Search

Background: Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study., Methods: In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/m 2 and cyclophosphamide 600 mg/m 2 ) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m 2 ) on day 1 every 3 weeks (q3EC-P group); four cycles of intravenous FEC (fluorouracil 600 mg/m 2 , epirubicin 90 mg/m 2 , and cyclophosphamide 600 mg/m 2 ) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m 2 ) on day 1 every 3 weeks (q3FEC-P group); dose-dense EC-P regimen, with the same doses and drugs as the q3EC-P group but administered every 2 weeks (q2EC-P group); and the dose-dense FEC-P regimen, with the same doses and drugs as the q3FEC-P group but given every 2 weeks (q2FEC-P). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. The primary endpoint was disease-free survival in the intention-to-treat population, comparing different chemotherapy schedule (dose-dense vs standard-dose intervals) and regimen (FEC-P vs EC-P). Safety population included all patients that received at least one dose of any study drug according to the treatment received. This trial is registered with ClinicalTrials.gov, NCT00433420, and is now closed., Findings: Between April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred., Interpretation: Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule., Funding: Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer., Competing Interests: Declaration of interests LDM reports grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, and Seagen; fees or honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, and Ipsen; support for attending meetings or travel from Roche, Pfizer, and Eisai; and participation on a data safety monitoring board or advisory board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, and AstraZeneca outside the submitted work. FPo reports support for attending meeting from Daichii Sankyo and Gilead; participation on advisory board from AstraZeneca; and fees or honoraria from Eli Lilly and Novartis outside the submitted work. SDP reports honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD outside the submitted work. MG reports fees or honoraria from Lilly, Novartis, Pfizer, Roche, Seagen, AstraZeneca, Daichii Sankyo, MSD, and Genomic Health outside the submitted work. MDL reports personal fees from Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Eli Lilly, Amgen, Pierre Fabre, MSD, Genomic Health, Daiichi-Sankyo, Gilead, and Seagen outside the submitted work. FC reports consulting fees or honoraria from GlaxoSmithKline, Roche, Astrazeneca, Eli Lilly, Pierre Fabre, Pfizer, Seagen, and Dompè outside the submitted work. AF reports consulting fees or honoraria and participation on an advisory board from Roche, Novartis, Lilly, Pfizer, MSD, Dompè, Pierre Fabre, Eisai, Sophos, Epionpharma, Gilead, Seagen, AstraZeneca, and Exact Science outside the submitted work. OG reports consulting fees or honoraria and participation on an advisory board from Daiichi Sanko, AstraZeneca, Seagen, Gilead, Eli-Lilly, and Novartis. MM reports consulting fees or honoraria and participation on an advisory board from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, AstraZeneca, and Gentili outside the submitted work. CB reports fees or honoraria from Novartis, Roche, and Eli Lilly outside the submitted work. FPu reports consulting fees or honoraria and participation on an advisory board from Amgen, Astrazeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Gilead, Ipsen, MSD–Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris outside the submitted work; and research grants and support from AstraZeneca, Eisai, and Roche outside the submitted work. FM reports fees or honoraria and participation on an advisory board from AstraZeneca, Eli Lilly, Roche, Novartis, Seagen, Pfizer, MSD, and Daiichi Sankyo outside the submitted work. ML reports consulting fees or honoraria from Roche, AstraZeneca, Novartis, Eli Lilly, Sandoz, and Takeda outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background:  Eribulin shows some activity in controlling brain metastasis in breast cancer. Methods: This observational, multicenter study evaluated brain disease control rates, survival and safety in patients with brain metastatic breast cancer treated with eribulin in clinical practice. Results:  A total of 34 patients were enrolled (mean age 49 years, 91% with visceral metastases) and 29 were evaluable for brain disease. Fourteen achieved disease control and showed a longer time without progression: 10 months (95% CI: 2.3-17.7) versus 4 months (95% CI: 3.3-4.7) in the control group (p = 0.029). Patients with clinical benefits at 6 months had longer survival. Leukopenia and neutropenia were the most frequent grade 3-4 toxicities. Conclusion:  Eribulin confirms its effectiveness in patients with brain metastatic breast cancer. Further studies on larger cohorts are needed to confirm the results.

Introduction: p53 and antiapoptotic B-cell leukemia/lymphoma 2 (BLC2) have been proposed as prognostic markers for early breast cancer (BC), although their relationship with conventional parameters and patient prognosis, as well as their distribution within the molecular BC subtypes remains uncertain., Patients and Methods: In this observational study, we analyzed the immunohistochemical expression of p53 and BLC2 in 1099 early BC patients surgically treated between 2000 and 2006 and followed for at least 5 years, also considering their association with pathologic factors and molecular subtypes, as well as their influence on disease-free survival., Results: p53 and BLC2 are distributed differently across molecular subtypes (P < .0001); in particular, p53 positivity and BLC2 negativity seems to be associated with more aggressive conventional tumor phenotypes. Moreover, BLC2 negativity seems to be a significant discriminating factor for disease-free survival (P = .003) according to Kaplan-Meier analysis, while p53 seems to have no discriminating effect. Among patients with discordant p53/BLC2 phenotype, the combination p53 + BLC2 - seems to be associated with the worst outcomes (P = .007) and significantly influenced the clinical course of node-negative patients treated only with hormone therapy (P = .004)., Conclusion: These two biomarkers, in addition to conventional pathologic factors and molecular subtype, could help define the risk and outcome of BC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes., Methods: Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%., Results: Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4-84.5) and 70.5% (66.5-74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2-94.1) and 85.1% (81.7-87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54-0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40-0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59-1.33]; unadjusted HR for OS 0.83 [95% CI 0.45-1.54])., Conclusions: No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule., Competing Interests: Conflict of interest statement L.D.M. declares honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and MSD and Seattle Genetics; a consulting and advisory role for Roche and Eli Lilly and fees for travel, accommodation and expenses from Roche, Pfizer and Celgene outside the submitted work. M.L. served as a consultant for Teva and received speaker honoraria from Theramex outside the submitted work. O.G. received personal fees from Celgene, Eisai, Pfizer, Amgen, Eli Lilly and Novartis; travel and accommodation expenses from Celgene, Roche and Pfizer and research funding from Eisai outside the submitted work. F.P. received honoraria for advisory boards, activities as a speaker, travel grants, research grants from Agmen, Celgene, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer and Takeda and received research funding from Astrazeneca, Eisai and Roche outside the submitted work. M.D.L. declares consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai and Celgene outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aim: To investigate the toxicity of nab-paclitaxel (wNP)/nonpegylated liposome-encapsulated doxorubicin (wNPLD) combination in HER2-negative metastatic breast cancer (MBC) patients as first-line treatment. Materials & methods: Phase I, single-arm study in metastatic breast cancer patients naive to previous chemotherapy for advanced disease. A 3 + 3 dose-escalation design was used to determine the safety. Primary endpoints were the identification of dose-limiting toxicity and maximum tolerated dose. Results: In total, 12 patients (mean age: 52 years; median metastatic sites: 2) were enrolled and 97 cycles were completed. Maximum tolerated dose was wNP + wNPLD 25 mg/m 2 . The most common adverse events were neutropenia, nausea, diarrhea and mucositis. The objective response rate was 68% (response mean duration: 12.6 months). Conclusion: wNP/wNPLD combination constitutes an active regimen with mild toxicity.

Background: We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in 'field-practice' breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs)., Methods: The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement., Results: Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1-55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4-8.6) in the BM group and 8 months (95% CI: 5.7-10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1-6.9) versus 11 (95% CI: 7.1-14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2-15.8) in the BM group and 32 months (95% CI: 24.4-39.6) in the non-BM group (p < 0.0001)., Conclusions: T-DM1 is active in breast cancer patients with BMs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen., Patients & Methods: Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73)., Results: Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01)., Conclusion: Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.

Introduction: The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC)., Methods: Clinical-pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well., Results: Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 ≤ 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 ≤ 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap., Conclusions: Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Bevacizumab in combination with taxanes in HER2-negative metastatic breast cancer (MBC) patients has shown improved progression-free survival (PFS), despite the lack of clear overall survival (OS) benefit. We performed a retrospective analysis to evaluate the impact of paclitaxel-bevacizumab and of maintenance therapy with bevacizumab (BM) and endocrine therapy (ET) in the real-world practice. We identified 314 HER2-negative MBC patients treated in 12 cancer centers. Overall, the median PFS and OS were 14 and 40 months, respectively. Among the 254 patients potentially eligible for BM, 183 received BM after paclitaxel discontinuation until progression/toxicity. PFS and OS were improved in patients who had received BM in comparison with those potentially eligible but who did not receive BM (P< 0.0001 and P = 0.001, respectively). Results were confirmed when adjusting for propensity score. Among the 216 hormone-receptor positive patients eligible for BM, a more favorable PFS and OS were observed when maintenance ET was administered (P < 0.0001). Multivariate analysis showed that PS, BM, number of disease sites and maintenance ET were related to PFS, while response and maintenance ET were related to OS. In hormone-receptor positive patients, BM produced a significant PFS and a trend towards OS benefit only in absence of maintenance ET (P = 0.0007 and P = 0.06, respectively). In the triple-negative subgroup, we observed a trend towards a better OS for patients who received BM (P = 0.06), without differences in PFS (P = 0.21). Our results confirmed the efficacy of first-line paclitaxel-bevacizumab in real-world practice; both BM and maintenance ET significantly improved PFS and OS compared to no maintenance therapies. J. Cell. Physiol. 232: 1571-1578, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival., Methods: In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420., Findings: Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p<0·0001). Addition of fluorouracil led to increased rates of grade 3-4 neutropenia (354 [34·5%] of 1025 patients on FEC-P vs 250 [24·2%] of 1032 patients on EC-P; p<0·0001), fever (nine [0·9%] vs two [0·2%]), nausea (47 [4·6%] vs 28 [2·7%]), and vomiting (32 [3·1%] vs 15 [1·4%])., Interpretation: In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome., Funding: Bristol-Myers Squibb, Pharmacia, and Dompè Biotec., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims and Background: The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study., Methods: A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers., Results: A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease., Conclusions: Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.

Objective: Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor (TKI), associated to capecitabine represents the treatment of choice in HER2-positive metastatic breast cancer (BC) patients in progression after trastuzumab-based therapy. Though lapatinib-based therapy prolongs the time to progression, its efficacy is often limited by the development of drug resistance. It is aimed to evaluate novel biomarkers predictive of lapatinib response, we analyzed EGFR protein and gene status in a series of 50 metastatic HER2-positive BC patients., Methods: Lapatinib was given at 1250 mg/day continuously and capecitabine at 2000 mg/m(2)/day every 3 weeks. EGFR protein expression and gene copy number (GCN) were assessed by immunohistochemistry and FISH, respectively. Receiver operating curve (ROC) analysis identified the value of > 3.36 EGFR copies/nucleus as the cut-off point able to discriminate responders versus non-responders., Results: A statistical significant correlation between EGFR GCN value > 3.36 and response to lapatinib (p = 0.01) was found. Cox regression analysis further supported these findings evidencing that HER2 score 3+ and EGFR GCN increase are positive predictor factors of lapatinib response., Conclusions: Though further investigations are needed to confirm these findings, EGFR GCN could be a suitable screening to identify the subset of BC patients particularly responsive to the dual TKI lapatinib.

Background: Data on efficacy of bevacizumab (B) beyond first-line taxane -including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT., Methods: Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not., Results: Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev., Conclusion: Maintenance bevacizumab with or without anti-hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti-hormonal agents.

Background: Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile., Methods: A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design., Results: Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS., Conclusions: Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.

Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression., Experimental Design: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide., Results: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04)., Conclusions: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.

A feasibility-phase II study was conducted to assess the cardiotoxicity of weekly trastuzumab, epirubicin, and paclitaxel in patients with human epidermal growth factor receptor-2-positive metastatic breast cancer. Untreated patients with human epidermal growth factor receptor-2-positive advanced breast cancer received trastuzumab (day 1), and epirubicin (25 mg/m2) and paclitaxel (80 mg/m2) (day 2) on a weekly basis. The rate of patients with left-ventricular ejection fraction (L-VEF) reduction greater than 10% after 12 weeks was the primary end point. According to a two-stage model, an initial step with 15 patients was required; after 11 patients without toxicity, a second step with 21 patients was planned. After 255 courses in 15 patients (median treatment weeks: 18), the relative dose intensity was 94.7%. At 12 weeks, three patients (20%) displayed a L-VEF reduction greater than 10%, six and six (40%) patients showed a L-VEF reduction < or =10% or no change, respectively. Baseline, -12 weeks, and -24 weeks median L-VEF was 69% (range 61-77), 65% (range 60-76), and 65% (range 55-73), respectively. No EKG/cardiac signs were present. Thirteen patients had grade 3 alopecia and two patients had grade 3 asthenia, in the absence of severe hematological toxicity. Objective responses were observed in 11 patients (73.3%, 95% confidence interval 51.0-95.7), with 10 partial. The weekly administration of trastuzumab-epirubicin-paclitaxel is extremely tolerable, also with regard to L-VEF reduction. These results allowed entrance to the second step of the study.

Background: In patients with locally advanced and operable breast cancer, neoadjuvant chemotherapy has been demonstrated to increase the chance of breast-conserving surgery (BCS) when compared with adjuvant treatment; moreover, patients who achieve a pathologic complete response (pCR) have a better outcome. A literature-based meta-analysis of randomized clinical trials (RCTs) to 'weigh' how much taxanes add to anthracyclines as primary treatment over standard chemotherapy was conducted., Methods: Event-based relative risk ratios (RR) with 95% confidence intervals (95% CI) were derived through both a fixed-effect and a random-effect model; a heterogeneity test was applied as well. Absolute differences (AD) and the number (of patients) needed to treat (NNT) were calculated. Primary endpoints were: 1) pCR rate and 2) BCS rate. A sensitivity analysis of 3 subgroups according to taxane strategies was conducted., Results: Data for primary endpoints were available for 7 RCTs (2455 patients). The rate of BCS was significantly higher for patients receiving taxanes, with an AD of 3.4% (P = .012), which translates into 29 patients NNT, without significant heterogeneity. The rate of pCR was higher for patients receiving taxanes, although not statistically significant. In the sensitivity analysis, patients receiving taxanes as a sequential schedule had a significant higher probability to achieve pCR, with an AD of 2.4% (P = .013), which translates into 41 patients NNT, without significant heterogeneity. Patients receiving taxanes as a concomitant schedule had a significantly higher probability to achieve BCS, with an AD of 5.3% (P = .027), which translates into 19 patients NNT, without significant heterogeneity. The complete response rate was significantly higher in the taxane arms, regardless of the adopted strategy, with an AD ranging from 6.7% to 15.5%., Conclusions: The combination of taxanes and anthracyclines as neoadjuvant chemotherapy for early breast cancer improves the chance of achieving both higher BCS and pCR rates.

Background: In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed., Methods: All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS)., Results: Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III-IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p < 0.00001), which translates into 62 treated patients required to harm one (NNH). When considering the asymptomatic L-FEV reduction, a significant increased risk of grade significant L-FEV reduction was found in the T-arm, although significantly heterogeneous, with an AD of 7.20% (p < 0.00001), which translates into 14 NNH. The incidence of BM was significantly higher in the T-arm, without significant heterogeneity, with an AD of 0.62 (p = 0.033), which translates into 161 NNH. The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT, respectively., Conclusions: The overall outcome results show that trastuzumab is one of the most important discoveries in oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse patterns.

Background: Tamoxifen is still the most widely used drug in hormone therapy for the treatment of breast cancer. Its benefits in adjuvant treatment are well documented in controlled and randomized clinical studies, which have demonstrated an increase in disease-free intervals of patients with positive hormonal receptors. However, the mechanisms involved in endocrine resistance are not clear. Laboratory and clinical data now indicate that bi-directional molecular cross-talk between nuclear or membrane ER and growth factor receptor pathways may be involved in endocrine resistance. We recently found a functional interaction between alpha6beta4 integrin and ErbB-3 receptor to maintain the PI3K/Akt survival pathway of mammary tumour cells. We sought to improve understanding of this process in order to provide the involvement of both receptors insight into mechanism of Tamoxifen resistance., Methods and Findings: Using human breast cancer cell lines displaying different levels of alpha6beta4 and ErbB-3 receptors and a series of 232 breast cancer biopsies from patients submitted to adjuvant Tamoxifen monotherapy for five years, we evaluated the functional interaction between both receptors in relationship to Tamoxifen responsiveness. In mammary carcinoma cells, we evidenced that the alpha6beta4 integrin strongly influence Akt phosphorylation through ErbB-3 protein regulation. Moreover, the ErbB-3 inactivation inhibits Akt phosphorylation, induces apoptosis and inhibits in vitro invasion favouring Tamoxifen responsiveness. The analysis of human tumors revealed a significant relationship between alpha6beta4 and ErbB-3 in P-Akt-positive and ERbeta1-negative breast cancers derived from patients with lower disease free survival., Conclusions: We provided evidence that a strong relationship occurs between alpha6beta4 and ErbB-3 positivity in ERbeta1-negative breast cancers. We also found that the association between ErbB-3 and P-Akt positivity mainly occurs in ERbeta1-negative breast cancer derived from patients with lower DFS indicating that both receptors are clinically relevant in predicting the response to Tamoxifen.

Background: Despite the advantages from using aromatase inhibitors (AIs) compared with tamoxifen for early breast cancer, an unexpectedly greater number of grade 3 and 4 cardiovascular events (CVAE) (as defined by National Cancer Institute of Canada-Common Toxicity Criteria [version 2.0] was demonstrated., Methods: Phase 3 randomized clinical trials (RCTs) comparing AI with tamoxifen in early breast cancer were considered eligible for this review. The event-based risk ratios (RRs) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Finally, absolute differences (ADs) in event rates and the number of patients needed to harm 1 patient (NNH) were determined., Results: Seven eligible RCTs (19,818 patients) reported CVAE results. When considering all RCTs, the AD of the primary endpoint (CVAE) between the 2 arms (0.52%), tamoxifen versus AI, was statistically significant (RR, 1.31; 95% CI, 1.07-1.60; P= .007). This translated into an NNH value of 189 patients; when only third-generation AIs were considered, the difference (0.57%) remained significant (RR, 1.34; 95% CI, 1.09-1.63; P= .0038). Thromboembolic events were significantly more frequent in the tamoxifen arm, regardless of the strategy adopted (RR, 0.53; 95% CI, 0.42-0.65; P< .0001), without significant heterogeneity (P= .21). An AD of 1.17% and an NNH value of 85 patients were observed., Conclusions: According to the results from this meta-analysis, the risk of grade 3 and 4 CVAEs in patients who were receiving AIs was higher compared with the risk in patients who were receiving tamoxifen, and the difference reached statistical significance. However, the AD was relatively low, and from 160 to 180 patients had to be treated to produce 1 event.

Introduction: Estrogen receptor-alpha (ER-alpha) and progesterone receptor (PgR) are consolidated predictors of response to hormonal therapy (HT). In contrast, little information regarding the role of estrogen receptor-beta (ER-beta) in various breast cancer risk groups treated with different therapeutic regimens is available. In particular, there are no data concerning ER-beta distribution within the novel molecular breast cancer subtypes luminal A (LA) and luminal B (LB), HER2 (HS), and triple-negative (TN)., Methods: We conducted an observational prospective study using immunohistochemistry to evaluate ER-beta expression in 936 breast carcinomas. Associations with conventional biopathological factors and with molecular subtypes were analyzed by multiple correspondence analysis (MCA), while univariate and multivariate Cox regression analysis and classification and regression tree analysis were applied to determine the impact of ER-beta on disease-free survival in the 728 patients with complete follow-up data., Results: ER-beta evenly distributes (55.5%) across the four molecular breast cancer subtypes, confirming the lack of correlation between ER-beta and classical prognosticators. However, the relationships among the biopathological factors, analyzed by MCA, showed that ER-beta positivity is located in the quadrant containing more aggressive phenotypes such as HER2 and TN or ER-alpha/PgR/Bcl2- tumors. Kaplan-Meier curves and Cox regression analysis identified ER-beta as a significant discriminating factor for disease-free survival both in the node-negative LA (P = 0.02) subgroup, where it is predictive of response to HT, and in the node-positive LB (P = 0.04) group, where, in association with PgR negativity, it conveys a higher risk of relapse., Conclusion: Our data indicated that, in contrast to node-negative patients, in node-positive breast cancer patients, ER-beta positivity appears to be a biomarker related to a more aggressive clinical course. In this context, further investigations are necessary to better assess the role of the different ER-beta isoforms.

We conducted a phase II study to determine the activity and tolerability of weekly epirubicin-paclitaxel and granulocyte colony-stimulating factor in breast cancer patients untreated for metastatic disease. The phase II study was designed following the Simon optimal-two stage method. Patients received epirubicin 25 mg/m and paclitaxel 80 mg/m every week, and granulocyte colony-stimulating factor on days 2 and 4 for 24 consecutive weeks in the absence of progression. From 1999 to 2004, 53 patients entered the study; 1093 weekly courses were delivered, with a median number of cycles of 22. Patients received a median relative dose intensity of 94%. No hematological grade 3-4 toxicities were observed. One patient had one episode of grade 3 mucositis and two patients (3.8%) suffered grade 2 asthenia. Eight patients (15.1%) experienced grade 2 neutropenia, grade 2 anemia was registered in seven patients (13.2%). No cardiotoxicity was observed. Ten out of 53 patients (18.9, 95% confidence interval 8.3, 29.4%) showed a complete response, whereas 28 (52.8, 95% confidence interval 39.4, 66.3%) had a partial response, with an overall response rate of 71.7% (95% confidence interval 59.6, 83.8%). In addition, 14 patients (26.4%) had stable disease. Median time to progression was 12 months (95% confidence interval 7, 17). Median response duration was 14 months (range 3-60). The 1-, 3- and 5-year survival rates were 90.1, 68.0 and 56.6%, respectively. In untreated metastatic breast cancer patients, the weekly administration of epirubicin and paclitaxel with granulocyte colony-stimulating factor support seems to be extremely tolerable and active, and deserves further investigation into a phase III trial.

To summarise the advances in the hormonal treatment of post-menopausal metastatic breast cancer, this paper reviews the published literature regarding the randomised trials comparing aromatase inhibitors (AIs) versus tamoxifen as a first-line therapeutic choice, or AIs versus megestrole acetate (MEG) as a second-line option. The pooled analysis of these authors on AI versus MEG as a second-line option for post-menopausal metastatic breast cancer suggested that AIs do not add any significant benefit over MEG in terms of overall response rate (ORR) and time to progression. According to the Cochrane Database, use of an AI as a second-line therapy versus any other endocrine therapy (mostly MEG) has shown a significant benefit in terms of overall survival, but not for progression-free survival, clinical benefit (CB) or ORR. Concerning the authors' comparisons between AIs versus tamoxifen as a first-line endocrine option in post-menopausal women with metastatic breast carcinoma, AIs seem to be superior to tamoxifen, with a significant benefit in terms of ORR, CB and time to progression being observed in favour of AIs over tamoxifen with fixed effects estimates. According to the Cochrane Database, there was an advantage to the use of AIs over tamoxifen in terms of progression-free survival and CB, but not for overall survival or ORR. With regards to toxicity, AIs show similar levels of hot flushes and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. Weight gain, dyspnoea and peripheral oedema seem to be more frequent with MEG. At present, there is no proved overall survival difference in patients who are treated first with an AI and then with tamoxifen compared with the opposite sequence. In the metastatic setting, results are limited and are based on retrospective analyses.

Purpose: The rationale for intensification strategies is that more frequent exposure to chemotherapeutics could enhance antitumor activity. Several trials investigated weekly paclitaxel administration, but there are no clear data concerning peripheral neurotoxicity. The aim of this study was to assess the incidence of peripheral neurotoxicity in patients affected by advanced breast cancer treated with weekly paclitaxel., Patients and Methods: Neurotoxicity was assessed with neurologic and neurophysiologic evaluation before treatment and after 12 weeks and 24 weeks. A total neurotoxicity score was assigned to each patient on the basis of neurophysiologic and neuropathic signs and symptom changes. Seventeen patients entered the study., Results: After 12 weeks of treatment, 71% showed moderate clinical and/or neurophysiologic signs of neurotoxicity; after 24 weeks, the incidence of neurotoxicity increased to 96%. Sural amplitude at the 24-weeks examination significantly decreased from basal mean value (13.5 microv, standard deviation [SD] 6 microv vs. 7 microv, SD 5.9 microv, respectively; P = 0.01), whereas median sensory amplitude decreased after 24 weeks from 10.3 microv, SD 6.2 microv to 4.9 microv, SD 3.8 microv (P = 0.001). In a subset of 11 patients, we obtained a follow-up examination after 6 months from the end of treatment. In all patients, examined signs and symptoms of neurotoxicity improved with recovery of subjective neuropathic symptoms and neurophysiologic findings., Conclusion: Our results demonstrate, in a little population of patients evaluated with a comprehensive neurologic assessment, that weekly paclitaxel is related to a very high incidence of peripheral neurotoxicity. Follow-up data obtained in a subset of patients indicate that peripheral neurotoxicity is reversible.

Increased serum level of troponin-T and myoglobin has been recently reported to be related to cumulative anthracycline exposure. Left ventricular ejection fraction seems accurate in monitoring systolic function according to the latest version of Toxicity Criteria by chemotherapeutics 3.0. From January 2002, 20 patients with untreated advanced breast cancer received epirubicin (25 mg/m/week) and paclitaxel (80 mg/m/week) for 24 weeks. Troponin-T, myoglobin and biochemical serum enzymes circulating levels were measured immediately before and 4 h after epirubicin administration every week. Patients underwent electrocardiography and echocardiography at weeks 0, 8, 16 and 24. The number of courses administered was 352 (median 18, range 4-24). Epirubicin median dose administered was 600 mg/m and paclitaxel median dose administered was 1760 mg/m. Troponin-T never overcame the upper normal limit; one patient experienced troponin-T elevation without any clinical or instrumental sign of cardiac failure. Myoglobin never significantly increased with the exception of a patient who underwent several abdominal fluid drainages. Creatine kinase MB and C-reactive protein never moved outside the upper normal limit. No symptomatic cardiac event was recorded. In 55 performed echocardiograms at weeks 0, 8, 16 and 24, neither left ventricular ejection fraction nor early peak flow/atrial flow velocity registered any significant decrease. No troponin-T or myoglobin serum elevations and Left ventricular ejection fraction/early peak flow/atrial flow velocity changes were registered in our series of nonsymptomatic women during epirubicin/paclitaxel weekly chemotherapy in the absence of clinical cardiac toxicity. Longer follow-up is needed, however, to understand whether the troponin-T or myoglobin circulating level measurement is able to detect subclinical, early-stage doxorubicin-induced cardiotoxicity.

Weekly chemotherapy administration represents an emerging option for the treatment of metastatic breast cancer. In order to identify clinical and biological prognostic factors for outcome, we performed a multivariate analysis in a 10-year experience of weekly chemotherapy for metastatic breast cancer patients. The original databases of phase II trials of metastatic breast cancer patients who had undergone first-line weekly chemotherapy were collected. Clinical and biological covariables were screened for a possible relationship with time to progression and overall survival in a Cox model. From 1990 to 2003, 184 patients were enrolled in three consecutive phase II studies, to evaluate activity and tolerability of weekly epirubicin with lonidamine or vinorelbine or paclitaxel. All patients were evaluable for clinical variables; histological samples were available in 40 patients. At a median follow-up of 24 months, median time to progression was 9 months (95% confidence interval 8-10) and median overall survival was 34 months (95% confidence interval 24-42). Independent variables were response (hazard ratio 2.34, P<0.0001), receptor status (hazard ratio 1.62, P=0.01) and performance status (hazard ratio 2.31, P<0.0001) for time to progression, and response (hazard ratio 1.86, P=0.005), performance status (hazard ratio 2.81, P<0.0001), dominant metastatic site (hazard ratio 2.27, P<0.0001) and enrollment period (hazard ratio 2.51, P=0.001) for overall survival. Although no biological factors were entered into the Cox model owing to the small sample size, some subpopulations showed a negative trend in survival. In our series of patients who had undergone weekly chemotherapy for metastatic breast cancer, independent prognostic factors for survival improvement were responders, performance status 0-1, nonvisceral dominant metastatic site and enrollment period. A greater sample population is needed to extensively screen for biological prognostic factors.

Background: The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2-3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a literature-based meta-analysis, to look how much advantages adjuvant the "early switch" strategy add over standard tamoxifen for 5 years., Methods: A pooled analysis of all phase-III trials was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths without progression, other cancers and toxicities), were explored. Magnitude outcome measures were absolute benefits and number of patients needed to treat. Heterogeneity test was applied as well., Results: Five trials (8794 patients) were gathered. The risk of any event is reduced with AIs of 23%, with an absolute benefit of 3.8% (RR 0.67, 95% CI 0.59, 0.76). Again, RFS (RR 0.68, 95% CI 0.59, 0.79) or both LRFS and DFRS, were significantly improved with AIs. OS was significantly prolonged with AIs, with an absolute benefit of 1.2% (RR 0.76, 95% CI 0.62, 0.93), without significant heterogeneity. Bone fractures were significantly higher in patients receiving AIs (RR 1.50, 95% CI 1.12, 2.02), and endometrial cancer in patients who continued to receive tamoxifen (RR 0.32, 95% CI 0.13, 0.77), without significant heterogeneity., Conclusions: The early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials.

Purpose: We report on the effects of granulocyte colony-stimulating factor (G-CSF) on hemoglobin (Hb) value in early breast cancer patients receiving high-dose epirubicin and cyclophosphamide (EC) adjuvant treatment., Methods: Five hundred and six stage I or stage II female breast cancer patients were treated with E 120 mg/m2 and C 600 mg/m2 with or without G-CSF and randomly assigned to receive in a factorial 2 x 2 design: EC; EC + lonidamine; EC + G-CSF; EC + lonidamine + G-CSF. Five consecutive G-CSF schedules tested 100 randomly assigned patients each: (1) 480 microg subcutaneously on days 8 to 14; (2) 480 microg on days 8, 10, 12, 14; (3) 300 microg on days 8 to 14; (4) 300 microg on days 8, 10, 12, and 14; and (5) 300 microg on days 8 and 12. The mean Hb level of 246 patients receiving EC plus G-CSF was compared with that of 240 patients receiving EC alone. The data presented are derived from an exploratory hypothesis-generating analysis., Results: The EC dose intensity did not statistically differ between the G-CSF and the control arm. From the third cycle onward, the mean Hb value resulted significantly lower in G-CSF arm compared with control at each time point of each cycle (P < .0001). No statistically significant difference in the mean Hb level was observed between schedule 5 and control. Of interest, from the second course onward, the mean Hb level tended to be lower in patients receiving seven or four G-CSF injections compared with those patients who received only two injections., Conclusion: Our data suggest that a G-CSF dose-related effect may play a role in worsening anemia in patients receiving adjuvant EC.

Purpose: To evaluate the comparative efficacy of varying intensity schedules of recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim) support in preventing febrile neutropenia in early breast cancer patients treated with relatively high-dose epirubicin plus cyclophosphamide (EC)., Patients and Methods: From October 1991 to April 1994, 506 stage I and II breast cancer patients were randomly assigned to receive, in a factorial 2 x 2 design, epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 every 21 days for 4 cycles +/- lonidamine +/- G-CSF. The following five consecutive G-CSF schedules were tested every 100 randomly assigned patients: (1) 480 microg/d subcutaneously days 8 to 14; (2) 480 microg/d days 8, 10, 12, and 14; (3) 300 microg/d days 8 to 14; (4) 300 microg/d days 8, 10, 12, and 14; and (5) 300 microg/d days 8 and 12., Results: All of the G-CSF schedules covered the neutrophil nadir time. Schedule 5 was equivalent to the daily schedules (schedules 1 and 3) and to the alternate day schedules (schedules 2 and 4) with respect to incidence of grade 3 and 4 neutropenia (P = .79 and P = .89, respectively), rate of fever episodes (P = .84 and P = .77, respectively), incidence of neutropenic fever (P = .74 and P = .56, respectively), need of antibiotics (P = .77 and P = .88, respectively), and percentage of delayed cycles (P = .43 and P = .42, respectively). G-CSF had no significant impact on the delivered dose-intensity compared with the non-G-CSF arms., Conclusion: In the adjuvant setting, the frequency of prophylactic G-CSF administration during EC could be curtailed to only two administrations (days 8 and 12) without altering outcome. This nonrandomized trial design provides support for evaluating alternative, less intense G-CSF schedules for women with early breast cancer.

Background: New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC., Methods: The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods., Results: No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance., Conclusions: This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.

Background: To assess the activity and toxicity of primary chemotherapy with epirubicin (60 mg/m2 every other week) and vinorelbine (25 mg/m2, weekly) plus granulocyte colony-stimulating factor (G-CSF) for 12 weeks, in patients with locally advanced breast cancer in a multicenter setting., Patients and Methods: Patients with stage IIIA or IIIB breast cancer, not older than 70, were eligible. A two-stage phase II design was applied. Response was assessed clinically, instrumentally and pathologically., Results: Out of 48 enrolled patients, 87.5% received all planned cycles, with a median dose-intensity of 30 mg/m2/week for epirubicin and 23.8 mg/m2/week for vinorelbine. A clinical or instrumental objective response was reached in 42 patients (87.5%, exact 95% CI: 74.7-95.3); significant downstaging was reached in all but one patient; 6 cases had a pathological complete response in the breast, and 2 cases in the lymph nodes too (pathological complete response rate 4.2%, exact 95% CI: 0.5-14.2); a further 2 patients had only microscopic cancer foci at pathological examination of the breast. Radiological tests underestimated the treatment effect on the breast. Toxicity was mild, neutropenia being the most frequent (grade 3-4 in 47% of patients), but never complicated with fever or sepsis. Mild constipation (< or =grade 2) occurred in 35% of patients. Moderate to severe asthenia occurred in 12% of 6 patients. No cardiac toxicity was reported. At 3 years, disease-free survival was 68% and overall survival 81%., Conclusion: Primary chemotherapy with epirubicin every other week, weekly vinorelbine and G-CSF support is highly active and well tolerated in patients with locally advanced breast cancer.

Background: The magnitude of the benefit of adding taxanes to anthracyclines in first-line chemotherapy for metastatic breast carcinoma is still unclear. The authors performed a pooled analysis as well as a meta-analysis of all Phase III trials, to determine whether the combination of anthracyclines plus taxanes provided an advantage over standard anthracyclines-based regimens., Methods: All Phase III peer-reviewed published or presented trials were considered eligible. A pooled analysis (Method A) and a literature-based meta-analysis (Method B) were accomplished, and event-based relative risk ratios (RR(A-B)) with 95% confidence intervals were derived. Both analyses were performed to examine for significant differences in time to disease progression (TTP), overall response rate (ORR), overall survival (OS), complete response rate (CR), neutropenia, and febrile neutropenia (FN). For both analyses, a heterogeneity test was applied., Results: Seven trials (2805 patients) were gathered. When data were pooled and plotted, significant differences in favor of taxanes were seen for ORR (RR(A-B) 1.21, P<0.001), CR (RR(A) 2.04; RR(B) 1.81, P<0.001), even though they caused a significant increase in neutropenia (RR(A) 1.19; RR(B) 1.15, P<0.001) and FN (RR(A) 2.82; RR(B) 3.44, P<0.001). A borderline significance in favor of taxanes was seen in TTP (RR(A) 1.10, P=0.05; RR(B) 1.06, P=0.07). A nonsignificant trend for taxanes was found in OS. No significant heterogeneity (except for neutropenia, P<0.01) was observed., Conclusions: The adjunction of taxanes to anthracyclines in first-line chemotherapy for metastatic breast carcinoma yielded a significant benefit in activity (ORR, CR), a slight advantage in TTP, and a trend in OS, although with a significant cost in hematologic toxicity., (Copyright (c) 2005 American Cancer Society.)

Objective: We conducted a phase I-II study to determine the maximum tolerated dose (MTD), toxicity and activity of weekly docetaxel administration in pretreated metastatic breast cancer patients., Methods: In phase I, cohorts of 3 women with pretreated metastatic breast cancer were treated with a 1-hour infusion of docetaxelat 30, 35, 40 mg/m2/week after premedication with two doses of dexamethazone 8 mg 12 h apart. Subsequently, a cohort of 28 women was treated at the MTD for 24 consecutive weeks in a phase II setting and was assessed for toxicity and activity., Results: Three patients were treated at each of the first two dose levels; 9 patients were treated at the 3rd level (40 mg/m2/week). Dose-limiting toxicities (DLTs) were experienced at that level by 2/6 patients of the first two accrued groups and in 2/3 patients of the 3rd (confirmation) group, thus establishing the subsequent phase II dose at 35 mg/m2/week. Two out of 28 evaluable patients (7.1%, 95% CI 0-16.7) showed complete responses, whereas 8 (28.6%, 95% CI 11.8-45.3) showed partial responses, and an objective response rate of 35.7% (95% confidence interval, CI 18-53.5%). In addition, 8 patients (28.6%) had stable disease. The median time to progression and overall survival were 5 (range 1-15) and 15 months (95% CI 7-23), respectively. One patient experienced 1 episode of grade 3 neutropenia. Severe asthenia was the main reason for interruption of chemotherapy (10 patients, 35.5%)., Conclusions: In pretreated metastatic breast cancer patients, the sustained weekly administration of docetaxel, even though it demonstrated an activity similar to a 3-weekly schedule could not be maintained for the planned 24 weeks due to the progressive emergence of nonhematological side effects that approached DLTs., ((c) 2005 S. Karger AG, Basel)