Association between the founder brazilian TP53 p.R337H mutation and HER2-positive status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22154-e22154
Author(s):  
Juliana Giacomazzi ◽  
Marcia S. Graudenz ◽  
Cynthia ABT Osorio ◽  
Patricia Koehler-Santos ◽  
Edenir Inez Palmero ◽  
...  
Keyword(s):  
General Population ◽  
Early Onset ◽  
Growth Factor Receptor ◽  
Tp53 Gene ◽  
Family Counseling ◽  
Her2 Positive ◽  
Tp53 Mutations ◽  
Mutation Carriers ◽  
Exploratory Approach ◽  
Epidermal Growth

e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8.9%) were mutation carriers. These cases were recruited from 3 centers and HER2 analysis was performed by immunohistochemistry (IHC) in each center according to validated protocols. Statistical analysis was done using SPSS software. Results: In 47 of 64 mutation carriers (73.5%), BC showed HER expression (either 1+, 2+ or 3+) while among 654 non-carriers, this immunophenotype was observed in 320 (48.9%) (p<0.001). This pattern was still observed after stratification of groups according to age at diagnosis (≤45 and ≥55 years) (p<0.001 and 0.03, respectively) and was independent of recruiting center. Conclusions: These results indicate that BC developing on a background of the founder Brazilian TP53 p.R337H mutation shows more frequently some amplification of HER2, consistent with recent studies showing an association between germline TP53 mutations and BC with HER2 hyperexpression. These findings should be confirmed in larger series to understand the significance of the association. If confirmed, this finding may justify germline TP53 p.R337H mutation testing in all HER2-positive Brazilian BC patients and would have a significant impact on patient and family counseling as well as on treatment.

scholarly journals Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 400 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hisato Kawakami
Keyword(s):  
Gastroesophageal Junction ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Gastroesophageal Junction Cancer ◽  
Development Of Resistance ◽  
Epidermal Growth ◽  
Antibody Drug

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

scholarly journals Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial

2021 ◽  
Vol 13 ◽  
pp. 175883592110090
Author(s):  
Hong-Fei Gao ◽  
Zhiyong Wu ◽  
Ying Lin ◽  
Xiang-Yang Song ◽  
Yin Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Primary Endpoint ◽  
Growth Factor Receptor ◽  
Group Versus ◽  
Complete Response ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Background: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. Methods: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). Results: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8–50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3–67.9) in the TCH group ( p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group ( p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group ( p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group ( p = 0.006). Conclusion: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. Trial registration: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

scholarly journals Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3427
Author(s):  
Reyhaneh Farghadani ◽  
Rakesh Naidu
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Progesterone Receptors ◽  
Drug Candidate ◽  
Molecular Signaling ◽  
Her2 Positive ◽  
Therapeutic Implications ◽  
Epidermal Growth

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.

scholarly journals Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3939
Author(s):  
Tianqi Xu ◽  
Anzhelika Vorobyeva ◽  
Alexey Schulga ◽  
Elena Konovalova ◽  
Olga Vorontsova ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor Receptor ◽  
Repeated Administration ◽  
Ovarian Cancer Cells ◽  
Her2 Positive ◽  
Efficient Treatment ◽  
Pseudomonas Exotoxin A ◽  
Epidermal Growth

Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targeting component. As the EpCAM-targeting component, we investigated the designed ankyrin repeat protein (DARPin) Ec1 fused to a truncated variant of Pseudomonas exotoxin A with reduced immunogenicity and low general toxicity (LoPE). Ec1-LoPE was radiolabeled, evaluated in ovarian cancer cells in vitro and its biodistribution and tumor-targeting properties were studied in vivo. The therapeutic efficacy of Ec1-LoPE alone and in combination with trastuzumab was studied in mice bearing EpCAM- and HER2-expressing SKOV3 xenografts. SPECT/CT imaging enabled visualization of EpCAM and HER2 expression in the tumors. Co-treatment using Ec1-LoPE and trastuzumab was more effective at reducing tumor growth and prolonged the median survival of mice compared with mice in the control and monotherapy groups. Repeated administration of Ec1-LoPE was well tolerated without signs of hepatic or kidney toxicity. Co-treatment with trastuzumab and Ec1-LoPE might be a potential therapeutic strategy for HER2- and EpCAM-positive OC.

scholarly journals Optimum duration of adjuvant trastuzumab in treatment of human epidermal growth factor receptor-2 positive early breast cancer: protocol for a network meta-analysis of randomised controlled trials

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e035802
Author(s):  
Qiancheng Hu ◽  
Xin Wang ◽  
Ye Chen ◽  
Xiaofen Li ◽  
Ting Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Early Breast Cancer ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

IntroductionControversy regarding optimum duration of trastuzumab treatment remains in patients with human epidermal growth factor receptor-2 (HER2) positive early breast cancer. The objective of applying network meta-analysis (NMA) is to integrate existing evidence based on direct and indirect comparisons of efficacy and safety, and then to determine the duration of trastuzumab treatments with the greatest impact on therapeutic outcomes in HER2-positive early breast cancers.Methods and analysisElectronic searching of trastuzumab treatments for early breast cancer by titles and abstracts will be conducted for the period from inception to 16 June 2019 in PubMed, Cochrane Library, Embase and ClinicalTrils.gov, as well as the annual meetings of San Antonio Breast Cancer Symposium (SABCS), European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) online archives. The outcomes of interest are overall survival, disease-free survival, acceptability, cardiotoxicities and grade 3 to 4 non-haematological toxicities. Two independent reviewers will screen and extract eligible data based on the inclusion and exclusion criteria, and then assess the risk of bias and evidence quality of individual studies using Cochrane Collaboration’s tool and Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The heterogeneity, transitivity and inconsistency of NMA will be evaluated. In addition, we will perform subgroup and sensitivity analyses to assess the robustness and reliability of findings in our NMA.Ethics and disseminationEthics approval is not required for our NMA. Findings from our NMA will be submitted as peer-reviewed journal manuscripts and international conference reports.Trial registration numberCRD42019139109.

scholarly journals Trastuzumab administration during pregnancy: un update

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Angeliki Andrikopoulou ◽  
Kleoniki Apostolidou ◽  
Spyridoula Chatzinikolaou ◽  
Garyfalia Bletsa ◽  
Eleni Zografos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
First Trimester ◽  
Systemic Review ◽  
Third Trimester ◽  
Her2 Positive ◽  
Exact Test ◽  
Metastatic Setting ◽  
Epidermal Growth

Abstract Background Over than one third (28–58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. Methods Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words “breast”, “cancer”, “trastuzumab” and “pregnancy”. This study was performed in accordance with the PRISMA guidelines. Results A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1–32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher’s exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. Conclusions Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

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