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Purpose: The most appropriate therapy for HR + /HER2-positive (HER2 +) advanced breast cancer (ABC) is a matter of debate. Co-targeting of both receptors represents an attractive strategy to overcome the cross-talk between them. Methods: The HERMIONE 9 is an observational retrospective multicentric study which aimed to describe the clinical outcome of patients with HR + /HER2 + ABC who received the combination of Fulvestrant (F) and Trastuzumab (T) as part of their routine treatment at 10 Italian Institutions. Results: Eighty-seven patients were included. Median age was 63 (range, 35–87) years. The median number of previous treatments was 3 (range, 0–10) and F and T were administered as ≥ 3rd line in 67 patients. Among the 86 evaluable patients, 6 (6.9%) achieved CR, 18 (20.7%) PR, and 44 (50.6%) had SD ≥ 24 weeks with an overall CBR of 78.2%. At a median follow-up of 33.6 months, mPFS of the entire cohort was 12.9 months (range, 2.47–128.67). No difference was observed in mPFS between patients treated after progression or as maintenance therapy (mPFS 12.9 and 13.9 months in 64 and 23 patients, respectively), neither considering the number of previous treatment lines (≤ 3 or < 3). Conclusion: The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression.

Introduction: Immune checkpoint inhibitors (ICIs) have become the standard of treatment for patients with non-small cell lung cancer (NSCLC). However, there are still many uncertainties regarding the selection of the patient who could benefit more from this treatment. This study aims to evaluate the prognostic and predictive role of clinical and biological variables in unselected patients with advanced NSCLC candidates to receive ICIs. Methods: This is an observational and prospective study. The primary objective is the evaluation of the relationship between clinical and biological variables and the response to ICIs. Secondary objectives included: safety; assessment of the relationship between clinical and biological parameters/concomitant treatments and progression-free survival at 6 months and overall survival at 6 and 12 months. Nomograms to predict these outcomes have been generated. Results: A total of 166 patients were included. An association with response was found in the presence of the high immunohistochemical PD-L1 expression, squamous cell histotype, and early line of treatment, whereas a higher probability of progression was seen in the presence of anemia, high LDH values and neutrophil/lymphocyte ratio (NLR), pleural involvement, and thrombosis before treatment. The nomogram showed that anemia, PD-L1 expression, NLR, and LDH represented the most informative predictor as regards the three parameters of interest. Conclusions: In the era of personalized medicine, the results are useful for stratifying the patients and tailoring the treatments, considering both the histological findings and the clinical features of the patients.

Background:The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials.Patients and methods:This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B).Results:In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47–79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6–32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively.Conclusions:Our data indicate that palbociclib plus ET is active and safe in HR+/HER2− MBC, also suggesting a better performance of the combinations in earlier treatment lines.

Background Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m2 (arm A) or 125 mg/m2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9–8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2–9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2–3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2–3 arm A vs B, 19% and 38%, respectively). Conclusion Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. Trial registration EudraCT, 2012-002707-18. Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222. Retrospectively registered on May 26, 2016.

Background: Progesterone receptor (PgR) negative breast cancer (BC) is an aggressive subtype with poor prognosis and reduced response to endocrine treatments. Several studies have suggested that androgen receptor (AR) expression is associated with a favorable tumor biology, longer recurrence free survival (RFS), and overall survival. In the literature no data exist regarding the role of AR expression in early stage estrogen receptor (ER)+/PgR– BCs. The aim of this study was to evaluate the prognostic role of AR expression in this setting. Patients and methods: This is a monocentric retrospective study in which 208 patients who underwent surgical intervention for ER+/PgR−/Human Epidermal growth factor Receptor 2 (HER2)– BC were included. The primary objective was to analyze the relationship between AR expression and RFS. Results: At a median follow-up of 77 months, 75 patients (36%) had a disease relapse (all sites included). AR expression was significantly higher in patients who did not relapse compared with those who relapsed with an impact on RFS (hazard ratio [HR] = 0.99, p = 0.025). Patients with AR expression ⩾80% had a lower risk of relapse compared with those with AR Conclusions: The results of this study support the potential prognostic role of AR in patients with ER+/PgR− BCs and may contribute to the identification of subgroups of high-risk patients.

Introduction Metastatic breast cancer (MBC) is a life-threatening disease, and although some data suggest a trend in survival improvement, it has not yet been unequivocally demonstrated. This study aimed to evaluate the overall survival (OS) of MBC patients, assessing its correlation with prognostic factors. Patients and Methods COSMO (Checking Overall Survival in a MBC Observational study) is an Italian longitudinal retrospective multicenter study that enrolled patients with MBC diagnosed between 2000 and 2008. The primary objective was to detect a temporal difference in OS; the secondary objective was to identify prognostic factors as causal factors of the temporal variation in OS. Results A total of 3721 of 3930 patients from 31 centers were distributed in 3 periods: 886 (23.8%), 1302 (35.0%), and 1533 (41.2%) in 2000-2002, 2003-2005, and 2006-2008, respectively. With a median follow-up of 9.3 years, median OS was 2.8 years (95% confidence interval, 2.6-2.9). No difference in OS was found in the 3 cohorts (P for trend = .563). The worst prognosis was observed for patients with triple-negative MBC (OS, 1.5 years) and for those with central nervous system metastases (1.7 years); the best prognosis was observed in those with bone metastases or nonvisceral disease (3.4 and 3.2 years, respectively) and in patients with a disease-free interval, defined as the time between resection of the primary malignancy and diagnosis of MBC, of > 2 years (3 years). Conclusions The COSMO study found improvement in OS between 2000 and 2008. Molecular subtype remained the strongest prognostic factor, and the role of other prognostic factors was confirmed, in particular disease-free interval, site of metastasis, and age.

Introduction: Vinflunine is a microtubule inhibitor approved in Europe as second-line treatment of advanced transitional cell cancer of the urothelium (TCCU). The inability to continue with a first-line platinum-based regimen beyond 6 cycles suggested investigating the use of vinflunine as switch maintenance therapy in patients with response or stable disease after first-line therapy. Methods: Patients with advanced TCCU and documented disease control after 3-6 cycles of first-line platinum-based chemotherapy received vinflunine maintenance therapy within 6 weeks of the last cycle. Our analysis aimed to examine the performance of vinflunine in terms of activity and safety in such a patient population. Results: 28 consecutive patients were studied. After a median follow-up of 25 months, vinflunine was associated with a median progression-free survival of 9 months (range 4 to > 16 months) and a disease control rate of 64%; median overall survival was not reached. Treatment was well tolerated, with no unexpected safety events. The most common adverse events of grade ≥ 3 were neutropenia (21%) and constipation (14%); no toxicity-related death occurred. Conclusions: Our results suggest that vinflunine may be a suitable maintenance treatment option for TCCU patients who received a maximum of 6 cycles of platinum-based chemotherapy commonly used as first-line treatment.

Nab-P is widely used in MBC, but limited data from clinical practice are available. This is an open-label, multicentre prospective cohort study prospectively collecting data of MBC pts treated with weekly, or every 3 week administration of Nab-P. For this survey a convenience sample was used. An attempt was made to get at least a sample of 200 pts, which guarantees a standard error of 3.5% for estimation of survival time at 1 year, overall response rate and grade 3-4 toxicity. Overall response rate was 32.1% in the whole population, without any significant difference according to schedule, previous paclitaxel exposure, presence of visceral metastases or line of treatment. Median time to progression was 6 months (95% confidence interval, 1-34), with no differences according to the schedule of treatment. No new data on toxicity were reported. Results from this real life experience suggest that Nab-P can be safely used with both the weekly and the 3-weekly schedule with comparable efficacy, leaving the choice to the physician according to the patient's needs and preference, with a carefully balance between activity and potential toxicity. Background Few data are available regarding efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel in advanced breast cancer patients outside a controlled trial, especially for the weekly schedule. Patients and Methods We prospectively collected data of advanced breast cancer patients who were candidates to be treated with weekly (125 mg/m2 for 3 consecutive weeks followed by a 1-week rest) or every 3 weeks (260 mg/m2) schedules of nab-paclitaxel, according to physician's decision. Results The study enrolled 209 patients, of whom 92 (39.3%) received weekly nab-paclitaxel. The median age was 58 (range, 31-84) years; 21.8% of the patients were classified as triple-negative breast cancer (estrogen-recetor/progesteron-receptor-negative). The median number of cycles was 5.5. The overall response rate was 32.1% in the whole population, without any significant difference according to schedule, previous paclitaxel exposure, presence of visceral metastases, or line of treatment. The median time to disease progression was 6 months (95% confidence interval, 1-34), with no differences according to the schedule of treatment. Severe adverse events (Grade 3-4) were observed in 60.6% of the patients. The main toxicities were alopecia (53.4%), neutropenia (3%), and sensory neuropathy (2.1%). Conclusion Our real-life data indicate that both schedules of nab-paclitaxel are manageable and safe in advanced breast cancer patients, even if previously treated with other taxanes.

Background: Fulvestrant 500 mg (F500) is the most active endocrine single agent in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Few data are available regarding the effectiveness of the drug in a real-world setting. Patients and methods: This prospective, multicenter cohort study aimed to describe the patterns of treatment and performance of F500 in a large population of unselected women with MBC, focusing on potential prognostic or predictive factors for disease outcome and response. The primary endpoints were progression-free survival (PFS) and clinical benefit rate. Results: From January 2011 to December 2015, 490 consecutive patients treated with F500 were enrolled. Overall, three different cohorts were identified and analyzed: the first received F500 after progression from previous chemotherapy (CT) or endocrine therapy; the second received the drug for de novo metastatic disease; and the third was treated as maintenance following disease stabilization or a response from a previous CT line. Median overall survival (OS) in the whole population was 26.8 months, ranging from 32.4 in first line to 22.0 and 13.7 months in second line and subsequent lines, respectively. Both the presence of liver metastasis and the treatment line were significantly associated with a worse PFS, while only the presence of liver metastasis maintained its predictive role for OS in multivariate analysis. Conclusions: The effectiveness of F500 was detected in patients treated both upon disease progression and as maintenance. The relevant endocrine sensitivity of 80% of patients included in the study could probably explain the good results observed in terms of outcome.

Purpose The present paper describes our experience in surgical treatment of laryngeal ACC, and discuss the effectiveness of conservative surgery. Methods We retrospectively reviewed the clinical charts of 17 patients with laryngeal ACC treated surgically at the Otolaryngology Unit of Vittorio Veneto Hospital (Italy) from November 1989 to April 2020. Results Fourteen patients underwent partial laryngectomy, and three had a total laryngectomy. Five patients (29%) experienced a laryngeal ACC relapse after a disease-free survival of 66.6 ± 50.1 months. The distant metastasis rate was 17%. At latest follow-up, two patients had died of distant metastatic disease after 156 and 243 months. Conclusions Radical surgery for laryngeal ACC does not warrant free margins and even cases with positive deep margins rarely experience any relapsing disease. We recommend that surgical treatment for laryngeal ACC be as conservative as possible.

Lombardy was the first area in Italy to have an outbreak of coronavirus disease 19 (COVID-19) at the beginning of 2020. In this context, cancer has been reported as a major risk factor for adverse outcomes and death, so oncology societies have quickly released guidelines on cancer care during the pandemic. The aim of this study was to investigate the management of cancer patients and oncological treatments during the COVID-19 pandemic and to describe the containment measures performed in our outpatient clinic at Pavia (Lombardy). A comparison with the same period of the four previous years (2019, 2018, 2017, and 2016) was also performed. Using our electronic databases, we evaluated the number and characteristics of patients accessing the hospital for anticancer drug infusion from 24 February, 2020 to 30 April, 2020 and the number of radiological exams performed. Although a significant reduction in access for therapy was seen when compared with 2019 (2590 versus 2974, access rate ratio (ARR) = 0.85, p &lt, 0.001), no significant differences in access numbers and ARR was evident between 2020 and 2018, 2017, or 2016 (2590 versus 2626 (ARR = 0.07), 2660 (ARR = 0.99), and 2694 (ARR = 0.96), respectively, p &gt, 0.05). In 2020, 63 patients delayed treatment: 38% for &ldquo, pandemic fear&rdquo, 18% for travel restrictions, 13% for quarantine, 18% for flu syndrome other than COVID-19, and 13% for worsening of clinical conditions and death. Only 7/469 patients developed COVID-19. A significant reduction in radiological exams was found in 2020 versus all the other years considered (211 versus 360, 355, 385, 390 for the years 2020, 2019, 2018, 2017, and 2016, respectively, p &lt, 0.001). The low incidence of COVID-19 among our cancer patients, along with the hospital policy to control infection, enabled safe cancer treatment and a continuum of care in most patients, while a small fraction of patients experienced a therapeutic delay due to patient-related reasons.

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.

DPD is the rate-limiting enzyme involved in the metabolism of 5-fluorouracil and its prodrugs, capecitabine and tegafur. Many cases of severe toxicities by fluoropyrimidines are reported in the literature, sometimes with lethal outcome, due to a poor or null metabolizer phenotype. The exon 14-skipping mutation IVS14+1G>A and the c.2846A>T are the most common deficient variants. However, many additional variants of the DPYD gene with unclear functional significance have been reported. We describe a patient with metastatic breast cancer who received capecitabine and trastuzumab at standard doses. Six days after beginning capecitabine, the patient developed fever, leucopenia and neutropenia, mucositis, hand–foot syndrome, multiple organ dysfunction and eventually died. Since the toxicity profile was compatible with capecitabine administration, complete exon sequencing of DPYD was carried out and the patient was found to be compound heterozygous for the rare mutation c.257C>T in exon 4, c.496A>G in exon 6, the new variant c.1850C>T in exon 14 and c.2194G>A in exon 18. Given the marginal role of c.496A>G and c.2194G>A in DPD deficiency, the cause of death was suggested to be dependent on the novel c.1850C>T in combination with c.257C>T. The complexity of DPD pharmacogenetics suggests the need to develop cost-effective screening approaches to identify patients at risk of severe toxicities.

[This corrects the article DOI: 10.18632/oncotarget.25874.].

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.

Despite the rich vascularization of the penis, metastases to thepenis are very rare events, and only sporadic cases have been re-ported in literature. According to a comprehensive review fromHizli et al., the most common primary tumor metastasizing to thepenis is bladder (34.7%), followed by prostate (29.8%), rectum-sigmoid colon (15.7%), and kidney (6.5%).

AIM: The aim of our retrospective study was to assess the usefulness of F-FDG PET/CT in the restaging of clear cell renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: Sixty-nine patients (median age = 62 years; range = 36-86 years) affected by clear cell RCC (TNM at staging: T1, 42 patients; T2, 13 patients; T3, 11 patients; T4, 3 patients; Fuhrman grade: G2, 47 patients; G3, 20 patients; G4, 2 patients) underwent whole-body F-FDG PET/CT to restage the disease after nephrectomy for clinical or radiological suspicion of metastases. Areas of abnormal uptake at PET/CT were classified, taking the liver uptake as reference, as follows: 1 = faint uptake, lower than liver; 2 = moderate uptake, equal to liver; and 3 = high uptake, higher than liver. Validation of F-FDG PET/CT results was established by (1) biopsy (23 patients) and (2) other imaging modalities (addressed BS; c.e.CT; MRI; F-fluoride PET/CT; subsequent F-FDG PET/CT), and/or clinical and radiological follow-up of 12 months (46 patients). RESULTS: F-FDG PET/CT was positive in 42 patients and negative in 27 patients. Sixteen patients presented single lesions and 26 patients presented multiple localizations of the disease. On a patient basis, 40 patients resulted true positive, 2 patient false positive, 23 patients true negative, and 4 patients false negative. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 90%, 92%, 91%, 95%, and 85%, respectively. On a lesion basis, PET/CT detected 114 areas of abnormal uptake in 42 positive patients of which 112 resulted to be true positive. FDG uptake of the true positive lesions resulted to be high in 83 cases, moderate in 17 lesions, and finally faint in 12 lesions. CONCLUSIONS: F-FDG PET/CT demonstrated a good sensitivity in the restaging of clear cell RCC. Most of the lesions showed intense activity. According to our results, it seems that the use of F-FDG PET/CT in the restaging of RCC is feasible because the number of false-negative cases is limited.

The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel ( nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m2, but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific ‘difficult-to-treat’ patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, ‘real life’ available experiences are also discussed with the aim of providing an update for daily clinical practice.

Background The purpose of this study was to assess the activity and safety of the combination of vinorelbine (VNR) and capecitabine (CAP) as first-line treatment in HER2–negative (HER – ) metastatic breast cancer (MBC). Patients and Methods Patients (42) enrolled in trial A received intravenous (i.v.) VNR 25 mg/m2 on days 1 and 8 of a 21-day cycle combined with CAP 1000 mg/m2 twice daily for 14 consecutive days followed by 1 week of rest. Trial B (46 patients) followed trial A when the oral formulation of VNR became available at our institution. Patients received oral VNR (60 mg/m 2 on days 1-8) combined with the same CAP schedule as in trial A. Results The response rate (RR) in trial A was 73.2% (95% confidence interval [CI], 56.4-82.8), including 12.2% complete responses (CRs). Clinical benefit was achieved in 78% of patients (95% CI, 63.2-87.9). In trial B, overall RR was 76% (95% CI, 62.0-86.0), with 13% CRs and clinical benefit of 80.4% (95% CI, 66.8-89.3). In trial A, median progression-free survival (PFS) was 8.2 months (range, 6-14+ months) and median overall survival (OS) was 32.4 months (range, 17-36+ months). In trial B, median PFS and OS were 8.8 months (range, 8-21+ months) and 34.3 months (14-39+ months), respectively. Treatment-related toxicity was manageable. Quality of life assessment showed a statistically significant difference regarding body image ( p = .001), sexual functioning ( p = .02), and future perspectives ( p = .03) in women receiving chemotherapy fully by the oral route. Conclusion This joint analysis shows that both tested schedules can produce high objective RRs with encouraging PFS, manageable toxicity profile, and suggested benefit on some aspects of quality of life for the fully oral combination.

Background: Women with metastatic breast cancer (MBC) are increasingly offered third line chemotherapy, but the usefulness of treatment beyond the second line remains a therapeutic challenge. The aim of this study was to determine which benefit could be brought by successive lines of chemotherapy (CT) in patients with MBC and to identify factors affecting outcome and survival. Patients and methods: This retrospective analysis included 980 women treated with CT for MBC at our Institution over a seven year period (September 1998-September 2006). With overall survival (OS) data updated at December 1, 2008, the median follow-up was 125 months (range 48-192), OS and time to treatment failure (TTF) were calculated according to the Kaplan-Meyer method for each CT line. Cox proportional hazards model was used to identify factors that could influence TTF and OS. Results: Median OS evaluated from day 1 of each CT line decreased with the line number from 34.8 months (980 patients, first line, range 4-208) to 22.6 months (838 patients, second line), 14.6 months (684 patients, third line), 12.4 months (302 patients, fourth line), 9.4 months (88 patients, fifth line), 8.2 months (45 patients, seven or more lines). Median TTF ranged from 9.2 months to 7.8 and 6.4 months for the first, second and third line, respectively, with no significant decrease observed beyond the third line (median 5.2 months, range 4.8-6.2). In univariate analysis factors positively linked to a longer duration of TTF for each CT line were positive hormonal receptor status, absence of liver metastasis, adjuvant CT exposure, response to CT for the metastatic disease; in the multivariate analysis the duration of TTF for each CT line was the only one factor with significant impact on survival benefit for subsequent treatments (P Conclusions: Our results stress that CT beyond the first line may be beneficial in a significant subset of women treated for MBC. For patients responding to a given CT regimen and asking for further treatment after disease relapse, it appears useful to deliver subsequent active lines to get prolonged TTF and OS benefit. Patients who do not respond to the first two lines of CT should be considered for clinical trials or supportive care. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-03.

Background: The work experience of women who have had a breast cancer (BC) is still an unexplored area of survivorship research, while the number of women who are employed when they are diagnosed with BC is growing. The purpose of our research was to examine the impact of sociodemographic, clinical and employment variables on return to work after breast cancer. Patients and methods: Eligibility requirements included histologically verified newly invasive breast carcinoma, age between 18 and 60 years, being employed in the month of diagnosis, and being able to respond an interview by questionnaires. The first questionnaire included three sets of questions focused on sociodemographic and personal characteristics, disease-related variables, and the work history. Quality of life and quality of work were assessed by EORTC QLQ-C30 and EORTC-Br23 and FACT-an and VBBA questionnaires. Follow-up assessments were carried out at 6 months, 12 months, 24 months and 30 months after surgery. Results: Two hundred thirty-five eligible patients referring at our Institution between January 2002 and December 2006 with a newly diagnosed BC were enrolled in this longitudinal prospective study. Median age was 45 years (68 patients >45, 63 60 days in 73% of patients. At baseline 80% of women were full-time, and 25% were self-employed; 47% of them were flexible hours working. At 24 months after BC diagnosis, 178 women (75.7%) had returned to work. Most were state-employed (85%), full-time working in 69% of cases, and > 60% did an intellectual job; 63% benefited from flexible hours working. Discrimination because of cancer diagnosis was reported by 35% of patients and occupational intervention by 25% of re-employed women. Among the 57 women who had not returned to work after 24 months from diagnosis, 21 were still sick-listed, 18 received a disability work pension, 11 were early retired, and 7 were out of work. Statistical analysis showed that the duration of disease (odds ratio= 2.96; 95%CI 1.25 to 7.03) and the nature of work (odds ratio= 3.9; 95%CI 1.57 to 9.82) were the strongest predictors factors of work disability. Analysis of factors related to quality of life and quality of work showed that fatigue adversely affected the return to work in our sample, while perceived good quality of job was associated with a greater likelihood of work resumption (p Conclusions: Our research confirm that work situation after BC is still an ongoing critical issue. In the present longitudinal study strictly disease-and work-related variables, as disease duration and nature of work, were the strongest predictors factors of work disability in employed BC survivors. While waiting for development of new therapeutic options that will leave even fewer survivors with work-related disabilities, the main challenge remains to identify survivors with working problems at all stages of survivorship, aiming to a better management of disabilities and improved occupational rehabilitation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-05.

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

To evaluate whether all-trans-retinoic acid (ATRA) is able to modulate the hemostatic system in patients with solid tumors, we studied patients with locally advanced breast cancer who were enrolled in a Phase Ib study of ATRA +/- Tamoxifen (Tam). In this study, two groups of 15 patients/each were treated for 21 days before operation with ATRA at three doses (15, 45, or 75 mg/m(2)/day on alternate days) given alone (group 1) or in combination with Tam (group 2). One additional group received Tam alone. Plasma samples were evaluated for hypercoagulation markers (FVIIa, F1+2, TAT, D-dimer), fibrinolysis proteins (t-PA, PAI-1), and coagulation inhibitors (protein C, AT). At baseline, cancer patients had FVIIa, F1+2, TAT, and PAI-1 significantly greater than control subjects. During treatment, in the patients given ATRA alone, hypercoagulation markers appeared unmodified. Instead, subjects given Tam alone had a significant elevation of FVIIa, F1+2, and TAT versus baseline. However, in the ATRA + Tam groups, hypercoagulation markers were decreased compared with Tam alone. These results suggest that in selected conditions, pre-operative ATRA may modulate the hypercoagulable state of breast cancer patients.

This phase II study was designed to verify the activity and safety of an intensive epirubicin/ifosfamide schedule in untreated soft tissue sarcoma (STS) patients by using both the agents at the identified maximal tolerated doses. 39 adult patients were treated with epirubicin at 55 mg/m2, on days 1 and 2 (total dose per cycle 110 mg/m2) combined with ifosfamide at 2.5 g/m2 days 1-4 (total dose per cycle 10 g/m2), with equidose mesna uroprotection and G-CSF support. Treatment was given on an ambulatory basis, at 3-week intervals. The overall objective response (OR) rate was 59% (95% confidence interval, CI, 43-72%), with 5 complete responses (13%) at 18 partial responses (46%); 12 partial responders were rendered disease-free following surgery. The median survival time was 19 months, being 23 and 13 months, respectively, for responding and non-responding patients. The median time to response was 40 days (range 21-60). Treatment-related toxicity was overall acceptable. The OR of 59% was the highest ever reported in our consecutive studies in advanced STS, confirming that improved therapeutic efficacy can be obtained with intensified regimens in such a disease; both the response duration and survival were also longer. The observed activity proved to be interesting with regard to the high response rate in the lung (86%), as well as the proportion of patients rendered disease-free by early surgery after the achievement of a partial response (55%). Both these findings may be important in the multimodality approach to patients with lesions potentially resectable for cure.

The outcome of patients with metastatic breast cancer (MBC) has clearly improved over the past decades and the proportion of women living with their disease for several years is increasing. However, the usefulness of multiple lines of treatment is still debated and under evaluation. The available data from both randomized trials and large retrospective series are reviewed and discussed in order to analyze management practices, with emphasis on potential prognostic and predictive factors for clinical outcome. At present, evidence-based medicine provides some support for the use of second-line and to a lesser degree and in selected cases, third-line chemotherapy in human epidermal growth factor receptor 2 (HER2) negative MBC. Beyond third-line treatment, messages from recently reported retrospective studies also suggest a clear potential gain for women receiving further therapies after disease progression, since each line can contribute to a longer survival. In HER2-positive disease, the data from observational and retrospective studies support a clinical benefit from the use of trastuzumab beyond disease progression and emerging evidences from randomized controlled trials are leading to the introduction of newer HER2-targeted therapies in multiple lines. The question ‘How many lines of treatment should we give patients?’ clearly needs further research through prospective, high-quality clinical trials, aiming for a better definition of factors with prognostic and predictive role. In the meantime, the ‘optimal’ treatment strategy should probably be to use as many therapeutic options as possible, either in sequence or combination, to keep the best efficacy/toxicity balance, considering MBC as a chronic disease.

Hepatocellular carcinoma is one of the most common malignancies in the world, with the liver being the second most frequently involved organ in metastatic disease. Although the gold standard treatment for malignant liver disease is surgical resection, only few patients can undergo such an intervention. This explains the current great interest in various loco-regional therapies, of which radiofrequency thermal ablation (RFA) is the most common. To date, only a few studies have evaluated the complications associated with this treatment. The aim of this study was to determine the rate of complications, divided into major and minor, in patients treated with RFA. A total of 373 hepatic lesions in 250 patients were treated with 292 sessions of percutaneous ultrasound-guided RFA. According to our data, ten patients (4%) had major, complications, twelve patients (4.8%) had minor complications, no deaths occurred. Around 30% of patients had a body temperature increase of up to 38 'C. All complications, except one, were treated with nonsurgical therapies. One patient with massive hemoperitoneum required surgery. In conclusion, percutaneous RFA is a loco-regional therapy associated with a low incidence of side-effects and a negligible risk of death.

Raffaella Palumbo,1 Federico Sottotetti,1 Giuseppe Trifirò,2 Elena Piazza,3 Antonella Ferzi,4 Anna Gambaro,3 Elena Giulia Spinapolice,2 Emma Pozzi,1 Barbara Tagliaferri,1 Cristina Teragni,1 Antonio Bernardo1 1Departmental Unit of Oncology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; 2Unit of Nuclear Medicine, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy; 3Medical Oncology Luigi Sacco Hospital, Milano, Italy; 4Medical Oncology, Legnano Hospital, Legnano, Italy Background: A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC).Patients and methods: Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m2 as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal.Results: All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%–61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52–86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0–11.6 months, range 5–21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment.Conclusion: Our results showed that single-agent nab-paclitaxel 260 mg/m2 every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that ‘difficult to treat’ patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes). Keywords: nab-paclitaxel, metastatic breast cancer, taxanes, quality of life

Bone metastases are a frequent complication in patients withclear cell renal cell carcinoma (RCC). Skeletal involvementfrequently shows lytic characte ristics and is related to eventssuch as pain, pathological fractures, spinal cord compressionand hypercalcaemia. Bone metastases often require palliativeradiation therapy and orthopaedic surgery [ 1, 2]. Bone scintig-raphy (BS) has long been the reference technique for thedetection of bony metastases, but is of limited value in aggres-sive osteolytic metastases andinthedetectionofearlyosteoblastic changes [3]. Instead

On the basis of the hypothesis that responsiveness of brain metastases (BM) to chemotherapy is primarily determined by the chemosensitivity of primary tumor, rather than the ability of cytotoxic agents to penetrate the blood-brain barrier, we addressed the role of a new combination regimen with Vinorelbine (VNR), Gemcitabine (GEM), and Carboplatin (CBDCA) as a primary treatment modality in non-small-cell lung cancer (NSCLC) patients with BM. Twenty-two consecutive chemotherapy-naive patients with documented BM from NSCLC and at least 1 evaluable extracerebral lesion were enrolled in this phase II study. Vinorelbine (25 mg/m2) and GEM (1000 mg/m2) were given on day 1, combined with a fixed daily dose of CBDCA at AUC = 5.0 for three consecutive days. The cycle was repeated every three weeks in an outpatient setting. A total of 116 cycles was given (median 4, range 3-9 per patient). Specific evaluation of BM by contrast-enhanced computed tomography (CT) scan showed an overall response rate of 45% in 20 evaluable patients (95% confidence interval, 26-66%), with 3 (15%) complete and 6 (30%) partial remissions; in addition, three minor regressions, five disease stabilizations, and three progressions were found. Patients who responded for the brain also had a response at the extracerebral sites, and a benefit by a remission of symptoms and improvement of performance index was observed in 77% of the whole group. Median time to response was 10 weeks (range 6-12 weeks) and median response duration was 25 weeks (range 12-32 weeks). Median survival time was 33 weeks (range 18-62 + weeks) in the whole group and 48 weeks in responders (range 26-62 + weeks). The adopted schedule was well tolerated and easy to use in the outpatient setting, with good patient compliance. Our results, which are consistent with the study hypothesis, suggest that BM respond to chemotherapy in the same way as systemic disease and primary tumor, and further support the need for reconsideration of the role of chemotherapy in such a clinical setting. Controlled trials comparing chemotherapy with radiotherapy or concomitant sequential chemo-radiotherapy would be appropriate.

Aim: Current guidelines recommend HER2 blockade across subsequent chemotherapy (CT) lines to provide effective control of HER2+ MBC, while the benefit deriving from multiple lines in patients (pts) with triple negative (TN) disease is uncertain. We sought to evaluate outcome of women affected with HR-/HER2+ or TN disease receiving multiple lines for their MBC, aiming to identify potential prognostic and/or predictive factors for treatment response and disease outcome. Methods: We evaluated 460 women who had received CT for metastatic disease from February 2004 to January 2011 at our Institution: 250 were affected with ER-/PR-/HER2+ (cohort A) and 210 with TN disease (cohort B).The overall survival (OS) for each woman was calculated from day 1 of 1st CT line to death or last follow-up, according to Kaplan-Meyer method. Association between baseline characteristics and OS were assessed using Cox proportional hazards model. Results: With cut-off data analysis as to March 2013, the median follow-up was 65 months (range 21-122). Median number of given CT lines was 3 (range 1-10); the percentages of pts receiving 2, 3, ≥4 lines of CT were 89%, 52%, 32% (cohort A) and 72%, 27%, 17% (cohort B), respectively. Median OS, evaluated from day 1 of 1st CT line, decreased from 28.6 months (1st line) to 6.7 months (≥4 lines) in cohort A, and from 10.2 to 3.8 months in cohort B. When calculated in function of the total number of lines received, survival increased from 28.6 (1st line) to 34.6 months (≥4 lines) in cohort A, and from 10.2 to 16.2 months in cohort B. In univariate analysis absence of liver metastasis, prior adjuvant trastuzumab and taxane exposure were factors positively linked to a longer OS in cohort A and B, respectively. In multivariate analysis the number of received CT lines resulted independent predictor of longer OS in both the cohorts (p = 0.003 and p Conclusions: Results of our analysis confirm that prognosis of women with TN MBC remains poor also when compared with outcome of other unfavorable tumor subtypes, as HR-/HER2+ disease. The observed OS benefit as a function of total number of CT lines received supports the concept that each treatment line could determine a survival gain also in this ‘difficult to treat’ patient population. Disclosure: All authors have declared no conflicts of interest.

Aim: A growing evidence supports the efficacy and safety of different dosing schedules of nab-paclitaxel (nab-P) through several treatment lines in MBC, also in taxane-pretreated patients (pts). We report the final results of a multicenter experience with single-agent nab-P as 2nd and further chemotherapy (CT) in MBC, focusing on potential predictive and/or prognostic factors for treatment response and disease outcome. Methods: From February 2011, 150 consecutive MBC pts were treated at 8 Italian Institutions, 85 (cohort A) with the 260mg/m2 q3w schedule (46 in 2nd line, 21 in 3rd and 18 in ≥ 4th) and 65 (cohort B) with the 125 mg/m2 (20 in 2nd line, 10 in 3rd and 35 in ≥ 4th). Visceral involvement: 72%; ≥3 metastatic sites: 60%; median DFI ≤24 months: 35%; taxane-based CT in the adjuvant or metastatic setting: 68% and 65%, respectively. Results: The objective response rate (ORR) in the whole population was 48% (6 CR, 65 PR, 51 SD ≥ 16 weeks), for an overall clinical benefit rate of 83%. At a median follow-up of 18 months (range 6-30), median PFS was 7.8 months (range 3-23+), median OS has not yet been reached. Major toxicities were expected and manageable with both the schedules, without differences in the ≥65 years pts (38%). Statistical analysis showed no predictive or prognostic value of the evaluated patient- and disease-related variables (DFI, tumor subtype, site and number of metastatic sites, previous taxane-based CT, prior lines for metastatic disease, dosing schedules), while the line of CT significantly affected both the probability of response (61% ORR in 2nd line versus 38% in ≥3 lines; p Conclusions: Our data confirm that both the tested nab-P regimens produce encouraging ORR and PFS values in taxane-pretreated MBC, in advanced lines of treatment too. The suggested higher activity of the q3w schedule in pts with more aggressive disease further supports the possibility of tailoring the dosing schedules according to the different patient profiles and clinical situations. Disclosure: All authors have declared no conflicts of interest.

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A - vinorelbine 30 mg/m2 i.v. weekly; Arm B - leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --5, q 28 days; Arm C - mitoxantrone 12 mg/m2 i.v. only day 1 + leucovorin 100 mg/m2 i.v. followed by 5-fluorouracil 370 mg/m2 i.v. days 1 --3, q 28 days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3-4 toxicities. Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.