Agents In Metastatic Breast Cancer Research Articles

Docetaxel, Doxorubicin and Cyclophosphamide (the TAC regimen): An Effective Adjuvant Treatment for Operable Breast Cancer

The introduction of taxanes in the armamentarium against breast cancer in the 1990s has been one of the landmarks in the treatment of this disease. Docetaxel in particular is considered one of the most active cytotoxic agents in metastatic breast cancer and has also been tested as adjuvant postsurgical therapy in earlier stages. A regimen including docetaxel, doxorubicin and cyclophosphamide (the TAC regimen) was the first combination that demonstrated the efficacy of docetaxel in the adjuvant setting. This combination has been approved by regulatory agencies for adjuvant therapy of node-positive breast cancer and is presently used worldwide. TAC is more toxic than the traditional anthracycline-containing combinations, but many of its side effects can be ameliorated with colony-stimulating growth factor support.

Docetaxel (T) followed by capecitabine (X) as first-line chemotherapy in patients (pts) with metastatic breast cancer (MBC): Preliminary findings from a phase II study

10692 Background: X and T are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-pretreated MBC [O’Shaughnessy et al. J Clin Oncol 2002]. The aim of this trial was to evaluate the efficacy and safety of sequentially administered T then X as first-line treatment in MBC. Methods: Pts ≥ 18 years with previously untreated, HER2neu-negative MBC, ECOG PS ≤ 2, were included in this prospective, multicenter, non-randomized, phase II study. Pts received 3 cycles of T (100mg/m2 d1) followed by 3 cycles of X (1250mg/m2 bid d1–14), every 3 weeks. Results: To date, 38 pts are evaluable for safety and 33 pts for efficacy. Baseline characteristics: median age 54.4 years (range 33–76); PS ≥ 1 50%; 36 (95%) pts had previous (neo)adjuvant anthracyclines, 8 (21%) concomitant with paclitaxel. The most frequent metastatic sites were: bone 47%, nodes 39% and liver 36%. 69% of pts had ≥ 2 metastatic sites. To date, 38 pts have received 3 cycles of T and 33 have also received 3 cycles of X. A total of 195 cycles have been administered: T 108 cycles (median 3, range 1–3); X 87 cycles (median 3, range 1–3). Dose reductions and interruptions for T vs. X were 32 vs. 21% and 21 vs. 21%, respectively. Median relative dose intensity: T 0.97 (range 0.62–1.00), X 0.93 (range 0.26–1.00). T grade 3/4 toxicities (37 evaluable pts): asthenia 19%, mucositis 16%, nausea 13%, febrile neutropenia 11%, rash 5%, diarrhea 5%, infection 3%. X grade 3/4 toxicities (33 evaluable pts): hand-foot syndrome 9%, diarrhea 9%, vomiting 9%, asthenia 6%, nausea 3%, anorexia 3%. In the 33 pts evaluable for efficacy, the RR was 61%, including 4 CRs and 16 PRs. At a median follow-up of 6.1 months, median TTP has not yet been reached. Conclusions: These preliminary results show that the sequential regimen of T followed by X is feasible, effective and well tolerated in first-line MBC, although giving X before T should also be investigated. Findings from a recent trial of XT vs. T followed by X [Beslija et al. ECCO 2005] suggest that XT should be standard in fit poor-prognosis pts with aggressive disease. No significant financial relationships to disclose.

Docetaxel (Do) and liposomal pegylated doxorubicin in metastatic breast cancer (MBC) patients (pts): The French GINECO group experience

10589 Background: Taxanes and anthracyclins are among the most effective agents in MBC. Ca has a favourable cardiac toxicity profile and we tested Ca in combination with Do. Methods: Two successive Ca-Do regimens (Reg) were evaluated in first line MBC pts with performance status ≤ 2, and good organ function including normal MUGA scan. Reg A (n = 53 pts): Ca 35 mg/m2/d1 q4wks + Do 40 mg/m2/d1 q2wks according to previous phase I study results (Guastalla JP et al, Proc Am Soc Clin Onc 2004) and Reg B (n = 14 pts): Ca 30 mg/m2/d1 + Do 75 mg/m2/d2 every 3wks (Alexopoulos A et al, Ann Oncol 2004). Pyridoxine (250 mg/d) was given continuously during treatment (Tt). Results: The 67 pts had a median age of 58 yrs (range 37–77 yrs); others characteristics (%): ER+ (75), PR+ (51), HER2+ (9), adjuvant anthracyclin (54) and hormonotherapy (60), visceral disease (78). Both regimens induced unbearable toxicities (Tox) leading to premature stopping of the trial. Dose reduction, Tt delay and early stopping due to Tox were noted (% pts) in A:68, 36, 48 and B:57, 64, 54. Mucositis-skin Tox was the most severe Tox (% Gr2/3; A:40/15, B:43/21) and was observed in 21 and 40% of pts at cycle 2 and 4. Hematotoxicity was worse in reg B: Gr3/4 neutropenia (A:28/9, B:14/57), anemia (A:0/0, B:7/7) and thrombopenia (A:0/0, B:14/0), febrile neutropenia (A:6, B:14), Gr2–3 infection (A:13, B:28). Others Gr2–3 toxicities (> 10%) included alopecia (A:64, B:78), fatigue (A:54, B:57), nausea/vomiting (A:19, B:50). Three pts had a reduction of LVEF without clinical cardiac toxicity Conclusions: The combination of Do and Ca according to the 2 schedules tested in this study induced an unexpected high rate of mucositis and skin toxicity. No significant financial relationships to disclose.

Phase II study of pegylated liposomal doxorubicin plus vinorelbine in metastatic breast cancer

10718 Background: Pegylated liposomal doxorubicin and vinorelbine are active single agents in metastatic breast cancer (MBC) and lack overlapping toxicity. The possibility of combining these two drugs therefore seems attractive. Methods: Twenty-five patients with MBC entered a phase II study of pegylated liposomal doxorubicin 40 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 25 mg/m2 i.v. on day 1 and vinorelbine 60 mg/m2 oral on day 14, every 4 weeks. A two-staged Simon accrual design was adopted for this phase II trial. Patients were required to have measurable disease, previous chemotherapy with or without an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Results: Twenty-one patients with MBC were eligible, assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 36% (9 of 25; 95% CI, 20%-54%). One complete response and 8 partial responses were noted. In addition, 11 patients (44%) had stable disease of > 4 months duration, and 5 patients (20 %) had disease progression. Median time to disease progression was 10 months (range, 3–38 months) and median overall survival was 15 months (range, 4 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 30% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 8%) and mucositis (14%). Late alopecia was seen in 51% of patients (grade 1 in 39%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Only one patient presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and this patient recovered normal values after cessation of therapy. Conclusions: The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population. Final data analysis will be presented. No significant financial relationships to disclose.

Randomized trial of sequence vs. combination of capecitabine (X) and docetaxel (T): XT vs. T followed by X after progression as first-line therapy for patients (pts) with metastatic breast cancer (MBC)

571 Background: Capecitabine (Xeloda [X]) and docetaxel (Taxotere [T]) are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-preatreated MBC [O’Shaughnessy et al. J Clin Oncol 2002], although only one third of pts in the T group received X after progression. We designed this study to determine whether XT is better than sequential T→X in first-line MBC. Methods: 100 pts with measurable MBC, prior adjuvant anthracyclines (100%) but no prior chemotherapy for MBC and KPS ≥70 received 3-weekly cycles of either XT (X 1250mg/m2 bid d1–14 + T 75mg/m2 d1) or T→X (T 100mg/m2 d1 followed after progression by X 1250mg/m2 bid d1–14). X monotherapy data were not considered in the RR or TTP analyses but were included for OS and safety. Results: The XT and T→X arms were well balanced for prognostic factors: median age 48 (29–59) vs. 51 (31–64) years; median KPS 100 (70–100) in both arms; hormone-responsive disease 20 vs. 16%; dominant metastatic sites (liver 42 vs. 44%, lymph nodes 34 vs. 36%, lung 28 vs 24%, bone 20 vs 18%); number of involved organs (1 = 58 vs. 52%, >1 = 42 vs. 48%); median interval since prior adjuvant anthracyclines (18.5 vs. 17.0 months). Efficacy findings are shown in the table . 74% of the pts in the T→X arm crossed-over to X on progression. The post-study treatment rate was similar in both arms. The most common grade 3/4 adverse events (>5% of pts) with XT vs. T→X were: hand-foot syndrome 18 vs. 4%; stomatitis 16 vs. 8%; neutropenia 12 vs. 14%; neutropenic fever 12 vs. 14%; diarrhea 12 vs. 8%; fatigue 8 vs. 12%; alopecia 6 vs. 8%; edema 4 vs. 8%. Dose reductions were necessary for 52% of pts on XT and 36% of pts on T→X. Conclusions: XT provides significant RR, TTP and OS advantages over T→X. XT should be the standard therapy in fit poor-prognosis pts with aggressive disease. [Table: see text] No significant financial relationships to disclose.

Tailored vinorelbine-capecitabine treatment in elderly metastatic breast cancer patients. A SICOG phase II study

10556 Purpose: To determine the antitumor activity of vinorelbine (VNR) and capecitabine (Xeloda) when given together, as first-line treatment, in elderly metastatic breast cancer (MBC) patients. Patients and Methods: MBC patients, aged >65 years, with no prior chemotherapy for metastatic disease, received capecitabine 1,000–1,250 mg/m2 d 1→14 and VNR 20–25 mg/m2 d 1–8, q3wk for a maximum of 6 cycles. Doses of VNR and Xeloda were alternately escalated in each patient (VNR 20→25 on 2nd cycle, Xeloda 1,000→1,250 on 3rd cycle), in absence or relevant hematologic/nonhematologic toxicity. Results: Forty-seven MBC pts., median age 72 (range: 66–82) were enrolled. Metastatic sites: visceral/other = 30/17. Adjuvant chemotherapy: Yes/no = 21/27. The doses were escalated as planned in 24/47 pts. To date, 41/47 pts. are evaluable for response. Three CRs and 25 PRs have been recorded, giving a 68% ORR (Visceral/other = 59%/85%). At a median follow-up of 15.3 months, 19 pts. have progressed, and 18 died, median PFS and OS being 14.1, and 20.3 months, respectively. Toxicity has been in general mild or moderate. Grade 3–4 neutropenia has occurred in 29% of pts., with only 2 episodes of neutropenic sepsis. Severe gastrointestinal side effects have been observed in only 2 pts., while severe mucositis and hand-foot syndrome have never occurred. Conclusions: VNR-Xeloda combination is highly active in elderly MBC patients. The adoption of an intrapatient dose escalation permits to minimize the risk of severe toxicity, without compromising efficacy. The accrual still continues until the planned sample size (60 pts.). No significant financial relationships to disclose.

Phase II and pharmacological study of oral paclitaxel plus cyclosporine A in anthracycline pretreated metastatic breast cancer

652 Purpose: Paclitaxel is an important chemotherapeutic agent for metastatic breast cancer and often used as second line treatment. Due to its high affinity for the drug efflux pump P-glycoprotein...

Phase II trial to study the efficacy and toxicity of combined docetaxel (D), carboplatin (C), +/- trastuzumab (T) administered weekly (W) in patients (pts) with HER2/neu +/- metastatic breast cancer (MBC)

832 Background: D as a single agent is associated with the highest reported response rates (RR) and response duration in MBC. Though D is commonly delivered a q 3 week dose, newer studies have shown that W delivery of the drug is safe and associated with an equal or greater RR and less toxicity. C is an active agent in MBC and has shown synergy with the taxanes. Synergism has been established between the taxanes, C and T. The use of D+C on a q3 week basis +/- WT in HER2neu +/- MBC has been shown to have very high RR. As it appears that W administration of a combination of Paclitaxel (P), C and T results in higher RR and less toxicity than q 3 week P + C with WT in HER2neu+ pts, the question is whether this is also true with D based regimens. Methods: We are studying the safety and efficacy of WD at 25mg/m2 iv and WC at AUC 2 iv, given days 1, 8, 15 q 28 days, with WT given iv only for FISH + HER2neu pts with a loading dose of 4mg/kg on week 1 and then 2mg/kg/week in previously untreated women with MBC. All pts receive 10mg dexamethasone pre-medication intravenously one hour before D administration. The objectives of the study are to evaluate RR, safety, and time to progression (TTP). All pts are restaged q 8 weeks. Results: We have to date enrolled 23 pts. Of the 20 evaluable pts, there is 1 CR, 3PR, 9SD, 7PD, yielding a 65% clinical benefit (CR, PR, SD) and a 20% RR. Of the 7 evaluable HER2neu+ pts on the DCT regimen, there are 3 PR, 2SD and 2PD, yielding a 43% RR and a median TTP of 217 days. Of the 13 evaluable pts on DC alone there are 7SD, 1CR, and 5PD, yielding a 62%CB, but only an 8% RR with a median TTP of 118 days. Toxicity: The regimen was well tolerated with no significant toxicity. Conclusions: Though q 3 week DC+/-T is established as highly active for MBC, the efficacy of WDC+/-T needs further testing. Clearly this is a safe and tolerable regimen, and it may be that the efficacy of the WDC is best seen in the HER2neu+ patients when T is also administered. Enrollment continues and updated data will be presented. A trial of q 3 week DC+/-T vs WDC+/-T is warranted to assess the best way to use DC in MBC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

Gemcitabine and capecitabine in metastatic breast cancer (MBC): A Brown University Oncology Group (BrUOG) phase II study

785 Background: Gemcitabine (G) and capecitabine (C) have antitumor activity as single agents in MBC. Each inhibits DNA synthesis, though by different mechanisms. By increasing the activity of pyri...

A Modified Weekly Docetaxel Schedule as First-Line Chemotherapy in Elderly Metastatic Breast Cancer: A Safety Study

Standard dose docetaxel is burdened by severe toxicity. Weekly schedules have been shown to be active as standard scheme with reduced side effects. In 20-30% of elderly patients (pts) the classic 6-week schedule induces grade 3/4 fatigue and other cumulative toxicities. We carried out this safety study in order to evaluate whether a modified weekly docetaxel schedule would improve the toxicity profile. Twenty-one untreated elderly (≥70 years) pts suffering from metastatic breast cancer were enrolled in the study. Pts were treated with a weekly dose of 35 mg/m2 docetaxel for 6 weeks, followed by a 2-week rest. Further cycles were performed with this modified schedule: docetaxel days 1, 8 and 15 every 29 days. All pts received at least the first cycle (6 weeks). A total of 261 doses were delivered. No toxic deaths occurred. The toxicity was mild: we recorded 1 episode of grade 3neutropenia and severe asthenia in only 2 pts (10%). We recorded an overall response rate of 33% (1 CR, 6 PR). Our data showed a reduced incidence of severe asthenia (2/21), obtained with a light modification of a weekly docetaxel schedule.

Biweekly administration of gemcitabine and vinorelbine as first line therapy in elderly advanced breast cancer

Gemcitabine and Vinorelbine both as a single agent or associated are active in advanced breast cancer patients as second line therapy, with low toxicity. In the elderly patients polichemotherapy is difficult for co-morbidity, but results with monotherapy are fewer. The use of this association as first line could be of help. Thirty-four patients over 65 were treated with 1000 mg/m2 of gemcitabine and 25 mg/m2 of vinorelbine on days 1 and 8 every 21 days. An analysis of toxicities, TTP and OS were performed. The ORR was 53%: a CR was obtained in five patients (15%) and a PR in 13 patients (38%). Moreover, seven patients (21%) had a stable disease maintained for 6 months. The mean duration of CR and PR were, respectively, of 10 (range 7-19) and 7 (range: 4-14), months. Toxicity was low, mainly haematological: grade 3-4 neutropenia occurred only in 7 (20%) cases without febrile neutropenia. The gemcitabine and vinorelbine combination shows significant activity in elderly metastatic breast cancer patients. The treatment is well tolerated and has an acceptable toxicity profile.

Phase III randomised trial of doxorubicin (A) and docetaxel (D) versus A and cyclophosphamide (C) as primary medical therapy (PMT) in women with breast cancer

521 Background: Use of PMT as pre-operative therapy for large primary, or locally advanced inoperable, breast cancer (BC)is increasing. Such regimens usually contain A,in combination with C (AC). D is among the most active single agents in metastatic BC and is increasingly used with A in advanced BC. Methods: Patients suitable for PMT (n=363) were randomised to receive up to 6 cycles of either (a) A (50mg/m2) and D (75mg/m2) i/v every 3 weeks, or (b) A (60mg/m2) and C (600mg/m2) i/v every 3 weeks. Patients with operable disease after completing chemotherapy had surgery followed by radiotherapy if indicated, and tamoxifen if ER+. We compared the response rates (clinical and pathological), relapse-free survival (RFS) after subsequent surgery, and overall survival (OS) of patients treated with AC and AD as PMT. Results: Patients with locally advanced inoperable (8%), inflammatory (15%) or large, operable (77%) primary BC, and with no evidence of metastatic disease, were randomised to AC (n=180) or AD (n=183). Clinical response rates (CR+PR) were 61% and 71% for AC and AD respectively (p=0.06). 7 patients treated with AC (4%) and 8 with AD (4%) received less than the planned 6 cycles of chemotherapy due to disease progression, with 14 patients (AC=8, AD=6) withdrawn early due to toxicity despite dose modifications. Pathological involvement of axillary LNs was present at surgery in 61% treated with AC and 66% with AD (p=0.28). Pathological CR rates for AC and AD were 24% and 21% respectively (p=0.61). No significant difference exists yet between the 2 groups for number of relapses. The median RFS and OS have not yet been reached with a median follow-up of 32 months. Conclusions: Both AC and AD are tolerated as PMT in primary BC. There is a trend to a superior clinical response rate with AD compared to AC, which does not reach statistical significance. There is no evidence of differences in the pathological CR rates or axillary LN involvement. In contrast to the positive results reported for sequential D following AC as PMT, our data do not suggest a benefit for simultaneous AD over AC. Updated analyses will be presented at conference. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

Phase III randomised trial of doxorubicin (A) and docetaxel (D) versus A and cyclophosphamide (C) as primary medical therapy (PMT) in women with breast cancer

521 Background: Use of PMT as pre-operative therapy for large primary, or locally advanced inoperable, breast cancer (BC)is increasing. Such regimens usually contain A,in combination with C (AC). D is among the most active single agents in metastatic BC and is increasingly used with A in advanced BC. Methods: Patients suitable for PMT (n=363) were randomised to receive up to 6 cycles of either (a) A (50mg/m2) and D (75mg/m2) i/v every 3 weeks, or (b) A (60mg/m2) and C (600mg/m2) i/v every 3 weeks. Patients with operable disease after completing chemotherapy had surgery followed by radiotherapy if indicated, and tamoxifen if ER+. We compared the response rates (clinical and pathological), relapse-free survival (RFS) after subsequent surgery, and overall survival (OS) of patients treated with AC and AD as PMT. Results: Patients with locally advanced inoperable (8%), inflammatory (15%) or large, operable (77%) primary BC, and with no evidence of metastatic disease, were randomised to AC (n=180) or AD (n=183). Clinical response rates (CR+PR) were 61% and 71% for AC and AD respectively (p=0.06). 7 patients treated with AC (4%) and 8 with AD (4%) received less than the planned 6 cycles of chemotherapy due to disease progression, with 14 patients (AC=8, AD=6) withdrawn early due to toxicity despite dose modifications. Pathological involvement of axillary LNs was present at surgery in 61% treated with AC and 66% with AD (p=0.28). Pathological CR rates for AC and AD were 24% and 21% respectively (p=0.61). No significant difference exists yet between the 2 groups for number of relapses. The median RFS and OS have not yet been reached with a median follow-up of 32 months. Conclusions: Both AC and AD are tolerated as PMT in primary BC. There is a trend to a superior clinical response rate with AD compared to AC, which does not reach statistical significance. There is no evidence of differences in the pathological CR rates or axillary LN involvement. In contrast to the positive results reported for sequential D following AC as PMT, our data do not suggest a benefit for simultaneous AD over AC. Updated analyses will be presented at conference. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines

The various treatments for advanced gastric cancer have limitations and induce only marginal survival benefit. HER-2/ neu protein is overexpressed in several types of human cancers and its amplification is associated with poor prognosis. Recombinant humanized anti-HER-2/ neu antibody (trastuzumab) not only inhibits the proliferation of HER-2/ neu overexpressing tumor cells but also augments the cytotoxicity of concomitant chemotherapeutic agents in metastatic breast cancer. In this study, we evaluated the growth inhibitory effects of trastuzumab in gastric cancer cells. HER-2/ neu protein was evaluated by immunohistochemical analysis in seven gastric cancer cell lines. MTT assay was performed to evaluate the growth inhibitory effects of trastuzumab and three chemotherapeutic agents, doxorubicin, cisplatin and paclitaxel, both alone and in combinations. The changes of cell cycle after trastuzumab treatment were analyzed by flow cytometry. Four of the cell lines, YCC-2 with strong positivity of HER-2/ neu expression, NCI-N87 with moderate positivity, YCC-3 with weak positivity, and SK-BR-3 as a positive control, were selected. After in vitro MTT assay for 1-day and 5 consecutive days' treatment of trastuzumab at various concentrations, growth inhibition was not observed in any cancer cell lines. However, there was variable dose-dependent sensitivity to doxorubicin, cisplatin and paclitaxel. YCC-2 and SK-BR-3 cancer cells were more sensitive to three chemotherapeutic drugs, constantly ( P<0.05). The combination of 5 consecutive days' treatment of trastuzumab with 1-day doxorubicin treatment showed significant growth inhibition only in YCC-2 and NCI-N87 gastric cancer cells. After 1-day trastuzumab treatment, the S-phase fraction was decreased by 52 and 70% in YCC-2 and SK-BR-3, respectively. In conclusion, the expressions of HER-2/ neu protein in gastric cancer cells are variable, and concomitant treatments of trastuzumab with doxorubicin increase cytotoxicity. This suggests that trastuzumab-based biologic therapy with chemotherapeutic agents can be applied in gastric cancer treatment.

371 In vivo-chemosensitivity adapted primary chemotherapy in patients with primary breast cancer. First results of the Gepartrio-Pilot trial

The rationale for the combined use of docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ) and trastuzumab (Herceptin; Genentech, South San Francisco, CA) in HER2/neu-overexpressing breast cancer patients are several-fold. Docetaxel is a highly active chemotherapeutic agent in metastatic breast cancer. Response rates, time to progression, and survival are improved when trastuzumab is combined with chemotherapy. Finally, preclinical findings demonstrate synergistic cytotoxic activity when docetaxel and trastuzumab are combined. In addition, their different mechanisms of action and a nonoverlapping toxicity profile suggest the potential for a highly useful combination while minimizing potential cardiotoxicity. An ongoing pilot phase II evaluation is being conducted with every-3-week docetaxel plus weekly trastuzumab. Preliminary findings suggest an active and well-tolerated regimen. Efficacy data indicate an encouraging overall major response rate of 45% in first- and second-line metastatic breast cancer patients. Preliminary results from a second phase II trial of weekly docetaxel and trastuzumab have been reported. In 14 patients treated to date, grade 34 toxicities are infrequent. An overall response rate of 54% is reported thus far with 26 cycles (156 weeks) of therapy delivered. The preliminary data for the docetaxel and trastuzumab combinations look favorable from both a safety and an efficacy perspective. The lack of cardiac function changes despite frequent cardiac monitoring is promising. For the adjuvant therapy of HER2/neu-overexpressing breast cancer, the high level of efficacy of docetaxel and the need to identify nonanthracycline agents for combined use with trastuzumab place a high emphasis on the potential utility of docetaxel and trastuzumab-based regimens.

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129

ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group. Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time. Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients. ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.

The Role of Anthracyclines/Anthraquinones in Metastatic Breast Cancer

Anthracyclines are considered to be one of the most active agents in metastatic breast cancer (MBC). At the eqiumolar doses of epirubicin and doxorubicin in MBC there is no difference in either response rates or time to progression but there is a statistically significant reduction in cardiac toxicity and myelosupression. The results received in studies evaluating the role of dose intensity, showed that the increase of dose intensity above the standard dose level (60 mg/m2 for doxorubicin and 90 mg/m2 for epidoxorubicin) in MBC, does not significantly improve outcome and should not be used outside clinical trials. There is no strong evidence that patients with MBC could benefit from aggressive polychemotherapy compared with single-agent treatment with anthracyclines or mitoxantrone. There is statistically significant data that longer treatment improves the duration of responses and the TTP but not an overall survival except in one study. Generally, the toxicities increased with the duration of treatment. The overall efficacy of mitoxantrone appears to be slightly lower than for either doxorubicin or epirubicin whether compared as single agents or in combination with other drugs. This observation has not been made consistently in all trials. The risk of hematologic and cardiotoxic side effects appears to be less common for mitoxantrone than for doxorubicin and epirubicin. The choice of chemotherapy for MBC should be based on tolerability, quality of life, prior treatments, and the patient's own opinion. The possibility of participating to the clinical studies has to be given to the very well-informed patients.

Commentary on “Platinum Compounds in the Treatment of Advanced Breast Cancer”

In this issue of Clinical Breast Cancer, Dr. Martin reviewed the results of studies reporting on the efficacy of platinum compounds in the treatment of advanced breast cancer.1 The clinical data reported to date indicate that both cisplatin and carboplatin have considerable activity as single agents in metastatic breast cancer when used as first-line therapy. Response rates range from 42%-54% for cisplatin and 16%-35% for carboplatin, depending on the dose and whether patients had received prior adjuvant therapy. Importantly, a number of small phase II studies in which many patients had received extensive prior chemotherapy demonstrated low response rates to cisplatin or carboplatin as single agents (8.5% and 6%, respectively), thereby prompting investigators to conclude that platinum salts had no significant activity in advanced breast cancer. The data presented, however, suggest that in appropriately selected patients without extensive chemotherapy pretreatment, platinum salts achieve levels of efficacy comparable to other therapeutic agents such as vinorelbine,2 paclitaxel, or doxorubicin3 when given as a single agent in first-line therapy for advanced breast cancer. As the current review highlights, higher activity has been reported for cisplatin as first- and second-line therapy of metastatic breast cancer, when combined with either etoposide (25%-58%), vinorelbine (25%-74%), 5-fluorouracil (29%-61%), or gemcitabine (29%-50%). Somewhat lower response rates were reported for carboplatin in combination with etoposide (22%-42%), vinorelbine (46%), or 5-fluororuracil (9%21%). Retrospective comparison of these response rates with those reported for any of the above-mentioned single agents suggests that both cisplatin and carboplatin do contribute to the overall activity of these combination regimens. As shown by Dr. Martin, high response rates have been reported in first-line therapy of metastatic breast cancer for combinations of cisplatin with paclitaxel or docetaxel, with response rates ranging between 23%90% and 34%-60%, respectively.1 Similarly, the use of carboplatin in combination with paclitaxel or docetaxel resulted in high response rates ranging between 43%-76% and 40%-60%, respectively. The combination of platinum salts with taxanes for the treatment of patients with advanced breast cancer is not only attractive because of the single-agent activity of these agents, but also because their major toxicity profiles do not overlap.4 Recently, trastuzumab, a novel humanized monoclonal antibody directed against the epithelial growth factor receptor HER2/neu, has been reported to have powerful synergistic interactions with platinum agents and docetaxel. These findings have prompted evaluation of the triplet docetaxel/platinum salt/trastuzumab in the therapy of metastatic breast cancer.5-7 Moreover, concomitant therapy of trastuzumab with doxorubicin is associated with significant cardiotoxicity. Class I-IV of cardiac dysfunction, as defined by the New York Heart Association (NYHA), occurred in 38 of 143 patients (27%) receiving trastuzumab plus doxorubicin/cyclophosphamide (AC) versus 6% receiving AC alone. The incidence of NYHA class III/IV cardiac dysfunction was highest among patients receiving trastuzumab plus AC, with a 16% versus 3% incidence in those receiving AC alone.8 Future studies will therefore require careful design to avoid the cardiotoxicity issues associated with use of trastuzumab/anthracycline administration. With recognition of the cardiotoxicity potential, nonanthracycline chemotherapy/trastuzumab regimens consisting of docetaxel/cisplatin or docetaxel/carboplatin have been proposed.7 Preliminary results of these studies demonstrate high activity of the triplet docetaxel/platinum salt/trastuzumab combination in HER2/neu-positive metastatic breast cancer. Importantly, this approach takes advantage of the observed syner

Comparison of Methods of Measuring HER-2 in Metastatic Breast Cancer Patients Treated With High-Dose Chemotherapy

HER-2 is overexpressed in 20% to 30% of human breast cancer and is associated with poor outcome. Studies suggest an association between HER-2 overexpression and resistance to alkylating agents. To further evaluate this relationship, we assessed the interaction of HER-2, measured by different methods, and outcome after dose intensification with alkylating agents in metastatic breast cancer. From 1988 to 1995 at Duke University, 425 patients with metastatic breast cancer were enrolled in a study of high-dose alkylating agents (HDC) with autologous cellular support after doxorubicin-based therapy (AFM). HER-2 was measured in serum for shed extracellular domain (ECD) and in tissue by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). HER-2 ECD was positive in 29% (19 of 65) of patients pre-AFM and in 11.7% (34 of 290) pre-HDC. Higher pre-AFM and higher pre-HDC HER-2 ECD predicted worse overall survival (P =.045 and P =.0096, respectively). HER-2 overexpression by IHC and FISH showed no correlation with worse disease-free survival or overall survival. FISH and ECD were highly specific for IHC (97.3% and 97.7% respectively). However, ECD had a low sensitivity for IHC-only 22% of patients with HER-2 in the primary tumor shed ECD into the serum. These data suggest that the method of measuring HER-2 is important in predicting clinical outcome. HER2 ECD may identify a poor prognosis subgroup of HER-2-positive tumors. Lack of association of HER2 by IHC/FISH with worse outcome suggests that therapy with AFM and/or HDC therapy may be able to overcome the effect of this prognostic factor or it may not be a prognostic factor in this setting.

Docetaxel (Taxotere) plus trastuzumab (Herceptin) in breast cancer.

The rationale for the combined use of docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ) and trastuzumab (Herceptin; Genentech, South San Francisco, CA) in HER2/neu-overexpressing breast cancer patients are several-fold. Docetaxel is a highly active chemotherapeutic agent in metastatic breast cancer. Response rates, time to progression, and survival are improved when trastuzumab is combined with chemotherapy. Finally, preclinical findings demonstrate synergistic cytotoxic activity when docetaxel and trastuzumab are combined. In addition, their different mechanisms of action and a nonoverlapping toxicity profile suggest the potential for a highly useful combination while minimizing potential cardiotoxicity. An ongoing pilot phase II evaluation is being conducted with every-3-week docetaxel plus weekly trastuzumab. Preliminary findings suggest an active and well-tolerated regimen. Efficacy data indicate an encouraging overall major response rate of 45% in first- and second-line metastatic breast cancer patients. Preliminary results from a second phase II trial of weekly docetaxel and trastuzumab have been reported. In 14 patients treated to date, grade (3/4) toxicities are infrequent. An overall response rate of 54% is reported thus far with 26 cycles (156 weeks) of therapy delivered. The preliminary data for the docetaxel and trastuzumab combinations look favorable from both a safety and an efficacy perspective. The lack of cardiac function changes despite frequent cardiac monitoring is promising. For the adjuvant therapy of HER2/neu-overexpressing breast cancer, the high level of efficacy of docetaxel and the need to identify nonanthracycline agents for combined use with trastuzumab place a high emphasis on the potential utility of docetaxel and trastuzumab-based regimens.