Search

Simple Summary: Breast cancer is one of the most common oncological diseases among women in Western Countries and Italy as well. GIM 13-AMBRA is a patient journey study regarding how the prognosis of metastatic breast cancer patients has changed in the last decades as a result of the introduction of new drugs in clinical practice. This study also provides information regarding the different natural histories of breast cancer according to the presence or absence of hormone receptors and HER2 receptors. GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes–based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79–19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months—95% CI 5.7–9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7–15.1) and Luminal B patients (11.8 months, 95% CI 10.3–12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3–6.5 vs. Luminal A—9.4, 95% CI 8.1–10.7, and Luminal B—7.7 95% CI 6.8–8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8–37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2–31.2) and TNBC (18.5 months, 95% CI 16–20.1, F-ratio 7.44, p = 0.0006). The GIM 13—AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients. [ABSTRACT FROM AUTHOR]

Background/Aim: There is controversy around the use of high-sensitive troponin T (hs-TnT) as an early biomarker of cardiac toxicity in patients with breast cancer on trastuzumab (T). Patients and Methods: Patients receiving adjuvant or neo-adjuvant T for early HER2- positive breast cancer were prospectively included. Transthoracic echocardiograms and matched hs-TnT before T and at 3, 6, and 9 months were performed on all patients. Congestive heart failure, cardiac death, a decline in left ventricular ejection fraction (LVEF) of more than 10% from baseline even if it is still within the normal range, or a drop in LVEF below 55% were all considered signs of cardiac toxicity. Results: In total, 24 patients (median age: 57; range=39-79 years) were enrolled. Anthracyclines were administered to all patients but three as part of neo/adjuvant treatment before T. Cardiovascular toxicity was observed in 3 out of 24 (12.5%) patients: two nonsymptomatic LVEF declines (8.3%) and one heart failure episode (4.2%). In the entire population, the mean baseline hs-TnT level was 10.1±8.8 pg/ml, and after 3, 6, and 12 months, no appreciable change was observed. Patients with cardiac toxicity had mean hs-TnT levels higher than those without (18.3±12.3 vs. 8.2±7.2 pg/ml; p=0.049). A definite trend was evident in the chi-square test (chi 2=3.52; p=0.06). Conclusion: In anthracycline-exposed patients with early breast cancer, hs-TnT may be able to identify those at risk of developing cardiac toxicity during neo/adjuvant T treatment. [ABSTRACT FROM AUTHOR]

Abstract Background International treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters. Methods An observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy. Results Data for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively). Conclusions This study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positve and triple negative.

Abstract Background The human epidermal growth factor receptor 2 (HER2) and p53 pathways may be involved in chemotherapy sensitivity and/or resistance. We explore the value of HER2 and p53 status to foretell docetaxel sensitivity in advanced breast cancer. Methods HER2 and p53 expression was analysed in 36 (median age 55 yrs; range 37-87) metastatic breast cancer patients receiving docetaxel-based first-line chemotherapy. HER2 was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), p53 was tested by IHC. We correlate the expression of study parameters with pathologic parameters, RECIST response and survival. The standard cut-off value of 2 was used to determine HER2 overexpression while p53 mean expression level was used to divide low/high expressors tumors. Results Median time to progression and overall survival were 9 (range 2 - 54) and 20 (range 3 - 101) months. Overall response rate was 41.6%. Nine cases showed HER2 overexpression. HER2 was more frequently overexpressed in less differentiated (p = 0.05) and higher stage (p = 0.003) disease. Mean FISH-HER2 values were significantly higher in responder than in non-responder pts (8.53 ± 10.21 vs 2.50 ± 4.12, p = 0.027). Moreover, HER2 overexpression correlates with treatment response at cross-tabulation analysis (p = 0.046). p53 expression was only associated with higher stage disease (p = 0.02) but lack of any significant association with HER status or docetaxel response. No significant relation with survival was observed for any parameter. Conclusion Our data seem to indicate that FISH-determined HER2 status but not p53 is associated with docetaxel sensitivity in metastatic breast cancer.

Expression levels of p27kip1, a negative regulator of the G1 phase of the cell cycle, and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were assessed by immunostaining in a series of renal cell carcinomas (RCCs) and their prognostic significance was evaluated. Expression of p27kip1 as well as of the α-subunit of the dystroglycan (DG) complex, previously reported to be altered in RCC, was also evaluated by western blot analysis. Nuclear expression of p27kip1 was reduced in a significant fraction of tumors and low p27kip1 staining correlated with higher tumor grade ( P < 0.01). Recurrence and death from clear cell RCCs were significantly more frequent in p27kip1-low expressing tumors and Kaplan–Meier curves showed a significant separation between high vs low expressor groups for both disease-free ( P = 0.011) and overall ( P = 0.002) survival. Low nuclear expression of p27kip1 as well as loss of α-DG were confirmed to be independent prognostic parameters at a multivariate analysis and the simultaneous loss of both molecules defined a “high-risk” group of patients with increased risk of recurrence (RR = 28.7; P = 0.01) and death (RR = 12.9; P = 0.03). No significant correlation with clinical or pathological parameters was found for 8-OHdG staining. Western blot analyses suggested a post-translational mechanism for the loss of α-DG expression and demonstrated that cytoplasmic dislocation of the protein contributes to the loss of active nuclear p27kip1. Loss of nuclear p27kip1 is a frequent event in human RCCs and is a powerful predictor of poor outcome which, in combination with low DG expression, could help to identify high-risk patients with clear cell RCC. ( Cancer Sci 2010; 00: 000–000) [ABSTRACT FROM AUTHOR]

Background: There are currently few data about the safety and effectiveness of chemotherapy for patients with metastatic non-small-cell lung cancer (NSCLC) who have progressed from prior immunotherapy. Methods: Data from patients with consecutive stage IIIB-IV, ECOG performance status (PS) 0-2, non-small-cell lung cancer (NSCLC) treated with combination or single-agent chemotherapy following progression on an earlier immunotherapy regimen were retrospectively gathered. Recorded were baseline attributes, outcome metrics, and toxicities. The neutrophil/lymphocyte (N/L) ratio's predictive usefulness was examined through an exploratory analysis. Results: The analysis comprised one hundred subjects. The adeno/squamous carcinoma ratio was 77%/23%, the M/F ratio was 66%/34%, the ECOG PS was 0/1/≥2 47%/51%/2%, and the median PD-L1 expression was 50% (range 0-100). The median age was 67 (range 39-81) years. Prior immunotherapy included a single-agent treatment in 83% of cases, with pembrolizumab use being prevalent, and a median N/L ratio of four prior to chemotherapy. The overall median time-to-progression on previous immunotherapy was 6 months. After immunotherapy, just 33% of subjects underwent chemotherapy. A median of 4 (range 1-16) cycles of chemotherapy were administered; platinum doublets (primarily carboplatin) were delivered in only 31% of cases, vinorelbine accounted for 25%, taxanes for 25%, and gemcitabine for 8%. The median clinical benefit was 55%, while the overall response rate was 21%. The median overall survival was 5 months (range 1-22) and the median time to progression was 4 months (range 1-17). Subgroups with low and high N/L ratios were compared, but there was no discernible difference in survival. Conclusions: After immunotherapy, a small percentage of patients with advanced NSCLC had chemotherapy. Following immunotherapy advancement, chemotherapy demonstrated a moderate level of therapeutic effectiveness; no adverse concerns were noted. The effectiveness of chemotherapy following immunotherapy was not predicted by the baseline N/L ratio.

Background/aim: The optimal therapeutic use of metronomic vinorelbine has not yet been defined. We aimed to assess the safety of metronomic oral vinorelbine in first-line treatment of elderly patients with advanced lung cancer who were unfit for polychemotherapy. Progression-free survival, response rate and overall survival were secondary end-points., Patients and Methods: Seventy-six patients received 50 mg of oral vinorelbine three times per week, until disease progression, patient refusal or unacceptable toxicity. Patients were evaluated for response and toxicity after one cycle of chemotherapy. The treatment was considered feasible with a grade 3/4 toxicity rate lower than 20%., Results: Clinical benefit was observed in 50% of patients. Median overall survival was 8.0 months. Grade 1/2 toxicity was observed in 53 patients (69.7%), grade 3 toxicity in eight patients (10.5%). One patient had grade 4 diarrhea., Conclusion: Metronomic oral vinorelbine is safe in elderly patients, allowing for long-term disease stabilization with optimal patient compliance., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The management of elderly patients with advanced non-squamous NSCLC includes several strategies., Patients and Methods: Patients (≥70 years) were randomly assigned to bevacizumab (7.5 mg/kg i.v. on day 1) plus gemcitabine (1,200 mg/m 2 i.v. on days 1-8) (arm A) or bevacizumab (7.5 mg/kg i.v.) and cisplatin (60 mg/m 2 i.v.) plus gemcitabine (1,000 mg/m 2 i.v. on days 1-8) (arm B), to independently evaluate treatments. The primary endpoint was progression-free rate at 6 months; secondary endpoints included progression-free survival (PFS) and safety profiles., Results: At 6 months, 5 (11.6%) patients in arm A and 5 patients (12.5%) in arm B were found to be progression-free. Median PFS was 4.8 months in arm A and 6.5 months in arm B, respectively., Conclusion: In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as first-line therapy in elderly patients with non-squamous NSCLC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR)., Aim: The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance., Methods: This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI., Results: p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively., Conclusions: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance.

Background: Bevacizumab has provided encouraging results in relapsed glioblastoma multiforme (GBM). Pre-clinical and clinical investigations also showed that continuous low-dose temozolomide has some antiangiogenic activity. Based on this evidence, a phase II trial was designed to investigate an oral regimen of sorafenib, an oral multikinase inhibitor, and metronomic temozolomide for relapsed GBM., Patients and Methods: Forty-three patients (median age=60.0 years) naive for antiangiogenic agents received 400 mg sorafenib twice daily plus TMZ 40 mg/m(2)/day until disease progression., Results: Toxicity, mostly grade 1-2, was manageable. Grade 3-4 toxicities were hand-foot syndrome (n=4), hypertension (n=2), and fatigue (n=3). Five patients (12%) achieved partial response, 18 (43%) stable disease, 20 (48%) showed progression. The median time-to-progression was 3.2 months, 6-month progression-free survival was 26%, and median overall survival was 7.4 months., Conclusion: This combination of sorafenib and temozolomide was feasible and safe, showing some activity in patients with relapsed GBM.

Background: In breast cancer (BC), metastases to the central nervous system usually arise in women with advanced disease. Diagnosis of leptomeningeal (LM) metastasis is based on neurological symptoms, imaging studies and cytological detection of malignant cells in the cerebrospinal fluid (CSF). However, often these approaches are not sensitive enough to recognize leptomeninges involvement and subsequently to make a diagnosis of LM carcinomatosis. This study investigated the employment of reverse transcriptase-polymerase chain reaction (RT-PCR) for the human mammaglobin (hMAM) gene in a case of BC with cerebral metastases in which the involvement of the leptomeninges was in doubt., Materials and Methods: Amplification of hMAM mRNA was performed from CSF cells by RT-PCR., Results: No amplification of hMAM was obtained from the CSF cells., Conclusion: RT-PCR for human mammaglobin mRNA of the CSF in BC patients with brain metastases may aid clinical determination of LM involvement and consequently the choice of the most effective therapy regimens for affected patients.