Francesca Pellini

Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials

The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.

Comparison between invasive breast cancer with extensive peritumoral vascular invasion and inflammatory breast carcinoma: a clinicopathologic study of 161 cases.

OBJECTIVES Extensive peritumoral neoplastic lymphovascular invasion (ePVI) is a marker of aggressiveness in invasive breast carcinoma (BC). METHODS We explored the impact of ePVI on different BC subtypes. In a total of 2,116 BCs, 91 ePVI-BCs, 70 inflammatory breast carcinomas (IBCs), and 114 casual BCs as a control group (CG-BC) were recruited. RESULTS Patients affected by ePVI-BC were younger, had larger tumors, higher histologic grade, elevated Ki-67 score, Her2/neu overexpressed, and more lymph node metastases compared with CG-BC (P < .001). Interestingly, only younger mean age at diagnosis differentiated patients with ePVI-BC from patients affected by IBC. ePVI-BC showed a clinical outcome intermediate between the prognoses of IBC and CG-BC. CONCLUSIONS Results suggest that ePVI-BC and IBC may share some pathologic processes, providing a novel perspective on the heterogeneity of BC. Epidemiologic data and molecular studies on gene expression features are needed to rationally classify these tumors into their identified subtypes.

Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: sensitivity analysis of randomized trials.

Paclitaxel and docetaxel represent the most adopted taxanes in the neoadjuvant treatment of HER2-positive breast cancer. Questions still remain with regard to their difference in terms of activity and tolerability. Events for pathological complete response (pCR), severe and febrile neutropenia (FN), and severe neurotoxicity were pooled by adopting a fixed- and random-effect model. A sensitivity analysis to test for the interaction between paclitaxel and docetaxel was accomplished. Absolute differences with 95% confidence intervals (CIs) and the number of patients needed to treat/harm (NNT/NNH) were calculated to derive the Likelihood of being Helped or Harmed (LHH). Data from 15 trials (3601 patients) were included. Paclitaxel significantly increases pCR rate by 6.8% in comparison with docetaxel (43.4%, 95% CI 41.1-45.7% versus 36.6%, 95% CI 34.3-39.0%, p=0.0001), regardless of the chemotherapy backbone, with an absolute difference of 9% and 9.2% for anthracycline-based or free-regimens. Paclitaxel significantly improves pCR versus docetaxel with a single HER2-inhibition by 6.7% (p=0.0012), with no difference if combined with a dual HER2-inhibition. Severe neutropenia and FN are significantly lower with paclitaxel, with an absolute difference of 32.4% (p<0.0001) and 2.5% (p=0.0059), respectively. Conversely, severe neurotoxicity is slightly higher with paclitaxel (3%, p=0.0001). The LHH ratio calculated for pCR and severe neutropenia is 2.0 and 0.7 for paclitaxel and docetaxel. Although the activity of neoadjuvant paclitaxel and docetaxel HER2-positive breast cancer is considered similar, the slight advantage in pCR, the significantly lower neutropenia and FN, do favor paclitaxel (in the weekly fashion) over docetaxel, despite the slightly worst neurotoxicity.

Clinical results of randomized trials and 'real-world' data exploring the impact of Bevacizumab for breast cancer: opportunities for clinical practice and perspectives for research.

ABSTRACT Introduction: Angiogenesis plays a fundamental role in breast cancer (BC) growth, progression and metastatic spread. After the promising introduction of bevacizumab for the treatment of advanced BC, the initial enthusiasm decreased when the FDA withdrew its approval in 2011. Nevertheless, several clinical studies exploring the role of bevacizumab have been subsequently published. Areas covered: The aim of this study is to review the available clinical trials exploring the potential effectiveness of bevacizumab in BC, regardless of the disease setting. Expert opinion: Even if the evidence suggests that bevacizumab must be ruled out from the HER2-positive and adjuvant setting, bevacizumab’s benefit remains uncertain in the neoadjuvant setting and in the advanced treatment of HER2-negative patients. In the first setting, the addition of bevacizumab to chemotherapy increased the pathological complete response (pCR) rate in most clinical trials. However, the current absence of evidence that pCR is a trial-level surrogate for survival requires waiting for long-term results. In the advanced setting, all trials showed a benefit in progression-free survival, but not in overall survival, highlighting an increase of adverse events. The lack of predictors of response represents the main unmet need in which future clinical research will undoubtedly invest.

Neoadjuvant Strategies for Triple Negative Breast Cancer: ‘State-of-the-art’ and Future Perspectives

Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.

Role of dual-point FDG PET/CT in prone position and fused PET/MR; correlation with biologic prognostic parameters in breast cancer

Aim: Inflammatory bowel disease (IBD) is defined as a chronic relapsing idiopathic inflammation of the gastrointestinal tract. The two main clinical forms of this disease family are Crohn’s Disease (CD) and Ulcerative Colitis (UC). IBD affects an estimated 3.6 million individuals in Europe and North America. To date it is thought that IBD is the result of continual activation of the mucosal immune system. In order to better understand this disease family an in-house developed animal model was implemented and characterized with [18F]FDG (used to illustrate the increased glucose consumption associated with inflammatory processes) and also with TSPO 18 kDa radioligand [18F]DPA-714, an established radiotracer for the study of inflammation within the central nervous system. Materials and Methods: Colonic inflammation was induced in male Wistar rats weighing between 200-250 g by rectal administration of trinitrobenzenesulfonic acid (TNBS) at 4cm from the anal orifice. Control animals were administered, 0.9% aq. sodium chloride analogously. A Siemens Inveon PET/CT tomograph, dedicated to small animals, was used to acquire [18F]FDG images on day 7 post TNBS administration and [18F]DPA714 images the following day. Rats were then sacrificed by an i.v. injection of pentobarbital, and then the lower intestine was extracted and analyzed by immunohistochemistry to determine macrophage infiltration and the presence of TSPO. Results: PET image analysis clearly shows an important accumulation of both radiotracers within the intestinal walls of treated animals in comparison to control animals. Mean levels of [18F]FDG uptake in treated and control animals were 1.20 ± 0.56 %ID/cc and 0.43 ± 0.18 %ID/cc, respectively. Comparable results were found when using [18F]DPA-714, with mean level of uptake in treated and control animals of 1.21 ± 0.62 %ID/cc and 0.46 ± 0.23 %ID/cc, respectively. Immunohistochemistry analysis revealed a higher presence of macrophages in TNBS treated animals. Expression of TSPO was largely increased in the treated animals, when compared to the controls animals, and mainly localized in macrophages cells. Conclusion: Preliminary results seem to indicate that [18F]DPA-714 is an adapted tracer for the study of inflammation of IBD in our animal model. Beyond this, data demonstrating that [18F]DPA-714 could be used to characterize and quantify the level of inflammation during the disease evolution, within the TNBS treated animals, will also be presented. OP366 Surface displayed SNAP-tag as a novel tool for study of Grampositive bacterial infections. B. Mills, V. Steele, J. C. A. Luckett, R. O. Awais, P. Duncanson, V. Griffiths, A. Cockayne, M. Xu, I. Correa, A. C. Perkins, P. Williams, P. Hill; School of Molecular Medical Sciences, University of Nottingham, Nottingham, UNITED KINGDOM, Radiological and Imaging Sciences, University of Nottingham, Nottingham, UNITED KINGDOM, School of Biological and Chemical Sciences, Queen Mary University of London, London, UNITED KINGDOM, New England Biolabs, Inc, Ipswich, ME, UNITED STATES, School of Biosciences, University of Nottingham, Nottingham, UNITED KINGDOM. Introduction: The design of specific probes for in vivo molecular imaging of microbial infections remains one of the greatest challenges to overcome before useful, functional data can be obtained. An increasingly attractive approach for probe design is to express a ligand-binding protein within a cell, which may then covalently bind specific synthetic ligands with attached imaging moieties. One such labelling system is the commercially available SNAP-tag. SNAP-tag specifically and covalently binds O2-benzylguanine (BG) compounds, which may have fluorophores or other functional elements attached at the 4’ position of their benzyl ring. We have designed a BG ligand labelled with Tc, suitable for SPECT imaging. We propose to utilise this technology for the imaging of Staphylococcal infection in vivo with the view to investigate bacterial pathogenicity and to visualise the effect potential antimicrobials may have on bacterial load. Methods: The SNAP-tag gene was codon optimised for expression in the Gram positive bacterium Staphylococcus aureus and fused with an N-terminal spa secretion leader sequence and a Cterminal spa cell-wall anchoring domain. The N-terminal fusion directs the expressed SNAP-tag towards the cell exterior where the C-terminal domain is recognised by the cell-wall sorting enzyme sortase A, covalently anchoring SNAPtag in such a way that the ligand binding domain decorates the cell surface. A novel 99m Tc-HYNIC–NH-BG ligand for SPECT imaging was prepared by coupling BG to HYNIC and radiolabelling with NaTcO4 in the presence of tricine as co-ligand. Radiochemical yields >99% were obtained. nanoSPECT-CT imaging will be used to assess the functional data produced by using SNAP-tag expressing S. aureus cells in in vivo infection models. Results: We have demonstrated that SNAP-tag was expressed and exported to the cell wall where it was covalently anchored. Deletion of the sortase A enzyme prevented attachment of the SNAP-tag to the cell wall, as determined by Western blot. Once situated within the cell wall, SNAP-tag was functional and able to specifically bind cell-impermeable fluorescent BG ligands and our synthesised precursor HYNIC-NH2-BG ligand, as determined by confocal microscopy and fluorometry assay. Pilot in vivo studies for fluorescence optical imaging and nanoSPECT-CT imaging with the novel 99m Tc-HYNIC-NH-BG ligand are currently under development to visualise S. aureus infections in mouse models. Conclusions: This approach should allow a higher sensitivity to be achieved when investigating bacterial infections in real time compared to current molecular imaging techniques, thus allowing bacterial virulence and the potential effects of new antimicrobials to be assessed. OP367 Dual imaging of lipopolysaccharides (LPS) by SPECT-CT and Confocal Microscopy. M. Moreau, V. Duheron, B. Collin, W. Sali, C. Bernhard, C. Goze, T. Gautier, J. Pais de Barros, V. Deckert, F. Brunotte, L. Lagrost, F. Denat; ICMUB UMR CNRS 6302, Dijon, FRANCE, INSERM UMR866, Dijon, FRANCE, Centre Georges-François Leclerc, Dijon, FRANCE, Centre Hospitalier Universitaire, Dijon, FRANCE. Introduction: Lipopolysaccharides (LPS) or endotoxins are found inserted in the outer membrane of Gram-negative bacterias. Their appearance in blood stream triggers a massive secretion of pro-inflammatory cytokines in mammals. A controlled response allows the neutralization and elimination of LPS, whereas an excessive inflammatory response leads to severe circulatory and respiratory defects. It is the endotoxemic shock or septic shock that can leads to death. Many approaches are used to study LPS, including labeling with radiochemicals (3H, 125I, 99mTc or 51Cr) or with fluorophores (FITC, Alexa488, Bodipy). Bimodality is attracting more and more interest in the field of molecular imaging since the combination of two different techniques may provide complementary information, thus improving the accuracy of diagnosis. Combining nuclear modalities (PET or SPECT) with optical imaging is of particular interest, and the similar sensitivities of the two techniques allows to fuse the signaling moieties into a unique molecule, called monomolecular multimodality imaging agent (MOMIA), ensuring a same biodistribution of the two probes. Method: A recently described bimodal probe, namely DOTA-Bodipy-NCS, has been covalently attached to LPS. The integrity of the LPS after labeling procedure was checked by SDS-PAGE electrophoresis and βhydroxymyristate titration (BHM). Pro-inflammatory activity of LPS was assessed by quantification of cytokines released by differentiated THP-1 cells. This bioconjugate was then radiometallated for SPECT-CT biodistribution imaging. Results: DOTABodipy-LPS was metallated with 111In to yield a high specific activity (600 MBq.mg1), with a radiochemical purity >98 % after purification. Biodistribution of the radiolabeled compound was then evaluated in vivo in WT mice by SPECT-CT imaging. Radiolabeled LPS is rapidly eliminated from the bloodstream and accumulates in spleen and liver. Liver slices were then analyzed by confocal microscopy, and specific fluorescent signals in the cytoplasm of hepatocytes were detected, confirming the accumulation of 111In-DOTA-Bodipy-LPS in the liver. Conclusion: These results demonstrate the efficiency of the conjugation process of our bimodal probe. It made it possible to perform both non-invasive SPECT and ex vivo fluorescence imaging of LPS biodistribution, underlining its liver uptake for further detoxification. The 111In-DOTA-Bodipy-LPS probe arises here as a relevant tool to identify key components of LPS detoxification in vivo paving the way to therapeutic issues in the field of sepsis. Acknowlegement: Support was provided by the CNRS, the University of Burgundy, the Conseil Régional de Bourgogne. O P _ M o nd ay S178 Eur J Nucl Med Mol Imaging (2013) 40 (Suppl 2):S89–S567Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of ...