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 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.

scholarly journals Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro

2021 ◽  
Vol 22 (20) ◽  
pp. 11273
Author(s):  
Natalia Magdalena Lisiak ◽  
Izabela Lewicka ◽  
Mariusz Kaczmarek ◽  
Jacek Kujawski ◽  
Barbara Bednarczyk-Cwynar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biological Activity ◽  
Cancer Cells ◽  
Oleanolic Acid ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells.

Survival Outcomes In Human Epidermal Growth Factor Receptor 2 (HER 2) Positive Breast Cancer Patients At Kenyatta National Hospital

2021 ◽  
Author(s):  
Gloria Tuwei ◽  
Amsalu Degu
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
Cancer Patients ◽  
Survival Outcomes ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Predictors Of Mortality ◽  
Her2 Positive Breast Cancer ◽  
The Mean ◽  
Positive Breast Cancer

Abstract Background: For several years, HER2-positive breast cancer was associated with poor outcomes and higher mortality rates than other breast cancer subtypes. Nevertheless, the advent of Trastuzumab has significantly changed the treatment paradigm of HER2-positive breast cancer. However, it is not an affordable treatment option in sub-Saharan African countries. Besides, there was a lack of comprehensive data about the survival outcomes of HER2-positive breast cancer patients in our setting. Hence, the present study aimed to determine the survival outcomes among HER2-positive breast cancer patients at the Oncology Department of Kenyatta National Hospital.Methods: A hospital-based retrospective cohort design was used to evaluate the survival outcomes, and associated factors among patients with HER2-positive breast cancer admitted between 2015 and 2019 at Kenyatta National Hospital. A total of 50 eligible HER2-positive breast cancer patients were included in the study. In the pre-designed data abstraction tool, the data were collected by reviewing the medical records of the patients. The data were entered and analyzed using the Statistical Package for the Social Sciences version 27 software. The mean survival time was estimated using Kaplan Meier survival analysis. Cox regression analysis was employed to estimate the predictors of mortality among HER2-positive breast cancer patients.Results: The study showed that the overall survival rate was 30%, with a significant decrease in the percentage survival rate across the five years. More than half of the study participants (26, 52%) showed cancer progression during the last follow-up period. The present study showed that the mean cancer-specific survival rate among the study patients was 26.74±18.395 months. The study showed that the mean survival time of patients aged below 60 years (32.513 months), without co-morbidities (34.40 months), and the early stage of the disease (50.639 months) was higher than their counterparts. Multivariate cox-regression analysis revealed that advanced stage (AHR=13.1, 95% CI=2.6-66.6, P=0.002 and distant metastasis (AHR=15.0, 95% CI=3.6-62.8, P≤0.001) were the significant predictors of mortality among HER2 positive breast cancer patients.Conclusions: The overall survival rate of HER 2 positive breast cancer was 30%. Advanced stage and distant metastasis were the significant predictors of mortality among HER2-positive breast cancer patients.

scholarly journals 227P Cardiotoxicity in HER2 positive breast cancer patients treated with trastuzumab

2020 ◽  
Vol 31 ◽  
pp. S332
Author(s):  
M. Lopez ◽  
C. Minguito Carazo ◽  
I. Delgado Sillero ◽  
M. Rojas Piedra ◽  
B. Távara Silva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer
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