:
  • Snippet 1 (score: 0.483) > Based on molecular markers, breast cancer is divided into four subgroups: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 (HER2)-enriched (Perou et al., 2000). Receptor tyrosine-protein kinase HER2, also known as erbB-2, is included in the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (Oh and Bang, 2020). HER2 is overexpressed in 20%-25% of breast cancer patients. HER2 over-expression is known as an aggressive tumor phenotype and is associated with worse survival (Parakh et al., 2017). Lapatinib, a reversible tyrosine kinase inhibitor with specificity for both EGFR and HER2, is approved for treating HER2-positive metastatic breast cancer after disease progression with trastuzumab therapy (Gradishar, 2013;Moasser and Krop, 2015). Compared with capecitabine monotherapy, lapatinib in combination with capecitabine improved objective response rate and progression-free survival (Geyer et al., 2006). Despite the effectiveness of lapatinib in HER2-positive breast cancer, acquired resistance remains a major clinical obstacle. D'Amato et al. have pointed out multiple mechanisms of ALR in breast cancers, including activation of compensatory pathways, mutation of the HER2 kinase domain, and gene amplification (D'Amato et al., 2015). Critically, there are currently no definite biomarkers to predict patients' responses to lapatinib. > With the development of gene sequencing and bioinformatics, increasing number of genetic studies have revealed the mechanism of tumorigenesis and drug resistance. By introducing microarray data and bioinformatic analysis that have been widely applied to investigate whole expression of genes in cancer, researchers have deepened their understanding of the differentially expressed genes (DEGs) and functional enrichment analysis among the complex diseases (Zhu et al., 2017). Although there are some bioinformatic studies corresponding to resistance to anti-HER2 therapies, scarce data and different laboratory conditions make it difficult to acquire reliable results.

[10] Use of a genetically engineered mouse model as a preclinical tool for HER2 breast cancer

  • Authors: H. Creedon, L. A. Balderstone, M. Muir, Jozef Balla, L. Gómez-Cuadrado et al.
  • Year: 2016
  • Venue: Disease Models & Mechanisms
  • URL: https://www.semanticscholar.org/paper/24515bdfdb4e1ac794736671d5eb6b8d00faeb3c
  • DOI: 10.1242/dmm.023143
  • PMID: 26721874
  • PMCID: 4770148
  • Citations: 12
  • Summary: The utility of a transgenic mouse model of HER2-driven breast cancer (MMTV-NIC) to define mechanisms of resistance to a pan-HER family inhibitor AZD8931 and identifies a link with EMT is demonstrated.
  • Evidence snippets:
  • Snippet 1 (score: 0.480) > Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression occurs in around 20% of breast cancers and is associated with poor prognosis. Several drugs capable of specifically targeting the HER2 pathway have been developed for use in both early and late HER2-positive disease and have had a significant impact on the treatment of HER2-positive breast cancer ; these include antibodies directed against HER2, such as trastuzumab and pertuzumab, and small molecule tyrosine kinase inhibitors that target the kinase activity of HER2 and HER1, such as lapatinib. Although initial response rates to the current HER2-targeted therapies are good, resistance is inevitable. Further tyrosine kinase inhibitors, including AZD8931 (sapatinib) and neratinib, have been developed in an attempt to improve efficacy rates and the duration of response. Preclinical studies have identified numerous mechanisms of both de novo and acquired resistance (Creedon et al., 2014;Rexer and Arteaga, 2012), although their clinical validation has been more difficult, which reflects the inability of the conventional cell-based approaches to model the complexity of the human disease adequately. > The limitation of conventional cell culture and mouse xenograft studies is well recognized as an obstacle to the effective translation of preclinical findings into clinical benefit (Sharpless and Depinho, 2006). Use of genetically engineered models in which tumours develop in situ in the context of an intact microenvironment is a viable alternative for preclinical assessment of both drug response and mechanisms of resistance (van Miltenburg and Jonkers, 2012). Generation of autochthonous tumours driven by cell-specific expression of oncogenic drivers or loss of tumour suppressors relevant to human tumours gives rise to tumours in which the histopathology and disease progression also recapitulate many aspects of the human disease, providing more relevant models with which to study drug response. > Here, we describe the use of a HER2-driven model of mammary tumorigenesis as a preclinical tool to study response and resistance mechanisms in HER2-positive breast cancer. We have used the MMTV-NIC (Neu-

[11] CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer

  • Authors: F. Xing, Hongli Gao, Guanglei Chen, Lisha Sun, Jiayi Sun et al.
  • Year: 2023
  • Venue: Molecular Cancer
  • URL: https://www.semanticscholar.org/paper/45639c735cdb62b0c3cbeaf290334def38df7947
  • DOI: 10.1186/s12943-023-01716-y
  • PMID: 36627608
  • PMCID: 9830830
  • Citations: 42
  • Summary: Findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTLF-like MARVEL transmembrane domain-containing 6 as a potential prognostic marker and therapeutic target for overcomingtrastuzuab resistance in HER2+ breast cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.480) > Globally, breast cancer (BC) has replaced lung cancer as the most commonly diagnosed cancer in women, with an estimated 2.26 million new cases in 2020 [1]. BC is the leading cause of cancer-related mortality in females [2]. Disease progression after therapy and metastatic disease are the underlying causes of death in the majority of patients. > BC originates in epithelial cells of the mammary glands. Based on gene expression profiling and molecular pathology, BC can be classified into four subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2+), and basal-like tumors. HER2+ BC accounts for 15-20% of all BC cases [3]. HER2+ BC is biologically and clinically aggressive, resistant to chemotherapy and hormone therapy, and associated with disease relapse, metastasis, and poor prognosis [4]. There is a urgent need for understanding the mechanisms underlying HER2-driven aggressiveness and drug resistance in BC to inform the development of more efficacious treatment regimens. > HER2 is a transmembrane tyrosine kinase receptor that belongs to the human epidermal growth factor (EGF) receptor family [5]. HER2 can be activated in a liganddependent or independent manner. HER2 overexpression serves as an oncogenic driver in the progression of BC, promoting constitutive activation of downstream signaling cascades that induce cell proliferation through the Ras-mitogen-activated protein kinase (MAPK) pathway, or inhibit cell death through the phosphatidylinositol 3′-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway [6,7]. > Trastuzumab, a humanized HER2-specific antibody drug, has changed the treatment paradigm for patients with HER2+ BC. Trastuzumab was approved in 1998 as the first anti-HER2 target therapy in metastatic HER2+ invasive BC [8]. Trastuzumab is currently used for adults with node-negative or node-positive HER2+ BC alone or in combination with anthracycline-or taxane-based chemotherapy [9].

[12] Prevalence and Outcomes of HER2-Low Versus HER2-0 Status in Patients with Metastatic Breast Cancer

  • Authors: Akshara Singareeka Raghavendra, Diane D Liu, S. Damodaran, S. Pasyar, Yu Shen et al.
  • Year: 2026
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/e8f237fcf852db5e15dc4c5470aacca8e0549b2e
  • DOI: 10.3390/cancers18020253
  • PMID: 41595172
  • PMCID: 12838560
  • Summary: It is found that HER2-low disease was common in both de novo and recurrent metastatic settings and was associated with longer overall survival compared with HER2-0 disease, supporting routine reassessment of HER2 status in metastatic breast cancer prior to changing therapy when feasible and underscore the need for more accurate and reproducible methods to measure low levels of HER2 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.479) > Since the US Food and Drug Administration (FDA) granted approval for T-DXd in patients with HR+/HER2-ultralow metastatic breast cancer on 27 January 2025, the distinction between HER2-0 and HER2ultralow has become clinically relevant. > The HER2 gene, also known as ERBB2, encodes the HER2 receptor protein, a transmembrane tyrosine kinase receptor that plays a crucial role in regulating cell growth, differentiation, and survival. Normal breast epithelial cells typically have one copy of the HER2 gene on each chromosome 17 and express HER2 protein at detectable levels [9]. When amplified or overexpressed, the HER2 gene drives oncogenic signaling that promotes proliferation, survival, and malignant transformation in breast cancer [10]. Historically, HER2-positive breast cancer, representing about 20% of all breast cancer cases, is characterized by high HER2 protein expression [11] and has been associated with aggressive tumor behavior and poorer clinical outcomes. > Breast cancer with low levels of HER2 protein expression below the positivity threshold represents a substantial proportion of cases, estimated to be around 40-50%, [12] and was previously categorized as HER2-negative. However, HER2-low breast cancer exhibits unique molecular characteristics that distinguish it from both HER2-positive and HER2negative subtypes. Gene expression profiling studies [13,14] have revealed differences in the genomic aberrations like copy number alterations and transcriptomic profiles of HER2-low breast tumors, indicating distinct signaling pathways; however, some studies [15,16] have shown no genomic difference between HER2-0 and HER2-low tumors. This heterogeneity suggests that distinct mechanisms may drive the growth and progression of HER2-low breast cancer, requiring tailored treatment strategies. > The main goals of this study were to measure the prevalence of HER2-low status (IHC 1+ or IHC 2+ and fluorescence in situ hybridization [FISH] negative) in a large cohort of patients with MBC, identify clinicopathological/treatment associations, and compare overall survival (OS) between patients with HER2-0 (IHC 0) and HER2-low MBC.

[13] The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review

  • Authors: Hanyi Zhong, Ziling Zhou, Han Wang, Ruo Wang, K. Shen et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/084bdeb907da87efa38b570773bb1a7aabe7ba30
  • DOI: 10.3390/ijms252413376
  • PMID: 39769140
  • PMCID: 11677710
  • Citations: 33
  • Influential citations: 1
  • Summary: Current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives are summarized, providing new insights for advancing targeted therapies in HER2+ BC.
  • Evidence snippets:
  • Snippet 1 (score: 0.474) > Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC.

[14] New developments in the treatment of HER2-positive breast cancer.

  • Authors: R. Nahta
  • Year: 2012
  • Venue: Breast cancer
  • URL: https://www.semanticscholar.org/paper/b85b07bb525a22e6926e3f9730c7265c827548fd
  • DOI: 10.2147/BCTT.S24976
  • PMID: 23869176
  • Citations: 18
  • Influential citations: 1
  • Summary: The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches, and may ultimately improve treatment of Her2-positive breast cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.473) > Multiple molecular mechanisms have been proposed to contribute to trastuzumab resistance (Figure 2). At the receptor level, mutations in the HER2 kinase domain have been associated with reduced response to trastuzumab in nonsmall cell lung cancer, 52,53 but this has not been reported in breast cancer. In addition, cell culture studies suggested that resistance is not due to changes in HER2 gene amplification, nor to reduced expression of the HER2 protein on the cell surface. 54 However, recent clinical studies suggest that metastatic lesions from primary HER2-positive breast cancers do not always maintain HER2 amplification. 55,56 In one study, up to one-third of patients with significant residual disease remaining after neoadjuvant trastuzumab-based therapy showed loss of HER2 amplification in association with poor survival rates. 55 Another study showed that 43 of 182 patients (24%) with HER2-positive primary tumors had HER2negative metastatic tumors. 56 Another plausible mechanism by which tumors may escape trastuzumab anticancer activity is epitope masking, meaning that the drug (trastuzumab) cannot recognize or physically interact with the antigen (HER2). Whether epitope masking is a clinically relevant mechanism remains unclear. However, preclinical studies suggest membrane proteins that interact with HER2 may impede accessibility of the epitope by trastuzumab. For example, MUC4 is a transmembrane glycoprotein that is overexpressed in some breast tumors. MUC4 interacts with and activates HER2, 57 impeding binding of trastuzumab to HER2. Exposure of cells to anti-MUC4 antibodies further reduced trastuzumab-HER2 interactions, suggesting that the mechanism of MUC4-mediated resistance is steric hindrance of the HER2-trastuzumab interaction. Partial masking of HER2 by MUC4 has been shown in a HER2-positive breast cancer cell line that has primary resistance to trastuzumab (JIMT1). 58

[15] Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

  • Authors: A. Moghaddas, A. Borhani
  • Year: 2016
  • Venue: Journal of Research in Pharmacy Practice
  • URL: https://www.semanticscholar.org/paper/8050a5680b6c550e4e7e8a5d9de570b35fc7dee0
  • DOI: 10.4103/2279-042X.192458
  • PMID: 27843957
  • PMCID: 5084478
  • Citations: 1
  • Summary: There is a paucity of data over the clinical evaluation of T-DM1 in human studies of non-breast cancer patients, so performing large and well-designed trials in this area is matter of interest and highly recommended.
  • Evidence snippets:
  • Snippet 1 (score: 0.471) > It has suggested that up to 20%, 9%, 30% of gastric, bladder, and uterine carcinosarcomas, respectively, overexpress HER2 and is associated with significantly worse outcomes. [23,31,34] n comparison to HER2 positive breast cancer by near 30% overexpression, [5] these quantities are large enough to be considering in treatment modalities. > By developing the new concern around trastuzumab resistance and on the other hand, documented efficacy of T-DM1 as better therapeutic option, T-DM1 is now in the spotlight. This review has discussed just some of the limited data showing the preclinical benefits of T-DM1 for treating HER2-positive non-breast cancer. All in vitro and in vivo study confirmed that T-DM1 administration led to prolonging overall survival and progression-free survival. Hence, by considering these promising results, it is time to assessed clinical responses by designing Phase I/II clinical trials. If future clinical results can demonstrate the similar results as preclinical data, then new era in the treatment of any HER2-positive non-breast cancer and survival prolongation will be created. > In March 2011, based on the results of the ToGA trial, [24] trastuzumab was intensively approved in gastric cancer. The introduction of trastuzumab made new term in gastric cancer entitled "HER2-positive gastric cancer," similar to HER2-positive breast cancer. This discovery gives us a clue that HER2-positive non-breast cancers are developing and identifying. Finding new agents for treatment of them are important future issues. > As an example, new advancing in the knowledge of urothelial carcinoma pathophysiology and underlying molecular mechanisms showed the most relevant molecular pathways that might demonstrate therapeutic potential. [34] The most important relevant overactive signaling networks are fibroblast growth factor receptor, PI3K/AKT/mTOR, and HER2. Any development in identifying the signaling networks on each cancer types leads to use of another possible effective treatment modality in the future. Furthermore, if clinical trials reach to same prominent results as we reviewed.

[16] Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case

  • Authors: E. Martinelli, T. Troiani, V. Sforza, G. Martini, C. Cardone et al.
  • Year: 2018
  • Venue: ESMO Open
  • URL: https://www.semanticscholar.org/paper/93a1dd02fd70dc7331d320f30960a5519aa78cc9
  • DOI: 10.1136/esmoopen-2017-000299
  • PMID: 29387480
  • PMCID: 5786925
  • Citations: 30
  • Summary: The clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies is reported, suggesting that sequential HER2 blockade could be a potential therapeutic strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.470) > Background Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients. Patient and methods HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay). Results We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease. Conclusion The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy.
  • Snippet 2 (score: 0.470) > Background Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients. Patient and methods HER2 gene amplification and HER2 protein overexpression analysis were performed in tumour tissue by fluorescence in situ hybridisation and immunohistochemistry. HER2 positivity was defined according to HERACLES CRC-specific HER2 scoring criteria. DNA analysis for multiple assessment of gene mutations or amplifications was carried out with the next-generation sequencing (NGS) Ion AmpliSeq Colon and Lung Cancer Panel and by using a more extensive targeted high-multiplex PCR-based NGS panel (OncoMine Comprehensive Assay). Results We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control. HER gene amplification was confirmed by NGS on two different metastatic lesions during the evolution of the disease. Conclusion The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy.

[17] Activation of PI3K/AKT/mTOR Pathway Causes Drug Resistance in Breast Cancer

  • Authors: Chao Dong, Jiao Wu, Yin Chen, J. Nie, Ceshi Chen
  • Year: 2021
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/1647736f4fbb0926492106e8551330e67e7734cc
  • DOI: 10.3389/fphar.2021.628690
  • PMID: 33790792
  • PMCID: 8005514
  • Citations: 312
  • Influential citations: 4
  • Summary: The critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3k/AKt/m TOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.469) > Breast cancer is the leading cause of cancer death in women around the world (Siegel and Miller, 2020). At the molecular level, breast cancer is a heterogeneous disease, divided into hormone/ estrogen-receptor-positive (HR+/ER+), human epidermal growth factor receptor-2-positive (HER2+) and ER/PR/HER2 triple-negative breast cancer (TNBC) with corresponding treatment strategies according to molecular subtypes (Nagini, 2017). Common treatments include endocrine therapy (ET) for HR+ disease, HER2 targeted therapy for HER2+ disease, chemotherapy, and immunotherapy for TNBC patients as well as PARP inhibitors for BRCA-mutated TNBC patients. Acquired resistance leads to tumor relapse in breast cancer, which is associated with multiple but relatively independent mechanisms, including overexpression of breast cancer resistance protein (BCRP, also called ABCG2), modification of cell cycle checkpoints, inhibition of apoptosis, and activation of multiple signaling pathways (Kartal-Yandim et al., 2016). > The PI3K/AKT/mTOR pathway has emerged as a novel target for overcoming drug resistance in recent years (Keegan et al., 2018;Verret et al., 2019). Dysregulation of this pathway is closely related to tumor progression and resistance to standard therapies in breast cancer (Guerrero-Zotano et al., 2016). The PI3K/AKT/mTOR pathway is one of the most frequently activated pathways in several types of cancers (Alzahrani, 2019). This is also one of the most important reasons for intrinsic resistance. Several drugs against the PI3K/AKT/mTOR pathway are in clinical development. In this review, we summarize the current knowledge of the PI3K/AKT/mTOR pathway related to drug resistance in breast cancer and propose an effective drug development strategy.

[18] ‘Breast Cancer Resistance Likelihood and Personalized Treatment Through Integrated Multiomics’

  • Authors: S. Mehmood, M. Faheem, Hammad Ismail, S. M. Farhat, Mahwish Ali et al.
  • Year: 2022
  • Venue: Frontiers in Molecular Biosciences
  • URL: https://www.semanticscholar.org/paper/c542ec176c594aeddb3790bb3d10767598b86ae4
  • DOI: 10.3389/fmolb.2022.783494
  • PMID: 35495618
  • PMCID: 9048735
  • Citations: 19
  • Influential citations: 1
  • Summary: This review has summarized therapeutic resistance associated with BC and the techniques used for its management, and identifies the biomarkers of disease progression and treatment progress by collective characterization and quantification of pools of biological molecules within and among the cancerous cells.
  • Evidence snippets:
  • Snippet 1 (score: 0.468) > Breast cancer is a very complex and heterogeneous disorder with unique molecular and morphological features relative to a disease which involves only a single gene or protein in a simple signaling pathway contributing toward the progression of disease in an independent and autonomous manner (Organization 2019). Various studies had represented BC heterogeneity through the differential response of the same type of BC patients to treatment and risk of developing side effects. One of the major clinical complications in the treatment of breast carcinoma patients is the development of therapeutic resistance (Luque-Bolivar et al., 2020). Recently drug resistance in BC treatment is not properly addressed, rather to focus on molecular pathways deeply; an alternative strategy of using a different drug is commonly applied. In order to reduce the adverse effects of BC treatment including drug resistance, a profound understanding of the molecular mechanism of the disease and the response to the drug is needed. Multidrug resistance (MDR) and consequent relapse on therapy are prevalent issues related to breast carcinoma as our understanding is incomplete related to the molecular mechanism of breast carcinoma disease (Waks and Winer, 2019a). Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. For the management of breast cancers, the treatment decision not only depends on the Treatment with exemestane alone or in combination with an mTOR inhibitor such as everolimus (Carlini et al., 2007Chin et al., 2007Geisler et al., 2008Bahrami et al. (2020) ER+/ HER2- assessment of prognosis factors but also on the evaluation of pathological and clinical factors. Integrated data assessments of these multiple factors of breast carcinoma through multiomics can provide significant insight and hope for making therapeutic decisions (Parsons and Francavilla 2020). Major BC treatment strategies rely on the tumor subtype, immunohistochemical evaluation of prognostic elements, and seek new genetic markers to improve the diagnostic strategies and to enhance treatment outcomes with minimal side effects.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.