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.

Combination pertuzumab, trastuzumab, and taxane for metastatic breast cancer after first progression: a single institution’s experience

Abstract: BackgroundThe addition of pertuzumab to trastuzumab and taxane therapy was shown to be an effective first-line treatment for patients with HER2-positive metastatic breast cancer.ObjectiveDescribe the progression-free survival of pertuzumab, trastuzumab, and taxane therapy for previously treated HER2-positive metastatic breast cancer.MethodsThis case-series reviews 19 patients with metastatic breast cancer receiving treatment with pertuzumab, trastuzumab, taxane after progression and exposure to previous lines of HER2-directed therapy. Progression-free survival and adverse effects such as changes in ejection fraction and episodes of neutropenic fever were assessed.ResultsThe median progression-free survival of pertuzumab, trastuzumab, taxane therapy for previously treated metastatic breast cancer was 4.1 months. The mean baseline left ventricular ejection fraction change experienced by patients was –1%. Neutropenic fever events were not encountered.ConclusionsPertuzumab, trastuzumab, and taxane therapy see...

Predictive Value of Positron Emission Tomography/Computed Tomography to Assess Early Treatment Response to Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade Without Chemotherapy for HER2-Positive Metastatic Breast Cancer: Are We Ready to Embrace This “Early Metabolic Look” Strategy?

Abstract: Since the US Food and Drug Administration approval of trastuzumab in combination with a taxane in 1998, which revolutionized the management of human epidermal growth factor receptor 2 (HER2) –positive breast cancer, three other anti-HER2 therapies have been approved: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). With these, we can consider using combinations of two or more anti-HER2 therapies hoping to increase effectiveness or, alternatively, eliminate some chemotherapy while maintaining efficacy. Dual HER2 blockade with lapatinib or pertuzumab added to chemotherapy/trastuzumab was superior to trastuzumab alone in both the metastatic and neoadjuvant settings, but regimens without conventional chemotherapy have not been as fully explored. In the accompanying article, Lin et al report a nonrandomized phase II Translational Breast Cancer Research Consortium (TBCRC) trial conducted in 87 patients with HER2-positive metastatic breast cancer (MBC) treated with lapatinib plus trastuzumab without chemotherapy. That study demonstrated overall response rates of 50% and 22% in cohort 1 (no prior lines of trastuzumab for MBC; 1 year from adjuvant trastuzumab, if given) and cohort 2 (one to two lines of chemotherapy for MBC, including trastuzumab, and/or recurrence 1 year from adjuvant trastuzumab), respectively. Of note, 10% (four of 40) of the patients in cohort 1 remained on protocol therapy more than 3 years after study entry, although three of these patients were trastuzumab naive. The progression-free survival (PFS) was 7.4 months in cohort 1 and 5.3 months in cohort 2. The most common adverse events were diarrhea, fatigue, and rash. Notably, there were no grade 4 toxicities, and less than 10% had grade 3 toxicities. To place the efficacy results from that study in context, consider the additional data that have become available since trial accrual began in 2007. Three randomized trials have reported PFS and overall survival benefits for HER2-positive MBC, including the phase III EGF104900 (Lapatinib In Combination With Trastuzumab Versus Lapatinib Monotherapy In Subjects With HER2-positive TrastuzumabRefractory Metastatic Breast Cancer) trial in patients with HER2-positive trastuzumab-refractory MBC (median of three lines of trastuzumabbased chemotherapy). In addition, with significant survival benefit noted in the CLEOPATRA (A Study to Evaluate Pertuzumab Trastuzumab Docetaxel vs. Placebo Trastuzumab Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer) and EMILIA (An Open-label Study of Trastuzumab Emtansine [T-DM1] vs Capecitabine Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) trials, pertuzumab and ado-trastuzumab emtansine are recommended in the firstand second-line metastatic setting by multiple clinical practice guidelines. Lapatinib plus trastuzumab could be a reasonable option upon disease progression on pertuzumab or T-DM1, given its acceptable toxicity profile and clinical activity.Thiscombinationcouldalsoplayanimportantroleinthefirst-or second-line setting for patients who have limited access to pertuzumab and/or T-DM1. The identification of so many new active agents for a distinct subtype of breast cancer over the past few years is cause for optimism. We have entered the era of precision medicine and moved away from the one-size-fits-all approach. At the same time, every advance opens new challenges, and we have yet to resolve how to reliably identify patients who might benefit the most from a particular targeted therapy. Historically, response assessment in the metastatic setting relies on identifying anatomic progression using the conventional response evaluation criteria for solid tumors (RECIST criteria), typically performed 8 to 12 weeks after the initiation of therapy. However, the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 24 AUGUST 2

Prevention of brain metastases in human epidermal growth factor receptor 2-positive breast cancer.

Abstract: Purpose of review For patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, treatments that could prevent or delay occurrence of brain metastases would improve outcome. Recent findings Few studies were specifically designed to assess brain metastasis prevention. Most evidence derives from subgroup analyses of randomized trials. In the first-line metastatic setting, lapatinib, was not superior to trastuzumab to prevent CNS metastases as first site of relapse. Pertuzumab when added to trastuzumab and taxane significantly delay occurrence of brain metastases. In the second line setting, trastuzumab-emtansine has shown to improve overall survival of patients with brain metastases when compared with capecitabine-lapatinib, but there was no significant delay in brain metastases progression. Neratinib, has shown that it was able to delay brain metastases progression. Finally, tucatinib, has demonstrated benefit in progression-free survival and overall survival in combination with trastuzumab and capecitabine over trastuzumab and capecitabine for patients with or without brain metastases. Summary There has been an impressive improvement of the outcome of patients with HER2-positive metastatic breast cancer, with improved control of systemic disease and delayed occurrence of CNS progression. Specific studies are needed to assess TKI for brain metastases prevention, particularly in the adjuvant setting.

Mouse models and anti-HER2 therapies

Abstract: Approximately one in four breast cancers is driven by amplification of the receptor tyrosine kinase HER2 (ERBB2). HER2 signals through oncogenic pathways, such as the phosphatidylinositol-3-kinase (PI3K)-Akt pathway. Blockade of HER2 with FDA-approved drugs such as trastuzumab, lapatinib, and pertuzumab has changed the natural history of HER2-positive (HER2+) breast cancers and improved patient survival. However, resistance to anti-HER2 therapies represents an enormous hurdle to the eradication of this subtype of breast cancer. Activating mutations in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, occur in 30-40% of HER2+ breast cancers. Several studies have found a correlation between PI3K pathway activation and resistance to anti-HER2 therapies (Esteva FJ, et al. Am J Pathol. 2010; 177:1647; Chandarlapaty S et al. Clin Cancer Res. 2012; 18:6784). However, clinical data on this topic have been inconsistent, and confirmation of a causal association between PIK3CA mutations and resistance to anti-HER2 therapies is lacking. To formally test this hypothesis, we generated a genetically engineered mouse model of HER2+/PIK3CA-mutant breast cancer [1]. In these HER2/PIK3CA mice, HER2 and mutant PI3K (containing the H1047R kinase domain mutation) strongly cooperated to promote mammary gland hyperplasia, tumor growth and lung metastasis (Fig. ​(Fig.1).1). In contrast to tumors expressing only HER2, HER2/PIK3CA tumors were completely resistant to single-agent trastuzumab and to combinations of anti-HER2 therapies. This resistance was partially reversed by combined treatment with a PI3K inhibitor currently in clinical trials. Figure 1 Comparison of phenotypes in MMTV-HER2 and HER2/PIK3CAH1047R mice Importantly, mutant PIK3CA altered the intrinsic phenotype of HER2+ tumors while increasing characteristics of cancer stem cells (CSCs) [1]. Whereas MMTV-HER2 tumors were histologically homogeneous, expressed luminal markers, and exhibited a gene expression profile most similar to human luminal tumors, HER2/PIK3CA tumors were highly heterogeneous, expressed both luminal and basal markers, and exhibited a gene expression profile reminiscent of human claudin-low breast cancers, a subtype characterized by poor differentiation and elevated expression of epithelial-to-mesenchymal transition (EMT) and CSC markers [2]. In agreement, HER2/PIK3CA tumors expressed elevated EMT and CSC markers. Further, HER2/PIK3CA tumor cells more efficiently formed mammospheres in culture, a surrogate assay for tumor-initiating capacity. Finally, cells from HER2/PIK3CA tumors formed substantially more and larger lung metastases than cells from HER2 tumors. These findings suggest that human HER2+ breast cancers harboring PIK3CA mutations may display a more virulent behavior, with greater plasticity to circumvent therapeutics. In support of this, a recent study found that human HER2+ breast cancers enriched in tumor initiating cell gene signatures contained higher PI3K pathway activity [3]. Thus, HER2+/PIK3CA-mutant breast cancers may benefit from treatments that target both the rapidly-dividing bulk populations and relatively quiescent tumor-initiating cancer cells. The discrepancies in the clinical data regarding PIK3CA mutation status and resistance to trastuzumab could potentially be due to discordance of PIK3CA mutations between primary and metastatic biopsies [4], clonal heterogeneity within the tumor [5] and/or the addition of chemotherapy to HER2-targeted drugs. Further, biopsies from primary tumors could miss PIK3CA mutations in metastatic sites. Thus, PIK3CA mutational status should also be assessed in cell-free plasma tumor DNA or in metastatic sites in order to stratify patients that may require PI3K inhibitors in addition to anti-HER2 therapies. PIK3CA mutations should also be assessed in HER2+ tumors that recur following anti-HER2 therapy as PIK3CA mutations may be enriched in recurrent disease. Clinical studies have shown that combinations of anti-HER2 therapies, such as trasuzumab + lapatinib or trastuzumab + pertuzumab, are more effective in HER2-amplified cancers than single-agent trastuzumab (Baselga et al. Lancet. 2012; 379:633). Interestingly, the CLEOPATRA study found that PIK3CA mutations were associated with a poorer prognosis following treatment with trastuzumab + pertuzumab + docetaxel (Baselga J et al. 2012 CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, TX). Concordant with these data, HER2/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. However, the PI3K inhibitor BKM120 in combination with anti-HER2 therapies inhibited tumor growth [1]. This suggests a causal association between PIK3CA mutations and resistance to HER2 inhibitors, and supports the prompt exploration of this drug combination clinically. Despite tumor growth inhibition, BKM120 combined with two HER2 inhibitors did not completely eliminate tumors, suggesting that additional treatments will be needed to cure metastatic PIK3CA mutant, HER2-amplified breast cancers. PI3K inhibition resulted in feedback activation of HER3 and MEK-ERK signaling, which was not circumvented by HER2 inhibition. Therefore, the addition of a HER3 or MEK inhibitor may prevent feedback compensation and maximize tumor regression. HER2/PIK3CA tumors may also respond to the antibody-drug conjugate trastuzumab emtansine (T-DM1), a recently approved drug for HER2+ breast cancer. In summary, our mouse model of HER2+/PIK3CA-mutant breast cancer provided novel insights into the pathogenesis of this disease that may be exploited therapeutically. This model will be instrumental for understanding mechanisms of acquired resistance to anti-HER2 combinations and optimizing therapeutic strategies for this subtype of breast cancer.

Targeting HER-2 in gastric cancer – incorporation of trastuzumab into the treatment of operable disease

Abstract: Correspondence: David Cunningham Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK Tel +44 208 661 3156 Fax +44 208 661 3890 email david.cunningham@rmh.nhs.uk Abstract: Gastric cancer is the fourth most common malignancy and second leading cause of cancer death world-wide, and is therefore a significant global health problem. Radical surgery with a D2 lymph node dissection is an accepted standard approach, and is a key component of multimodality therapy. Perioperative chemotherapy significantly improves 5-year overall survival compared with surgery alone. A significant improvement in overall survival has also been demonstrated with postoperative 5-fluorouracil-based chemoradiotherapy and adjuvant oral S-1 chemotherapy; approaches commonly used widely in North America and Japan, respectively. Approximately 10% to 20% of gastric cancers and 20% to 30% of esophago-gastric junction cancers are HER-2 positive. The effect of HER-2 overexpression and HER-2 gene amplification on gastric cancer prognosis remains unresolved. The results of the first randomized phase III trial of trastuzumab, a monoclonal antibody directed at the HER-2 receptor, in patients with metastatic gastric cancer were reported recently. Response rate, median progression-free survival, and median overall survival were all significantly improved with the addition of trastuzumab to a cisplatin/fluoropyrimidine doublet. Evaluation of trastuzumab in HER-2 positive operable esophago-gastric cancer is now underway. Lapatinib, a small-molecule inhibitor targeting EGFR and HER-2 is well established in the treatment of trastuzumab-refractory HER-2 positive breast cancer and phase III trials in advanced esophago-gastric cancers are ongoing. Novel, small molecule pan-HER inhibitors have entered early phase evaluation and the antibody-drug conjugate, trastuzumab-DM1, and pertuzumab, a monoclonal antibody which prevents HER-2/ HER-3 dimerization, are currently undergoing phase II/III evaluation in breast cancer. It is our hope that advances in the targeted treatment of HER-2 positive breast cancer will be replicated in HER-2 positive esophago-gastric cancers.