Her2 Positive
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2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv9-iv9
Jose Pablo Leone ◽  
Nabihah Tayob ◽  
Alyssa Pereslete ◽  
Jennifer Ligibel ◽  
Heather Parsons ◽  

Abstract BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.

2021 ◽  
pp. clincanres.1600.2021
Sara Pizzamiglio ◽  
Chiara Maura Ciniselli ◽  
Tiziana Triulzi ◽  
Chiara Gargiuli ◽  
Loris De Cecco ◽  

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Yi-Qun Han ◽  
Zong-Bi Yi ◽  
Pei Yu ◽  
Wen-Na Wang ◽  
Qu-Chang Ouyang ◽  

Objective. To better understand the status of medical treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer and the differences between the Chinese and the international clinical practice. Methods. This was a retrospective, nationwide, multicenter, epidemiological study of advanced breast cancer patients from China. Between January 01, 2012, and December 31, 2014, a total of 3649 patients, covering 7 geographic regions and 21 institutions, participated in this series of studies. HER2-positive breast cancer was selected among the group and adopted into this study. In comparison, we summarized the demographics and clinical characteristics of HER2-positive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) database. Results. A total of 918 patients diagnosed as HER2-positive breast cancer patients were included. The median age at diagnosis was 46 years (ranging, 23 to 78) with a single-peak incidence. The proportions of stages II–IV at diagnosis and distance metastasis in viscera were more than half of the participants. In comparison, the prevalence of estrogen or progesterone receptor-positive expression and luminalB subtype was relatively lower than that of the United States. The receipt of chemotherapy was fairly higher, while the usage of targeted therapy was seriously insufficient. Tumor size was in significantly positive associations with the duration of targeted therapy (Kendall’s correlation coefficient = 0.3, P < 0.0001 ), while no prohibitive variables among clinical characteristics were detected. Conclusion. Our study suggested that HER2-positive breast cancer patients were characterized as a younger trend, a lower prevalence of hormonal receptor (HR)-positive expression, and less accessible to anti-HER2 targeted therapy with insufficient duration over the past few years in China. Concerted efforts should be exerted for promising survival benefits in the future. The trial registration number is https://clinicaltrials.gov/ct2/show/NCT03047889.

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257298
Joohyun Woo ◽  
Jong Bin Kim ◽  
Taeeun Cho ◽  
Eun Hye Yoo ◽  
Byung-In Moon ◽  

The response rate to treatment with trastuzumab (Tz), a recombinant humanized anti-HER2 monoclonal antibody, is only 12–34% despite demonstrated effectiveness on improving the survival of patients with HER2-positive breast cancers. Selenium has an antitumor effect against cancer cells and can play a cytoprotective role on normal cells. This study investigated the effect of selenium on HER2-positive breast cancer cells and the mechanism in relation to the response of the cells to Tz. HER2-positive breast cancer cell lines, SK-BR-3 as trastuzumab-sensitive cells, and JIMT-1 as Tz-resistant cells were treated with Tz and sodium selenite (selenite). Cell survival rates and expression of Her2, Akt, and autophagy-related proteins, including LC3B and beclin 1, in both cell lines 72 h after treatment were evaluated. Significant cell death was induced at different concentrations of selenite in both cell lines. A combined effect of selenite and Tz at 72 h was similar to or significantly greater than each drug alone. The expression of phosphorylated Akt (p-Akt) was decreased in JIMT-1 after combination treatment compared to that after only Tz treatment, while p-Akt expression was increased in SK-BR-3. The expression of beclin1 increased particularly in JIMT-1 after only Tz treatment and was downregulated by combination treatment. These results showed that combination of Tz and selenite had an antitumor effect in Tz-resistant breast cancer cells through downregulation of phosphorylated Akt and beclin1-related autophagy. Selenite might be a potent drug to treat Tz-resistant breast cancer by several mechanisms.

Oncology ◽  
2021 ◽  
pp. 1-10
Amelie de Gregorio ◽  
Thomas Wolfram Paul Friedl ◽  
Eva Hering ◽  
Peter Widschwendter ◽  
Nikolaus de Gregorio ◽  

<b><i>Introduction:</i></b> Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. <b><i>Material and Methods:</i></b> Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (<i>n</i> = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. <b><i>Results:</i></b> 595 (64.9%) patients had a Ki67 &#x3c;20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1–90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2−) disease (<i>n</i> = 717), 20% for HR+/HER2+ (<i>n</i> = 76), 30% for HR−/HER2+ (<i>n</i> = 45), and 60% for HR−/HER2− (<i>n</i> = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (&#x3c;20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). <b><i>Conclusion:</i></b> This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.

Toheeb Adewale Balogun ◽  
Muhammad Nasir Iqbal ◽  
Oluwatosin Abideen Saibu ◽  
Michael Olawale Akintubosun ◽  
Olubodun Michael Lateef ◽  

2021 ◽  
Vol 11 (1) ◽  
Andreia Borges ◽  
Filipa Pereira ◽  
Patrícia Redondo ◽  
Luís Antunes ◽  
Cláudia Vieira ◽  

Abstract Background Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20–25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). Methods Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012–2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015–2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. Results AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p < 0.001). Clinical staging and hormone receptors (HR) were significantly associated with pCR. ICER was 1.370€ per percentage point of pCR. Conclusions ICER was more favourable in stage III HR negative BC patients compared to other patient profiles. Innovative treatments access is critical to deliver high-quality healthcare, but sustainability must be considered. These results suggest the importance of establishing a cost-effectiveness profile of Pertuzumab in NeoT for HER2-positive BC.

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