Metastatic Breast Cancer In Combination Research Articles

A phase II study of a combination of pemetrexed (Pem) and gemcitabine (Gem) in patients with metastatic breast cancer (MBC): An NCCTG study

639 Background: Pem inhibits folate-dependent enzymes involved in thymidine and purine synthesis, has broad clinical activity, and exhibits synergistic cytotoxicity with Gem in preclinical models. We conducted a phase II study to assess the efficacy and toxicity of this combination in MBC. Methods: Eligible patients (pts) must have had an anthracycline and a taxane in either adjuvant or metastatic setting with no more than 1 chemotherapy regimen for metastatic disease (unless a taxane and anthracycline). Pts received Gem 1250 mg/m2 (IV; d1, 8) and P 500 mg/m2 (IV; d8) q21 days. Results: Fifty-nine pts were enrolled with median age of 51 (range 32–74), prior adjuvant chemotherapy regimens 0 (5 pts, 8%) or 1 (54 pts, 92%), prior metastatic chemotherapy regimens 0 (23 pts, 39%), 1 (35 pts, 59%), or 2 (1 pt, 2%). Twenty-eight (48%) had received prior hormonal therapy. Pts received treatments for a median of 5 cycles (range: 1–21) with median follow-up of 426 days. Considering grade 3 and 4 toxicities, 48 (81%) pts had neutropenia (gr 3: 11, gr 4: 37), but only 7 (12%) had febrile neutropenia. Fifteen pts (25%) had thrombocytopenia (gr 3: 13, gr 4: 2). Grade 3+ non-hematologic toxicity included 10 (17%) pts with dyspnea, 10 (17%) with fatigue, 4 (7%) with rash, 3 (5%) with nausea, and 3 (5%) with anorexia. Overall, 14 (24%; 95% CI: 16–39%) pts achieved PR with a median duration of at least 5 months. Nine (15%) had SD for ≥ 6 months with a median of 334 days (range 205–786). Median time to progression was 3.8 months (95% CI 2.6–5.7). Median survival was 10.3 months (95% CI 8.4–26.4) and the 1-year survival rate was 49% (95% CI 37–64%). Conclusions: The combination of Pem and Gem has activity and produces clinical benefit (CR + PR + SD ≥ 6 months) in 39% of pts with MBC who have previously been treated with an anthracycline and a taxane. No significant financial relationships to disclose.

Phase II trial of docetaxel plus doxorubicin and cyclophosphamide in locally advanced breast cancer (LABC)

855 Introduction: It has been show that patients achieving a pathological complete response to primary chemotherapy benefit in terms of prolonged overall survival (NSABP B18). Docetaxel (D) plus doxorubicin (d) is a highly active combination in metastatic breast cancer (Mackey JR, Proc ASCO 2002) as well as in the neo-adyuvant setting (Ian C, JCO 2002). A three-drug combination could improve these results. Methods: In this study, females diagnosed of stage II-III LABC between May 2001 to October 2003 with 18–75 years, PS 0–1, and adequate renal, liver and hematological functions were included. Chemotherapy schema (TAC): D 75 mg/m2, Cyclophosphamide 500 mg/m2 and d 50 mg/m2 on day 1, every 21 days plus G-CSF days 5th to 11th. Four to six courses (c) were scheduled and assessment for clinical response (CR) was made after 2nd, 4th and 6th c. Results: 33 patients (p) were enrolled and pathological response (PR) was already available in 26p. Patient characteristics: median age 53 years (39–73); 25p had PS=0 (75,7%); 36,4% presented with stage IIA, 30,3% stage IIB, 30,3% stage IIIA, and 3,0% stage IIIB; 27p had ductal invasive histology and 6p had a lobular invasive cancer; ER were positive in 22p (66,6%) and negative in 11 p (33,4%); c-erb-B2 was +++/+++ in 7p (21,2%), ++/+++ in 9p (27,3%) and negative in 17p (51,5%). Chemotherapy: 137c were given (median 4 c/p). Surgery had been performed in 78,8% of p. Toxicity: all p had grade 3 alopecia and 4p had grade 3 asthenia; 9p had a neutropenic fever episode but none resulted in septic death. No other severe toxicity was recorded (including clinical cardiotoxicity). CR rate was assessed in 30p (90%) and it was complete in 9p and partial in 21p (overall 100%). 6p achieved a complete pathological response (PR) (18%) and 8 p a partial PR (24,2%). 15 p had a mastectomy performed (45,4%). Conclusions: This phase II study of TAC as induction chemotherapy in patients with LABC showed a high (both clinical and pathological) response rate. The main significant toxicity was the high incidence of neutropenic fever despite the routine use of stimulating factors. Final results will be presented. No significant financial relationships to disclose.

Phase II trial of docetaxel plus doxorubicin and cyclophosphamide in locally advanced breast cancer (LABC)

855 Introduction: It has been show that patients achieving a pathological complete response to primary chemotherapy benefit in terms of prolonged overall survival (NSABP B18). Docetaxel (D) plus doxorubicin (d) is a highly active combination in metastatic breast cancer (Mackey JR, Proc ASCO 2002) as well as in the neo-adyuvant setting (Ian C, JCO 2002). A three-drug combination could improve these results. Methods: In this study, females diagnosed of stage II-III LABC between May 2001 to October 2003 with 18–75 years, PS 0–1, and adequate renal, liver and hematological functions were included. Chemotherapy schema (TAC): D 75 mg/m2, Cyclophosphamide 500 mg/m2 and d 50 mg/m2 on day 1, every 21 days plus G-CSF days 5th to 11th. Four to six courses (c) were scheduled and assessment for clinical response (CR) was made after 2nd, 4th and 6th c. Results: 33 patients (p) were enrolled and pathological response (PR) was already available in 26p. Patient characteristics: median age 53 years (39–73); 25p had PS=0 (75,7%); 36,4% presented with stage IIA, 30,3% stage IIB, 30,3% stage IIIA, and 3,0% stage IIIB; 27p had ductal invasive histology and 6p had a lobular invasive cancer; ER were positive in 22p (66,6%) and negative in 11 p (33,4%); c-erb-B2 was +++/+++ in 7p (21,2%), ++/+++ in 9p (27,3%) and negative in 17p (51,5%). Chemotherapy: 137c were given (median 4 c/p). Surgery had been performed in 78,8% of p. Toxicity: all p had grade 3 alopecia and 4p had grade 3 asthenia; 9p had a neutropenic fever episode but none resulted in septic death. No other severe toxicity was recorded (including clinical cardiotoxicity). CR rate was assessed in 30p (90%) and it was complete in 9p and partial in 21p (overall 100%). 6p achieved a complete pathological response (PR) (18%) and 8 p a partial PR (24,2%). 15 p had a mastectomy performed (45,4%). Conclusions: This phase II study of TAC as induction chemotherapy in patients with LABC showed a high (both clinical and pathological) response rate. The main significant toxicity was the high incidence of neutropenic fever despite the routine use of stimulating factors. Final results will be presented. No significant financial relationships to disclose.

Novel association with gemcitabine and docetaxel as salvage chemotherapy in metastatic breast cancer previously treated with anthracyclines: Results of a multicenter phase II study

The goals of this study were to evaluate the efficacy and toxicity of the gemcitabine/docetaxel combination in metastatic breast cancer previously treated with anthracyclines. Fifty-three patients with metastatic breast cancer who had failed or relapsed after anthracycline-based chemotherapy entered the study and were evaluable. Patients received gemcitabine (1,000 mg/m 2 days 1 and 8) and docetaxel (80 mg/m 2 day 8), every 3 weeks. The regimen was generally well tolerated with good feasibility. A complete response occurred in six patients (9.4%) and partial response in 23 (43.4%) for an overall response rate of 53% (95% confidence interval, 38.9% to 66.7%). Median survival rate was 70%; and the duration of response, time to progression, and overall survival were 6, 7.5, and 16.5 months, respectively. We conclude that the gemcitabine/docetaxel combination constitutes a manageable and tolerable combination as salvage chemotherapy in metastatic breast cancer and may represent a valid treatment option in patients previously treated with anthracyclines.

Adjuvant targeted therapy with trastuzumab may decrease metastatic capacity in specific group of oropharyngeal cancer patients: downregulation of E-cadherin–catenin complex by cooperative effect of erbB-2 and human papillomavirus type 16 E6/E7 protooncogenes

Human papillomavirus (HPV) type 16 is causally associated with a subset of oral cancers, predominantly those cancers arising in the oropharynx (OP). Increased HPV16 E6 and E7 oncogene expressions are responsible for the malignant transmission in these cancers. ErbB-2 is the family member most closely implicated in human cancer, where it is overexpressed in about 30% of carcinomas including head and neck squamous cell carcinoma. Coexpressions of E6/E7 and ErbB-2 downregulate E-cadherin and catenin expression, therefore induces metastatic process. Trastuzumab is a humanized monoclonal antibody that recognizes the ErbB-2 protein receptor and breakthrough in the treatment of metastatic breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment of breast cancer. We propose that trastuzumab as an adjuvant treatment may decrease process of tumor metastasis in oropharyngeal cancer patients who completed primary treatment (surgery and/or radiotherapy) and show expression of both HPV16 E6/E7 and erbB-2 oncoproteins. In vitro and in vivo studies with trastuzumab in these subgroup of patients may support our hypothesis.

Clinical and pharmacokinetic data of a docetaxel-epirubicin combination in metastatic breast cancer.

In order to explore activity and pharmacokinetic data of a docetaxel-epirubicin combination we analyzed a population of 60 metastatic breast cancer patients. All the patients had an ECOG performance status < 3; 41 patients (68%) had visceral metastases as dominant site of disease, including 33% with liver metastases. Three or more involved organs were present in 43% of patients; 35% had received prior hormonotherapy; 10% for metastatic disease. Twenty-five patients (42%) had received prior adjuvant chemotherapy; 15% a CAF regimen. Twenty per cent of patients had less than 12 months disease-free interval. Docetaxel and epirubicin were both given at a dose of 75 mg/m2 i.v. d. 1 every 3 weeks. After a median of six cycles we had 5 CR (8.3%), 40 PR (66.6%), 7 NC (11.6%), and 8 PD (13.3%). Response rates in patients with visceral and liver metastases were 78% and 55% respectively. Premenopausal status, < 1 year disease free survival and > 3 metastatic sites were associated with a lower response rate. After a median follow-up of 19 months (12-36), median disease-free survival is 11 months and median overall survival has not been reached. Grade 4 neutropenia was observed in 75% of courses but with febrile neutropenia in 6.2% of courses only. Non-hematologic toxicity wasn't clinically important. A NYHA class III reversible cardiac failure was observed in one patient (1.6%). The pharmacokinetic evaluation in 16 patients has shown that docetaxel transiently interfered with epirubicin plasma level when docetaxel was administered 1 h after epirubicin.

From HER2 to Herceptin

SUMMARYSUMMARYHER2 overexpression occurs in 25% of breast cancers and seems to correlate with poor prognosis. HER2 overexpression may predict tamoxifen failure and different response rates to chemotherapeutic agents such as the taxanes and anthracyclines. The detection of HER2 and its overexpression is performed using fluorescent in situ hybridisation (FISH) and/or immunohistochemistry (IHC).Trastuzumab [Herceptin (H)] is a humanised IgG monoclonal antibody specific for the growth factor receptor HER2. Pre-clinical trials using monoclonal antibodies have shown inhibition of breast tumour growth in athymic nude mice. Phase II and III clinical trials have evaluated the efficacy and safety of Herceptin in women with metastatic breast cancer in combination with other agents and as a single agent. Currently, Trastuzumab and paclitaxel is the only combination indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2. It is also indicated as a single agent in women with HER2-overexpressing metastatic breast cancer that has progressed after previous chemotherapy. Herceptin is a well-tolerated drug and the side-effects that are commonly seen with chemotherapy, such as neutropenia, alopecia and mucositis, are rarely observed.The main risk factors for cardiotoxicity are concurrent or previous anthracycline exposure The potential role of Herceptin in the adjuvant setting is currently being evaluated.Keywords: : HER2Metastatic breast cancerHerceptin

From HER2 to Herceptin

SUMMARYHER2 overexpression occurs in 25% of breast cancers and seems to correlate with poor prognosis. HER2 overexpression may predict tamoxifen failure and different response rates to chemotherapeutic agents such as the taxanes and anthracyclines. The detection of HER2 and its overexpression is performed using fluorescent in situ hybridisation (FISH) and/or immunohistochemistry (IHC).Trastuzumab [Herceptin (H)] is a humanised IgG monoclonal antibody specific for the growth factor receptor HER2. Pre-clinical trials using monoclonal antibodies have shown inhibition of breast tumour growth in athymic nude mice. Phase II and III clinical trials have evaluated the efficacy and safety of Herceptin in women with metastatic breast cancer in combination with other agents and as a single agent. Currently, Trastuzumab and paclitaxel is the only combination indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2. It is also indicated as a single agent in women with HER2-overexpressing metastatic breast cancer that has progressed after previous chemotherapy. Herceptin is a well-tolerated drug and the side-effects that are commonly seen with chemotherapy, such as neutropenia, alopecia and mucositis, are rarely observed.The main risk factors for cardiotoxicity are concurrent or previous anthracycline exposure The potential role of Herceptin in the adjuvant setting is currently being evaluated.