scholarly journals Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Maria Gaibar ◽  
Laura Beltrán ◽  
Alicia Romero-Lorca ◽  
Ana Fernández-Santander ◽  
Apolonia Novillo
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Tyrosine Kinase Domain ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

scholarly journals Targeted Therapies in HER2-Positive Breast Cancer - a Systematic Review

Breast Care ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Amelie Schramm ◽  
Nikolaus De Gregorio ◽  
Peter Widschwendter ◽  
Visnja Fink ◽  
Jens Huober
Keyword(s):  
Breast Cancer ◽  
Targeted Therapies ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Increased Risk ◽  
Positive Breast Cancer

About 20% of all breast cancer patients have a human epidermal growth factor receptor 2 (HER2)-positive breast tumor. This entity underwent an impressive change in prognosis, with notable improvement of progression-free survival and overall survival. Due to more aggressive tumors and no specific therapy, HER2 overexpression was historically seen as a negative prognostic marker, with worse prognosis and increased risk of recurrent disease. Trastuzumab, the first anti-HER2 antibody, revolutionized the systemic therapy options in HER2-positive breast cancer and initiated several targeted therapies and more personalized treatment strategies. Over the years, multiple HER2-targeting drugs stepped into clinical practice, for the curative as well as the metastatic situation. This review summarizes the targeted treatment options in HER2-positive breast cancer and their current impact in the clinical routine. Results of the most outstanding trials in HER2-targeted therapies and important ongoing trials are subsequently described for an up-to-date overview.

scholarly journals Concurrent Mutations Associated With Trastuzumab-resistance Revealed by Single Cell Sequencing

2021 ◽  
Author(s):  
Yan Gao ◽  
Ning Wu ◽  
Shuai Wang ◽  
Xue Yang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Signaling Pathways ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Pathway Level ◽  
Positive Breast Cancer

Abstract Purpose: HER2-positive breast cancer patients benefit from HER2 targeted therapies, among which the most commonly used is trastuzumab. However, acquired resistance typically happens within one year. The cellular heterogeneity of it is less clear. Methods: Here we generated trastuzumab-resistant cells in two HER2-positive breast cancer cell lines, SK-BR-3 and BT-474. Cells at different time points during the resistance induction were examined by exome sequencing to study changes of genomic alterations over time. Single cell targeted sequencing was also used to identify resistance associated concurrent mutations.Results: We found a rapid increase of copy number variation (CNV) regions and gradual accumulation of single nucleotide variations (SNVs). On the pathway level, nonsynonymous SNVs for SK-BR-3 cells were enriched in the MAPK signaling pathway, while for BT-474 cells were enriched in mTOR and PI3K-Akt signaling pathways. However, all of the three signaling pathways were in the downstream of the HER2 kinase. Putative trastuzumab-resistance associated SNVs included AIFM1 P548L and ERBB2 M833R in SK-BR-3 cells, and OR5M9 D230N, COL9A1 R627T, ITGA7 H911Q and ADAMTS19 V451L in BT-474 cells. Single cell targeted sequencing identified several concurrent mutations. By validation, we found that concurrent mutations (AIFM1 P548L and IL1RAPL2 S546C) led to a decrease of trastuzumab sensitivity. Conclusion: Taken together, our study revealed a common pathway level trastuzumab-resistance mechanism for HER2-positive breast cancer cells. In addition, our identification of concurrent SNVs associated with trastuzumab-resistance may be indicative of potential targets for the treatment of trastuzumab-resistant breast cancer patients.

scholarly journals Trastuzumab in Combination with Traditional Chemotherapy is better than Chemotherapy Alone in HER2 Positive Breast Cancer Patients

2018 ◽  
Vol 30 (1) ◽  
pp. 30-35
Author(s):  
Md Dayem Uddin ◽  
Md Anwar Ul Islam
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Her2 Gene ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
College Hospital ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Breast cancer is one of the most common types of cancer, making up about 25% of all cancer. Despite the high incidence rates, in Western countries, 89% of women diagnosed with breast cancer are still alive 5 years after their diagnosis, which is due to proper detection and treatment. Mainly there are several types of breast cancer. One of the classes is determined by the expression of proteins or receptor and genes. Breast cancer cells may or may not have many different types of receptors, the three most important in the present classification being: estrogen receptor (ER), progesterone receptor (PR), and HER2/neuHER2/neu (human epidermal growth factor receptor 2) receptors. Cells with or without these receptors are called ER positive (ER+), ER negative (ER-), PR positive (PR+), PR negative (PR-), HER2 positive (HER2+), and HER2 negative (HER2-). Cells with negative receptors are called triple negative. Around 25% to 30% of breast cancers show amplification of the HER2 gene. Trastuzumab is a humanized monoclonal antibody targeting the extracellular domain of HER2 receptor. In the metastatic breast cancer setting, Trastuzumab significantly improves overall survival, and is responsible for a change in the natural course of this disease. In this study we have gone to assess the outcome of HER2 positive breast cancer patients with trastuzumab along with cytotoxic chemotherapy in comparison to the conventional chemotherapy. All tumours were tested for HER2/neu status. A randomized control trial was run with 130 patients having HER2 positive breast cancer in Rajshahi Medical College Hospital and different private hospitals and clinics of Rajshahi city in this study.TAJ 2017; 30(1): 30-35

scholarly journals Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3540
Author(s):  
Hamid Maadi ◽  
Mohammad Hasan Soheilifar ◽  
Won-Shik Choi ◽  
Abdolvahab Moshtaghian ◽  
Zhixiang Wang
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Cancer Patients ◽  
Mechanism Of Action ◽  
Mechanisms Of Action ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Insight Into ◽  
Positive Breast Cancer

Trastuzumab as a first HER2-targeted therapy for the treatment of HER2-positive breast cancer patients was introduced in 1998. Although trastuzumab has opened a new avenue to treat patients with HER2-positive breast cancer and other types of cancer, some patients are not responsive or become resistant to this treatment. So far, several mechanisms have been suggested for the mode of action of trastuzumab; however, the findings regarding these mechanisms are controversial. In this review, we aimed to provide a detailed insight into the various mechanisms of action of trastuzumab.

scholarly journals Safety and Clinical Evaluation of Dual Inhibition with Pertuzumab and Trastuzumab Biosimilar SB3 in HER2-Positive Breast Cancer Patients

Breast Care ◽  
2021 ◽  
pp. 1-7
Author(s):  
Christoph Suppan ◽  
Daniel Steiner ◽  
Eva Valentina Klocker ◽  
Florian Posch ◽  
Elisabeth Henzinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Her2 Positive Breast Cancer ◽  
Tumor Stages ◽  
Positive Breast Cancer

<b><i>Background:</i></b> The addition of trastuzumab to standard chemotherapy has improved survival in patients with HER2-positive breast cancer in neoadjuvant, adjuvant, and metastatic settings. In higher tumor stages, the addition of pertuzumab is now a standard of care and associated with a favorable toxicity profile. We evaluated the safety and efficacy of the trastuzumab biosimilar SB3 in combination with pertuzumab in HER2-positive breast cancer patients. <b><i>Methods:</i></b> Seventy-eight patients with HER2-positive breast cancer treated at the Division of Oncology at the Medical University of Graz were included. Summary measures are reported as medians (25th to 75th percentile) for continuous variables and as absolute frequencies (%) for count data. <b><i>Results:</i></b> Thirty-five patients received a median of 4 (3–7) cycles of trastuzumab biosimilar SB3 plus pertuzumab. All patients had a normal baseline left ventricular ejection fraction (LVEF; &#x3e;50%) prior to the initiation of SB3 plus pertuzumab treatment with a median LVEF of 60% (60–65). Twenty-one patients had a median absolute LVEF decline of 1% (–5 to 0). Two patients (5.7%) had a LVEF reduction ≤50%, but none ≥10%. There were no unexpected adverse events. Twenty-two of 35 patients (63%) were treated with trastuzumab biosimilar SB3 and pertuzumab in the neoadjuvant setting and 11 patients (50%) achieved a pathological complete response. The safety and the efficacy in this setting was comparable to the trastuzumab plus pertuzumab combination in neoadjuvantly treated matched samples. <b><i>Conclusion:</i></b> In this series of HER2-positive breast cancer patients, the combination of SB3 plus pertuzumab was consistent with the known safety and efficacy profile of trastuzumab and pertuzumab combination.

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