Nicole McCarthy

Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer

PURPOSE Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis. PATIENTS AND METHODS Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7. RESULTS A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone. CONCLUSION Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.

Primary Results of ROSE/TRIO-12, a Randomized Placebo-Controlled Phase III Trial Evaluating the Addition of Ramucirumab to First-Line Docetaxel Chemotherapy in Metastatic Breast Cancer

PURPOSE Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. PATIENTS AND METHODS In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m(2) plus ramucirumab 10 mg/kg or docetaxel 75 mg/m(2) plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. RESULTS Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. CONCLUSION Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

Care of the breast cancer survivor: Increased survival rates present a new set of challenges

Earlier detection of invasive and noninvasive breast cancer and more effective treatments have led to both an improved prognosis for women with breast cancer and an increasing number of long-term survivors. However, such advances present various physical and emotional health challenges to patients facing breast cancer and its aftermath. Thus, understanding of the specific medical and psychosocial problems associated with survivorship is paramount in primary care.

Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors

Background Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)‐&agr; signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients. Materials and Methods We reduced ESR1 (gene encoding the ER‐&agr; protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER− breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER‐&agr; IHC, and patient survival. Results Genes differentially expressed in both analyses were associated with ER‐&agr; IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen‐driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v‐myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER‐associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies. Conclusion A biomarker of ER‐&agr; pathway activity, generated using ESR1‐responsive mRNAs in MCF7 cells, when used alongside ER‐&agr; IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients. Micro‐Abstract We investigated the transcriptional pathways activated by estrogen receptor‐&agr; and their relationship with patient survival after treatment with endocrine therapy. From this analysis, we propose that multimodal assessment of breast tumors, using a combination of estrogen receptor‐&agr; status, estrogen receptor‐&agr; mRNA expression, and genomic indicators of estrogen pathway activity, could be useful for both research and treatment stratification.

Abstract S5-04: Primary results of ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer

Background: To date, anti-angiogenic strategies in metastatic breast cancer have demonstrated benefits confined to modest improvements in progression-free survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab, an anti-VEGF receptor 2 antibody, is a human IgG1 antibody that specifically binds VEGF receptor 2 and blocks ligand stimulated activation. Early phase studies suggested anticancer effects in several solid tumors, and a phase III study demonstrated survival improvements in gastric cancer. The ROSE trial was designed to evaluate ramucirumab in the setting of HER2 negative, unresectable locally recurrent or metastatic breast cancer. Methods: In this placebo-controlled randomized multinational phase III trial, patients with HER2 negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomized 1:2 to receive docetaxel 75 mg/m2 + placebo IV every three weeks, or to the same chemotherapy + ramucirumab 10 mg/kg IV every three weeks. Treatment was continued with each agent until investigator determined progressive disease using RECIST criteria, or until unacceptable toxicity. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographical region. An independent data monitoring committee oversaw the trial conduct, the efficacy database resides with TRIO, and this analysis was conducted by the TRIO statistical team in collaboration with Eli Lilly and Co. The primary endpoint was investigator-assessed PFS. The sample size was calculated to provide for this event-driven final PFS analysis and interim OS analysis, and a final OS analysis (to be conducted when at least 792 OS events are observed). ROSE also includes evaluation of potential predictive biomarkers. Results: Between Aug 2008 and Dec 2011, 1144 patients were randomized. At data cut-off (March 31, 2013), median follow-up was 16.2 months. Safety, final PFS and interim OS results will be presented. Anticipated data availability is early November 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-04.

Final Survival Analysis of ROSE/TRIO-012

TO THE EDITOR: No antiangiogenic strategy in breast cancer has yet demonstrated a clinically meaningful improvement in the ultimate end point of all-cause mortality despite improvements in progression-free survival and response rates in metastatic disease and improvements in pathologic complete response rates in the neoadjuvant setting. Why antiangiogenic studies have not produced long-term survival effects is unclear, triggering speculation that interrupting antiangiogenic treatment increases the aggressiveness of the disease, or that resistance mechanisms circumventing the vascular endothelial growth factor pathway evolve rapidly. The ROSE/TRIO-012 (Phase III Study of Docetaxel 1 Ramucirumab or Placebo in Breast Cancer) trial was a study in women with metastatic breast cancer receiving first-line docetaxel; the primary analysis showed no significant improvement in progressionfree survival with the addition of ramucirumab over placebo, and the interim survival analysis was immature. We now report the completed protocol-specified final analysis for overall survival. In the intention-to-treat population, there were 492 survival events in the ramucirumab group (492 of 759 [65%]) and 264 in the placebo group (264 of 385 [69%]). Median survival was 30.3 months (95% CI, 27.5 to 33.5 months) for the ramucirumab group and 28.7 months (95% CI, 25.6 to 32.3 months) for the placebo group, with the stratified hazard ratio of 0.95 (95% CI, 0.81 to 1.10) for overall survival showing no difference (stratified log-rank P 5 .49; Fig 1). We conclude that ramucirumab, like other antiangiogenic strategies used in the therapy of metastatic breast cancer does not influence all-cause mortality. Given that the goals of treatment of metastatic breast cancer are to improve duration and quality of life, there remains no indication for the addition of ramucirumab to docetaxel in the first-line therapy of metastatic breast cancer.

Perspectives in post-transplantation immunotherapy in breast cancer.

High risk and metastatic breast cancer remain a major therapeutic challenge. Although the role of high dose chemotherapy followed by stem cell transplantation (SCT) in the overall treatment strategy is not yet well defined, it is clear that new forms of therapy such as immunotherapy will be needed to cure the majority of patients with advanced disease. We review important considerations for immunotherapy in the post-transplantation period. Experimental and clinical data suggest that immunotherapy may be most effective in a state of minimal residual disease such as that achieved following SCT. However, high dose therapy and autologous SCT result in an iatrogenic immune deficiency, which compounds the suppression of the immune system associated with tumor itself. Understanding reconstitution of a functional immune system post transplantation is critical in devising clinically effective immune interventions. A review of the clinical studies of post transplant immunotherapy for breast cancer is presented including autologous and allogeneic strategies, as well as perspectives for future development.