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The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of using tissue surgically resected from lung metastatic lesions and comparing their gene expression profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis–associated genes. Using a cohort of 72 lymph node–negative breast cancer patients, we developed a 6-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the 6-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we show that the signature improves risk stratification independently of known standard clinical variables and a previously established lung metastasis signature based on an experimental breast cancer metastasis model. [Cancer Res 2008;68(15):6092–9]

Supplementary Table 1 from A Six-Gene Signature Predicting Breast Cancer Lung Metastasis

Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

Background Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients. Methods Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects. Results HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1–2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P Conclusions HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

Background Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy. Methods HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters. Results From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046). Conclusions The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.

Background This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it

The study of hereditary syndromes is fundamentally based on the finding and identification of susceptibility genes underlying the pathology. Although hereditary tumors account for only a small fraction of all the tumors, the knowledge of underlying genetics changed the clinical management of affected patients and their families, also providing important information on the molecular mechanisms involved in the development of sporadic tumors. In the subjects who inherit a germline mutation, all the cells of the organism are carriers of that mutation, predisposing such subject to develop neoplasm more easily and earlier compared to the general population. The identification of individuals with a hereditary risk of cancer is based on an accurate reconstruction of their personal and family clinical history. Oncogenes and tumor suppressor genes are generally considered genes whose alterations are involved in the tumor onset and progression, promoting an abnormal cell growth and division. Hereditary predisposition syndromes are associated with germline mutations which determine the activation of oncogenes or inactivation of tumor suppressor genes. Tumor suppressor genes responsible for the heredofamilial cancer syndromes can be schematically divided into three main categories: gatekeepers, caretakers, and landscapers. Gatekeeper genes act by directly controlling cell growth, thus inhibiting proliferation, and leading to the apoptosis. Caretakers are responsible for maintaining genomic stability, by reducing the mutation rates of different genes involved in DNA repair, including gatekeepers and oncogenes.

Objectives The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31–65 % and 2–5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy. Materials and Methods We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis. Results Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p Conclusions This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome.

Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129–5923 C>G, HapB3), 4.1–4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10–15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.

// Valentina Cocciolone 1, 2, * , Katia Cannita 2, * , Alessandra Tessitore 1 , Valentina Mastroiaco 1 , Lucia Rinaldi 2 , Stefania Paradisi 2 , Azzurra Irelli 2 , Paola Lanfiuti Baldi 2 , Tina Sidoni 2 , Enrico Ricevuto 1, 3 , Antonella Dal Mas 4 , Giuseppe Calvisi 4 , Gino Coletti 4 , Antonietta Ciccozzi 5 , Laura Pizzorno 6 , Valter Resta 6 , Alberto Bafile 6 , Edoardo Alesse 1 and Corrado Ficorella 1, 2 1 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 2 Medical Oncology Department, S. Salvatore Hospital, University of L’Aquila, L’Aquila, Italy 3 Oncology Network ASL1 Abruzzo, UOSD Oncology Territorial Care, S. Salvatore Hospital, University of L’Aquila, L’Aquila, Italy 4 Pathology Department, S. Salvatore Hospital, L’Aquila, L’Aquila, Italy 5 Radiology Department, S. Salvatore Hospital, L’Aquila, L’Aquila, Italy 6 Breast Unit, S. Salvatore Hospital, L’Aquila, L’Aquila, Italy * These authors have contributed equally to this work Correspondence to: Valentina Cocciolone, email: vale.cocciolone@tiscali.it Keywords: neaodjuvant; dose-dense; PIK3CA; real life Received: July 27, 2017 Accepted: April 06, 2018 Published: June 08, 2018 ABSTRACT Background : Dose-dense chemotherapy is one of the treatments of choice for neoadjuvant therapy in breast cancer (BC). Activating mutations in PIK3CA gene predict worse response to neoadjuvant chemotherapy for HER2-positive patients, while their role is less clearly defined for HER2-negative tumors. Methods : We conducted a phase I/II study of neoadjuvant, sequential, dose-dense anthracycline/taxane chemotherapy, plus trastuzumab in HER2-positive patients and investigated the correlation of pre-treatment PIK3CA mutation status with pathologic complete response (pCR) and long-term outcome in a real-life setting. Results : we established a dose-dense docetaxel recommended dose of 60 mg/m 2 and 65 mg/m 2 , with or without trastuzumab, respectively, according to HER2-status, following dose-dense epirubicin-cyclophosphamide (90/600 mg/m 2 ), every 2 weeks. The overall pCR rate was 21.4%; median disease-free survival (DFS) was 52 months and median overall survival (OS) was not yet reached. PIK3CA mutation status was not significantly associated with the pCR rate: 18% for both mutated and wild-type patients. The pCR rate was: 25% in the mutated and 24% in the wild-type (p 0.560) cohort of the HER2-positive subgroup; 33% both in the mutant and wild-type cohort of the triple-negative subgroup; no pCR neither in the mutant nor in the wild-type cohort of the HR-positive/HER2-negative subgroup. Among the HER2-positive population, a trend toward worse DFS was observed in case of mutation, as opposed to the triple negative population. Conclusions : This study proposes an effective and safe neoadjuvant dose-dense anthracycline/taxane schedule and suggests that PIK3CA mutation analysis can be usefully performed in real-life clinical practice.

// Gemma Bruera 1, 2, * , Francesco Pepe 3, * , Umberto Malapelle 3 , Pasquale Pisapia 3 , Antonella Dal Mas 4 , Daniela Di Giacomo 1, 2 , Giuseppe Calvisi 4 , Giancarlo Troncone 3 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Department of Public Health, University Federico II, Napoli, Italy 4 Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy * These authors equally contributed to this work Correspondence to: Enrico Ricevuto, email: enrico.ricevuto@univaq.it Keywords: FIr-B/FOx intensive first line triplet chemotherapy plus bevacizumab; metastatic colorectal cancer; next generation sequencing; RAS/BRAF mutations; 50 genes panel Received: October 06, 2017 Accepted: April 05, 2018 Published: May 29, 2018 ABSTRACT Background: First line triplet chemotherapy/BEV significantly improved clinical outcome of MCRC. KRAS/NRAS/BRAF mutations were evaluated by next generation sequencing (NGS) in MCRC patients treated with first line FIr-B/FOx. Methods: KRAS exons 2-4 ( KRAS 2-4 ), NRAS 2-4 , BRAF 15 were evaluated in 67 tumours by ION Torrent platform. Mutation detection criteria: >500×sequence coverage (cov); >1% mutant allelic fraction (AF). Clinical outcomes were compared by log-rank. Results: In 63 samples, KRAS 2-4 / NRAS 2-4 / BRAF 15 wild-type (wt) were 14 (22.2%), mutant (mut) 49 (77.8%): KRAS 2-4 42 (66.7%); NRAS 2-4 11 (16.4%); BRAF 15 5 (7.5%). Sixty mutations were detected, range 1-3 mut: 43 (71.7%) >1000×cov/>5% AF; 9 (15%) >500×cov/>5% AF; 8 (13.3%) >1000×cov/ 1000×cov/>5% AF, 8 (12.7%) >500×cov/>5% AF, 1 (1.6%) >1000×cov/ 500×cov/>5% AF, 4 (6%) >1000×cov/ A; c.1406 G>C; c.1756 G>A, 2 samples; c.1796 C>T. At 21 months (m) follow-up, clinical outcome wt compared to mut was not significantly different: in KRAS 2-4 / NRAS 2-4 / BRAF 15 , progression-free survival (PFS) 18/12 m, overall survival (OS) 28/22 m; 1/≥2 mutations, PFS 14/11, OS 37/22. PFS was trendy worse in RAS / BRAF wt vs ≥2 mut genes ( P 0.059). Conclusions: Most MCRC harboured KRAS 2-4 / NRAS 2-4 / BRAF 15 mutations by NGS, often multiple and affecting few tumoral clones; 22% were triple wt. Clinical outcome is not significantly affected by KRAS 2-4 / NRAS 2-4 / BRAF 15 genotype, trendy different in triple wt, compared with KRAS 2-4 / NRAS 2-4 / BRAF 15 ≥2 mut.

BACKGROUND Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy may be candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. METHODS Thirty-seven patients with unresectable recurrent rectal cancer in progression after standard treatments underwent repeated HPP with mitomycin C (25 mg/m2) and cisplatin (70 mg/m2). Twenty patients, exhibiting epidermal growth factor receptor (EGFR) overexpression, also received cetuximab targeted-therapy, following the ultimate HPP treatment. RESULTS Following initial HPP treatment, median progression-free survival was 7 months (range: 5-19 months), median time-to-death or termination of follow-up was 13 months (range: 9-18 months), one-year survival-rate was 59.45%, two-year survival rate was 10.81%, and three-year survival rate was 2.7%. Survival was significantly influenced by cetuximab targeted-therapy post-HPP and the presence of additional metastatic sites (P

Background: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. Methods: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, β20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1–2, 8–9, 15–16, 22–23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose. Results: A total of 29 patients 2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3–4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% ( p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. Conclusions: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. Trial registration: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3–4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

The median overall survival of metastatic breast cancer (MBC) patients is still approximately 2 years. This is even lower in triple-negative breast cancer (TNBC) patients with concomitant lung metastases. These patients are often not suitable for surgery and not responsive to systemic chemotherapy. Isolated thoracic perfusion (ITP) followed by chemofiltration has been used for palliation in selected specialised centres. A retrospective observational study evaluating 162 MBC patients who underwent 407 ITP procedures was performed. The primary objective was the evaluation of the feasibility, safety, tolerability and efficacy of ITP in the complete cohort of 162 patients with LM from breast cancer. The secondary objective of the study was the evaluation of responses and median survivals in 43 TNBC patients with LM. In the 162 patients, ITP appeared safe and well tolerated with MST from LM diagnosis to death or last contact of 19.5 months. In the subgroup of patients treated with systemic chemotherapy followed by ITP at progression, the MST from LM diagnosis to death or last contact was 29 months. In the subgroup of TNBC patients treated with systemic chemotherapy followed by ITP at progression, the MST from LM diagnosis to death or last contact was 19 months (ITP overall response rate was 65.52%). ITP followed by chemofiltration could be adopted in the sequential palliation treatments of BC patients with LM in progression after systemic chemotherapy, especially with TNBC. The present data allow interesting considerations about tolerability and responses, but do not allow robust conclusions about survival.

The current availability of new Poly(ADP-ribose) Polymerase (PARP)-inhibitors for the treatment of ovarian cancer patients independently of the presence of a BRCA pathogenic variant, together with the validation of somatic test for the analysis of BRCA1/2 genes, involves the need to optimise the guidelines for BRCA testing. The AIOM-SIGU-SIBIOC-SIAPEC-IAP Italian Scientific Societies, in this position paper, recommend the implementation of BRCA testing with 2 main objectives: the first is the identification of ovarian cancer patients with higher probability of benefit from specific anticancer treatments (test for response to therapy); the second goal, through BRCA testing in the family members of ovarian cancer patients, is the identification of carriers of pathogenic variant, who have inheredited predisposition to cancer development (test for cancer risk). These individuals with increased risk of cancer, should be encouraged to participate in dedicated high-risk surveillance clinics and specific risk-reducing measures (primary and/or secondary prevention programs).

Between January 2003 and January 2015, women at genetic risk of developing breast and/or ovarian cancer were selected for a surveillance program. The monitoring strategy consisted of the association of breast ultrasound (US), every six months, and Rx-mammography (XM) and breast MRI (MRI) to be performed annually. To date, 29 women have been included in the surveillance program: BRCA1 mutation carriers, 18; BRCA2 mutation carriers, 11. Eight women (28%) had already developed breast and/or ovarian cancer, while 21 (72%) were unaffected carriers. At a median surveillance time of 33 months (range 0-144), 4 incidental breast cancers were diagnosed in 4 BRCA1/2 mutation carriers (4/29, 14%), 2 BRCA1+ and 2 BRCA2+; 3/21 (14%) unaffected carriers and 1/8 (13%) previously affected carriers. Two cancers (50%) were detected by all three diagnostic tools; 2 (50%) were identified only by US and MRI in patients aging 33 and 43, respectively. Characteristics of patients with breast cancer diagnosed during surveillanceagemutated geneprevious cancerUSXMMRIhistologysurveillance time (months)33BRCA2-+-+ductal74+43BRCA2-+-+ductal40+45BRCA1-+++ductal60+40BRCA1yes+++ductal74+ One of these four patients, affected by breast cancer, died at 31 months of overall survival; three underwent surgery, chemotherapy and radiotherapy and are still disease free, in follow-up at 59, 28 and 26 months, respectively. In conclusion, 29 BRCA1/2 carriers have been included in the surveillance program, the median age was 42.5 months (range 27-68) and the median surveillance time was 33 months (range 0-144). Our preliminary data confirm the 3% expected rate of diagnosed cancers and the effectiveness of performing the triple diagnostic surveillance with US, XM and MRI. Citation Format: Sidoni T, Cocciolone V, Cannita K, Di Giacomo D, Ciccozzi A, Bafile A, Pizzorno L, Resta V, Marsecano C, Ferrari F, Di Cesare E, Ficorella C, Ricevuto E. Surveillance program for women carrying BRCA1/BRCA2 genetic predisposition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-14.

// Gemma Bruera 1, 2 , Silvia Massacese 3 , Antonio Galvano 4 , Antonella Dal Mas 5 , Stefano Guadagni 6, 2 , Giuseppe Calvisi 5 , Eugenio Ciacco 3 , Antonio Russo 4 , Enrico Ricevuto 1, 2 , on behalf of Oncology Network ASL1 Abruzzo, Italy 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy 4 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy 5 Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy 6 Universitary General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: docetaxel, 5-fluorouracil, and oxaliplatin; FD/FOx intensive regimen; dose-finding study; first-line triplet chemotherapy; metastatic gastric cancer Received: January 24, 2018 Accepted: March 07, 2018 Published: April 17, 2018 ABSTRACT Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Methods: Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m 2 /d 1-2, 8-9, 15-16, 22-23, with 100 mg/m 2 /d increase for dose level; DTX 50 mg/m 2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m 2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. Results: Ten fit

673 Background: Intensive first line bevacizumab added to triplet, and cetuximab (CET) to doublet in RAS wild-type MCRC significantly increased outcomes. We investigated safety/activity of FIr-C/FOx-C adding CET to triplet in RAS wild-type. Methods: Phase II study according to Simon two-step design: delta 15% (p070%, p185%), power80%, α5%, β20%; projected ORR I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-TFI 900 mg/m2 days (d) 1-2,8-9,15-16,22-23 associated to weekly alternating irinotecan (CPT-11) 160 mg/m2 d1,15 or oxaliplatin 80 mg/m2 d8,22; CET loading dose, then 250 mg/m2 d1,8,15,22; every 28d. Toxicity, LTS evaluated/compared by chi-square test; activity/efficacy by log-rank. Pharmacogenomic biomarkers of 5-FU/CPT-11, 5-FU degradation rate (5-FUDR), Single Nucleotide Polimorphisms (SNP) ABCB1, CYP3A4, DYPD, UGT1A1, evaluated in individual patients with limiting toxicity syndromes (LTS) and at recommended dose. Results: 29 patients < 75 years, primary/intermediate CIRS. From April 2014, KRAS/NRAS wild-type eligible: median age 59; young-elderly (yE) 7, 24%; liver-limited (L-L) 7, 24%. Recommended CPT-11/5-FU doses 120/750 mg/m2. Activity met primary endpoint: OR 14/18 evaluable as-treated (76%), confirmed in preliminary phase II, 17/23 intent-to-treat (74%). Liver metastasectomies 14%, 57% L-L. At median follow-up 18 months, PFS 12, OS 23 months. At recommended doses, received DI > 80% for each drug; cumulative G3-4 toxicities: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS, consisting of the LT, associated or not to G2 or other LT, in 19 patients (65.5%), 83% yE. LTS prevalently multiple than single site (59 vs 7% p0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, frequently associated, prevalently in patients with gastrointestinal LTS, while not without LTS. Conclusions: Intensive first-line FIr-C/FOx-C at recommended dose is tolerable, highly effective in RAS wild-type. Reduced FUDR, CYP3A4, UGT1A1 SNPs may predict individual LTS to select fit patients. Prospective studies will confirm efficacy and personalization by companion toxicity biomarkers. Clinical trial information: EudraCT 2009-016793-32.

// Gemma Bruera 1, 2 , Mario Di Staso 3 , Pierluigi Bonfili 3 , Antonio Galvano 4 , Rosa Manetta 5 , Gino Coletti 6 , Roberto Vicentini 7 , Stefano Guadagni 2, 8 , Corrado Ficorella 2, 9 , Ernesto Di Cesare 2, 3 , Antonio Russo 4 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Radiotherapy, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 4 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy 5 Radiology, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 6 Pathology, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 7 Hepatobiliar-pancreatic Surgery, S. Salvatore Hospital, L’Aquila, Oncology Network ASL1 Abruzzo, Italy 8 Universitary General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 9 Medical Oncology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: capecitabine; chemoradiotherapy; dose-finding; locally advanced rectal cancer; oxaliplatin Received: December 07, 2017 Accepted: February 27, 2018 Published: April 03, 2018 ABSTRACT Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform two-drugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC). This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity. Methods: Schedule: oxaliplatin dose-levels, 35-40 mg/m 2 /week; capecitabine 825 mg/m 2 / twice daily, radiotherapy on rectum/nodes, 50/45 Gy, 45 and 9 boost/45 Gy, in first 5 and subsequent patients, 5 days/week, respectively; for 5 weeks. Pathologic complete response (pCR) 10% was projected in order to positively affect clinical outcome. Results: Seventeen fit

Summary We describe a metastatic colorectal cancer patient, treated with first-line 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS , NRAS , BRAF , and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-Akt Ser473 , phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-Akt Ser473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2–mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies.

Dose-dense chemotherapy is one of the treatments of choice for neoadjuvant therapy in breast cancer (BC). Activating mutations inWe conducted a phase I/II study of neoadjuvant, sequential, dose-dense anthracycline/taxane chemotherapy, plus trastuzumab in HER2-positive patients and investigated the correlation of pre-treatmentwe established a dose-dense docetaxel recommended dose of 60 mg/mThis study proposes an effective and safe neoadjuvant dose-dense anthracycline/taxane schedule and suggests that

Background The aim of the study is to present the results in a consecutive series of patients affected by aortic abdominal aneurysm and to underline the aneurysmal growth and evolution in oncological patients submitted to dedicated oncological medical therapy. Methods Between January 2010 and June 2016 we treated in our center 19 patients for coexisting aortic aneurysms (>3 cm) and malignancy. We observed patients undergoing oncological treatment and patients who did not undergo medical treatment. We studied computed tomography (CT) scan at the time when patients were addressed at our follow-up or treatment and we analyzed retrospectively prior CT scan at 6 and 12 months. Results Among those 19 patients, 7 patients were affected by colorectal cancer (36.8%), 6 by urinary tract cancer (31.6%), 4 by lymphoma (21%), and 2 by lung cancer (10.6%). In 8 patients who did not undergo oncological therapy, we did not observe any aortic growth; instead, in other 4 patients who underwent oncological medical therapy (3 abdominal aortic aneurysms and 1 thoracic aneurysm), we observed a mean sac growth of 2.9 cm in 6 months with 2 cases of aortic rupture treated in urgent fashion. The treatment was open surgery in 2 cases and endovascular in other cases. Conclusions We observed that oncological drugs may play a role in aneurysm growth. Few case reports are found in the literature and more evidences are to be found. Those information may influence intention-to-treat small aneurysms in short life expectancy patients.

// Valentina Cocciolone 1, 2 , Katia Cannita 1 , Maria Letizia Calandrella 1 , Enrico Ricevuto 2, 3 , Paola Lanfiuti Baldi 1 , Tina Sidoni 1 , Azzurra Irelli 1 , Stefania Paradisi 1 , Laura Pizzorno 4 , Valter Resta 4 , Alberto Bafile 4 , Edoardo Alesse 2 , Alessandra Tessitore 2 and Corrado Ficorella 1, 2 1 Medical Oncology, S. Salvatore Hospital, University of L'Aquila, Via Vetoio, 67100 L’Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy 3 Oncology Network ASL1 Abruzzo, UOSD Oncology Territorial Care, S. Salvatore Hospital, University of L'Aquila, Via Vetoio, 67100 L’Aquila, Italy 4 Breast Unit, S. Salvatore Hospital, L’Aquila, Via Vetoio, 67100 L’Aquila, Italy Correspondence to: Valentina Cocciolone, email: vale.cocciolone@tiscali.it Keywords: clinicopathological prognostic factors, early breast cancer, clinical practice, survival, 20-year follow-up Received: November 08, 2016 Accepted: June 02, 2017 Published: June 16, 2017 ABSTRACT Background: To quantify the effect of traditional prognostic factors [nodal status, estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2)] on long-term outcome of patients with early breast cancer (EBC), treated in clinical practice over a period of about twenty years. Results: 1198 consecutive patients were identified. Median DFS (disease-free survival): ER+/PR±/HER2−, 165 months (mo) if node-negative (N0) and 114mo if node-positive (N+) ( p < 0.001); triple-negative (TN), 109mo if N0 and 65mo if N+ (p 0.144); ER+/PR±/HER2+ in patients not-treated with adjuvant trastuzumab (T−), not reached if N0 and 114mo if N+ (p 0.297); ER+/PR±/HER2+ in patients treated with trastuzumab (T+), 95mo if N0 and 85mo if N+ (p 0.615); ER−/PR−/HER2+ T−, not reached if N0 and 26mo if N+ (p 0.279); ER−/PR−/HER2+ T+, not reached if N0 and 66mo if N+ (p 0.014). Median OS (overall survival): ER+/ PR±/HER2−, 166mo if N0 and 144mo if N+ (p 0.028); TN, 158mo if N0 and 96mo if N+ (p 0.384); ER+/PR±/HER2+ T−, not reached if N0 and 157mo if N+ (p 0.475), ER+/PR±/HER2+ T+, not reached if N0 and 106mo if N+ (p 0.436); ER−/PR−/HER2+ T−, not reached if N0 and 34mo if N+ (p 0.273); ER−/PR−/HER2+ T+, not reached neither if N0 nor if N+ (p 0.094). Materials and Methods: Disease-free survival (DFS) and overall survival (OS) were evaluated according to tumor characteristics, based on information retrospectively retrieved from patients’ medical records. Conclusions: Pathological tumor characteristics and nodal status still represent useful tools in treatment selection and follow-up decision making of EBC patients in clinical practice.

// Gemma Bruera 1, 2 , Antonio Russo 3 , Antonio Galvano 3 , Sergio Rizzo 3 and Enrico Ricevuto 1, 2 1 Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3 Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy Correspondence to: Antonio Russo, email: antonio.russo@usa.net Keywords: elderly, intensive treatment, metastatic colorectal cancer, triplet chemotherapy plus bevacizumab, unfit Received: June 07, 2016 Accepted: November 24, 2016 Published: December 28, 2016 ABSTRACT Introduction: Bevacizumab addiction to triplet chemotherapy, according to FIr-B/FOx schedule, as first-line treatment in young-elderly metastatic colorectal CANCER (MCRC) patients may be more effective. Tailored treatments show worse clinical outcome in unfit patients. Methods: Elderly patients were clinically evaluated according to age and comorbidity (Cumulative Illness Rating Scale) to select FIr-B/FOx regimen in fit or tailored treatments in unfit elderly. Limiting toxicity syndromes (LTS) were evaluated. Results: At 17 months follow-up, in 28 young-elderly patients treated with first line FIr-B/FOx: objective response rate (ORR) 79%, progression-free survival (PFS) 11 months, overall survival (OS) 21 months. Clinical outcome was not significantly different according to KRAS genotype. G3-4 toxicities were diarrhea 21%, mucositis 11%, neutropenia 11%. LTS were 46%, significantly more multiple than single site. At 8 months follow-up, in 37 unfit patients: ORR 37%, PFS 7 months, OS 13 months. PFS was significantly different in KRAS wild-type compared to mutant patients, while not OS. PFS and OS were significantly worse in KRAS c.35 G > A compared to wild-type and/or other mutant. Conclusions: Careful decision-making process including evaluation of patient’s fitness, and individual safety should be included to select FIr-B/FOx intensive first line regimen in young-elderly MCRC patients. KRAS , and specifically c.35 G > A mutant genotype, may significantly affect clinical outcome in patients unfit for FIr-B/FOx.

Background: α-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration. Materials and Methods: In vitro effects of TFIP were verified by using three non-tumour prostate epithelial cell lines, a series of eight PCa cell lines and six cell derivatives. In vivo experiments were performed using PC3 and 22rv1 xenografts grown in nude mice with TFIP administered intraperitoneally or by oral gavage. Results: AMACR was expressed in PCa cell lines but was absent in normal and BPH cells. Although androgen-independent (AI) cell lines originating from androgen-dependent (AD) LnCaP cells displayed increased AMACR expression, the levels of this enzyme were higher in AI with respect to AD cell lines. TFIP induced: (1) down-modulation of AMACR expression; (2) suppression of the survival Akt/mTOR signalling pathway and (3) down-modulation of cyclin D1 and survivin with G2/M arrest and apoptosis. TFIP exhibited antitumour effects independently of the administration method. Nevertheless, oral administration was associated with acute toxicity at doses >75 mg/Kg/day. A dose of 75 mg/Kg administered biweekly reduced the toxicity whereas limited toxic effects were observed at 50 mg/Kg/day. Intraperitoneal administration of 75-100 mg/Kg/day was not toxic. Conclusions: AMACR is a good pharmacological target for treatment of PCa and TFIP is a suitable anticancer compound with parenteral administration being the preferred route.

e15013 Background: Cancer treatments induce symptoms and signs superimposing on clinical and cancer-related status of individual patient, defining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens developed in fit metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule including fluorouracil and weekly alternating irinotecan and oxaliplatin. Methods: Metastatic colorectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making in real life phase II studies: FIr-B/FOx, adding bevacizumab (BEV), in overall, and FIr-C/FOx-C, adding cetuximab (CET), in KRAS/NRAS wild-type mCRC, respectively; FIr/FOx in mPDAC; FD/FOx, adding docetaxel (D), in mGC. Toxicity, and individual limiting toxicity syndromes (LTS), classified as limiting toxicity alone (LTS-single site, LTS-ss) or associated to other limiting or G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated and compared by chi-square test. Results: FIr-B/FOx and FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, respectively reported activity, efficacy and limiting toxicities similar to other triplet chemotherapy-based regimens. Reported LTS: FIr-B/FOx in mCRC 44%, LTS-ms 24% and LTS-ss 20%, in young elderly (yE) 46%, LTS-ms significantly increased vs LTS-ss; FIr-C/FOx-C in KRAS/NRAS wild-type mCRC 65.5%, significantly increased LTS-ms vs LTS-ss, in yE 83%; FIr/FOx in mPDAC 27.5%, mostly LTS-ms, in yE 38.4% all LTS-ms; FD/FOx in mGC 30%, all LTS-ms, in yE 25%. Conclusions: LTS meet the need of an innovative clinical parameter of patient-related toxicity burden, indicating global and individual tolerability, including differential spectrum and intensities of TS related to cancer treatment and according to clinical status of the individual patient. LTS integrated with conventional toxicity evaluation may help properly select patients fit for intensive medical treatments in mGI cancers.

Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first-line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib–axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93–7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6–17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39–13.40 months) vs. 5.46 months (95% CI 4.04–6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95–10.51 months, p = 0.01) and 8.67 (95% CI 4.0–13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65–5.27 months, p = 0.01) and 2.97 months (95% CI 0.66–5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib–Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4–51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

Angiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first‐line treatment of unselected, HER2‐negative, metastatic breast cancer (MBC) patients, in a real‐life setting. Thirty‐five patients (median age 56 years, range 40–81) with HER2‐negative MBC were treated with paclitaxel (70 mg/m2) dd 1,8,15 q21 (60 mg/m2 if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty‐two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple‐negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow‐up of 13 months (range 1–79 months), the median progression‐free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real‐life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.

Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control. The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference. The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients. We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease.

The choice of chemotherapy for patients with metastatic breast cancer (MBC) depends on disease- and patient-related factors, but there is little guidance on dosing modifications for patients unable to receive the licensed dose. Nab-paclitaxel is a solvent-free form of paclitaxel that uses albumin as a drug carrier and exploits endogenous albumin transport pathways to achieve enhanced drug targeting and tumour penetration with reduced toxicity. It is approved for use at a dose of 260 mg/m(2) every three weeks in adults who have failed first-line treatment for MBC and for whom standard anthracycline-based therapy is not indicated. Emerging data suggest that weekly dosing schedules of nab-paclitaxel may provide clinical benefit in some patients, but the utility of these alternative dosing schedules remains unclear. A panel of breast cancer experts convened to review available literature for nab-paclitaxel in MBC and, taking into account their clinical experience, recommended that alternative dosing schedules may be considered according to the aggressiveness of disease and patient condition as follows: 125 mg/m(2) QW 3/4 (aggressive disease and fit), 100mg/m(2) QW 3/4 (aggressive or indolent disease and unfit). All dosing schedules were considered acceptable for fit patients with indolent disease. These recommendations are based on current evidence, and emerging data from ongoing trials may reinforce or modify the recommendations provided.