Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial.

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/m2 and cyclophosphamide 600 mg/m2) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m2) on day 1 every 3 weeks (q3EC-P group); four cycles of intravenous FEC (fluorouracil 600 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m2) 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.

Nanoparticle albumin-bound paclitaxel/liposomal-encapsulated doxorubicin in HER2-negative metastatic breast cancer patients.

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/m2. 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.

Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials.

Background: We aim to understand whether all patients with hormonal receptor (HR)-positive (+)/human epidermal growth factor receptor-2 (HER2)-negative (-) metastatic breast cancer (MBC) should receive cyclin D-dependent kinase (CDK) 4/6 inhibitor-based therapy as a first-line approach. METHODS: A network meta-analysis (NMA) using the Bayesian hierarchical arm-based model, which provides the estimates for various effect sizes, were computed. RESULTS: First-line treatment options in HR+/HER2- MBC, including CDK 4/6 inhibitors combined with aromatase inhibitors (AIs) or fulvestrant (F), showed a significantly longer progression-free survival (PFS) in comparison with AI monotherapy, with a total of 26% progression risk reduction. In the indirect comparison across the three classes of CDK 4/6 inhibitors and F endocrine-based therapies, the first strategy resulted in longer PFS, regardless of specific CDK 4/6 inhibitor (HR: 0.68; 95% CrI: 0.53-0.87 for palbociclib + AI, HR: 0.65; 95% CrI: 0.53-0.79 for ribociclib + AI, HR: 0.63; 95% CrI: 0.47-0.86 for abemaciclib + AI) and patient's characteristics. Longer PFS was also found in patients with bone-only and soft tissues limited disease treated with CDK 4/6 inhibitors. CONCLUSIONS: CDK 4/6 inhibitors have similar efficacy when associated with an AI in the first-line treatment of HR+ MBC, and are superior to either F or AI monotherapy, regardless of any other patients or tumor characteristics.

Activity of Eribulin Mesylate in Brain Metastasis from Breast Cancer: A Stone in a Pond?

BACKGROUND: Brain metastases develop in approximately 10-25% of patients with metastatic breast cancer (MBC) and are associated with a very poor prognosis. CASE REPORT: We report the case of a 40-year-old woman with MBC and associated lung, bone, liver, and brain metastases, who experienced a time to progression of several months with eribulin after whole-brain radiotherapy (WBRT), 2 lines of chemotherapy, and 1 line of hormonal therapy, maintaining a good toxicity profile. DISCUSSION: Eribulin, in association with local treatment such as WBRT, can be well tolerated and effective in achieving a long progression-free survival and a good control of brain metastases in patients with MBC who have received multiple lines of treatment. The vascular remodeling properties of eribulin, combined with brain radiotherapy, might facilitate the passage of eribulin across the blood brain barrier, improving brain response. CONCLUSION: Our anecdotal experience suggests that eribulin may have a potentially beneficial effect on brain metastases while maintaining a good systemic control of the disease in patients with MBC.

Impressive Long-term Response with Pertuzumab and Trastuzumab in HER2-positive Breast Cancer with Brain Metastasis.

This is a case report of a 40-year-old woman who, after conservative breast cancer treatment, developed a HER2 positive solitary brain metastasis in the left temporal lobe, without extracranial disease. She underwent surgery resection followed by stereotactic radiotherapy and, because of early brain progression, she was submitted to the first line therapy with pertuzumab, trastuzumab and weekly paclitaxel. After six months of treatment, a brain magnetic resonance imaging revealed a complete disappearance of brain recurrence, which persisted for more than 24 months.

Ado-trastuzumab emtansine (T-DM1) in HER2+ advanced breast cancer patients: does pretreatment with pertuzumab matter?

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.

Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a single-center phase 2 trial.

BACKGROUND: The aim of the current study was the investigation of the value of bevacizumab+5-fluorouracil(5-FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options. METHODS: The authors included 48 heavily pretreated patients (colon:rectum, 33:15; men:women, 23:25; median age, 63 years; range, 27-79 years) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy, an irinotecan-based second-line regimen, and a third-line treatment with cetuximab plus weekly irinotecan. Bevacizumab was given at a dose of 5 mg/kg. 5-FU/folinic acid was administered according to the de Gramont schedule. RESULTS: The response rate was 6.25%, and 30.4% of patients demonstrated stable disease as the best response. The median time to disease progression was 3.5 months (95% confidence interval [95% CI], 2.3-6.9 months), and the median survival time was 7.7 months (95% CI, 3.9-11.9 months). The most common grade 3 to 4 side toxicities (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) were: diarrhea (20.8%), fatigue (14.5%), and stomatitis (12.5%). Grade 3 to 4 hemorrhage occurred in 8 patients (16.6%), including 4 cases of bleeding in the gastrointestinal tract. Other relatively common adverse events such as hypertension, thrombosis, and bowel perforation were reported in 50%, 18.7%, and 4.16%, of patients respectively. CONCLUSIONS: The data from the current study suggest a modest but significant clinical benefit of bevacizumab+de Gramont schedule in heavily pretreated colorectal cancer patients.

Phase I study of intermittent and chronomodulated oral therapy with capecitabine in patients with advanced and/or metastatic cancer.

BACKGROUND: The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. FDR gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. The goals of this phase I study were to determine the maximum-tolerated dose (MTD) of chronomodulated capecitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT), the safety profile of this way of administration. METHODS: Patients with advanced solid tumours who had failed to response to standard therapy or for whom no standard therapy was available were eligible for this study. Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days, followed by a 7-day rest period. RESULTS: All 27 patients enrolled onto the study were assessable for toxicity. The most common toxicities during the first two cycles of chemotherapy were fatigue, diarrhoea and hand foot syndrome (HFS). Only one out of the nine patients treated at capecitabine dose of 2,750 mg/m2 met protocol-specified DLT criteria (fatigue grade 4). However, at these doses the majority of cycles of therapy were delivered without dose reduction or delay. No other episodes of DLT were observed at the same dose steps and at the lower dose steps of capecitabine (1,500/1,750/2,000/2,250/2,500 mg/m2). The dose of 2,750 mg/m2 is recommended for further study. Tumor responses were observed in patients with metastatic breast and colorectal cancer. CONCLUSION: High doses of chronomodulated capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.

Last generation of amino-bisphosphonates (N-BPs) and cancer angio-genesis: a new role for these drugs?

Bisphosphonate (BPs) therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that BPs exert their direct or indirect antitumoral effects on cancer growth factor release, on cancer cell adhesion, invasion and viability, on cancer angiogenesis and on cancer cell apoptosis. Here, after a brief analysis on clinical indications, on the last generation amino-bisphosphonates (N-BP) and on biochemical pathways as molecular targets of BPs, we will discuss the molecular mechanisms of these antitumor effects. Recent evidence suggests that part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect. For this reason, we will analyse all the in vitro and in vivo preclinical reports and the first clinical evidence of anti-angiogenic activity exerted by this class of drugs. Several patents have been reported in the review, considering the recents activities observed for these drugs. Taking together all the major results obtained in the described studies, it is possible to affirm that BPs, particularly zoledronic acid and pamidronate, could potentially represent a very powerful tool for angiogenesis inhibition leading to a better control of cancer growth and progression. The translation into the clinical setting of the preclinical evidence of an antiangiogenic power of these drugs is becoming an imperative need and should represent the objective of future clinical trials.

Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

A novel Q3034R BRCA2 germline mutation identified in a fallopian tube cancer patient.

Fallopian tube cancer (FTC) accounts for 0.1-0.5% of all gynaecological malignancies, so that very few studies have demonstrated a significant linkage between this cancer type and BRCA1/BRCA2 mutations. We report the identification of a novel germline mutation (Q3034R) in BRCA2 gene in a 41-year-old patient. The nucleotide change (CAG > CGG) abolishes a DdeI restriction site, making genotype identification rapid and inexpensive. Our findings support the hypothesis that the primary FTC should be considered, at least in a subset of patients, as a BRCA2-associated tumor. Genetic counselling could result, in these cases, in early diagnosis of genetically predisposed individuals.