Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

Abstract PD5-04: NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer

Abstract: Background: Trastuzumab (T), the first anti-HER-2-directed therapy, dramatically changed the natural history of operable HER-2 positive breast cancer. A subsequent improvement occurred when pertuzumab was added to a T/docetaxel regimen in NeoSphere, a phase II randomized neoadjuvant trial, in which the pathologic complete response rate (pCR) in breast and nodes was increased from 21.5% to 39.3%, leading to accelerated approval of this combination by the FDA. Another dual anti-HER trial, NeoALTTO, which combined lapatinib with T, resulted in pCR (breast and nodes) increase from 27.6% to 46.8%. Neratinib (N) + paclitaxel (P) followed by AC was tested in the neoadjuvant I-SPY 2 trial resulting in pCR of 55% for hormone-negative, HER2-positive breast cancer. A 300-patient phase III trial of N or T with standard chemotherapy is planned. In the FB-7 phase II trial in HER2-positive patients (pts) with locally advanced disease, pts were randomly assigned to N or T or the combination (N+T) with weekly P followed by standard AC. Arm 3 of this trial, N+T+P, was based on the phase Ib results from NSABP FB-8, a study in heavily pretreated HER2-positive metastatic breast cancer pts, which demonstrated an overall response rate of 38% and clinical benefit rate of 52%. Methods: NSABP FB-7 opened in October 2010 as a two-arm trial (Arm 1, N+P→AC and Arm 2, T+P→AC). After accrual of 30 pts, accrual was suspended in December 2011 as NSABP FB-8, a phase Ib trial of neratinib, trastuzumab, and paclitaxel (N+T+P), was conducted and a recommended phase II dose for the combination of N+T+P was determined. NSABP FB-7 reopened in September 2012 adding Arm 3 (N+T+P→AC). 141 pts enrolled in this trial between October 2010 and November 2014. Three withdrew consent before treatment and were replaced. A total of 126 US, Canadian, and European pts were randomized to Arm 1 (N+P→AC), Arm 2 (T+P→AC) or Arm 3 (N+T+P→AC). 12 additional pts from the US were treated on Arm 3 as nonrandomized (NR) pts. These NR pts are included for toxicity but not for efficacy. Eligibility criteria included women >18 years of age, ECOG PS 0-1, stage IIB-IIIC invasive breast cancer, HER2-positivity by IHC 3+, FISH, or CISH as determined by local laboratories, hormone receptor positive or negative, LVEF >50%, and adequate laboratory parameters. The primary endpoint is pCR in breast and nodes. Conclusions: The last patient enrolled on this trial in November 2014. Datalock for the primary endpoint will occur on or before September 1, 2015. Pathologic complete response data and toxicity will be reported on the entire cohort of pts. Biomarkers will be analyzed on a subset of pts. Support: Puma Biotechnology, Inc. Citation Format: Jacobs SA, Robidoux A, Garcia JMP, Abraham J, La Verde N, Orcutt JM, Cazzaniga ME, Calvo L, Aguirre E, Buyse M, Pogue-Geile KL, Srinivasan A, Song N, Balousek AD, Wolmark N. NSABP FB-7: A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD5-04.

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer

Abstract: Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 < 80 nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

British Society for Echocardiography and British Cardio-Oncology Society guideline for transthoracic echocardiographic assessment of adult cancer patients receiving anthracyclines and/or trastuzumab.

Abstract: The subspecialty of cardio-oncology aims to reduce cardiovascular morbidity and mortality in patients with cancer or following cancer treatment. Cancer therapy can lead to a variety of cardiovascular complications, including left ventricular systolic dysfunction, pericardial disease, and valvular heart disease. Echocardiography is a key diagnostic imaging tool in the diagnosis and surveillance for many of these complications. The baseline assessment and subsequent surveillance of patients undergoing treatment with anthracyclines and/or human epidermal growth factor (EGF) receptor (HER) 2-positive targeted treatment (e.g. trastuzumab and pertuzumab) form a significant proportion of cardio-oncology patients undergoing echocardiography. This guideline from the British Society of Echocardiography and British Cardio-Oncology Society outlines a protocol for baseline and surveillance echocardiography of patients undergoing treatment with anthracyclines and/or trastuzumab. The methodology for acquisition of images and the advantages and disadvantages of techniques are discussed. Echocardiographic definitions for considering cancer therapeutics-related cardiac dysfunction are also presented.

Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer: Results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard?

Abstract: Background: Neoadjuvant therapy produces high rates of pathological complete response (pCR) and is the standard of care in HER2 positive breast cancer; however, the optimal treatment regimen remain ...

Targeted Therapies in HER2-Overexpressing Metastatic Breast Cancer.

Abstract: Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30% of breast cancers and is associated with aggressive disease and poorer survival. Multiple anti-HER2 targeted therapies have dramatically changed management and outcome of this subgroup, both in adjuvant and metastatic settings. Despite the improvement of survival thanks to trastuzumab, unclear mechanisms of resistance occur, which has led to the development of new anti-HER2 therapies such as lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). The optimal sequence of the available drugs is still not well established. All this progress raises the question of toxicity that need to be managed, especially with longer survival of patients. In this article, we review different anti-HER2 therapies used in HER2-positive m etastatic breast cancer.