[Show abstract][Hide abstract] ABSTRACT: Introduction:
Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments.
Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy.
Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting.
Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy.
[Show abstract][Hide abstract] ABSTRACT: Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
Science translational medicine 04/2015; 7(283). DOI:10.1126/scitranslmed.aaa4442 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The discovery of HER2 and development of trastuzumab pioneered the field of targeted therapy in breast cancer. Hoping to emulate the same clinical success, pharmaceutical companies have developed several antibodies against newly identified membrane-bound targets. Unfortunately, none of these agents has yet matched the thousands of lives saved by trastuzumab. In this article we review the most advanced therapeutic antibodies in breast cancer. While acknowledging their unquestionable benefit, we emphasize the need to better understand their biology and mechanisms of action in order to optimize their use in defined patient populations.
Seminars in Oncology 07/2014; 41(5). DOI:10.1053/j.seminoncol.2014.07.002 · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances in breast cancer research have allowed deconstruction of the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in treatment options, including more personalized therapy and considerable improvements in patient outcomes. Although there are only a few targeted therapies approved for advanced breast cancer, several novel strategies targeting different tyrosine kinase receptors currently are under evaluation. Fibroblast growth factors and their receptors (FGFRs) are involved in different physiologic processes and also play a critical role in cancer cell proliferation and survival. This article focuses on the main molecular alterations of FGFRs, as well as the available preclinical and clinical data regarding FGFR inhibitors in breast cancer. In addition, we analyze the management of specific adverse events, such as hyperphosphatemia, and discuss unanswered questions regarding the clinical development of these agents.
Current Breast Cancer Reports 06/2014; 6(2). DOI:10.1007/s12609-013-0138-4
[Show abstract][Hide abstract] ABSTRACT: Although the outcome of small (T1a/b) node-negative breast tumors is generally excellent, in the absence of prospective clinical trials, we are limited to data derived from retrospective analyses. Overall, the 10-year overall mortality rate is approximately 20%, while the 10-year breast cancer-specific mortality is in the range of 4% to 8% among this population in the absence of systemic therapy. This clearly reflects that many patients die of causes not related to breast cancer. Due in large part to breast cancer screening programs, the incidence of small tumors is increasing. There is consequently a growing interest in identifying factors that negatively affect the prognosis of these patients. Several studies have shown that patients with triple-negative and HER2+ tumors have a worse prognosis compared with hormone-receptor-positive, HER2- small breast cancers. However, the recent explosion of knowledge of the molecular characteristics of tumors is opening a new way to address cancer. Different genomic assays are currently available to help better predict the outcome of breast cancer patients. However, none of these techniques have been specifically evaluated in patients with small (T1a/b) node-negative tumors, and only a small number of patients with these tumors were included in those studies. In addition, very limited data are available about the role of these assays in patients with triple-negative or HER2-positive cancers. Although a chemotherapy-based strategy might be useful for triple-negative or HER2-positive T1b tumors, more information is urgently needed in order to optimize the treatment of our patients.
[Show abstract][Hide abstract] ABSTRACT: The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro and in vivo tumor models harboring FGFR aberrations, a growing number of research groups have selected FGFRs as targets for anticancer drug development. Multikinase FGFR/vascular endothelial growth factor receptor (VEGFR) inhibitors have shown promising activity in breast cancer patients with FGFR1 and/or FGF3 amplification. Early clinical trials with selective FGFR inhibitors, which may overcome the toxicity constraints raised by multitarget kinase inhibition, are recruiting patients with known FGFR(1-4) status based on genomic screens. Preliminary signs of antitumor activity have been demonstrated in some tumor types, including squamous cell lung carcinomas. Rational combination of targeted therapies is expected to further increase the efficacy of selective FGFR inhibitors. Herein, we discuss unsolved questions in the clinical development of these agents and suggest guidelines for management of hyperphosphatemia, a class-specific mechanism-based toxicity. In addition, we propose standardized definitions for FGFR1 and FGFR2 gene amplification based on in situ hybridization methods. Extended access to next-generation sequencing platforms will facilitate the identification of diseases in which somatic FGFR(1-4) mutations, amplifications and fusions are potentially driving cancer cell viability, further strengthening the role of FGFR signaling in cancer biology and providing more possibilities for the therapeutic application of FGFR inhibitors.
Annals of Oncology 11/2013; 25(3). DOI:10.1093/annonc/mdt419 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.
Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).
Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer.
Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.
Clinical Cancer Research 05/2013; 19(13). DOI:10.1158/1078-0432.CCR-13-0190 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current understanding of the molecular biology of breast cancer presents an extremely complex portrait of the disease. Based on this knowledge, considerable efforts are being made to identify biomarkers that will predict the response to a specific treatment while minimizing the risk of unnecessary side effects. In breast cancer, the Ki67 index has been associated with poor prognosis and might play a relevant role in predicting benefit from adjuvant docetaxel, as observed in the article accompanying this editorial. Taxanes are one of the most active cytotoxic agents for breast cancer. However, the role of taxane-based chemotherapy as adjuvant treatment of early breast cancer remains controversial in some subsets of patients. For this reason, the Ki67 index might help to better define the group of patients who could have the optimal benefit.
Breast cancer research: BCR 01/2012; 14(1):104. DOI:10.1186/bcr3093 · 5.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metastatic breast cancer (MBC) remains an incurable disease, with the goals of care aimed at maximizing the patient's duration and quality of life. Treatment options for MBC have become more efficacious and numerous. In addition to endocrine and chemotherapy agents, a number of targeted agents, including trastuzumab and bevacizumab, have further enhanced the landscape of therapeutic options. Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor, and a structurally simplified synthetic analog of the natural marine product, halichondrin B, with a novel mechanism of action that has shown antitumor activity in pretreated MBC. Eribulin has shown a manageable tolerability profile in Phase I-II clinical trials and an improvement in overall survival compared with treatment of physician's choice, without relevant toxicities in a recently published Phase III trial. This review will focus on eribulin as a new active agent for MBC and its role in the management of breast disease.
OncoTargets and Therapy 11/2011; 4:185-92. DOI:10.2147/OTT.S16392 · 2.31 Impact Factor