Predictive role of haemoglobin on disease response to neoadjuvant chemotherapy in breast cancer.

Background: Tumour hypoxia has been shown to play an important role in the outcome of cancer patients. Data on the predictive role of haemoglobin (Hb) on disease response to primary therapies in breast cancer (BC) are lacking. The purpose of this study is to evaluate the influence of Hb level throughout treatment course in predicting the response to neoadjuvant chemotherapy. Methods: 252 patients diagnosed with stage I-III BC treated with anthracycline-taxane based primary chemotherapy were evaluated. Patient and tumor characteristics and treatment information were collected. Standard biological parameters (Ki67, nuclear grade, hormone receptors and HER2 status) were correlated with pathologic complete response (pCR). We focused on Hb (baseline and after therapy levels, drop in Hb throughout treatment) and its correlation to pCR rate. The Hb cut-off to discriminate anaemic vs non-anaemic patients was set at 12,0 g/dl. Results: Globally, pCR was achieved in 58 patients (23%), mainly in case of younger age ( 20% = 26%, < 20% = 12%; p = 0.02) and hormone receptor negative status (Luminal B/HER2 negative = 9%, Luminal B/HER2 positive = 32%, HER2 enriched = 46%, triple negative = 37%; p < 0.0001). Median baseline Hb was 13,3 g/dl while median Hb level after chemotherapy was 11.6 g/dl: pCR was not influenced by Hb level before and after primary chemotherapy. No difference in Hb levels were observed stratifying patients according to nuclear grade, tumour stage and cancer subtypes. Anaemia due to chemotherapy was reported in 56% of patients. The decrease in Hb levels from baseline was greater in patients with lower response rate. On univariate analysis, a decrease in Hb ≥ 2 g/dl was associated with a significantly lower rate of pCR (15% vs 43%; p = 0.047). This correlation was even more evident in the subgroup of anaemic patients (17% vs 32%; p = 0.037). Conclusions: A decrease in Hb ≥ 2 g/dl during neoadjuvant chemotherapy may negatively affect the rate of pCR in BC patients, thus suggesting that anaemia should be avoided in order to obtain the best response to primary treatments

Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus

Background. Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Patients and Methods. Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. Results. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (, , and ). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. Conclusions. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study

Osteonecrosis of the Jaw in a Breast Cancer Patient Treated with Everolimus and a Single Dose of Zoledronic Acid.

The first case of ONJ after the first infusion of zoledronic acid in a patient receiving everolimus and bisphosphonates for metastatic BC

Molecular profile in primary and metastatic breast cancer treated with Exemestane and Everolimus.

Background. The PI3K/Akt/ mTOR pathway plays a significant role in endocrine resistance breast cancer (BC). Everolimus (EVE) has been approved after BOLERO-2 study, which showed a significant increase of PFS thanks to EVE plus Exemestane (EXE), compared to EXE alone. Hortobagyi et al. performed Next Generation Sequencing on 227 BOLERO-2 samples of primary BC to study the potential correlation between genetic alterations and EVE efficacy: a greater incidence of mutations in PI3KCA, PTEN, CCND1 and FGFR1 was detected, but treatment effect was independent from the genetic status. The aim of this study was to evaluate the molecular profile of both primary and secondary lesions in 25 metastatic BC patients treated with EVE+EXE in Modena University Hospital since 2014. Materials and methods. Thirty-three DNA samples from 25 patients were examined, 13 from primary BC and 20 from metastatic lesions. In 8 patients both primary tumor and metachronous metastasis were evaluated. Genomic DNA samples from FFPE tissues was conducted using panel OncoCarta 2.0 on MassArray Sequenom platform that detect more than 150 single nucleotide variations from 18 genes (AKT1, BRAF, CTNNB1, FBX4, FBXW7, FGFR2/3, GNAQ, KIT, KRAS, MAP2K1/2, NRAS, PDGFR, PIK3CA, PTPN11, SOS1, TP53). Differences between mutational status of primary and metastatic BC have been evaluated using χ2 and Fisher tests. Results. The median age was 54 years (range 50-67). 70% of patients had visceral involvement, 62% received more than 3 previous therapies, and for 8% of them an AI constituted the last treatment before EVE. Overall, 11 DNA samples were mutated (33%). 5 mutations were detected in the primary lesion with a frequency of 3% (PI3KCA, FBX4, KIT, MAP2K1, FBXW7) - 6 mutations in the metastasis (BRAF, KIT, TP53, FBXW7, CTNNB1, PI3KCA, AKT). Notably, mutations were found exclusively in primary lesion or in metastatic site, while only in one case both primary and secondary cancer were mutated, even if in two different genes. No significant correlation with treatment efficacy was evidenced. Conclusions. The genes most frequently mutated in MBC were PI3KCA, AKT1 and FBXW7, even if the percentage of PIK3CA and AKT1 mutations was less than expected. No correlation between primary and metastatic mutational status was detected. Involving new patients maybe could be the way for more encouraging results

Clinical and molecular analysis of long-term HER2 positive metastatic breast cancer survivors.

ackground: Several multigene tests have been developed in Metastatic Breast Cancer (MBC) disease, in order to identify predictive factors correlated to clinical outcomes. The purpose of this study is to investigate the clinico-pathological and molecular characteristics that could differentiate long term responders from patients experiencing early progression during anti-HER2 treatments. Methods: A total of 34 HER2 positive MBC patients were included: 20 patients with a time to progression longer than 3 years in Long Responders group (LR) and 14 patients with a progression disease within one year of anti-HER2 therapy in Poor Responders group (PR). Tumor characteristics and treatment information were collected. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on BC formalin-fixed paraffin-embedded tissues from diagnostic core biopsy or surgical resection. Results: Baseline patients and tumor characteristics were similar between the two groups, although PR patients were more likely to have CNS spread and more metastatic burden of disease compared to LR (29% vs. 0, p = 0.02 and 57% vs. 20%, p = 0.04, respectively). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five of these were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down-regulated, all in PR group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways (9 and 8, respectively). MAPK pathway was differently expressed between LR and PR (p = 0.05). Even if not statistically significant but clinically relevant, PI3K was the only pathway overexpressed in PR patients (median expression LR: 1441 ± 485 vs 1759 ± 762 in PR group; p= 0.1). Conclusions: Whole genome expression analysis comparing LR vs. PR identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathways could be a positive predictive factors. Further clinical implications are warranted

Genetic counselling and testing of susceptibility genes for therapeutic decision-making in breast cancer-an European consensus statement and expert recommendations

An international panel of experts representing 17 European countries and Israel convened to discuss current needs and future developments in BRCA testing and counselling and to issue consensus recommendations. The experts agreed that, with the increasing availability of high-throughput testing platforms and the registration of poly-ADP-ribose-polymerase inhibitors, the need for genetic counselling and testing will rapidly increase in the near future. Consequently, the already existing shortage of genetic counsellors is expected to worsen and to compromise the quality of care particularly in individuals and families with suspected or proven hereditary breast or ovarian cancer. Increasing educational efforts within the breast cancer caregiver community may alleviate this limitation by enabling all involved specialities to perform genetic counselling. In the therapeutic setting, for patients with a clinical suspicion of genetic susceptibility and if the results may have an immediate impact on the therapeutic strategy, the majority voted that BRCA1/2 testing should be performed after histological diagnosis of breast cancer, regardless of oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status. Experts also agreed that, in the predictive and therapeutic setting, genetic testing should be limited to individuals with a personal or family history suggestive of a BRCA1/2 pathogenic variant and should also include high-risk actionable genes beyond BRCA1/2. Of high-risk actionable genes, all pathological variants (i.e. class IV and V) should be reported; class III variants of unknown significance, should be reported provided that the current lack of clinical utility of the variant is expressly stated. Genetic counselling should always address the possibility that already tested individuals might be re-contacted in case new information on a particular variant results in a re-classification.status: publishe