Ruolo dei determinanti molecolari nel predire la resistenza al trastuzumab nelle pazienti con diagnosi di carcinoma della mammella metastatico con iperespressione di HER-2

In Italia ogni anno si registrano circa 40.000 nuovi casi di carcinoma mammario e 11.000 decessi legati a questa patologia. Si stima che il 25-30% delle pazienti svilupperà nel corso della vita una malattia metastatica e circa il 5% delle pazienti si presenta in uno stadio avanzato di malattia già al momento della diagnosi. Il 25-30% dei carcinomi mammari mostrano l’iperespressione della proteina di membrana HER-2. Le pazienti i cui tumori presentano una iperespressione di HER-2 hanno generalmente una prognosi peggiore ed un andamento maggiormente aggressivo della malattia rispetto alle pazienti i cui tumori non esprimono tale proteina di membrana. L’utilizzo nella pratica clinica di Trastuzumab, anticorpo monoclonale umanizzato diretto contro la porzione extracellulare di HER-2, ha significativamente modificato la storia naturale dei carcinomi mammari iperesprimenti HER2. I risultati di diversi studi clinici randomizzati hanno dimostrato come, in pazienti con diagnosi di carcinoma mammario metastatico con HER-2 iperespresso, l’aggiunta di trastuzumab ad una trattamento chemioterapico migliori significativamente il tasso di risposte globale, il tempo a progressione di malattia e la sopravvivenza globale. Attualmente, quindi, trastuzumab in associazione alla chemioterapia, rappresenta il trattamento standard di prima linea nelle pazienti con diagnosi di carcinoma mammario metastatico con iperespressione di HER-2. Tuttavia circa il 40% delle pazienti con diagnosi di tumore mammario HER-2 positivo trattate con trastuzumab non beneficia di questa terapia perché ha sviluppato una resistenza primaria o secondaria al farmaco. I risultati di uno studio clinico randomizzato di fase III hanno dimostrato come Lapatinib, un inibitore intracellulare delle tirosin-kinasi di EGFR e HER-2, in associazione alla capecitabina migliori significativamente il tempo a progressione di malattia (TTP) e la sopravvivenza libera da malattia (PFS) in pazienti con diagnosi di carcinoma mammario metastatico HER-2 positivo precedentemente trattate con antracicline, taxani e trastuzumab. Attualmente, quindi, in questo setting di pazienti, lapatinib in associazione alla capecitabina rappresenta una valida opzione terapeutica dopo un trattamento di prima linea per la malattia metastatica. Ad oggi sono stati individuati diversi determinanti molecolari che sembrano implicati nei meccanismi di resistenza al trastuzumab, sebbene nessuno di questi sia ancora stato validato nella pratica clinica. In particolare, molteplici esperienze precliniche e analisi retrospettive condotte in pazienti trattati con trastuzumab hanno dimostrato come la presenza sulla membrana cellulare di p95-HER2 (una porzione “tronca” di HER-2), la perdita di PTEN, la mutazione di PI3K/Akt e risultino associate ad una resistenza al trattamento con trastuzumab. Questi risultati suggeriscono come il lapatinib potrebbe rappresentare una migliore opzione terapeutica. Tuttavia non è al momento possibile discriminare se la resistenza al trastuzumab sia primitiva oppure acquisita e derivante, in questo ultimo caso, da un processo di selezione di cloni cellulari tumorali trattati con l’anticorpo per un periodo di tempo prolungato. Rimane quindi la necessità di classificare biologicamente i carcinomi mammari al fine di personalizzare la terapia e migliorare la prognosi delle pazienti. Tali evidenze inducono a cercare strategie terapeutiche alternative che riescano a superare tale resistenza, quali l’utilizzi di lapatinib, risultata in studi preclinici non cross-resistente nei confronti di trastuzuma

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study

Aims: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. Methods: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. Results: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and,  of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. Conclusions: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Loss of PTEN expression in colorectal cancer (CRC) metastases (mets) but not in primary tumors predicts lack of activity of cetuximab plus irinotecan treatment

ntroduction: PTEN is a key tumor suppressor that inactivates PI3K, a downstream effector of the EGFR cascade. Mutations resulting in PTEN loss lead to uncontrolled activation of PI3K/AKT signalling pathway that may result in resistance to EGFR-blockade. Methods: We retrospectively investigated the role of PTEN immunoreactivity loss (anti-PTEN antibody clone 17.A, Immunomarkers) both on primary CRC and related mets in predicting the activity of cetuximab plus irinotecan combination treatment in EGFR-positive irinotecan-refractory metastatic CRC patients (pts). Results: As of today 102 pts have been included. M/F=60/42, median age=62 (38- 78), median number of previous lines of chemotherapy=2 (1-5). Among the 100 pts evaluable for response we observed a partial (PR) or a complete response (CR) in 13 and 1 cases respectively for an overall response rate of 14%. PTEN immunostaining resulted positive (+), negative (-) or unconclusive (NE) in respectively 48, 36, 11 out 98 primary tumors. On 57 mets PTEN analysis was +, - or NE in 31, 22, 4 cases respectively. PTEN positivity or negativity on primaries was confirmed on 45 related mts in 27 cases (60%) while 7 (16%) + and 11 (24%) - primaries resulted respectively - and + on mets. PTEN status tested on primary tumor was not significantly predictive of response nor PFS. Defining as responders those pts obtaining a PR or CR (RECIST) or SD lasting >6 mos and clearly progressed on previous irinotecan-based regimen with a TTP<3 mos (5 pts), analysis of PTEN on mets showed: 1- vs 12+ responders and 21- vs 19+ non responders (p=0.008). Median PFS in pts with PTEN+ mets was 4.8 vs 3.3 mos in PTEN- (p= 0.009, HR=0.50, 95% CI 0.23-0.81). Conclusions: Loss of PTEN immunoreactivity tested on mets may predict the activity of cetuximab plus irinotecan combination treatment. Further analysis on KRAS mutational status and p-AKT immunostaining are ongoing. Final data will be presented at the meeting. Supported by A.R.C.O. Foundatio

Gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome: Common overlapping gastrointestinal disorders

Several studies have indicated an overlap between gastroesophageal reflux disease (GERD) and various functional gastrointestinal disorders (FGIDs). The overlapping conditions reported have mainly been functional dyspepsia (FD) and irritable bowel syndrome (IBS). The available literature is frequently based on symptomatic questionnaires or endoscopic procedures to diagnose GERD. Rarely, among patients with heartburn, pathophysiological evaluations have been considered to differentiate those with proven GERD from those without. Moreover, both GERD and IBS or FD showed enormous heterogeneity in terms of the criteria and diagnostic procedures used. The GERD-IBS overlap ranges from 3-79% in questionnaire-based studies and from 10-74% when GERD has been diagnosed endoscopically. The prevalence of functional dyspepsia (after normal upper endoscopy) is 12-15% and an overlap with GERD has been reported frequently. Only a few studies have considered a potential overlap between functional heartburn (FH) and IBS using a 24-h pH-metry or impedance-pH evaluation. Similar data has been reported for an overlap between FH and FD. Recently, a revision of the Rome criteria for esophageal FGIDs identified both FH and hypersensitive esophagus (HE) as potential functional esophageal disorders. This might increase the potential overlap between different FGIDs, with FH and HE rather than with GERD. The aim of the present review article was to appraise and discuss the current evidence supporting the possible concomitance of GERD with IBS and FD in the same patients and to evaluate how various GERD treatments could impact on the quality of life of these patients

PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer

Purpose: PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC). Patients and methods: A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated. Results: One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001). Conclusion: PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition

Beyond KRAS: perspectives on new potential markers of intrinsic and acquired resistance to epidermal growth factor receptor inhibitors in metastatic colorectal cancer

The monoclonal antibodies cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), are licensed for the treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Such ‘molecular restriction’ derived from post-hoc analyses of randomized trials and from other retrospective series all indicate how tumors bearing KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations are resistant to EGFR inhibition. Even if highly sensitive for nonresponse, KRAS testing is not very specific. In fact, a limited but still considerable proportion of KRAS wild-type patients rapidly progress on treatment with an EGFR inhibitor. New potential molecular determinants of benefit from such treatment are under investigation and may further refine the selection of patients. Pharmacogenomic analyses and translational studies are also ongoing for exploring the field of acquired resistance to anti-EGFRs, since all patients eventually progress. New biological data are awaited for optimizing the use of molecular agents in colorectal cancer and for identifying promising targets that could allow to better understand and, potentially, overcome mechanisms of primary or secondary resistance to EGFR inhibitors