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The stock of therapeutic weapons available in metastatic colorectal cancer (mCRC) has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy. 5-Fluorouracil (5FU) seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate Synthase (TS), an enzyme playing a pivotal role in DNA synthetic pathway. TS overexpression is an acknowledged poor prognosis predicting factor. The simultaneous combination of 5FU and folinate salt synergistically strengthens fluorouracil cytotoxic effect. In our experience, levofolinate and 5FU together in continuous infusion prolong progression free survival of patients suffering from mCRC, moreover decreasing death risk and showing a clear clinical benefit for patients, irrespective of RAS mutational status, primitive tumor side and metastases surgery.

Background Primary intracranial sarcomas of the central nervous system are rare tumors. They mainly arise from intracranial mesenchymal tissue present in the meninges and can occur at any age. Sometimes osteosarcoma can involve the skull rather than long body bones. In this latter case it is the more common subtype. Surgery, when possible, is a mandatory option often associated with radiation therapy (RT) and chemotherapy. Brain radionecrosis (BRN) is commonly observed due to the growing use of radiosurgery and higher cumulative doses of radiation therapy. The combination of perfusion magnetic resonance imaging and 18fluoro-deoxy-glucose positron emission tomography can help to differentiate tumor progression from radiation injury. Steroids, anticoagulants, and bevacizumab usually control BRN. However, BRN can also have an unfavorable course. Case Description Here, we present a case of a 60-year-old male who underwent surgery for a brain tumor. The examination showed a primary undifferentiated high-grade sarcoma. Adjuvant RT was given with a total dose of 60 Gy. Six months later, the patient underwent a second surgery that revealed a BRN progressing despite different pharmacologic attempts. Conclusions Primary intracranial sarcomas of the central nervous system are less prevalent among older adults with respect to the younger population. The use of RT alone or combined with chemotherapy is aimed at prolonging survival. However, it is not clearly defined if adjuvant treatments affect this parameter in older patients. RT should be carefully discussed owing to its potential severe neurologic toxicity. Indeed, a BRN can have a significant impact on quality of life and lead to death in certain cases.

Despite relevant medical advancements, metastatic breast cancer remains an uncurable disease. HER2 signaling conditions tumor behavior and treatment strategies of HER2 expressing breast cancer. Cancer treatment guidelines uniformly identify dual blockade with pertuzumab and trastuzumab plus a taxane as best first line and trastuzumab emtansine as preferred second line choice. However, there is no prospectively designed available study focusing on the sequence and outcomes of patients treated with T-DM1 following the triplet. In the following report, data concerning a wide series of patients treated in a real-life setting are presented. Results obtained in terms of response and median progression free survival suggests a significant role for T-DM1 in disease control of metastatic HER2 expressing breast cancer.

Background: TNBC shows a very bad prognosis: median time to relapse is 18 months and median overall survival (OS) is less than 24 months. Methods: AMBRA is a longitudinal cohort study, describing the choice of 1st- and subsequent treatments in HER2-ve MBC pts in the years 2012-2015. The present analysis is focused on TNBC pts (127 out of 879 evaluable; 14.4%) and CHT strategies, overall and according to adj treatment. Kaplan Meyer probability of survival from primary (DFS), 1st(PFS1) and 2nd(PFS2) progression and Time from last CHT and death were calculated for the whole population and according the main adj regimens. Results: Median age at primary diagnosis was 53 years. The most used regimens in the adj setting were anthra/taxane(tax) 50.7%, anthra 22.1% or others (CMF included) 20.6%. Median time to events was: DFS 23.2, PFS1 6.5 and PFS2 4.3 months, respectively. CHT choices in the metastatic setting according to adj treatment were: Adj Anthra-basedAdj Taxane-basedAdj other1st-lineTax* 57.6% - VRL/CAPE 18.2% - Plat 15.2% Other 3% - None 6.1%Tax* 46.2% - VRL/CAPE 24.6% Plat 24.6% - Other 4.6%Tax*52% - VRL/CAPE 16% - Anthra 16% - Anthra/Tax 8%2nd-lineTax**18.2% - Anthra 13.6% - VRL/CAPE 22.7% - Plat 27.3% - Erib 9.1% - Other 9.1%Tax**22% - VRL/CAPE 22% Plat 22% - Erib 14.6% - Other 17.1%VRL/CAPE 38.5% - Anthra 23.1% - Tax**23.1% - Plat 15.4%3rd lineVRL/CAPE 37.5% - Erib 25% - Anthra 18.8% - Tax***12.5% - Plat 6.3%Erib 26.9% - VRL/CAPE 23.1% - Plat 15.4% - Anthra 11.5% - Tax***11.5% - Other 11.5%VRL/CAPE 42.9% - Erib 28.6% - Plat 14.3% - Other 14.3%*docetaxel 8.4%, nab-paclitaxel 7%, paclitaxel 59%**docetaxel 7%, nab-paclitaxel 71.4%, paclitaxel 21%***docetaxel 20%, nab-paclitaxel 80%At a median follow up of 3.3 years 50% of pts are still alive. OS rates at 5 and 8 years from primary are 50% and 40%. OS rates from 1st progression are 50% and 20% at 22 and 40 months. Median OS (months) according to 1st line regimen was similar (ns) across the regimens (paclitaxel+bevacizumab: 17.8; Platinum-based: 14.1; CAPE/VRL: 16.3). Median time from last CHT and death was 1.5 months (29.6%< 1 month; 14% < 2 weeks) Conclusion: Our results show that taxanes play a crucial role in MBC even if used in 50% of Adj. CAPE/VRL, Platinum regimens and Eribuline are also widely used. Time from last CHT administration and Death is very short in 30% of cases Citation Format: Giorgio Mustacchi, Alessandra Beano, Alessandra Fabi, Lorenzo Livi, Antonio Bernardo, Ferdinando Riccardi, Paolo Marchetti, Ornella Garrone, Lucrezia Diodati, Laura Biganzoli, Monica Giordano, Anna Turletti, Livio Blasi, Andrea Milani, Clara Natoli, Marta Riemma, Alessia D'Alonzo, Grazia Arpino, Paolo Pronzato, Marina E Cazzaniga, on behalf of GIM-13 AMBRA Study Group. Triple negative (TNBC) metastatic breast cancer (MBC) patients (pts): Is chemotherapy (CHT) choice influenced by adjuvant (adj) treatments? Results from the GIM-13 AMBRA 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 P2-15-14.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Background: The appearance of symptoms that may be related to the worsening of the disease, as well as the toxicity of chemotherapy treatment or an acute complication, are the most frequent reasons for access to the emergency room (ER) for patients with cancer. To date, the Italian territorial health services, as well as local preventive medicine, are unable to provide adequate management of patients with cancer and, for this reason, diagnostic delays and inappropriate hospitalization in the oncology departments have occurred; moreover, it has been observed that many patients receive the first diagnosis of cancer directly in the ER, where the experience in the oncology field is often inadequate. Objectives: Cardarelli Hospital, in Naples, started twenty-two month Experimental Oncological Emergency Service, under the supervision of its own Oncology Department, with the double main objectives of encouraging de-hospitalization and improving diagnostic and therapeutic performance. Methods: We have developed a methodological protocol for patients’ admission to the ER, assuming that the host physician transfers patients with suspected cancer to a new hospital figure, the ER oncologist, who acts as supervisor and coordinator. The first consultation was carried out together with one or more specialists, identified by the supervisor. Based on their characteristics, the patients were divided into 4 categories: (1) Patients with a known diagnosis of cancer and already undergoing anticancer treatments; (2) patients who show complications due to ongoing cancer treatments; (3) patients who no longer respond to anticancer treatments due to the worsening of the disease; (4) patients who are first diagnosed with cancer in the ER. Each individual cohort of patients was directed towards what we have called diagnostic-therapeutic assistance paths (PDTA), specific protocols for each type of patient, which allowed us to reduce the time to diagnosis. Results: According to the data, the average hospitalization time for patients with lung cancer who followed the study was 10 days, compared to 16 days for patients who did not undergo cancer screening in the ER. Another relevant result demonstrated the improvement in the quality and efficiency of medical services by including first aid in the management of cancer patients regards de-hospitalization. In fact, thanks to the experimental protocol we applied, we were able to de-hospitalize 484 patients directly from the ER, which are over 34% of the total. Conclusions: Close integration between hospital medical fields and territorial medicine could improve the quality of cancer treatment and the efficiency of health services management. All of this without affecting the costs of public healthcare because of the considerable improvement in performance which allowed important savings.

Tonic pupil, or Adie’s pupil, is an autonomic disorder due to a loss of function of parasympathetic ciliary ganglion cells. Upon examination, the pupil appears tonically dilated and shrinks poorly to light, while reacting better to accommodation stimulus. The denervated iris sphincter is very sensitive to topical parasympathomimetic pilocarpine drops. Indeed, if Adie is present, the dilated pupil will constrict more than the normal pupil. Most cases are idiopathic or due to a viral infection and have a benign course. They usually occur in women between 20 and 40 years of age. Other reported causes of tonic pupils can be vascular, traumatic, inflammatory, paraneoplastic, and neoplastic. Breast cancer generally metastasizes to the brain in advanced stages and orbital localizations have sometimes been reported. In our case, a meningeal and retro-orbit cancer invasion caused a dysfunction of the parasympathetic fibers which lead to the pupil through the optical foramen. Indeed, first ophthalmic symptoms were only an enlarged pupil poorly responsive to light. This unusual clinical sign led to the discovery of an unknown breast cancer in an advanced stage. In young adult women, unilateral tonic pupils are considered a benign parasympathetic ocular disorder that is rarely observed in clinical practice. However, it can be found in numerous systemic diseases; thus instrumental and laboratory findings are mandatory. Tumors can also represent etiologic agents and secondary localizations from breast cancer to extra parenchymal CNS structures should be considered in differential diagnosis hypothesis.

BACKGROUND Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. PATIENTS AND METHODS AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test RESULTS Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of 1st-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from 1stprogression was 32.9 24.2 and 15.8 months respectively. CONCLUSIONS Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminals and disappointing for TNBC. Median time from last CHT and Death is quite short and similar. Luminal ALuminal BTNBCMean DFS (months)87.28 [95%CI: 72.9-101.7]61.37 [95%CI: 52.3-70.4] p=0003623.9 months [95%CI: 18.5-29.3] p=0.000000Mean PFS (months)17.9 [95%CI: 12.5-23.5]11.7 [95%CI:9.8-13.7]7.8 months [95%CI: 5.9-9.6]Mean OS from 1st progression (months)32.9 [95%CI:25.4-40.4]24.2 [95%CI: 21.3-26.9]15.8 [95%CI: 13.0-18.6]Median time from last CHT and Death (months)2.231.951.53Lum A/Lum B HR (p value)Lum A/TNBC HR (p value)Lum B/TNBC HR (p value)PFS 1st-Line0.73 (0.02)0.49 (0.0000)0.63 (0.003)OS from diagnosis (years)0.59 (0.0003)0.25 (0.0000)0.34 (0.0000)OS from 1st-PD0.72 (0.02)0.47 (0.0000)0.50 (0.0002) Citation Format: Marina Elena Cazzaniga, Sabino De Placido, Alessia D'Alonzo, Michela Piezzo, Clara Natoli, Andrea Milani, Alessandra Bologna, Massimiliano Alu, Anna Turletti, Palma Pugliese, Laura Biganzoli, Claudia De Angelis, Ornella Garrone, Paolo Marchetti, Ferdinando Riccardi, Antonio Bernardo, Lorenzo Livi, Alessandra Fabi, Cristiana Taverniti, Emanuela Romagnoli, Paolo Pronzato, Giorgio Mustacchi, on behalf of GIM-13 AMBRA Study Group. Progression-free survival (PFS) and overall survival (OS) in HER2-ve advanced breast cancer (ABC) patients (pts) according to the molecular subtype in the era of modern agents. Results from the GIM-13 AMBRA 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 P5-07-10.

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.

Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also in vitro where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.

There is scant evidence about optimal management of poorly differentiated neuroendocrine carcinoma of the bladder (BNEC). We performed a multicenter retrospective study on BNEC patients from 13 Italian neuroendocrine-dedicated centers to analyze strategies associated with better outcomes. Mixed adeno-neuroendocrine carcinomas (MANEC) were included. We analyzed overall survival (OS) in the overall cohort, relapse-free survival (RFS) in radically operated patients and progression-free survival (PFS) in patients who received chemotherapy for metastatic disease. Fifty-one BNEC patients were included (male: 46, median age: 70 years). Overall, median OS was 16.0 months, radical tumor resection was performed in 37 patients (72.5%) and 11 of these (29.7%) also received peri-operative platinum-etoposide chemotherapy. Median OS was longer in patients with better performance status (PS) and in those with stage I&ndash, III disease at diagnosis compared to stage IV. Among patients who underwent radical tumor resection (N = 37), RFS was longer in patients with better PS and showed a trend towards a longer RFS in those treated with peri-operative chemotherapy than with surgery alone (11 vs. 6 months, p = 0.078). Among 28 patients receiving chemotherapy for metastatic disease, PFS was 5.0 months and there was a trend towards improved PFS in patients receiving carboplatin-etoposide chemotherapy compared to other regimens. A multivariate model unmasked a significant association between carboplatin-etoposide chemotherapy and risk for disease progression or death (HR: 0.39 (95%CI: 0.16&ndash, 0.96) p = 0.040). Performance status might be associated with improved RFS in radically operated patients, while type of chemotherapy might affect PFS in patients receiving chemotherapy for metastatic BNEC.

Purpose To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. Methods A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. Results Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. Conclusions HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.

Background Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). Conclusions Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. Clinical Trial registration Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Objectives Given their inclusion and exclusion criteria, randomized clinical trials (RCT) might not include a population that truly mirrors real life (RL). This raises concerns about the applicability of RCT results in clinical practice. We evaluated the efficacy of anti-HER2 treatment with pertuzumab combined with trastuzumab and a taxane as first-line treatment for HER2-positive metastatic breast cancer in a RL setting, and compared the safety results obtained in our population versus the experimental cohort of the CLEOPATRA RCT, which led to the approval of this therapy. Materials and methods Patients treated with trastuzumab, pertuzumab and a taxane were enrolled in this retrospective study. We compared the tumor features and the patients' characteristics of the RL cohort to those of the CLEOPATRA cohort. We also compared the median progression-free survival (PFS) in the RL population versus specific patients' subgroups. Results RL patients were more frequently HR-positive, less likely to have visceral metastases (P

Objectives Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. Materials and methods This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients’ outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). Results and conclusion Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62–10.0), median PFS1 was 4.61 months (95%CI 4.31–4.84) and median PFS2 was 2.76 months (95%CI 2.57–3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line.

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Aim The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor–positive (HR+) tumours. Patients and methods In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3–4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. ( NCT00412022 )

Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy.

Background: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting. Methods: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies). Results: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35–82) for the EVA and 57.8 years (range 35.0–82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1–48) and 12.4 months (range 2.9–70.0) in the two data sets, respectively. Conclusion: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

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.

Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous malignancies presenting a wide range of pathological and clinical manifestations. Herein, we retrospectively characterize ten patients diagnosticated with LNEC, five of which were defined as well-moderately differentiated neuroendocrine carcinomas, and five that were defined as poorly differentiated neuroendocrine carcinomas, according to the latest WHO classification. Clinical features were analyzed and compared between the two subgroups together with a microRNA study which evidenced a peculiar signature likely related to poorly differentiated larynx neuroendocrine carcinomas. These findings may offer new useful insights for clinicians to improve diagnosis efficiency, therapy response, and patients’ outcome for this aggressive neoplasm.

Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC.In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months).Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met.Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762.

Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2‑) metastatic breast cancer (MBC), which was previously treated with non‑steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2‑ MBC patients who received Exe‑Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow‑up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe‑Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow‑up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe‑Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long‑term survival. Overall, Exe‑Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe‑Eve is an active and safe therapeutic option for endocrine‑sensitive MBC patients in a real‑world clinical setting, regardless of treatment lines.

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non–small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Horner’s syndrome (HS) is caused by an interruption of the cervical sympathetic pathway to the eye and the face. Acquired HS is mainly caused by benign or malignant neoplasms, and in patients with a history of cancer, it is almost always the result of tumor infiltration into the periphery or the central region of the cervical sympathetic chain. We present the case of a 52-year-old patient with long-term disease-free survival (6 years) after a radical mastectomy for breast cancer who presented with cervicobrachialgia and typical HS due to a left lateral-cervical and supraclavicular lymph nodal mass. Treatment of the metastatic disease with taxanes and concurrent trastuzumab resulted in a complete pain resolution, as well as long-term clinical and radiologic remission; however, the neurological cohort of HS remained as the expression of permanent damage to the sympathetic pathway. This report presents a highly rare case of HS as the first and solitary appearance of metastatic disease in a breast cancer patient. This neurologic involvement should always raise suspicion of metastatic infiltration, and the early recognition of the syndrome may prevent permanent nerve injury.

Background Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). Patients and Methods Patients are randomized to receive either cisplatin 25 mg/m2 and etoposide 100 mg/m2 intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. Conclusion An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized.

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome.

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3–4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3–4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

About 80% of all pancreatic ductal adenocarcinoma patients suffer from a wasting syndrome referred to as the “cancer anorexia–cachexia syndrome” (CACS) characterized by abnormally low weight, weakness and loss of skeletal muscle mass with or without loss of body fat, which directly impacts overall survival, quality of life, and physical activity. The aim of this review was to examine recent findings about CACS’ pathophysiology and to describe the current pharmacological approaches. In recent years many efforts were made to improve our knowledge of CACS; currently we know that cachexia arises from a complex and multifactorial interaction between various mechanisms including inflammation, anorexia/malnutrition, alterations of protein and lipid metabolism; consequently its management requires multidisciplinary and multipharmacological approach that should address the different causes underlying this clinical event. On these premises, several drugs have been proposed starting from the first pharmacological treatment based on progestational agents or corticosteroids; most of them are in the preclinical phase, but some have already reached the clinical experimentation stage. In conclusion, to date, there is no standard effective treatment and further studies are needed to unravel the basic mechanisms underlying CACS and to develop newer therapeutic strategies with the hope to improve the quality of life of pancreatic cancer patients.

Background Tumor phenotype may change during breast cancer (BC) progression and discordance between primary and metastases ranges between 16% and 21% for Hormone Receptor (HR) expression in some series. The impact of this change on patient (pts) management and outcome is not yet clear, even though preliminary data indicate that the molecular characterization of recurrent breast cancer may induce clinicians to modify the treatment choice in ∼14% of the cases and that a change in the receptor status is associated with poorer survival. This analysis evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. Methods We used data of 879 pts of the longitudinal cohort AMBRA study, identifying 3 different groups: Group A: HR+ BC remaining HR+ at relapse; Group BHR+ BC becoming TNBC; Group C:TNBC remaining TNBC. Change in HR status was evaluated on the biopsy done at the moment of relapse. Time to event was evaluated by Cox-Mantel Hazard Ratio and Logrank Test; Mean/median by Wilcoxon Rank-Sum Test. Results Pts who underwent biopsy at the time of relapse were 545/879 (62%), of those 462 (84.4%) were classified as Luminal tumors and 83 (15.2%) TNBC on primary. Change in tumor phenotype occurred in 31 (6.7%) of Luminal BC and 16 (19.3%) TNBC, probably due to a higher genomic instability (p = 0.021). Median DFS between Luminal BC was not different: HR+aHR+: 74.56 months (95%CI 66.8-82.1) vs HR+aTNBC: 89.73 months (95%CI:44.73-103.46). Table summarizes main data in time to event in the 3 identified groups. *PFS at 1strelapse; **PFS at 2nd relapse; ***Time to Treatment Change at 1strelapse; °OS at 1strelapse; §OS from 1stPD. Table . 325P HR+/HR + (range) Group A HR+/TNBC (range) Group B p value Group A vs C TNBC/TNBC (range) Group C PFS1* (months) 13.65 (0,77-162,03) 9.45 (3,97-52,73) 0.36 8.13 (6.3-10.9) PFS2** (months) 6.83 (0,00-57,13) 6.12 (2,67-26,30) 0.84 4.20 (0,33-22,17) TTC1*** (months) 12.43 (0,13-163,10) 8.88 (0,00-48,40) 0.50 7.88 (0,23-27,80) TTC2**** (months) 7.45 (0,00-55,97) 6.73 (3,77-26,80) na na OS1° (months) 23.1 (20-26) 15 (8.7-26.3) 0.031 3.60 (0,60-25,38) OS (years) 8.52 (0,26-115,92) 7.86 (0,19-30,67) 0.43 3.58 (2.91-2.39) OS from PD1§ (months) 25.8 (0,00-207,53) 17.23 (2,67-104,30) 0.82 17.90 (2,37-53,57) Conclusions Change in tumor phenotype has a significant impact on OS; BC pts who become TNBC at relapse should be treated in the same way as TNBC pts at diagnosis. Anyway, OS of Luminal BC who change phenotype seems to be better than TNBC. Legal entity responsible for the study GIM - Gruppo Italiano Mammella. Funding Celgene. Disclosure All authors have declared no conflicts of interest.

Rationale:There is an association between the presence of neuroendocrine neoplasms and incremented risk to develop second primary malignancies. This risk is estimated to be 17%. The most common secondary neoplasms were found in the Gastrointestinal and Genitourinary tracts.Patient concerns:A

e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]

e12528 Background: Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test. Results: Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of first-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from first progression was 32.9 24.2 and 15.8 months respectively. Statistical details. Conclusions: Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminal and disappointing for TNBC. Median time from last CHT and Death is quite short and similar.[Table: see text]

Rationale:This article describes the case of a patient with 2 simultaneous malignant diseases: Follicular lymphoma and ‘castration sensitive prostate cancer. Patients with multiple cancers are not easy to manage and it is difficult to find the appropriate approach and resources to use with t

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC). Unfortunately, with the exclusion of SCLC, no large phase II and III trials for pulmonary neuroendocrine tumours have been published. Thus, several treatment approaches are available for their treatment but none of them has been validated in appropriately designed and adequately sized clinical trials. The main problem of the published studies is that they include neuroendocrine tumours from various sites of origin with different clinical behaviour. It is important that future studies consider these tumours separately. In this regard, increased awareness and referral of these patients to tertiary centres, in which a multidisciplinary management is available, may be of value. The aim of this review is to evaluate the state of the art and discuss future developments in the management of pulmonary neuroendocrine tumours excluding SCLC which we consider should be addressed in a different issue.

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥ 5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.

Background: Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC. Patients and methods: From January to December 2012, 650 consecutive patients with HER2-positive early BC, treated in 36 different types of Italian healthcare facilities, were enrolled in this study. Age, treatment, tumor size (T), nodes (N), grade (G), estrogen receptor (ER) and progesterone receptor (PgR) status were prospectively collected in these CP patients. The same data were extracted from the main adjuvant trastuzumab RCTs and pooled using the random-effects model of DerSimonian and Laird. RCT and CP patients were compared by using the Cochran Q statistics. Results: Versus RCT patients, CP patients were more likely to be older than 50years (65 vs. 49%; p2cm (T≥2cm 39 vs. 59%; p&nbsp

Traditional therapeutic approaches for patients with advanced neuroendocrine tumors (NETs) have included treatment with somatostatin analogs, hepatic-directed therapies, interferon and cytotoxic chemotherapy. Current knowledge about biological behavior of pancreatic neuroendocrine tumors (pNETs) has increased in the last decade, and some studies have been conducted to translate in the clinical setting. Among several molecular agents investigated in patients with progressive pNETs, everolimus and sunitinib have been studied in large Phase III trials. Both have produced significant benefit, with improvement in progression-free survival. These results were published last year by NEJM and were updated at the ASCO Annual Meeting in June 2011.This review focuses on the potential molecular targets in pancreatic NETs in the light of recent advances. Furthermore, it summarizes the available data for targeted agents from Phase II and III trials open to patients with this tumor.These new agents are likely to play an increasingly important role in the future management of advanced pNETs. Their use in earlier phases of the disease could improve clinical outcome, avoiding side effects of the more toxic chemotherapy. The challenge in medical treatment of pNET is to define the patients who can benefit from this innovative therapy; future research should be directed to find predictive markers for response to the targeted agent.

Background: In the early 2000s, we identified treatment patterns of early breast cancer (EBC) in Italy (NORA study). To ascertain whether attitudes have changed, we conducted a similar study in 2008. Patients and methods: In this retrospective study (NEMESI), we recorded the clinical, tumour and treatment characteristics of 1.894 EBC patients in 63 Italian oncological centres in 2008, and compared the results with those of NORA, on 3.515 patients in 70 same/similar Italian institutions, in 2000–2003. Tumor stage, surgery and endocrine-responsiveness are not comparable because of different recruitment protocols, patients charactheristics and adjuvant treatment strategies are perfectly comparable as a reliable picture of adjuvant strategies in Italy. Results: There was no difference in age class distribution, menopausal status, ECOG performance status, tumor grade, ki67 and estrogen receptors content. HER2 status was simila but determined in 98% of cases in NEMESI vs 46.2% in NORA. The overall use of endocrine treatment (HT) increased from 80.3% in NORA to 83.5% in NEMESI (p = 0.005); the overall use of chemotherapy (CHT) decreased from 68.4% to 57.8% (p = 0.00001). HT alone increased from 31.6% to 42.2% (P = 0.00001) and CHT alone decreased from 18.8% to 16.2% (p = 0.017). The use of both treatments decreased from 49.2% to 41.6% (p = 0.00001). Trastuzumab was never given in NORA and in 15% of cases in NEMESI (85% of all HER2 positive cases). The choice for HT was tamoxifen for 5 years in 32.5% of cases in NEMESI and 86.6% in NORA (p = 0.000001), and aromatase inhibitors for 5 years in 55.2% vs 13.3% of cases, respectively (P = 0.000001). The “switch” from tamoxifen 2–3 years to aromatase inhibitors 2–3 years was planned in 10.1% of cases in NEMESI and actually done in 12.9% of cases in NORA (p = 0.001). The overall use of LHRH analogues was significantly higher in NEMESI vs NORA (26.7% vs 3.0%, p = 0.00001). CMF-like regimens decreased from 37.0% in NORA to 9.1% (p = 0.000001). Anthracycline-containing regimens decreased from 52.1% in NORA to 48.8% in NEMESI; p = 0.0001) in favour of of regimens containing anthracyclines and taxanes, either in combination or sequential (0.9% in NORA vs 38.4% in NEMESIS, p = 0.000001). The use of taxanes alone regimens remained low (3.5% vs 3.7%, ns). The overall use of anthracyclines and taxanes increased from 53.0% to 87.5% and from 4.3% to 42.1%, respectively (both p =0.00001). Conclusions: EBC treatment has changed significantly in 6 years. Adjuvant strategies are significantly different, with a great increase of aromatase inhibitors and LHRH analogues associated with tamoxifen; anthra-taxane combinations have also significantly increased. Financial Support by Sanofi Aventis Italy Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-04.

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75 mg/m(2) cisplatin plus 75 mg/m(2) docetaxel, both administered on day 1 every 21 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm A), or three cycles of 25 mg/m(2) cisplatin plus 25 mg/m(2) docetaxel on days 1, 8 and 15 every 28 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm B).Of the evaluable patients, 61% in arm A (n = 41) and 36% (n = 44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3 months in arm A, respectively, 3.1 and 7.7 months in arm B. Grade 3-4 adverse events were more common in arm A. Grade 3-4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B).Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).

Evidence on adjuvant chemotherapy for elderly early breast cancer patients is poor, due to the low number of phase 3 trials. ELDA shows that weekly docetaxel does not prolong DFS compared with standard CMF and worsens quality of life. Non-hematological toxicity is worse with weekly docetaxel. Age, comorbidities and functioning geriatric scales may be predictive of non-hematological side effects. Background Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. Patients and methods We carried out a multicenter, randomized phase III study. Women aged 65–79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m2 days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. Results From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83–1.76,P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80–2.22,P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. Conclusions Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. ClinicalTrials.gov NCT00331097.

1057 Background: ESO/ESMO recently developed consensus guidelines for MBC treatment, potentially applicable worldwide. Aim of the present analysis is to verify the adherence to ABC recommendations for HR+ve MBC in the context of the AMBRA study. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving at least one Chemotherapy (CHT) (SABCS 2016, P5-15-07 & P5-14-09). For the present analysis, we selected 6 statements from the ABC1 & ABC2 Conferences, comparing them with the clinical choices of 1st-line therapy in all evaluable cases. Results: So far, 791/1500 pts have been registered into the study, 673 of them (85%) with HR+ MBC. Main characteristics are: N+=422 (62.2%), adjuvant chemotherapy=288 (42.4%), median DFI=70 months. 26 pts were excluded due to change into HR-ve (26; 3.8%). Endocrine Therapy (ET) was the 1st-line of treatment in 187/647 (27.8%), CHT in 310 (47.9%) and CHT followed by ET in 135 (20.8%). Viscera was the main site of disease in 328 pts (48.7%): 56 (17%) received ET, 209 (63.7%) CHT alone, the remaining CHT followed by ET. Median DFI was similar in all the 3 groups. Selected recommendations and percentages of adherence are reported in the table below. Conclusions: The adherence to clinical recommendation about the use of ET as 1st-line treatment in HR+ pts is very low; a potential bias could be due to the selection of the study population. Visceral disease appears to be often a key factor for selecting CHT as 1st-line treatment. In pts receiving ET, the recommendation to use AIs, TAM or F is transposed in almost all the cases. [Table: see text]