Agents In Metastatic Breast Cancer Research Articles

Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c‐Jun N‐terminal kinase, Akt and mammalian target of rapamycin signaling

Metastasis is one of the most important factors related to breast cancer therapeutic efficacy. Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, we first observed that ursolic acid exerted a dose- and time-dependent inhibitory effect on the migration and invasion of highly metastatic breast MDAMB231 cells at non-cytotoxic concentrations. This effect was associated with reduced activities of metalloproteinase-2 (MMP-2) and u-PA, which correlated with enhanced expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFkappaB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFkappaB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer.

Phase II study of the combination of gemcitabine plus carboplatin as neoadjuvant treatment in locally advanced breast cancer.

652 Background: Although anthracycline-based regimen is standard neoadjuvant chemotherapy for locally advanced breast cancer (LABC), there is some concern about its toxicities such as alopecia and cardiotoxicity. Gemcitabine is another active agent in metastatic breast cancer after failure to anthracycline with less toxicity. The objective of this study is to evaluate efficacy and safety of combination of gemcitabine and carboplatin as induction chemotherapy in LABC. Methods: Patients with histologically confirmed LABC (T3, T4 or N2 and M0) were included. Patients were scheduled to receive 3 cycles of neoadjuvant GC (gemcitabine 1,000 mg/m2 D1, D8 and carboplatin AUC×5) every 21 days. Patients with clinical response underwent surgery and additional 3 cycles of adjuvant GC. Those with clinical stable or progressive disease were taken off study and received standard anthracycline-based regimen. All patients were scheduled for adjuvant radiation and hormonal treatment depending on hormonal status. Primary end point was pathological response rate whereas secondary end points included PFS, OS and toxicity. Results: Between July 2004 and July 2007, 40 patients were enrolled. The median age was 46 years. Twenty-three patients (57.5%) had T4 lesion and 17 (42.5%) had T3. Out of 40 patients, 37 were evaluable for efficacy and 40 for toxicity. Twenty-four out of 37 patients (65%) obtained cPR. Among 23 patients who had clinical response underwent modified radical mastectomy, overall pathological response rate was 51.4% with 1-pCR (2.7%) and 18-pPR (48.6%). All 6 triple-negative patients had pathological response (1-pCR, 5-pPR). At median follow up of 35 months, median PFS and OS were not reached. Two-year OS and PFS were 81.2 % and 60.8 %, respectively. Common grade III and IV adverse effects were neutropenia (67.5%), anemia (45%) and thrombocytopenia (37.5%). Four patients developed grade III hepatitis with complete resolution after discontinuation of GC. No patient developed febrile neutropenia or fatal complications. Conclusions: Combination GC was efficacious, feasible and well-tolerated for LABC in neoadjuvant setting. Triple-negative subgroup seems to have high response to GC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly

Pilot Neoadjuvant Trial with Combination of Lapatinib and Nab-Paclitaxel in HER2+ Breast Cancer.

Abstract Background: Lapatinib, a dual kinase inhibitor against EGFR and HER2, has activity in metastatic HER2+ breast cancer. Nab-paclitaxel has been found to be one of the most active agents in metastatic breast cancer. Its combination has not been studied in the neoadjuvant setting. We have conducted a pilot neoadjuvant trial in HER2+ patients (pts) combining lapatinib with nab-paclitaxel.Methods: Females with newly diagnosed breast cancer (stage I-III) received four cycles of lapatinib 1000 mg po/day and nab-paclitaxel 260mg /m2 IV every three weeks. Postoperative therapy was at the discretion of the investigator. The accrual goal of 30 pts has been met. The primary endpoint was clinical response rate (CRR) with secondary endpoints including pathologic complete response (pCR), toxicity, and proliferation, apoptosis and angiogenesis markers.Results: A total of 28 pts have completed all therapy to date. The most common toxicities were rash, neuropathy, fatigue and myalgias. Most toxicities were grade 1/2 although one pt developed grade 3 rash and five pts grade 3 diarrhea. Nab-paclitaxel was dose reduced in 8 and lapatinib in 10 of 104 cycles. No cardiac toxicity was observed. Response data is available on 25 pts. CRR was 88% with four complete clinical responses and 18 patients with partial clinical response. Three patients had stable disease. Four patients achieved pCR.Summary of efficacy and toxicityResponse Non-hematologic ToxicityGrade 1/2Grade 3/4Hematologic toxicity Overall response22 (88%)Nausea7 (25%)1 (3.6%)Anemia9 (32.1%)Complete response4 (16%)Rash19 (67.8%)1 (3.6%) Partial response18 (72%)Fatigue17 (60.7%)2 (7.2%) Stable disease3 (12%)Neuropathy14 (50%)0 pCR4 (19.0%)Arthralgias/17 (60.7%)1 (3.6%) Diarrhea15 (53.6%)5 (17.9%) Conclusions: The combination of lapatinib and nab-paclitaxel is very active as first-line treatment in HER2+ breast cancer. Toxicities, including rash and diarrhea were observed and medically managed. Patients did not receive prophylactic medications for rash or diarrhea Updated clinical data on all 30 patients as well as correlative markers will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1091.

EIF4E Expression Predicts Apoptosis in Response to Epidermal Growth Factor Receptor Inhibition and Mammalian Target of Rapamycin Inhibition in Triple Negative Breast Cancers.

Abstract Background: Triple negative (TN) breast cancers account for 15% of all breast cancers, are two-fold higher in African American women, have high histological grade, a poor prognosis and until recently no viable therapeutic targets. Epidermal growth factor receptor (EGFR) is over-expressed in more than 50% of triple negative breast cancers, but the use of agents blocking EGFR has produced disappointing results in metastatic breast cancer. Inhibitors of Mammalian Target of Rapamycin (mTOR) have demonstrated moderate activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated synergistic antitumor effects with combined mTOR and EGFR inhibition in TN breast cancers. Eukaryotic translation initiation factor (eIF4E) is a protein downstream of mTOR and a target of PI3K/Akt and Erk signaling, and is important in mRNA translation, cell proliferation and apoptotic resistance. We evaluated the effects of EGFR and mTOR inhibition on apoptotic markers, and correlated these effects with eIF4E protein expression.Methods: Apoptotic assay and colony formation analysis were performed following mTOR inhibition with rapamycin and EGFR inhibition with lapatinib or erlotinib in TN breast cancer cells (MDA-MB-231, MDA-MB-468, HCC1806). Effects of EGFR and mTOR inhibition on downstream proteins in TN breast cancer in vitro and in vivo were examined through western blotting analysis with p-EGFR, pAkt, p-Erk, p-S6, and p-eIF4E.Results: We observed differential apoptotic effects of EGFR and mTOR inhibition in TN breast cancers cells. The combination resulted in a significant increase in apoptosis in MDA-MB-468 cells in vitro, but no increase in apoptosis was seen in MDA-MB-231 or HCC1806 cells. As expected, correlating with the apoptotic effects, expression of p-eIF4E was decreased in MDA-MB-468 cells treated with the combination of mTOR and EGFR inhibition in vitro. In contrast, both MDA-MB-231 and HCC1806 cells had high baseline levels of eIF4E, which increased in response to treatment with EGFR and mTOR inhibitors. Using a colony forming assay, we demonstrated that the combination of EGFR and mTOR inhibition resulted in cytostatic effects in HCC1806 cells. The combination of EGFR and mTOR inhibition did not result in apoptosis in MDA-MB-231 cancers in vivo, and these xenograft tumors had high level of eIF4E at baseline.We are currently evaluating the effects of lapatinib and rapamycin on apoptotic pathways in MDA-MB-468 cancers in vivo.Conclusion: Based on our previous findings, we are developing a clinical trial in which patients with metastatic TN breast cancers are treated with lapatinib and everolimus. These results suggest that this combination may be more effective in TN breast cancers with low levels of eIF4E, and this will be explored using metastatic research biopsies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5078.

Preliminary safety and activity results of trabectedin in a phase II trial dedicated to triple-negative (ER-, PR-, HER2-), HER2+++, or BRCA1/2 germ-line-mutated metastatic breast cancer (MBC) patients (pts)

1010 Background: Trabectedin ([T]; Yondelis) binds to the minor groove of DNA; its cytotoxicity is determined by the synergistic action of two DNA repair mechanisms, the efficient nucleotide excision repair (NER) and deficient homologous recombination repair (HRR) machinery. T has EMEA authorization in soft tissue sarcoma after failure of standard treatment. Preliminary data have shown activity of T as single agent in MBC. Clinical and preclinical data suggested T may display specific activity among certain NER-intact or HRR-deficient MBC, and prompted this phase II trial dedicated to 3 subgroups: triple-negative (TN), HER-2-overexpressed, and BRCA1/2 germline-mutated MBC. Methods: T was given at 1.3 mg/m2 as a 3- hour iv infusion every 3 weeks to pts with pretreated progressive MBC: Group A: TN; Group B: HER-2+++; Group C: BRCA1/2 mutation carriers. Endpoints were objective response (OR) rate by RECIST, duration of response, progression free survival (PFS), tumor volume changes, safety and exploratory pharmacogenomics (PGx). Results: A total of 95 women (median [med] age 52, ECOG 0/1 48/52%) have been enrolled (A:50, B:24, C:21) with data available for 72 pts. Med number of prior chemotherapy regimens: 4 (1–10). Med number of T cycles administered: 2 (1–12) for all groups. The most commonly reported grade 3/4 AEs are neutropenia (29/21%), ALT (28/2%) and AST (13/0). Alopecia/stomatitis, only G1, was reported in <2% each. Long-lasting disease stabilizations were described in all groups. While OR were rare among TN MBC pts (2PR/43 evaluable), preliminary analysis by investigator shows efficacy in group C (4PR/11 evaluable). Tissue samples from 36 pts were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Preliminary results show high XPG is associated with longer PFS: 4.1 months (95% CI 2.6-not reached) versus 1.3 months (95% CI 1.2–3.7), p = 0.01. Analyses are ongoing. Conclusions: Trabectedin shows a manageable safety profile in the 3 groups of MBC with promising efficacy in certain DNA-repair machinery sub-categories defined molecularly. TN group was closed due to low response. More mature PGx results will be discussed to help selecting the patients who are at highest chance for response. [Table: see text]

Phase III trial of gemcitabine plus docetaxel (GD) compared to capecitabine plus docetaxel (CD) with planned crossover to the alternate single agent in metastatic breast cancer (MBC)

1000 Background: GD and CD are efficacious in patients (pts) with MBC. This study compared safety and efficacy of GD and CD induction regimens, where the alternate, single-agent, crossover therapy (GD to C or CD to G) was predetermined. Primary endpoint was time to progressive disease (TTP). Secondary endpoints included toxicities, overall response (ORR), and overall survival (OS). Methods: This multicenter, open-label, phase III study enrolled MBC pts with possible prior anthracycline therapy, adjuvant or neoadjuvant taxane therapy, but no taxane therapy for MBC ≤6 months prior to entry. Enrollment of 442 pts (221 per arm) was planned with 385 progressions required to achieve 80% power for a 2-month observed difference in median TTP between arms. Pts were randomized to: GD: G 1,000mg/m2 Days 1, 8 plus D 75 mg/m2 Day 1, q21 days; or CD: C 1,000 mg/m2 BID, Days 1–14 plus D 75 mg/m2 Day 1, q 21 days. Upon disease progression, pts were given crossover C or G at doses and schedules identical to induction. ORR was assessed by RECIST. Results: Demographics of 472 enrolled pts were balanced between arms; 57% had prior anthracycline. GD caused greater myelosuppression than CD, but without greater febrile neutropenia. Gastrointestinal toxicities, mucositis, and hand-foot syndrome were greater with CD. More pts in the CD arm (n=61, 26.2%) versus the GD arm (n=41, 17.2%) discontinued due to toxicity (p=0.023). ORR, TTP, and OS were not significantly different comparing GD and CD. However, ORR and TTP were significantly greater for the GD to C crossover monotherapy compared to CD to G. Post-hoc analysis of crossover pts showed that the TTP sum from induction through crossover was 6.1 months greater for GD to C. Conclusions: GD and CD had similar efficacy with toxicity profiles consistent with prior clinical experience. Results suggest that the GD to C crossover sequence may provide a clinical benefit over CD to G. [Table: see text] [Table: see text]

Effect of mTOR inhibition on sensitivity of triple-negative breast cancer cells to epidermal growth factor inhibition

1055 Background: The outcome for patients with triple negative (TN) cancers is poor at least in part because of a lack of targeted therapies. Although 50% of TN breast cancers over-express EGFR, the use of EGFR inhibitors as single agents in patients with unselected and TN metastatic breast cancers has produced disappointing results. Likewise, mTOR inhibitors have modest activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated that EGFR inhibitors in combination with rapamycin (RAPA) decrease cell survival, increase apoptosis, and are synergistic in TN breast cancer cells, compared to any of the agents alone (AACR 2008). We, therefore, evaluated the combination of mTOR and EGFR inhibition in vivo. Methods: Athymic mice were inoculated with TN (MDA-MB-231) breast cancer cells. One week after cell inoculation, mice were treated with vehicle, lapatinib 75mg/kg by mouth daily, RAPA 3mg/kg IP biweekly, or the combination. After 4 weeks of treatment, mice were sacrificed and tumors were assessed for target proteins by Western blotting and immunohistochemistry Results: The combination of RAPA and lapatinib resulted in a significant decrease in TN breast tumor volume (76 mm3), compared to rapamycin alone (133 mm3, p = 0.01), lapatinib alone (183 mm3, p < 0.0001) or control (188 mm3, p = 0.005). Neither lapatinib nor RAPA alone inhibited tumor growth significantly compared to control (p > 0.05). Interestingly, in contrast to our findings in vitro, the increase in pAkt noted in RAPA treated tumors was not decreased by lapatinib, despite the significant decrease in tumor size in tumors treated with the combination. Conclusions: These studies demonstrate that the combination of mTOR inhibition and lapatinib significantly inhibit TN breast cancer growth, compared with either agent alone. Given the lack of targeted therapies in TN breast cancers, these data support the possibility that mTOR inhibition can sensitize TN breast cancers to EGFR inhibitors. A clinical trial evaluating the combination of lapatinib and RAD001 as second-line therapy for TN metastatic breast cancer is planned. [Table: see text]

Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern

The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved in Germany in September 2000 after evaluation in clinical trials involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.

Docetaxel and carboplatin followed by sequential capecitabine as first line treatment in patients with locally advanced or metastatic breast cancer.

Abstract Abstract #2155 Background: Anthracyclines and docetaxel (D) are the most active agents in metastatic breast cancer (BC). New regimens are being assesed to improve chemotherapy efficacy. D and carboplatin (C) has shown to be an active treatment in metastatic BC. Capecitabine (X) and D is also an active combination, despite the fact the toxicity profile needs to be improved. Sequential administration of D and X could lead to an improved toxicity profile compared with concomitant administration. We designed this study to evaluate activity and toxicity profile of treatment with D and C followed by sequential X in patients with locally advanced or metastatic BC.
 Methods: Patients with locally advanced or metastatic BC, at least one measurable lesion, age ≥ 18 years, ECOG PS ≤ 2, and adequate bone marrow and hepatic functions, were included in the study. Prior chemotherapy or radiotherapy for advanced disease was not allowed. Patients received 6 cycles of D 75 mg/m2 iv D1 and C AUC5 iv D1, every 21 days followed by 12 cycles of X 2000 mg/m2/day o.r. D1-14 in a 21 days course.
 Results: twenty patients have been analyzed. Median age was 55 years old (range 36-73), ECOG PS 0-1 94.4%; 90.0% of patients had infiltrating ductal carcinoma and 57.9% of patients had stage I-II at diagnosis. Main sites of metastatic disease were bone (35.0%), liver (25.0%) and lung (25.0%). Conservative surgery was performed in 35% of patients and mastectomy in 40%. Previous radiotherapy and chemotherapy was administered in 50.0% and 70.0% of patients, respectively. A total of 108 cycles of D and C (median 6, range 2-6) and 71 cycles of X (median 6, range 2-10) were administered. Median relative dose intensity was 96% for D and C and 95% for X. Over 17 evaluable patients for efficacy, 2 achieved complete response and 4 partial response; the ORR was 35.3% (95% CI:12.6-58.1). During D and C treatment, grade III/IV toxicities per patient were neutropenia (25.0%), leucopenia (10.0%), mucositis (5.0%), oedema (5.0%), febrile neutropenia (5.0%) and thrombophlebitis (5.0%). Most common grade II toxicities were nausea (20.0%), vomiting (15.0%) and asthenia (20.0%). During X treatment, grade III/IV toxicities per patient were neutropenia (7.1%) and hand-foot syndrome (7.1%). Main grade II toxicity was hand-foot syndrome (14.3%). Two patients finished treatment after 2 and 6 cycles of X due to diarrhea, oedema and anorexia, and hand-foot syndrome.
 Conclusion: In this preliminary analysis, D and C followed by sequential X seems to be an active and well-tolerated regimen as first line treatment in patients with locally advanced or metastatic BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2155.

Angiogenesis/tumor hypoxia: new treatment options?

Angiogenesis/tumor hypoxia: new treatment options?

Delivered relative dose intensity and febrile neutropenia rate with common adjuvant chemotherapy regimens: A review

11505 Background: Adjuvant chemotherapy for early-stage breast cancer decreases the risk of recurrence and improves survival. Prior work has pointed out that <85% of relative dose intensity (RDI) could result in compromised outcome. Methods: Among consecutively treated patients, one hundred patients treated with (AC-T) doxorubicin, cyclophosphamide (4 cycles) followed by paclitaxel (4 cycles), one hundred patients treated with (FEC-D) 5FU, epirubicin and cyclophosphamide (3 cycles) followed by docetaxel (3 cycles) and 75 patients treated with (FEC100) 5FU, epirubicin and cyclophosphamide (6 cycles) were retrospectively analyzed. Summation dose intensity (SDI) is used as a reference for RDI. To calculate SDI of each regimen, a unit dose intensity (UDI) of each drug in the combination regimen is calculated, defined as the dose of the drug required to produce 30% complete plus partial response when used as a first-line single agent in metastatic breast cancer. The dose intensity of each drug in a combination is expressed as a fraction of that drug’s UDI and fractions for all the drugs are added together. The incidence of FN was recorded as well. Results: Almost 30% of patients receiving FEC-100, 4% with AC-T and 10% with FEC-D were over 65 years. Only 4% with AC-T, 5% with FEC-D but 21% patients receiving FEC-100 had <85% RDI. About 1/3rd of FEC-100 patients but 63% of AC-T and 77% patients of FEC-D had 100% of RDI delivered. FN rates were 7% for AC-T and 23% for FEC-D. Almost all FN cases were seen with the dose of Docetaxel (19/23) in patients receiving FEC-D. Conclusions: To our knowledge, delivered RDI and/SDI for these regimens have not been reported previously and the results show the experience of an academic cancer centre. The delivered RDI for AC-T and FEC-D is excellent but for FEC-100 is sub-optimal. This variability could be due to a smaller sample, relatively elderly population and various other factors. Although the FN rate for AC-T appears to be similar as previously reported, the FN rate for FEC-D is higher. This higher rate combined with the fact that the most FN cases occurred with docetaxel appears to reflect the experience for the patients outside the clinical trial. No significant financial relationships to disclose.

Clinical Efficacy of Taxane–Trastuzumab Combination Regimens for HER-2–Positive Metastatic Breast Cancer

The taxanes docetaxel (Taxotere; Sanofi-Aventis U.S. LLC, Bridgewater, NJ) and paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) are highly active agents in metastatic breast cancer and may represent a safer alternative to anthracycline-based regimens when combined with the human epidermal growth factor receptor (HER)-2-targeted agent trastuzumab (Herceptin(R); Genentech Inc., South San Francisco, CA). A number of preclinical and early clinical studies have evaluated the feasibility, duration, and appropriate dosing schedule(s) for taxane-trastuzumab combinations in HER-2-positive metastatic breast cancer. Preclinical studies of the taxanes in combination with trastuzumab demonstrate synergistic interactions of trastuzumab with docetaxel and additive interactions with paclitaxel. Even though not supported by head-to-head studies, clinical trial results indicate the response rates with docetaxel-trastuzumab combinations may be higher than those with paclitaxel-trastuzumab, although there is a lack of clear crosstrial differences in other clinical benefits. Weekly taxane-trastuzumab regimens have been shown to offer superior disease control. Results from two large, phase III trials that examined the addition of carboplatin to a taxane-trastuzumab doublet did not demonstrate a difference in survival with carboplatin. In one study, the addition of carboplatin to paclitaxel-trastuzumab therapy resulted in a higher response rate and longer progression-free survival time; in the second study, the docetaxel-trastuzumab and docetaxel-trastuzumab-carboplatin combinations were equally effective. Ongoing correlative studies of taxanes, as well as newer formulations such as nanoparticle albumin-bound paclitaxel, in combination with trastuzumab will inform clinical practice regarding the optimal agent, schedule, and use of these highly effective regimens.

The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: Clinical experience with anti-angiogenic agents, focusing on bevacizumab

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in breast cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in metastatic breast cancer (MBC). This review describes the function of VEGF in normal and tumour angiogenesis, explores the rationale behind the use of anti-VEGF therapy in MBC and details the therapeutic impact of such agents on tumour vasculature. Clinical data from trials of anti-VEGF agents in MBC are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in this tumour type. Future potential uses of bevacizumab in breast cancer are introduced.

Biweekly administration of gemcitabine and cisplatin chemotherapy in patients with anthracycline and taxane-pretreated metastatic breast cancer

Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately active and extremely safe in patients with metastatic breast cancer previously treated with anthracycline and taxanes.

Pegylated Liposomal Doxorubicin (Caelyx®) in Metastatic Breast Cancer: A Community-Based Observation Study

Objectives: Pegylated liposomal doxorubicin (PLD) has improved therapy options significantly, as it causes less myelosuppression, nausea, vomiting, and alopecia than conventional doxorubicin, while maintaining efficacy. The goal of this survey was to determine whether the use of PLD in a community-based patient group is comparable regarding chemotherapeutic doses and side effects to preselected study patients. Methods: 100 questionnaires were randomly sent to Swiss oncologists in private practices, general hospitals and university hospitals. Results: The patient cohort was heterogeneous with respect to prior treatments. PLD was an active agent in metastatic breast cancer and was well tolerated by the majority of patients. The most common non-hematological side effects were hand-foot syndrome (HFS) and mucositis while only patients receiving a dose of 50 mg/m² (recommended dose) experienced grade 4 HFS. The reported mean dose of PLD was 38.5 mg/m². Conclusions: This community-based observational study supports previous reports indicating that PLD at a median dose of ≤40 mg/m² every 4 weeks is an active, well-tolerated agent in non-selected, pretreated patients with metastatic breast cancer.

Taxanes for adjuvant treatment of early breast cancer

Adjuvant chemotherapy improves survival in pre- and post-menopausal women with early breast cancer. Taxanes are highly active chemotherapy agents in metastatic breast cancer. Their role in early breast cancer was examined in this review. To review the randomised evidence comparing taxane containing chemotherapy regimens with non-taxane containing chemotherapy regimens as adjuvant treatment of pre- or post-menopausal women with early breast cancer. The Cochrane Breast Cancer Group Specialised Register was searched on 9th January 2007 using the codes for 'early breast cancer' and keywords for taxanes. Details of the search strategy used to create the register are described in the Group's module in The Cochrane Library. The reference lists of other related literature reviews and articles were also searched. Randomised trials comparing taxane containing regimens with non-taxane containing regimens in women with operable breast cancer. Women receiving neoadjuvant chemotherapy were excluded. Data were collected from published trials and abstracts. Studies were assessed for eligibility and quality and the data extracted independently by two review authors. Hazard ratios (HR) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity and quality of life data were extracted when reported. We identified 20 studies, 12 of these (7 full publications, 5 abstracts) had sufficient data published for inclusion (11 for OS and 11 for DFS) in the review. The weighted average median follow up was 60.4 months. All studies fulfilled quality criteria either adequately or well. Amongst 18,304 women with 2483 deaths, the HR for OS was 0.81 (95% CI 0.75 to 0.88, P < 0.00001) favouring taxane containing regimens. Amongst 19,943 women with 4800 events, the HR for DFS was 0.81 (95% CI 0.77 to 0.86, P < 0.00001) favouring taxane containing regimens. There was no statistical heterogeneity for either OS or DFS. This meta-analysis of studies supports the use of taxane containing adjuvant chemotherapy regimens with improvement of overall survival and disease-free survival for women with operable early breast cancer. The review did not identify a subgroup of patients where taxane containing treatment may have been more or less effective. Dosage and scheduling of the taxane drug is not clearly defined and we await results of the next generation of studies to determine the optimal use of taxanes in early breast cancer.

Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in elderly metastatic breast cancer patients

19565 Background: Although the majority of metastatic breast cancer (MBC) patients (pts) responds to endocrine therapy, treatment failure is a concern, as well as front-line therapy for pts with ER/PR negative disease.The combination of anthracyclines (A) and cyclophosphamide (C) is active in younger pts, but cardiac toxicity of A in elderly MBC pts has to be considered. Pegylated liposomal doxorubicin (PLD) (Caelyx®) is active in MBC and has much less cardiotoxicity than A, and we present the preliminary data of the PLD/C in elderly MBC pts. Methods: This was a multicentric phase II trial. Inclusion criteria included: pts aged between 65 and 75, histologically proven measurable MBC, ECOG PS 0–1, LVEF = 50%, first-line chemotherapy for MBC. Prior adjuvant chemotherapy was allowed if stopped for = 6 or 12 months without and with anthracyclines, respectively. Endocrine therapy either in the adjuvant or metastatic setting had to be stopped for = 1 month. All pts gave a written informed consent. The treatment schedule was : PLD 40mg/m2 and C 500mg/m2 d1 every 4 weeks. Efficacy as well as response duration and tolerance were the primary and secondary end-points, respectively. Results: 35 patients were enrolled (Median age 71.3, range 65.6–75.9). A total of 166 cycles have been administered. The median number of cycles was 6 (range 1–9). No toxic death was reported, one patient died of diabetes mellitus decompensation. No congestive heart failure or decrease in LVEF was reported, although 1 pt experience grade 3 dyspnea and stopped treatment. Other (gr3–4) NCI-CTC toxicity included: neutropenia in 7 (gr3) and 3 (gr4) pts; gr3 mucositis (4). No febrile neutropenia was reported. Grade 3 hand-foot syndrome occurred in 1 pt, whereas treatment was stopped due to a generalized rash in 1 pt. An objective response (CR + PR) was achieved in 10 (28,6%) pts (1 CR and 8 PR), and a disease control in 24 (68.6%) with a progression free survival of 8.8 months and a median survival of 20.4 months Conclusions: The LPD-C combination is active in elderly MBC pts, with an acceptable toxicity profile. No significant financial relationships to disclose.

Single-agent docetaxel (TXT) as first-line treatment in metastatic breast cancer (MBC)

11515 Background: Historically anthracyclines have been considered the most active agents in metastatic breast cancer (MBC). Docetaxel (TXT) has challenged this belief. Aims: Evaluate response rates, toxicity and time to progression in patients with MBC receiving single agent TXT as first line treatment. Methods: MBC patients received first line single agent treatment according to one of the following schedules: TXT 35 mg/m2 iv weekly for 6 wks q 8 wks (Group 1) or TXT 100 mg/m2 iv day 1 q 3 weeks (Group 2). Adjuvant chemotherapy was FAC (600,50,600) day 1 q 21 days for 6 courses in all cases so treated. Results: Conclusions: It appears that results with single agent TXT obtained in clinical practice are comparable to those reported in Phase II-III trials (Group 1 and Group 2, respectively ) using the same regimens. [Table: see text] No significant financial relationships to disclose.

A retrospective review of breast cancer patients with central nervous nystem metastasis treated with capecitabine

1098 Background: In all of the major studies on the effects of capecitabine in metastatic breast cancer (MBC) patients with central nervous system (CNS) metastasis were categorically excluded, understandably due to the poor outcome associated with such advanced disease, and as a consequence, the data are limited on such cases. The aim of this study was to evaluate the effectiveness and toxicity of capecitabine in breast cancer patients with CNS metastasis. Methods: The records of all patients with MBC presenting to the Department of Medical Oncology at Hacettepe University Hospital, Ankara, Turkey, for treatment between December 2001 and December 2005 were evaluated. Patients who recieved capecitabine as a sole agent for MBC with CNS metastasis were included in the study. All patients recieved capecitabine at a dose of 2,500mg/m2/day for 14 days at 3 weeks intervals. Results: Twenty patients were included in this retrospective analysis. All were female with a median age of 38 years (range, 20–58) at the diagnosis and the median time to brain metastasis was 3.9 years (range, 0.5–19.6). Three patients had undergone surgery for CNS metastasis, and all patients had recieved whole brain radiotherapy before the capecitabine treatment. A total of 159 cycles of chemotherapy were introduced and for each patient median number of chemotherapy cycles were 6.5 (range 1–28 cycles). Nine of them were given capecitabine as first-line chemotherapy after brain metastasis. There were 2 (10%) complete (one patient had metastasectomy for brain metastasis), and 7 (35%) partial responses with 6 (30%) patients having stable disease. Progressive disease was observed in 5 (25%) patients. Overall response rate was 45%. Median progression free survival time was 7.3 months (range 1.8–26.7). Adverse effects were seen in 13 patients, with grade 3 hand food syndrome occuring in 5 patients resulting in dose reduction. Grade II neutropenia was observed in 1 patient. Conclusions: Capecitabine is effective and well tolerated in the treatment of breast cancer patients with CNS metastases. No significant financial relationships to disclose.

Dutch Breast Cancer Trialists' Group (BOOG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Dutch breast cancer trialists' group (BOOG). Clinical trials include:An open label randomized (inter)national multicenter comparative trial of 5 years adjuvant endocrine therapy with an LHRH agonist plus an aromatase inhibitor (goserelin + anastrozole) versus five courses FE90C chemotherapy followed by the same endocrine therapy in pre- or perimenopausal patients with hormone receptor-positive primary breast cancer (PRemenopausal Optimal Management IS Endocrine therapy). BOOG 2002-01/PROMISE. ISRCTN23561723Open label, comparative, randomized, multicenter, study of trastuzumab (Herceptin) given with docetaxel (Taxotere) versus sequential single agent therapy with trastuzumab followed by docetaxel as first-line treatment for metastatic breast cancer (MBC) patients with HER2neu overexpression. BOOG 2002-02/HERTAX ISRCTN13770586Micro-metastases and Isolated tumour cells: Robust and Relevant Or Rubbish? The MIRROR study in BREAST CANCER. BOOG 2003-03/ZonMW 3214Radiation dose intensity study in breast cancer in young women: a randomized phase III trial of additional dose to the tumor bed. BOOG 2004-01/Young Boost SRCTN45066831Microarray analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens, a randomized phase III study. MATADOR, BOOG 2005-02, CKTO 2004-04 ISRCTN61893718A prospective randomised, open, multicentre, phase III study to assess different Durations of Anastrozole therapy after 2–3 years Tamoxifen as Adjuvant therapy in postmenopausal women with breast cancer. 2006-01/DATAA randomized, open-label phase III study of first line chemotherapy in elderly metastatic breast cancer patients, comparing intravenous pegylated liposomal doxorubicin with oral capecitabine; and the incorporation of a complete geriatric assessment. 2006-02/OMEGABOOG participation in International studies:. BOOG 2001-01/TEAM trial. BOOG 2001-02/AMAROS (EORTC 10981/22023). BOOG 2002-04/HERA (BIG 1-01/EORTC 10011/BO16348B). BOOG 2003-02 (BIG 1-02/IBCSG 27-02). BOOG 2003-04 (GBG 29). BOOG 2004-02/TBP (GBG 26, BIG 3-05). BOOG 2005-01/CASA (IBCSG 32-05/BIG 1-05). BOOG 2005-03/MINDACT (EORTC 10041, BIG 3-04). BOOG 2006-03/SUPREMO (BIG 2-04). BOOG 2006-04/Adjuvant lapatinib study (BIG 2-06/EGF106708)