Long-term safety of aromatase inhibitors in the treatment of breast cancer

Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI), anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects) or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction) class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profil

Main implications related to the switch to BRCA1/2 tumor testing in ovarian cancer patients: a proposal of a consensus

Since the approval of the first poly (adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi; olaparib [Lynparza\u2122]) for platinum-sensitive relapsed high grade ovarian cancer, with either germline or somatic BRCA1/2 deleterious variants, the strategies for BRCA1/2 are dynamically changing. Along with germline testing within the context of familial or sporadic ovarian cancer, patients are now being referred for BRCA1/2 genetic assay above all for treatment decisions: in this setting tumour BRCA assay can allow to identify an estimated 3-9% of patients with peculiar somatic BRCA1/2 mutations. These women could also benefit from PARPi therapy. This new type of approach is really challenging, in particular due to the technical and analytical difficulties regarding low quality DNA deriving from formalin-fixed, paraffin-embedded (FFPE) specimens. Aim: in this manuscript, we try to a) underline many issues related to BRCA1/2 analysis by next generation sequencing technologies (NGS), b) provide some responses to many questions regarding this new paradigm related to OvCa patients' management. Some considerations for incorporating genetic analysis of ovarian tumour samples into the patient pathway and ethical requirements are also provided. Methods: we used our retrospective data based on thousands of ovarian cancer women sequenced for BRCA1/2 genes. Discussion: tumor BRCA1/2 assay should be rapidly introduced in routine laboratory practice as first line testing by using harmonized pipelines based on consensus guidelines

Estrogen Receptor Expression and Docetaxel Efficacy in Patients with Metastatic Breast Cancer: A Pooled Analysis of Four Randomized Trials

The present study assessed the efficacy of docetaxel in patients with metastatic breast cancer according to estrogen receptor expression. Docetaxel produced a higher response rate and lower risk for disease progression to a statistically similar extent regardless of estrogen receptor expression in patients with metastatic breast cancer

Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34 cells and their transmigration through reconstituted basement membrane

The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may facilitate this process. First, we investigated whether CD34 stem/progenitor cells express gelatinases A (MMP-2) and/or B (MMP-9) and whether growth factors and cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], stem cell factor [SCF], macrophage colony-stimulating factor [M-CSF], interleukin-3 [IL-3], IL-6, IL-8, and tumor necrosis factor-α [TNF-α]) are able to modulate their expression. Next, we examined the transmigration of these stem/progenitor cells through reconstituted basement membrane (Matrigel) and its modulation by growth factors and cytokines. CD34 cells were obtained from steady-state bone marrow and peripheral blood (from leukapheresis products collected either in steady-state hematopoiesis or after mobilization with G-CSF plus chemotherapy or G-CSF alone). We found that peripheral blood CD34 cells, regardless of whether they were mobilized or not, strongly expressed both gelatinases (MMP-2 and MMP-9) in contrast to steady-state bone marrow CD34 cells, which did not. However, all the growth factors and cytokines tested could induce MMP-2 and MMP-9 secretion by the latter cells. Moreover, the stimulatory effects of G-CSF and SCF on both MMP- 2 and MMP-9 secretion were found to be significantly higher in CD34 cells isolated from bone marrow than in those from peripheral blood. In addition TNF-α, GM-CSF, and IL-6 increased the secretion of a partially active form of MMP-2. Basal transmigration of bone marrow CD34 cells through Matrigel was lower than that of peripheral blood CD34 cells (P .9). The stimulatory effect of G-CSF was significantly greater on the migration of CD34 cells from bone marrow than on those from peripheral blood (P= .004). Moreover, CD34 cell migration was reduced to approximately 50% by antibodies to MMP-2 and MMP-9, tissue inhibitors of metalloproteinases (rhTIMP-1 and -2), and o-phenanthroline. TNF-α-induced gelatinase secretion and migration of CD34 cells and of clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythroid [BFU-E], colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU- GEMM], and colony-forming unit-megakaryocyte [CFU-MK]) were dose-dependent. Therefore, this study demonstrated that CD34 cells that are circulating in peripheral blood express both MMP-2 and MMP-9 and transmigrate through Matrigel. In contrast, CD34 cells from steady-state bone marrow acquire similar properties after exposure to growth factors and cytokines, which upregulate expression of gelatinases and transmigration of these cells when they enter the bloodstream. Hence, we suggest that growth factors and cytokines induce release of stem/progenitor cells from bone marrow into peripheral blood during mobilization, as well as during steady-state hematopoiesis, by signaling through gelatinase pathways