Neratinib for the treatment of early-stage, hormone receptor-positive, HER2-overexpressed breast cancer

2020 ◽  
Vol 16 (17) ◽  
pp. 1165-1177
Author(s):  
Yolanda Jerez ◽  
Blanca Herrero ◽  
Marta Arregui ◽  
Blanca Morón ◽  
Miguel Martín ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Future Directions ◽  
Her2 Positive Breast Cancer ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

HER2-positive breast cancer accounts for 18–20% of all breast cancers. Despite significant advances and the currently available adjuvant treatments for management of the disease, approximately 25% of HER2-positive early-stage breast cancer patients show relapse and die. Neratinib is an irreversible tyrosine kinase inhibitor. Multiple studies have reported its significant antitumor activity in metastatic HER2-positive breast cancer. It is administered orally and has also been tested in the adjuvant setting. In this article, we present a comprehensive review of the pharmacokinetics and pharmacodynamics of neratinib as well as its clinical efficacy, with an emphasis on early HER2-positive breast cancer and suggestions for future directions for neratinib research.

scholarly journals Suboptimal Therapy Following Breast Conserving Surgery in Triple Negative and HER2-Postive Breast Cancer Patients

2021 ◽  
Author(s):  
Jeffrey E. Johnson ◽  
Paula D Strassle ◽  
Guilherme C de Oliveira ◽  
Chris B. Agala ◽  
Philip M. Spanheimer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Systemic Therapy ◽  
Triple Negative ◽  
Early Stage ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Optimal Therapy ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Purpose To assess potential disparities in guideline-concordant care delivery among women with early stage triple-negative and HER2-positive breast cancer treated with breast conserving therapy. Methods Women ≥40 years old diagnosed with pT2N0M0 triple-negative or HER2-positive breast cancer treated with primary surgery and axillary staging between 2012 and 2017 were identified using the National Cancer Database (NCDB). The primary outcome was receipt of adjuvant systemic therapy and radiation concordant with current guidelines. Multivariable log binomial regression was used to assess the prevalence of optimal therapy use across patient and cancer characteristics. Kaplan-Meier curves were used to assess 5-year overall survival. Multivariable Cox proportional hazards regression was used to compare the impact of optimal therapy on 5-year mortality. Results 11,785 women were included with 7,843 receiving optimal therapy. Receipt of optimal therapy decreased with age even after adjusting for comorbidities and cancer characteristics; other sociodemographic factors were not associated with differences in receipt of optimal therapy. Among patients who did not receive adjuvant systemic therapy, most were not offered the treatment (49%) or refused (40%). Overall 5-year survival was higher among women who received optimal therapy (89% [95% CI 88.0-89.3] vs. 66% [95% CI 62.9-68.5]). Patients who received suboptimal therapy were over twice as likely to die within 5-years of their diagnosis (adjusted HR 2.44, 95% CI 2.12-2.82). Conclusion Age is the primary determinant of the likelihood of a woman to receive optimal adjuvant therapies in high-risk early stage breast cancer. Patients who did not receive optimal therapy had significantly diminished survival.

Increased FoxP3 and PD-L1 in non-pCR tissue from early stage HER2 positive breast cancer patients treated with trastuzumab-pertuzumab based regimens.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 602-602
Author(s):  
Jeremy Meyer Force ◽  
Lynn Jackson Howie ◽  
Sara Abbott ◽  
Rex C. Bentley ◽  
Paul K. Marcom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Early Stage ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals Cardiotoxicity of concomitant radiotherapy and trastuzumab for early breast cancer

2014 ◽  
Vol 48 (2) ◽  
pp. 105-112 ◽  
Author(s):  
Tanja Marinko ◽  
Jure Dolenc ◽  
Cvetka Bilban-Jakopin
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Left Breast ◽  
Thoracic Wall ◽  
Breast Cancer Patients ◽  
Long Term Effects ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

AbstractBackground. Trastuzumab therapy given in combination with one of several chemotherapy regimens is currently considered the standard of care for the treatment of early-stage, human epidermal growth factor receptor-2 (HER2) -positive breast cancer. The treatment with trastuzumab is due to a significant impact on the survival part of the standard adjuvant treatment of patients with HER2-positive breast cancer. Patients treated with postoperative breast or chest wall irradiation receive trastuzumab concomitant with radiotherapy. In a small proportion of patients trastuzumab causes cardiotoxicity. Preclinical findings indicate a radiosensibilizing effect of trastuzumab in breast cancer cells, but it is not yet clear whether it radiosensibilizes cells of healthy tissues too.Conclusions. Special attention is required when left breast or left thoracic wall is irradiated in patient receiving trastuzumab, because long-term effects of the concurrent treatment with trastuzumab and radiotherapy are not yet known. In an era where more patients are surviving a diagnosis of breast cancer, better understanding and earlier detection of therapy-induced cardiac toxicity will be of paramount importance.

scholarly journals CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-TKI via suppressing PI3K/AKT

2020 ◽  
Author(s):  
Hui Li ◽  
Jinsong Wang ◽  
Zongbi Yi ◽  
Chunxiao Li ◽  
Haijuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
High Throughput Sequencing ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background : While anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumor progression.Methods : To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using CRISPR/Cas9 knockout technique based on data mining across TCGA datasets and verified the candidate target in pre-clinical models and breast cancer high-throughput sequencing datasets.Results : We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitize or re-sensitize HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids (PDO) in vitro and cell-derived xenograft (CDX) or patient-derived xenograft (PDX) in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumor tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harboring a markedly shortened progression free survival (PFS) (median PFS: 4.3 months verse 6.9 months; HR 2.26 [95% CI 1.32-3.86]; P=0.0028).Conclusions : Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of HER2-positive breast cancer patients by sensitizing or re-sensitizing the tumors to anti-HER2 TKIs treatment.

scholarly journals The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Zahi Mitri ◽  
Tina Constantine ◽  
Ruth O'Regan
Keyword(s):  
Breast Cancer ◽  
Cardiac Myocyte ◽  
Early Stage ◽  
Standard Of Care ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20–30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The effectiveness of Trastuzumab has been well validated in research as well as in clinical practice. The addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer. The most clinically significant side effect of Trastuzumab is the risk of cardiac myocyte injury, leading to the development of congestive heart failure. The emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive breast cancers.

Correlation between mutation landscape and clinical outcomes of neoadjuvant therapy in HER2-positive breast cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 579-579
Author(s):  
Ning Liao ◽  
Yulei Wang ◽  
Kai Li ◽  
Bo Chen ◽  
Guo-Chun Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Early Stage ◽  
Pathologic Response ◽  
Stage I ◽  
Missense Mutations ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

579 Background: The standard management of early stage human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer (BC) involves neoadjuvant therapy with combination of chemotherapy and HER2-targeted therapy followed by surgery. However, diverse pathologic responses were observed. We interrogated whether baseline genomic heterogeneity contributes to the varied therapeutic responses. Methods: Capture-based targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6MB of human genome, was performed on tissue biopsy samples, obtained prior to neoadjuvant therapy, of 33 HER2+ women with stage I-III BC. The median age of the cohort was 53. The correlation between genomic alterations and pathologic response were analyzed by multivariate analysis. Results: A majority of them was diagnosed with stage II (67%, 22/33), while 30% (10/33) had stage III and 3% (1/33) had stage I disease. 58% (19/33) were HR+ and 42% (14/33) were HR-. Mutation profiling of baseline samples revealed 349 mutations spanning 145 genes, with TP53, CDK12 and PIK3CA being the top 3 most frequently mutated genes. Neoadjuvant regimen was comprised of trastuzumab and HER2 inhibitor (i.e. pertuzumab or lapatinib). 15 patients used single HER2 inhibitor;18 used dual HER2 inhibitors. Endocrine therapy was also administered to HR+ patients (19/33) in combination with trastuzumab and HER2 inhibitor. Complete pathologic response (pCR) was observed in 45.5% (15/33) of patients. Interestingly, ROS1 copy number amplifications (CANs) were only identified in patients achieved pCR (p = 0.033). In contrast, missense mutations in PIK3CA and CNAs in CCND1, FGF19, FGF3, FGF4, SPOP, HNF1B and BRIP1 showed a trend of being less likely to mutate in pCR patients (p values between 0.05-0.1). Previous reports have suggested that pCR rates in HER2+ patients are associated with HR status. However, our data revealed comparable pathologic response of patients based on either HR status or neoadjuvant regimen. Conclusions: Our data revealed a distinct mutational profile between patients achieved pCR vs patients did not. Further studies with a larger cohort are required to confirm these findings.

scholarly journals Cost of Illness of HER2-Positive and Recurrent HER2-Positive Breast Cancer – A Danish Register-Based Study from 2005 to 2016

2021 ◽  
Author(s):  
Maria Spanggaard ◽  
Jens Olsen ◽  
Kenneth Forsström Jensen ◽  
Michael Andersson
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Healthcare Costs ◽  
Early Stage ◽  
Labour Productivity ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background: Information and knowledge about cost of illness and labour productivity in patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. The aim of this study was to estimate the direct and indirect costs associated with treatment of HER2-positive breast cancer among patients with early-stage and metastatic breast cancer, treated with trastuzumab, in a 10-year period after diagnosis. Materials and Methods: This study included all Danish HER2-positive breast cancer patients (≥18 years) treated with trastuzumab between 2005 and 2016 identified in the Danish national registers. Among this population, patients experiencing metastatic breast cancer were identified. For the study populations, we estimated total healthcare costs and indirect costs for one year prior to the breast cancer diagnosis and up to 10 years after diagnosis compared with a group of matched controls free of breast cancer.Results: We identified 4,153 HER2-positive breast cancer patients, whereof 27% were identified with metastatic breast cancer. During the follow-up period of 10 years, we estimated excess healthcare costs of EUR 115,000 among the total study population compared to controls; EUR 211,000 among patients with recurrence; and EUR 89,000 among patients without recurrence. Healthcare costs were found to be highest in the first year after diagnosis and also peaked in the year after recurrence. Labour productivity was significantly lower among patients with recurrence 10 years after breast cancer diagnosis compared with controls.Conclusions: In this study, we estimated the direct and indirect cost associated with HER2-positive breast cancer to be significantly increased during the 10 years after diagnosis, specifically among patients experiencing recurrence of breast cancer.

Expression of hormone receptors ERα, ERβ and PgR in HER2-positive breast cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10525-10525
Author(s):  
M. Litwiniuk ◽  
V. Filas ◽  
J. Moczko ◽  
R. Kaleta ◽  
J. Breborowicz
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Detection System ◽  
Statistical Significance ◽  
Her2 Status ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

10525 Background: HER-2/neu gene is amplified and overexpressed in 15–20% of invasive breast cancers. HER2-positive breast cancers have a worse prognosis than HER2-negative tumors and distinctive clinical features. They express hormone receptors for estrogen (ERα) and for progesterone (PgR) less frequently than HER2-negative tumors. The identification of the other human estrogen receptor, receptor beta (ERβ), raises a question of ERβ occurrence in HER2-positive breast cancer. Patients and methods: Formalin-fixed, paraffin embedded tissues from 90 patients with invasive HER2-positive breast cancer and from 99 patients with HER2-negative breast cancer were used in this study. The HER2 status was analyzed using HercepTest TM (IHC), and IHC 2+ results were confirmed with FISH test. Immunostaining for ERα, ERβ and PgR was performed using monoclonal antibodies against ERα, PgR (DakoCytomation) and against ERβ (CHEMICON). The EnVision detection system was applied. The data were analyzed using nonparametric Fisher-Freeman-Halton test; the statistical significance was considered when p < 0.5. Results: Only 33% of the HER2-positive breast cancers were ERα-positive compared with 63% in the HER2-negative group (p < 0.001). The expression of ERβ protein was observed in almost equal frequency in both groups (57% of HER2-positive breast cancers and 57.7% of HER2-negative tumors, p = 0.889). The expression of PgR was observed in 30% of HER2-positive breast cancers and in 68.7% of HER2-negative tumors (p < 0.001). Conclusion: The expression of ERβ (unlike that of ERα and PgR) was similar in HER2-positive and in HER2-negative breast cancers. Thus, ERβ may be a potential target in future endocrine therapy for women with HER2-positive breast cancers. No significant financial relationships to disclose.

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