Search

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Background: to compare the effects of two different expansion protocols in terms of bi-dimensional linear, angular measurements, and three-dimensional analysis of palatal area on digital casts in patients with mixed dentition. Methods: digital casts of 32 children treated with the RME (RG: 17 subjects), or with clear aligners (FG: 15 subjects) were collected. Linear and angular values were measured in both groups on the upper arch for each pre (T1) and post-treatment (T2) models, as well as palatal area. Unpaired t-test was used to test significant differences between groups (pResults: the comparison of T2-T1 changes for linear measurements between groups showed significant differences in the inter-canine width (+1.5mm in FG), in the first inter-deciduous molar width (+1.5mm in FG), in the first inter-molar distal width (-1.2mm in FG), in the inter-canine transpalatal width (+1.5mm in FG) and in the first inter-deciduous molar transpalatal width (+1.4mm in FG). The analysis of angular measurements showed a significant increase of the crown angulation for all the teeth in FG except for the second deciduous molars and for the first molars. First molars showed a reduction of this parameter. FG patients showed a greater increase of the palatal area. Conclusions: the comparison between FG and RG groups pointed out that clear aligners system seems to be more efficient than RME in terms of expansion obtainable at the anterior segment of the arch with a better control of upper first molar crown angulation and a greater increase of the palatal area.

PURPOSE Despite extensive research on cancer and work-related outcomes, evidence from longitudinal cohort studies is limited, especially in young women with breast cancer (BC). We aimed to investigate employment trajectories in young BC survivors and to identify potential factors associated with changes in work activity. METHODS The HOHO European prospective multicenter cohort study enrolled 300 young women (≤ 40 years) with newly diagnosed BC. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years to assess, among other variables, employment status, sociodemographic, medical, and treatment data. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Univariable and multivariable multinomial logistic regression analyses identified factors associated with changes in employment status. RESULTS Among the 245 women included in this analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). At 5 years, women had a 29.4% probability (95% CI: 23.6-35.5) of experiencing any reduction and a 14.9% probability (95% CI: 10.6-19.9) of experiencing any increase in work activities. Being enrolled in Switzerland (vs. Italy) and reporting more trouble in performing daily activities were significantly associated with work reduction. CONCLUSION Our results suggest that most young BC survivors remain employed in the long-term. IMPLICATIONS FOR CANCER SURVIVORS Regular evaluation of symptoms which may interfere with daily life and identification of financial discomfort is critical in providing timely and individually tailored interventions and in limiting unwanted reductions in work activities.

Aims: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres.Materials and methods: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care.Results: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively.Conclusion: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.

Background: Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with increased therapeutic efficacy of trastuzumab/pertuzumab-based neoadjuvant therapy (NT) in patients (pts) with HER2-positive breast cancer (BC). Subcutaneous (SC) trastuzumab has non-inferior efficacy to intravenous (IV) administration, with a similar safety profile. Interestingly, SC trastuzumab has been observed to be more immunogenic than IV trastuzumab and act at different immunologic levels. Therefore, by modifying the modality of administration of trastuzumab, it could be possible to interfere with different immune pathways and exert a favorable immunomodulation in HER2-positive BC. Methods: In this non-comparative, phase II, neoadjuvant, randomized study, pts were eligible if they had previously untreated, histologically confirmed, locally advanced, inflammatory, or early-stage HER2-positive BC. Pts were treated with FEC (fluorouracil 500 mg/m2; epirubicin 75 mg/m2; cyclophosphamide 500 mg/m2) q21 × 3 cycles. Then, they were randomly assigned (1:1) to receive: docetaxel (75 mg/m2) plus pertuzumab (840 mg loading dose (LD), then 420 mg) plus IV trastuzumab (8 mg/kg LD, then 6 mg/kg) q21 × 4 cycles (arm A) or, docetaxel plus pertuzumab plus SC trastuzumab (fixed dose of 600 mg) q21 × 4 cycles (arm B). After surgery, pts received trastuzumab q21 × 14 cycles using the same formulation (SC or IV) of the preoperative phase. The primary endpoint was the rate of stromal TILs (sTILs) on residual disease after surgery. Tumor biopsy and posttreatment surgical samples were centrally analyzed for TILs. Blood samples were also collected during NT for tumor-specific lymphocyte cell activity analysis. Feasibility, efficacy and safety were also evaluated. ClinicalTrials.gov: NCT03144947. Results: Between November 2016 and September 2017, according to an adaptive Simon's two-stage optimal design, we enrolled 65 pts, of whom two were deemed ineligible for the study. Thus, 63 pts (31 in arm A and 32 in arm B) were assessed for the primary and secondary endpoints. The pathologic complete response (pCR; no invasive tumor in breast and axilla) rates were 64.5% (95% CI, 47-81) in arm A, and 59.4% (95% CI, 42-76) in arm B. The most common adverse events of grade 3 or higher were neutropenia (15 [48.4%] pts in arm A, and 11 [34.4%] in arm B), neurotoxicity (1 [3.2%], and 2 [6.2%], respectively), and diarrhea (1 [3.2%], and 1 [3.1%], respectively). There were no events of congestive heart failure. At surgery, 11 pts in arm A and 13 pts in arm B were evaluable for TIL analysis. The median value of sTILs (7.5%) on pre-treatment tumor biopsies was used as the cut-off value, and high sTIL levels were observed in 27.3% and in 46.1% of residual tumors after treatment arm A and B, respectively. There was a positive correlation between pretreatment sTILs and PD-L1 expression on stromal immune cells (Kendall’s τ =0.80). Interestingly, a significant inverse correlation was observed between PD-L1 expression on pretreatment sTILs and the T cell co-receptor CD3 expressed on posttreatment sTILs (Pearson’s ρ = -0.70). This finding was particularly evident in the arm B group (ρ = -0.85). Conclusions: NT with either SC or IV trastuzumab in combination with pertuzumab and chemotherapy had a significant effect on sTIL expression at surgery. In particular, the SC trastuzumab-based arm exerted the most relevant enrichment of sTILS in posttreatment residual tumors. These findings suggest a role for the SC administration of trastuzumab in determining favorable variations of host immune response parameters among pts with HER2-positive early BC who had residual disease after NT. Citation Format: Antonino Musolino, Stefania Gori, Elisabetta Cretella, Alessandra Marabese, Luigi Cavanna, Antonio Frassoldati, Giancarlo Bisagni, Chiara Casarini, Emilio Bria, Luisa Carbognin, Elena Fiorio, Alba A Brandes, Claudio Zamagni, Lorenzo Gianni, Alberto Zambelli, Filippo Montemurro, Michele Tognetto, Renata Todeschini, Giuseppe Maglietta, Gabriele Missale, Enrico M Silini. Phase II, open label, randomized, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer. ImmunHER trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-19.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses mainly on prolonging patients (pts) survival and improving their quality of life. As a consequence, management of treatment related adverse events (AE) is very important. Eribulin (E) is a microtubule inhibitor that has shown to increase overall survival in pre-treated MBC pts. Its most common AEs are asthenia, neutropenia and peripheral neuropathy (N). PATIENTS AND METHODS: PAINTER (Clinical trial registration: NCT 0286403) is a multicenter, interventional, single-arm, phase IV study, aimed at surveying the tolerability of E (dose 1.4 mg/m2 day 1, 8 every 21 days) in an unselected MBC pts population pre-treated with taxanes and antracyclines. The secondary objective was to investigate the relationship between specific polymorphisms and incidence and severity of peripheral N. Toxicity (T) was reported according to the NCI CTCAE v4.0. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit-Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment N was evaluated by medical examination. RESULTS: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centres and 170 were evaluable. Pts and tumors characteristics were as follows: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1. Pts received E for 4.5 median cycles (Q1-Q3: 3.0-7.0; min-max: 1-23); 48.8% of pts experienced dose reduction, due to neutropenia (23.9%) and liver injury (12%) and 5.2% of pts discontinued E for T or for pts refusal. Previous neuropathy was reported in 15.9% of pts. Table 1 shows the incidence of expected AEs. N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). The risk of N occurrence in the first 5 cycles was 32.5% (for any grade N) and 13.2% (for severe N). Other G1-G4 toxicities were: dermatological in 8.6% pts, liver injury in 13.6%, pulmonary in 13.6%. Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and at tumor site. Ten serious AEs were reported and only two were E related. 159 pts were evaluable for the analysis of polymorphism. Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (Fisher test p CONCLUSIONS: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pre-treated pts, but T rarely led to treatment discontinuation. Importantly, we found for first time that the SNPs rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene were associated with E induced N. These data on pharmacogenetic testing, if validated, could allow a tailored treatment with E. Table 1. Incidence of expected AEsAEsG1G2G3G4Severe T (G3+G4) N=170n (%)n (%)n (%)n (%)% [%95%CI]Neuropathy 31 (18.2)20 (11.8)5 (2.9)0 (0.0)14.7 [9.75 - 20.9] #Neutropenia 15 (8.8)11 (6.5)16 (9.4)10 (5.9)15.3 [10.2 - 21.6]Constipation 16 (9.4)8 (4.7)1 (0.6)0 (0.0)0.6 [0.02 - 3.23]Alopecia 25 (14.7)13 (7.6)N.A.*N.A.*7.6 [4.13 - 12.7]Asthenia 38 (22.4)38 (22.4)10 (5.9)0 (0.0)5.9 [2.86 - 10.6]Nausea 19 (11.2)6 (3.5)0 (0.0)0 (0.0)0.0#: G2 for neuropathy and alopecia were considered as severe T *N.A.: Not applicable Citation Format: Nicla La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro S Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Eliana Rulli, Anna Moretti, Barbara Bocci, Gabriella Farina. Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-01.

There is no sufficient evidence to establish a standard of care for patients with brain metastases (BM) from HER2Data of 154 patients were retrospectively collected at 14 Italian institutions through a specifically designed database.Median overall survival (OS) was 24.5 months. Patients receiving surgery/stereotactic radiosurgery experienced longer OS compared to those receiving whole-brain radiotherapy or no treatment (33.5 vs. 11.4 months; hazard ratio = 0.34; 95% confidence interval, 0.22-0.52; P .001). Interestingly, whole-brain radiotherapy did not improve OS compared to no treatment (11.4 vs. 9.8 months; hazard ratio = 0.99; 95% confidence interval, 0.62-1.62; P = .99). HER2-targeted therapy was associated with better OS compared to systemic therapy without HER2-targeted therapy or no systemic therapy (27.5 vs. 5.4 months; hazard ratio = 0.26; 95% confidence interval, 0.17-0.41; P .001). At multivariate analysis stratified by local treatments, systemic therapy, Karnofsky performance status, and neurologic symptoms significantly affected OS. Age, number of BM, steroid therapy, number of previous lines of systemic therapy, status of extracranial disease, and period of diagnosis had no significant impact on OS.Patients with BM from HER2

Purpose Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting. Methods We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%). Results Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9–7.2) and 12.1 months (95% CI: 9.6–16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0–18.4), 6.1 months (95% CI: 4.0–8.9) for CTX-based and 5.3 months (95% CI: 4.1–9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3–16.7 and CTX-based ones (95%CI: 8.7–52.8). Tumour response, PFS and OS decreased proportionally in later lines. Conclusion This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation.

In previous studies, steady‐state Z‐endoxifen plasma concentrations (ENDOss) correlated with relapse‐free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen‐adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N‐desmethyl‐tamoxifen (ND‐TAM), Z‐4OH‐tamoxifen (4OH‐TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log‐transformed ENDOss (log‐ENDOss). Genotype‐derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log‐ENDOss. Genotype‐phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients’ age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log‐ENDOss = 0.162 ‐ log(DM/DX) × 0.170 + age × 0.0063 ‐ weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R 2 = 0.51). In conclusion, log(DM/DX) seems superior to genotype‐derived CYP2D6 phenotype in predicting ENDOss.

Objective To evaluate the role of treatment timing on long-term dentoskeletal effects of Class II treatment with removable functional appliances followed by full-fixed appliance therapy. Materials and methods A group of 46 patients (23 females and 23 males) with Class II malocclusion treated consecutively with either Bionator or Activator, followed by fixed appliances was compared with a matched control group of 31 subjects (16 females and 15 males) with untreated Class II malocclusion. The treated sample was evaluated at T1, start of treatment (mean age: 9.9 ± 1.3 years); T2, end of functional treatment and prior to fixed appliances (mean age: 11.9 ± 1.3 years); and T3, long-term observation (mean age: 18.3 ± 2.1 years). The treated and the control samples were divided into pre-pubertal and pubertal groups according to skeletal maturity observed at the start of treatment. Statistical comparisons were performed with independent sample t-tests. Results When treatment was initiated before puberty, Class II correction was mostly confined to the dentoalveolar changes, with significant improvements of both overjet and molar relationships. On the other hand, treatment with the outset at puberty produced significant long-term improvement of sagittal skeletal relationships, which were mainly sustained by mandibular changes. Conclusions Treatment with removable functional appliances (Bionator or Activator) followed by full-fixed appliances produced significant skeletal long-term changes when it begins at puberty. Prepubertal Class II treatment results primarily in dentoalveolar changes.

Objective The aim of this investigation was to analyze the effects of RME and FM on the airway dimensions in Class III patients compared with untreated controls. Methods A sample of 47 Class III patients treated with RME and FM was analyzed. The treated group was compared with 18 untreated controls. Lateral cephalograms for each patient at T1, T2, and T3 were digitized. Results At long-term evaluation a significant increase in airway size and a significant decrease in adenoid size were found in the treated group as well as an improvement in the pharynx dimension. During active treatment the treated group showed a significant improvement in lower airway size and in lower pharynx dimension. A significant decrease in adenoid size was also found. Conclusion The treatment with RME and FM produced favorable stable changes in the airway dimensions in Class III subjects when compared with untreated controls.

Many of the molecular mechanisms affected by ubiquitylation are highly conserved from yeast to humans and are associated to a plethora of diseases including cancers. To elucidate the regulatory role of epigenetic factors such as the catalytic subunits of SAGA complex, KAT-Gcn5 and Ub-protease Ubp8, on ubiquitylation of non-histone proteins we have performed a comprehensive analysis of the Ub-proteome in yeastSaccharomyces cerevisiaein strains disrupted in Gcn5, Ubp8 or both respect to wild type. We found significative alteration of ubiquitylation in proteins belonging to different functional categories with a recurrence of identical proteins in absence of Gcn5 or Ubp8 indicating shared targets and their interlaced function. Among the processes involved we noteworthy identified all major enzymes engaged in energy metabolism and glycolysis such as PFK1, PFK2 and others showing increased ubiquitylation respect to WT. We showed that the higher degree of ubiquitylation found is at post-translational level and does not depend on transcription. Noteworthy, we foundin vivosevere defects of growth in poor sugar medium and inability to adaptive switch from fermentative to respiratory growth in strains lacking Gcn5 and Ubp8. Our findings data provide a novel, direct link, between metabolism and epigenetic control with a novel role of DUB-Ubp8 and KAT-Gcn5 on the ubiquitylation marking all the main glycolytic enzymes required for an effective execution of the glycolytic flux. Collectively our experimental results and the proposed model can lead to future research and innovative strategies that by targeting epigenetic modulators might be able to lower sugar utilization also in human cells.Author SummaryMolecular mechanisms dissected in simple yeast might be translated to similar circuitries in human cells for new discoveries in human diseases including cancer. Ubiquitylation of proteins is an evolutionary conserved mechanism required for many biological processes. Different post-translational modifications (PTMs) such as ubiquitylation, acetylation, methylation etc. are reciprocally regulated for deposition or removal. Epigenetic factors writing the PTMs code are often components of multiproteic complexes such as SAGA complex that holds the K-acetyltransferase (KAT) Gcn5 and the Ubiquitin-protease (DUB) Ubp8 highly conserved in Evolution. Cells respond to environment and nutrients by changing metabolism and group of enzymes involved in specific pathways are often coregulated by the deposition of selected PTMs. This study analyses the composition and quantitation of Ub-proteins differentially modified in absence of KAT-Gcn5 and DUB-Ubp8 in yeast. Interstingly, we highlighted the role of Gcn5/Ubp8 dependent ubiquitylation in marking major glycolytic enzymes necessary for glucose utilization. Our study suggests a novel regulatory pathway and, considering that lowering glycolysis is a promising strategy to target tumor metabolism, we propose this study as an interesting perspective to lower enhanced glycolysis in tumors.

Aims and objectives To assess the effectiveness of a specific home care nursing programme in addition to standard care in patients (pts) receiving oral anticancer treatments. Background Oral anticancer therapy present challenges for pts since treatment is a home-based therapy. This study evaluates the potentiality of a home care nursing programme in decreasing hospital accesses for not severe toxicity. Methods This is an open-label, multicentre, randomised trial including pts who were receiving an anticancer oral drug. The study complies with the CONSORT checklist published in 2010. Concomitant use of radiation therapy, intravenous or metronomic therapies, or the intake of previous oral drugs was not allowed. Pts were randomly assigned to home care nursing programme (A) or standard care (B). In arm A, dedicated nurses provided information to pts, a daily record on which pts would take note of drugs and dosages and a telephone monitoring during the first two cycles of therapy. The primary outcome was the reduction in improper hospital accesses for grade 1-2 toxicity according to CTCAE v4.0. Results Out of 432 randomised pts, 378 were analysed (184 pts in arm A and 194 in arm B). Hospital accesses were observed in 41 pts in arm A and in 42 pts in arm B (22.3% vs. 21.6%, respectively). No difference was detected in proportion of improper accesses between arm A and arm B (29.3% vs. 23.8%, respectively). Conclusions Our experience failed to support the role of a specific home care nursing programme for pts taking oral chemotherapy. An improved attention to specific educational practice and information offered to pts can explain these results. Relevance to clinical practice Our results underline the role of nurse educational practice and information offered to patients. A careful nurse information of patients about drugs is essential to reduce toxicities avoiding the opportunity of a specific home monitoring.

(1) Background: The nature of the changes that contribute to Class II correction with functional appliances is still controversial. A broad variation in treatment responses has been reported. The purpose of this study was to find cephalometric predictors for individual patient responsiveness to twin-block treatment in patients with Class II Division 1 malocclusion, (2) Methods: The study was performed on a sample of 39 pubertal patients (21 females, 18 males) treated with the twin block appliance. Lateral cephalograms were available at the start of the treatment (T1) and at the end of functional therapy (T2). The outcome variable was the T2&ndash, T1 change in the sagittal position of the soft tissue pogonion with respect to the vertical line perpendicular to the Frankfort plane and passing through point subnasale. The predictive variables were age, gender at T1, and all the cephalometric parameters measured T1. Forward stepwise linear regression with p value to enter 0.05 and p value to leave 0.10 was applied, (3) Results: The only significant predictive variable that was selected was the Co&ndash, Go&ndash, Me angle (p = 0.000), (4) Conclusions: A greater advancement of the soft tissue chin on the profile is expected with smaller pretreatment values of Co&ndash, Me angle.

Currently there are no reliable biomarkers to predict outcome of exemestane treatment. We designed a prospective study to investigate whether constitutive genetic background might affect response to therapy. In a population of 302 advanced breast cancer patients treated with exemestane we showed that a 5-polymorphism-based genetic score could be used to identify patients with different risks of progression and death.Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

Background In HER2+ breast cancer (BC) patients (pts) the pathological complete response (pCR) is associated with improved survival. With regimens based on the combination of trastuzumab (T), pertuzumab (P) and chemotherapy, pCR rates are slightly over 48%. We conducted a retrospective analysis on HER2+ BC pts to describe the outcomes of neoadjuvant combination of P+T and chemotherapy in the real-life setting. Methods Our cohort included 64 pts treated between Sept 2015 and Mar 2018 in 15 Italian Cancer Centers. Treatment outcomes were analyzed in terms of pCR (defined as ypT0/Tis, ypN0i-) and toxicities, recorded according to National Cancer Institute Common Toxicity Criteria. Statistical analysis was performed with T di Student test and χ2 test. Results Overall, in the 55 evaluable pts median age was 50 (range 28-77) and 29 pts (53%) were pre-menopausal. 24 pts (45%) were ER-/PgR-, 12 (21%) ER+/PgR-, 16 (29%) ER+/PgR+, median ki67 was 40. 9% of pts were cT1, 73% cT2, 13% cT3 and 5% cT4; 42 pts (76%) were cN+. All pts received 4 cycles of T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) and P (loading dose 840 mg, followed by 420 mg every 3 weeks). In 42 pts T+P were administered with docetaxel (75 mg/mq every 3 weeks), in 8 pts with paclitaxel (80 mg/mq) and 5 pts received docetaxel and carboplatin (AUC5). In 13 pts also 3 cycles of anthracyclines, according to the FEC scheme, were administered. A pCR was achieved in 29 pts (53%). No significant associations were found between pCR and baseline characteristics or treatments schedule. Seven out of 55 (13%) pts reported G3-G4 toxicities (5 pts neutropenia G3-G4, 1 pt vomiting G3, 1 pt diarrhoea G3, 1 pt anemia G3). Three out of 4 pts treated with docetaxel, carboplatin and P+T reported G3/G4 toxicities. A significant association was found between chemotherapy schedule and toxicities (p = 0.004). Conclusions The association of P+T+chemotherapy improved pCR rate in HER2+ BC pts treated in the real-life setting. Our results showed that the selection of chemotherapy that will be associated with the dual blockade of HER2 is of paramount importance in order to avoid severe toxicities and increase the compliance with treatment. Legal entity responsible for the study Department of Oncology, Belcolle Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background. The management of small (≤ 1 cm), node-negative, HER2+ve BC is controversial, since data from randomized clinical trials specifically addressing the benefit of adjuvant systemic treatment with or without Trastuzumab in this setting are still lacking. The aims of this retrospective study are to assess how pts are managed in routinary clinical practice in Italy, whether clinical or biological features may influence the choice of adjuvant systemic therapy and if there is any difference in the outcome between treated and not treated pts. Patients and methods. Data of 268 consecutive pts who underwent surgery from January 2007 to December 2012 for HER2+ve, pT1a-b pN0 BC, were collected from 25 Italian centres. Descriptive statistical analyses and multivariate logistic regression models were used, with the aim of investigating the relationship between the baseline clinical and biological features and the adjuvant treatment strategy. Results. Pts characteristics were: median age 57, 69% postmenopausal status, 77% had conservative surgery, 32% pT1a, 68% pT1b, 48% G3, 66% ER+ve, 75% Ki67 ≥14%. Ninety percent of pts received adjuvant systemic therapy: 19% hormone therapy (HT) alone, 3% chemotherapy (CT) +/- HT, 64% Trastuzumab + CT +/- HT and 4% Trastuzumab + HT. At the multivariate analysis, the odds of being treated with adjuvant systemic therapy with or without Trastuzumab, resulted higher in presence of conservative surgery (p=0.002), pT1b (p Conclusion. This preliminary analysis shows that in Italy the majority of these pts received systemic adjuvant treatment and about 2/3 were treated with Trastuzumab. Pathological tumor size (pT1b) and negative hormone receptor status represent the main factors influencing the choice of including Trastuzumab in the adjuvant treatment. Survival data are still not mature to drive definitive conclusions about outcome. Citation Format: Stefania Gori, Monica Turazza, Simona Duranti, Elena Fiorio, Jennifer Foglietta, Marcella Gulisano, Ilaria Marcon, Marta Gubbiotti, Maria Giovanna Cavazzini, Simon Spazzapan, Valeria De Simone, Giancarlo Bisagni, Chiara Saggia, Luigi Cavanna, Emilio Bria, Laura Iezzi, Elisabetta Cretella, Patrizia Vici, Daniele Santini, Alessandra Fabi, Ornella Garrone, Antonella Ferro, Silvana Saracchini, Lucia Evangelisti, Sandro Barni, Lucia Mentuccia, Lucio Laudadio, Alessandro Inno, Gianluigi Lunardi, Francesca Coati, Luca Boni. The Promher Study: An observational Italian study on HER2+ve, pT1a-b, pN0, M0 breast cancer (BC) patients (pts) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-05.

ABSTRACT Aim: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. Patients & methods: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed. Results: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. Conclusion: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

Objective To evaluate the craniofacial changes induced by functional appliances with special regard to the oro and nasopharyngeal sagittal airway dimensions in subjects with dentoskeletal Class II malocclusions when compared with an untreated Class II control group immediately after therapy and at long-term observation. Methods A group of 40 patients (21 females and 19 males) with Class II malocclusion treated consecutively either with a Bionator or an Activator followed by fixed appliances was compared with a matched control group of 31 subjects (16 females and 15 males) with untreated Class II malocclusion. The treated sample was evaluated at T1, start of treatment (mean age: 9.9 ± 1.4 years); T2, end of functional treatment and prior to fixed appliances (mean age: 11.9 ± 1.3 years); and T3, long-term observation at the end of growth (mean age: 18.2 ± 2.1 years). Statistical comparisons were performed with independent sample t tests at T1 (baseline characteristics) and for the T1−T2, T2-T3, and T1-T3 changes. Results During active treatment the treated group showed a significant increment in lower airway dimension (PNS-AD1), as well as a significant improvement in the upper airway dimension (PNS-AD2). A significant decrease in the upper adenoid size (AD2-H) was also found. In the longterm evaluation, a significant increase in both lower and upper airway thickness (PNS-AD1; PNS-AD2) and a significant decrease in the upper adenoid thickness were still present in the treated group. Conclusion The treatment with functional appliances produced significant favorable changes during active treatment in the oro- and nasopharyngeal sagittal airway dimensions in dentoskeletal Class II subjects when compared with untreated controls, and these changes were stable in the long-term.

3116 Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]

e13076Background: mCHT is the minimum biologically effective dose of a CHT agent, given at regular dosing regimen with no prolonged drug free interval. Aim of this observational retrospective study...

The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p

BACKGROUND Eribulin is a synthetic analogue of halichondrin B which inhibits microtubule dynamics. It has been approved in Europe for the treatment of locally advanced or metastatic breast cancer (mBC) progressed after at least two chemotherapy regimens for advanced disease. The most common adverse events (AEs) were fatigue, neutropenia and peripheral neuropathy, which occurs with an incidence ranging from 13.9% to 35%. It was severe only in a small proportion of patients, suggesting an individual susceptibility. The neurotoxicity mechanisms associated with microtubulin interfering agents have not been fully defined. Few studies reported an association between some SNPs (Single Nucleotide Polymorphisms) and microtubulin interfering agents-induced neuropathy, mainly taxanes. As the use of Eribulin becomes more widespread, a better knowledge of its safety profile, outside of clinical trials, is warranted. Given that Eribulin toxicity can result in treatment discontinuation, the ability to anticipate which patients will experience severe toxicity could allow for either early intervention or even possibly for prophylactic therapy, or for a better selection of patients eligible for treatment. METHODS This is a multicenter, interventional, single-arm, phase IV study. The primary objective is the evaluation of the safety and tolerability profile of Eribulin in an unselected population of patients with mBC. Secondary objectives are the description of compliance to treatment and efficacy. ENDPOINTS •Incidence, time of onset, severity and duration of all AEs experienced during treatment with Eribulin, especially the most common reported in previous studies but also other possible unexpected toxicities. •Association between a set of selected SNPs and the onset of any grade peripheral neuropathy. Specifically, 15 SNPs located in genes involved in microtubule dynamics or resulted from genome wide association studies, will be analyzed. •Evaluation of quality of life during treatment using validated questionnaires. •Assessment of dose intensity and dose schedule maintenance. •DOT (Duration Of Treatment) and OS (Overall Survival). STATISTICAL METHODS Summary statistics will be used in order to describe patient characteristics. Safety endpoints will be estimated by means of absolute and relative frequencies and associated 95%CI. The relationship between baseline variables and the risk of severe toxicity, as well as the relationship between SNPs and risk of neuropathy will be described by means of contingency tables and their association with outcome will be assessed by χ2 test of Mantel-Haenzel and a logistic regression model. DOT and OS will be described using Kaplan-Meier curves. A sample size of 200 patients will also allow us to get a good fitting for statistical analysis of the relationship between primary endpoint and not more than 10 factors. Regarding the relationship between SNPs and risk of neuropathy it will be feasible to screen for association about 10-15 SNPs, with known prevalence >15%. PRESENT ACCRUAL AND TARGET ACCRUAL 98 of 200 patients were enrolled until 18/05/2016. Target accrual is open for 200 patients. CONTACT INFORMATION Nicla La Verde: nicla.laverde@asst-fbf-sacco.it. Citation Format: La Verde N, Moretti A, Damia G, Paternò E, Santini D, Garrone O, Fabi A, Ciccarese M, Cretella E, Torri V, Generali D, Grasso D, Puglisi F, Collovà E, Roila F, Bertolini A, Barni S, Vici P, Luigi C, Scandurra G, Bramati A, Dazzani MC, Farina G. PAINTER: Evaluation of eribulin tolerability and correlation between a set of polymorphisms and neuropathy in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-05.