Trials In Metastatic Breast Cancer Research Articles

High-dose chemotherapy with autologous stem-cell support versus standard-dose chemotherapy: meta-analysis of individual patient data from 6 randomized metastatic breast cancer trials.

Abstract Abstract #6113 Background: The role of high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation for metastatic breast cancer has not been well defined. The statistical power of the available trials has limited precision for determining whether HDC has any benefit for this indication, or for any subset of patients.
 Methods: Individual patient data from the 6 known randomized trials were merged into a single database. The primary endpoint was overall survival (OS): time from randomization to death. The secondary endpoint was progression-free survival (PFS). Cox proportional hazards regression compared the effect of HDC vs standard-dose chemotherapy (SDC) on PFS and OS adjusted for age, trial and hormone receptor (HmR) status (positive if either estrogen (ER) or progesterone (PgR) receptor positive), and other variables. Among the subset analyses considered were by age, HmR status, number metastatic sites, and soft tissue metastases.
 Results: A total of 846 patients (433 HDC, 413 SDC) had median follow-up of 1.9 years. Median age was 47 years (range 23 to 65). Preliminary analyses show that after adjusting for age and trial, HDC significantly prolonged OS (hazard ratio (HR) 0.86; 95%CI 0.73-1.00; p=0.05) and PFS (HR 0.73; 95%CI 0.63-0.84; p<0.0001). Mean improvement (out to 8 yrs) was 4 months for both OS and PFS. Both age (p=0.023) and soft tissue disease (p=0.0025) had statistically significant interactions with treatment for OS, but neither remain significant after adjusting for multiple comparisons.
 Conclusions: HDC may have a modest benefit on OS that may be greater in patients younger than 50 years. However, we were not able to draw firm conclusions about age or other subset analyses.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6113.

Final results of a first line multicenter phase II metastatic breast cancer trial of vinflunine monotherapy and in combination with trastuzumab in HER2+ patients.

Abstract Abstract #3148 Background: Vinflunine (VFL) is a novel microtubule inhibitor agent of the vinca alkaloid class that inhibits tubulin polymerization without stabilization, resulting in cell cycle arrest in mitosis and apoptosis. Weak tubulin binding at the vinca-binding site accounts for its reduced neurotoxicity. VFL has demonstrated activity in anthracycline and taxane pretreated patients (pts) and in combination with capecitabine. This trial evaluates the activity and safety of VFL monotherapy and in combination with trastuzumab (T) in HER2+ pts as 1st line therapy metastatic breast cancer (MBC).
 Methods: Eligibility: 0 prior regimens for MBC, > 6 mo from adjuvant therapy, RECIST criteria measurable disease, ECOG PS 0-2, adequate organ function, peripheral neuropathy < G2. Treatment: HER2 unspecified: VFL 320 mg/m2 IV q3 wks; FISH HER2+ pts: VFL 280 mg/m2 plus T 6 mg/kg q3 wks. Response evaluations q9 wks; treatment continued until disease progression or toxicity.
 Results: Due to termination of VFL licensing between BMS and Pierre Fabre Medicament, the study closed prematurely with only 31 evaluable pts of a planned 48 pts in each treatment arm of VFL monotherapy or VFL in combination with T. 10 pts received VFL and 21 pts were treated with VFL + T. Median age: 59 yrs (35-78). ECOG PS 0-18 pts, 1-11 pts, 2-2 pts. 48% were ER+. Prior adjuvant anthracyclines and taxanes noted in 17 and 19 pts respectively. 4 pts presented with de novo stage IV disease, all HER2 positive. 45% had 3 or more metastatic disease sites with bone (17 pts), liver (16 pts) and lung (15 pts) predominating. Median of # cycles: 4 (range 1-19). There were 10 PRs (32%), all in VFL + T, and 9 pts (29%) with PD (VFL-4 pts, VFL + T-5pts). SD was reported in 10 pts (32%). 2 pts (7%) were unevaluable, divided equally between the two arms. G3/4 neutropenia occurred in 11 pts (35%); none with fever. G3 nonhematologic toxicity consisted of pain, attributed to treatment in 5 pts (16%) (sites: abdomen-2, chest, back, and infusion site each in 1 pt), and GI toxicity characterized by N/V 3 pts (10%) as well as abdominal pain, diarrhea, constipation, occurring each in 2 pts (6%). There were no G4 events. 10 pts were hospitalized (GI -4 pts, pain 2 pts, pulmonary 2 pts, and other 2 pts). Median PFS was 3.5 months for VFL and 6.6 months for VFL + T. Median overall survival was 9 months for VFL and has not been reached for VFL + T.
 Conclusions: The combination of vinflunine and trastuzumab is active in the first line treatment of MBC, producing a 48% response rate. Adverse events were as expected, manageable and consisted primarily of neutropenia, pain and GI toxicity. This encouraging activity compares favorably with other trastuzumab combination regimens and merits further evaluation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3148.

Preferential Killing of Breast Tumor Initiating Cells by N,N-Diethyl-2-[4-(Phenylmethyl)Phenoxy]Ethanamine/Tesmilifene

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is thought to potentiate the antineoplastic effect of cytotoxic drugs. In a phase III randomized trial for metastatic breast cancer using doxorubicin with or without DPPE, addition of the latter resulted in a significant improvement in overall survival and a trend toward a difference in progression-free survival but, paradoxically, no difference in objective tumor response. Here we tested the hypothesis that DPPE targets breast tumor-initiating cells (TICs). Human breast TICs from pleural effusions were identified as CD44(+):CD24(-/low) cells by flow cytometry and functionally by their ability to form nonadherent spheres in culture. Mouse mammary TICs from two different models of breast cancer were identified as cells capable of initiating spheres in culture and secondary tumors following transplantation into the mammary gland of syngeneic mice. We show that at physiologically attainable concentrations, treatment with DPPE alone reduced tumorsphere formation and viability of CD44(+):CD24(-/low) breast cancer cells. The kinetics of killing varied for the different breast tumor cells and required continuous exposure to the drug. Whereas doxorubicin killed CD44(+):CD24(-/low) and CD44(-):CD24(+) cells equally well, DPPE induced apoptosis preferentially in CD44(+):CD24(-/low) cells. Treatment of Her2/Neu(+) mammary tumor cells with DPPE in vitro efficiently killed TICs, as determined by flow cytometry and transplantation assays; DPPE further cooperated with doxorubicin to completely eradicate tumorigenic cells. Our results show that continuous treatment with DPPE alone directly targets breast TICs, and provide rationale to test for cooperation between DPPE and known drugs with efficacy toward breast cancer subtypes.

Elevated plasma endoglin (CD105) predicts decreased response and survival in a metastatic breast cancer trial of hormone therapy

Background Endoglin (CD105) is a co-receptor for TGF-beta, is expressed by human vascular endothelial cells, and plays a major role in angiogenesis. Materials and methods Pretreatment EDTA plasma from 224 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial and 50 control subjects were assayed for endoglin using an ELISA. Results The female control group (n = 50) plasma endoglin upper limit of normal was defined as the mean + 2 SD (8.7 ng/ml). The breast cancer patient plasma endoglin was 6.40 +/- 2.23 ng/ml (range 3.00-19.79 ng/ml). Elevated plasma endoglin levels were detected in 26 of 224 patients (11.6%). Patients with elevated plasma endoglin had a reduced clinical benefit rate (CR + PR + Stable) (15 vs. 42%) (P = 0.01) to hormone therapy. TTP was shorter for patients with elevated plasma endoglin, but did not reach statistical significance (P = 0.2). Patients with elevated plasma endoglin had decreased overall survival (median 645 vs. 947 days) (P = 0.005). Conclusion Elevated pretreatment plasma endoglin levels predicted for decreased clinical benefit and a shorter overall survival in metastatic breast cancer patients treated with 2nd-line hormone therapy.

Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer

The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R2=0.30) with a slope of 0.32 (P<0.001) and a non-significant intercept. Thus, a treatment effect on TTP/PFS translated into a concordant effect on OS, but with attenuated effect size. Similar results were found in models of subsets and sensitivity analyses. These results demonstrate that treatment effects on progression end points in MBC trials are expected to result in treatment differences on OS that are smaller yet consistently in the same direction.

Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+ <PC3 <HT29. In these HER2-positive tumors, nab-paclitaxel was equal to or better than polysorbate-based docetaxel in tumors with medium to high SPARC levels (PC3 and HT29), but not in MDA-MB-231/HER2+ tumors with low SPARC expression. These results demonstrated that the relative efficacy of nab-paclitaxel was significantly higher compared with polysorbate-based docetaxel in HER2-negative tumors (three of three) and in HER2-positive tumors with high levels of SPARC. HER2 and SPARC expression may be useful biomarkers in determining antitumor effectiveness for taxanes.

Correlation of HER2 gene amplification, HER2 and EGFR expression (protein and mRNA) with lapatinib efficacy in women with metastatic breast cancer

1007 Background: Lapatinib (L), an oral small molecule tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine for the treatment of women with HER2+ metastatic breast cancer (MBC). The optimal method to select patients (pts) for L therapy has not been determined. To address this issue, selected biomarkers were analyzed in pts from two randomized phase III MBC trials. Methods: In available BC tissue from EGF30001 pts (paclitaxel ± L in HER2-negative/unknown MBC, N=579) and EGF100151 pts (capecitabine ± L in HER2+ MBC, N=399), HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH), HER2 messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction (RT-PCR), protein expression by HercepTest immunohistochemistry (IHC), EGFR mRNA level by RT-PCR, and EGFR protein by IHC. HER2 and EGFR status was compared with clinical outcome across treatment arms to assess potential marker associations. Results: HER2 was amplified in 47% (345/733) and had IHC3+ immunostaining in 30.6% (224/730), with a significant correlation between HER2 gene and protein status (p<0.01). EGFR immunostaining (IHC 1+, 2+ or 3+) was identified in 27.9% (214/767). Any EGFR IHC correlated with EGFR mRNA levels determined by RT- PCR (R=0.59, p<0.01). HER2 gene amplification/overexpression, but not EGFR expression, was associated with significantly improved time-to-progression, objective response rate, and clinical benefit in separate and pooled analyses of both trials. No similar improvement in outcome was seen in pts with FISH-negative and IHC 1+ or 2+ tumors. mRNA expression for HER2 as performed here does not add value beyond FISH or IHC evaluation, although the mRNA sample set was small (N=138). There was no correlation between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER2 status. Conclusions: Benefit from L in women with HER2+ MBC appears to be limited to patients with positive FISH or IHC3+ intensity. Evaluation of HER2 by mRNA analysis did not improve patient selection in these studies. EGFR determination did not contribute to improved pt selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline Genentech, Inc., GlaxoSmithKline, Roche Genentech, Inc., GlaxoSmithKline

Results of the German IPEP study evaluating the tolerability, efficacy, and acceptance of fulvestrant (Faslodex(r)) under routine clinical conditions in advanced breast cancer

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium due to liganded ER activating target genes in these different types of cell. Several novel anti-estrogen compounds have been developed which have a reduced agonist profile on breast and gynaecological tissues. These compounds offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for two groups of agents: the selective estrogen receptor modulators (SERMs), further divided into ‘tamoxifen-like’ (e.g. toremifene, droloxifene and idoxifene) and ‘fixed ring’ compounds (e.g. raloxifene, arzoxifene and EM-800), and the selective estrogen receptor down-regulators (SERDs; e.g. fulvestrant (ICI 182780), SR 16234 and ZK 191703) also termed ‘pure anti-estrogens’. In phase II trials in tamoxifen-resistant metastatic breast cancer the SERMs show low objective response rates (range 0–15%), suggesting cross resistance with tamoxifen. Randomized phase III trials for toremifene and idoxifene in over 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the ‘fixed ring’ SERMs and it remains unclear whether any clinical advantage exists for the ‘fixed ring’ SERMs over tamoxifen as first-line therapy. The main advantage for SERMs such as tamoxifen and raloxifene probably remains in early-stage disease (adjuvant therapy or prevention).Fulvestrant and the other SERDs have a high affinity for the estrogen receptor (ER) compared to tamoxifen, but none of its agonist activities. Of the SERDs, only fulvestrant has entered the clinic and this new agent is showing promising clinical activity in the treatment of advanced breast cancer. Recently published phase III studies have shown fulvestrant to be at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or progressed on prior endocrine therapy. Surprisingly, however, in a phase III trial versus tamoxifen for the first-line therapy of advanced breast cancer fulvestrant did not attain the requirements for equivalence to tamoxifen, and in terms of time-to-treatment failure was inferior (5.9 versus 7.8 months for fulvestrant and tamoxifen, respectively; P=0.029). Future clinical studies will evaluate fulvestrant in the neoadjuvant setting together with its optimal sequencing in relation to tamoxifen and other endocrine therapies in advanced disease.

Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group.

Trastuzumab has been shown to be an effective therapy for women with breast cancer that overexpresses the human epidermal growth factor receptor 2 (her2) protein. In the pivotal metastatic breast cancer trials, cardiac dysfunction was observed in women treated with trastuzumab and chemotherapy. The incidence and severity of cardiac dysfunction was greatest among patients who received trastuzumab in combination with anthracycline-based therapy. Those findings influenced the design of subsequent trastuzumab trials to include prospective evaluations of cardiac effects and protocols for cardiac monitoring and management. The risk of cardiotoxicity has also driven efforts to develop non-anthracycline-based regimens for women with her2-positive breast cancers.With the increasing use of trastuzumab, particularly in the curative adjuvant setting, the need for a rational approach to the treatment and cardiac management of the relevant patient population is clear. The mandate of the Canadian Trastuzumab Working Group was to formulate recommendations, based on available data, for the assessment and management of cardiac complications during adjuvant trastuzumab therapy. The panel formulated recommendations in four areas: Risk factors for cardiotoxicity, Effects of various regimens, Monitoring, Management. The recommendations published here are expected to evolve as more data become available and experience with trastuzumab in the adjuvant setting grows.

Capecitabine and paclitaxel combination chemotherapy for inoperable or recurrent breast cancer: a phase I dose-finding study by the Kinki Breast Cancer Study Group

The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. Three-weekly XP regimens have demonstrated excellent efficacy in phase II and III trials in metastatic breast cancer. We conducted a dose-finding study to identify the recommended 4-weekly XP regimen in patients with inoperable or recurrent breast cancer for phase II evaluation. Eligible patients had inoperable or recurrent breast cancer previously treated with chemotherapy (but not capecitabine or paclitaxel) in the (neo)adjuvant or metastatic setting. Each 4-week treatment cycle consisted of escalating doses of capecitabine (628 or 829 mg/m(2) twice daily [b.i.d.] on days 1-21) and paclitaxel (80 or 90 mg/m(2) on days 1, 8, and 15). Dose-limiting toxicities (DLT) were evaluated during the first two cycles. Nine patients were treated. At dose level 1 (capecitabine 628 mg/m(2) b.i.d. plus paclitaxel 80 mg/m(2)), one patient experienced a DLT (grade 3 non-hematologic toxicity). There were no further DLTs at dose level 1 or 2. Although the MTD was not reached, dose level 2 (capecitabine 829 mg/m(2) b.i.d., days 1-21, plus paclitaxel 80 mg/m(2), days 1, 8, and 15, every 28 days) is recommended for phase II evaluation, taking into consideration the single-agent doses used in Japan and the doses identified in Western studies of 3-weekly XP. The overall response rate was 44%; all patients treated at dose level 2 achieved a partial response. This 4-weekly XP regimen was well tolerated, active in patients with pretreated advanced breast cancer, and could be given as outpatient treatment. These results are consistent with findings of phase II and III trials evaluating 3-weekly regimens, and indicate that further investigation of a 4-weekly XP regimen is warranted.

Multiple uses for a clinical research database

17037 Background: In Sept 2000, the research staff at The Center for Cancer Care and Research (TCCCR) developed an excel data base to track new consults referred to the practice. It is used to identify pts for participation in Cooperative Group Clinical Trials and to identify gaps in the active protocol list. Several additional uses for the data base have evolved. Methods: Medical records provided by referring physicians for each new consult are evaluated by a Research Coordinator. Information including the pt's name, date of visit, physician, referring physician, diagnosis, protocol for which the pt is evaluated, and eligibility information is entered in the data base. Results: The data base provides a method by which we can follow pts through the protocol selection and informed consent process. Early on, the data base identified a site need for trials in metastatic breast cancer prompting us to search other sources such as the CTSU and industry. Additionally, the percentage of new consults actually enrolled on a clinical trial can be determined as well as tracking eligibility/ineligibility trends. The Pharmaceutical Research Dept can use the information to complete feasibility studies prior to participating in industry trials. The data base can be used to evaluate trends in referral patterns and has helped identify referring physicians who support our research efforts. In 2006, TCCCR had a protocol available for 45% of new consults with a cancer dx. Of those pts, 16% enrolled on a Cooperative Group Clinical Trial. According to published evaluations, 16% is well above the national average of pts who participate in oncology clinical trials. It is our assessment that TCCCR's success is due in part to the data base. Conclusions: It is well known that in order to improve treatment outcomes and diminish treatment toxicity, oncology practices and pts must participate in clinical research. It is also well known that the numbers of pts who participate in oncology clinical trials is dismal. This data base has become a valuable tool providing a method to identify and evaluate some of the reasons why pts do not enroll in clinical trials and given our practice guidance to increase pt participation. Our next goal is to evaluate the differences between the rural and urban population at TCCCR's two sites to identify additional trends in clinical trial participation. No significant financial relationships to disclose.

Gemcitabine plus paclitaxel and gemcitabine plus docetaxel in first- or second-line metastatic breast cancer: A phase II randomized trial

1046 Background: The combination of gemcitabine (G) with paclitaxel (P) has proven efficacy in the first-line treatment of metastatic breast cancer (MBC). In addition, the combination of G with docetaxel (D) has shown activity in several nonrandomized, Phase II, MBC trials. This randomized Phase II trial was conducted to assess the efficacy and safety of G plus P and G plus D combination regimens in previously treated patients with MBC. Methods: Patients with locally advanced or metastatic breast cancer were randomized equally into two groups to receive either GP (G 1,250 mg/m2 IV on Days 1 and 8 plus P 175 mg/m2 IV on Day 1) or GD (G 1,000 mg/m2 IV on Days 1 and 8 plus D 75 mg/m2 IV on Day 1). Treatment was administered every 21 days and continued until disease progression or undue toxicity. Planned enrollment was 112 patients (56 per group). The primary study objective was tumor response assessed using RECIST criteria. Toxicities were assessed using the NCI Common Toxicity Criteria, Version 2.0. Results: Twenty-five patients were enrolled in each treatment group and accrual was stopped due to slow enrollment. In the GP group, only 23 patients were evaluable for response and 24 patients were monitored for safety. One patient did not receive study medication and was not assessed for efficacy or safety. A second patient was determined to have nonmeasurable disease at baseline and was not assessed for response. Overall response rate was 39% (95% CI 20, 61) for the GP group and 40% (95% CI 21, 61) for the GD group. The median number of cycles administered was 6.5 in the GP group and 6.0 in the GD group. Detailed study results are summarized in the table below. Conclusions: These results show that GP and GD combination regimens are both efficacious in the treatment of MBC, with similar response rates and manageable toxicity profiles. [Table: see text] No significant financial relationships to disclose.

BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC)

LBA1008 Background: Based on preclinical synergism between docetaxel (T), carboplatin (C) and trastuzumab (H), BCIRG conducted a phase III trial in HER2-positive MBC to evaluate efficacy and safety of H in combination with T or TC. Methods: 263 patients (pts) with HER2 FISH+ MBC were randomized to TH (H with T 100mg/m2) or TCH (H with T 75mg/m2 and C AUC=6). Chemotherapy was given every 3 weeks (q3w) for 8 cycles with weekly H at 2mg/kg (loading dose of 4 mg/kg) followed by H q3w at 6 mg/kg until progression. Pts were stratified by centre and prior (neo) adjuvant taxane chemotherapy. Primary endpoint was Time To disease Progression (TTP). Secondary endpoints include overall survival, response rate, duration of response (DR), clinical benefit (CB) and safety. Results: 131 pts were treated in each arm Pt characteristics were well balanced in both groups. A first efficacy analysis was conducted at 204 events. There was no significant difference between TH and TCH in median TTP (11.1 vs 10.4 mos, p=0.57), ORR (73% in both arms), DR (10.7 vs 9.4 mos) and CB (67% in both arms). At 39 months of median follow-up, median overall survival was 36.40 and 36.57 months in TH and TCH arms respectively. More patients on TCH received the max number of chemotherapy cycles, and numerically fewer patients on TCH discontinued treatment as a result of non hematological toxicity. The most common gr 3/4 toxicities were: Neutropenic infection that was 16.8% vs 9.2% respectively for TH and TCH, thrombocytopenia (2% vs 15%), asthenia (5% vs 12%), anemia (5% vs 11%), and diarrhea (2% vs 10%). Two pts died (1.5%) due to sepsis in TCH. Absolute LVEF decline &gt; 15 % were seen in 5.5 % vs 6.7 % of pts. One pt (0.8%) had a symptomatic CHF in TH arm. Conclusion: Both TH (T 100) and TCH (T 75) were highly effective treatment regimens in women having HER2-positive MBC, demonstrating high response rates, median TTP &gt; 10 months, and median overall survival &gt; 36 months in both TH and TCH. Cardiac toxicity was no significant problem with either treatment. [Table: see text]

BS04 TRASTUZUMAB (HERCEPTIN): REVIEW OF ADJUVANT TRIALS IN EARLY BREAST CANCER

Trastuzumab (Herceptin) is a humanized, monoclonal antibody to the Her2 neu receptor which is over‐expressed in approximately 15 to 20% of patients with breast cancer. The presence of this growth factor gene over‐expression is associated with more aggressive disease. The pivotal trials in metastatic breast cancer in the late 1990s demonstrated that Herceptin combined with chemotherapy produced significantly higher response rates, improved time to progression and superior overall survival compared to chemotherapy alone. There have been five clinical trials conducted to evaluate the effectiveness of Herceptin when used in combination with chemotherapy in women with early breast cancer. For the four larger trials, more than 13,000 women were essentially randomly assigned to either standard chemotherapy alone or the same chemotherapy plus Herceptin for one or two years. A small Finnish trial of 232 women, evaluated 9 weeks of Herceptin given with chemotherapy. Each trial confirmed a statistically improved disease‐free survival with a 42% to 50% reduction in the risk of relapse. In the four larger trials, a statistically significant overall survival benefit with a 33% to 41% reduction in the risk of death was seen. The only significant side effect associated with the inclusion of Herceptin was a higher incidence of cardiac dysfunction. This ranged from 1.7% to 4.1% in those patients receiving Herceptin, compared to &lt;1% in the control group.

A Clinical Phase II Study of a Non-Anthracycline Sequential Combination of Cisplatin-Vinorelbine Followed by Docetaxel as First-Line Treatment in Metastatic Breast Cancer

Background: We tested a sequential combination regimen using cisplatin and vinorelbine (PVn) followed by docetaxel as first-line chemotherapy in a phase II clinical trial in metastatic breast cancer (MBC). Patients and Methods: Thirty-five patients were enrolled. Cisplatin 80 mg/m² was given on day 1 and vinorelbine 30 mg/m² on days 1 and 8 every 3 weeks for 4 cycles. Responding patients received docetaxel 75 mg/m² every 21 days for a maximum of 4 cycles. Three patients were excluded from analysis because of death unrelated to treatment. Results: After a median follow-up of 14 months, 32 patients completed the study. The overall response rate was 53.1%. Complete remission was seen in 5 patients (15.6%), partial response in 12 (37.5%), stable disease in 6 (18.75%), and progressive disease in 9 patients (28.1%). Median time to disease progression was 8 months (range 1–24). At 24 months, 12 (37.5%) patients were alive. A total of 183 cycles were administered. Febrile neutropenia was observed in 4 patients (2.2%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and grade III vomiting in 31/183 cycles (16.9%). Discussion: PVn is a feasible non-anthracycline option as first-line chemotherapy in patients with metastatic breast cancer and has acceptable toxicity. The sequential addition of 4 cycles of docetaxel following 4 cycles of PVn did not improve the overall response rate and results.

A Phase II Trial of Docetaxel Plus Capecitabine in Patients with Previously Treated Non-Small Cell Lung Cancer

A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m(2) i.v. on days 1 and 8 plus X 1000 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level I) or T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level II). A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle.

Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-alpha (ERalpha) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERalpha as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

Capecitabine plus docetaxel (XT): A first line, phase II clinical trial in metastatic breast cancer

10624 Background: The XT combination originally published at (X) dosed at 1250 mg/m2 bid po x 14 days and (T) at 75 mg/m2 q3 weeks I.V. respectively yielded good response rates and an overall survival advantage compared with single agent docetaxel at 100 mg/m2. However, the toxicity profile of this regimen has led to major dose and schedule modifications by most oncologists. Methods/Results: We initiated a Phase II trial at doses of X at 900 mg/m2 bid po x 14 days and T at 36 mg/m2 d 1 and 8. Three responded and the mean no. of cycles for these patients was 3.8. Since four of 6 went off study because of toxicity two additional dose levels were studied in 6 patients each. A second cohort received X at 650 mg/m2 bid and T at 30 mg/m2. With 6 evaluable patients, four of 6 responded but all 4 required further dose reductions. Mean no. of cycles received was 4.2. A third cohort of 6 patients received X at 825 mg/m2 plus the lower T at 30mg/m2 who received a mean no. of cycles of 6. While only 1/6 responded 3 additional patients had stable disease with marked decreases in CEA or CA 15–3 suggestive of anti-tumor response. Only 1/6 required a dose reduction. Among the 18 patients, epiphora was described by 5 (28%). Only 3 patients developed significant leukopenia, and thrombocytopenia was not seen. T-induced nail changes were uncommon but were severe in one patient. Two patients at the first dose level, but only one at lower levels developed mucositis. Grade 1 anemia was common but managed easily with growth factor support. Conclusions: The response rate of 44% is encouraging with these lower doses of XT. We recommend further studies using X at 825 mg/m2 and T at 30mg/m2 since these doses were associated with encouraging response rate and a better toxicity profile than higher doses. Even at this higher dose of X dose reductions may well be needed. (Supported by a grant from Roche Laboratories, Inc.) No significant financial relationships to disclose.

SWOG 0338: A phase II trial of imatinib mesylate in combination with capecitabine in metastatic breast cancer

10529 Background: Imatinib mesylate targets c-kit and platelet derived growth factor receptor (PDGFR) tyrosine kinases, and both are variably expressed in breast cancer. Inhibition of PDGFR by imatinib mesylate may decrease tumor interstitial pressure and improve delivery of chemotherapy. Based on preclinical synergy, SWOG conducted a phase II trial in metastatic breast cancer. Methods: Patients were eligible if they had adenocarcinoma of the breast that had progressed on at least 1 but ≤ 2 prior chemotherapy regimens for metastatic disease. No prior 5-FU or capecitabine for metastatic disease was allowed. Patients had to be &gt; 18 years with a Zubrod performance status ≤ 2 and have adequate organ function. Patients with brain metastases were ineligible. Patients received imatinib mesylate 400 mg orally daily and capecitabine 1000 mg/m2 orally twice daily on days 1–14 of a 21-day cycle. If tolerated, the imatinib mesylate was increased to 600 mg daily in subsequent cycles. This was a 2-stage design with 25 patients with measurable disease accrued in the first stage. A total of 70 patients was planned, including those with nonmeasurable disease, if accrual proceeded to the second stage. The primary endpoint was to determine the confirmed response rate (RR) to the combination therapy. Secondary endpoints were to estimate the 6-month progression free survival, to determine the toxicities, and to explore c-kit and PDGFR in this population. Results: 27 patients were accrued; 6 were ineligible. 19 patients received therapy and were evaluable for toxicity. The median age was 59 years (36–78). Four responses were seen: 1 complete, 1 confirmed partial, and 2 unconfirmed partial (RR 21%). The 6-month progression free survival was 16%. There were no grade 4 toxicities. The most common grade 3 toxicities, seen in 7 patients, were diarrhea, fatigue, and hand-foot syndrome. As 2 of the 4 responses were unconfirmed, accrual did not proceed to the second stage. Conclusions: The combination of imatinib mesylate and capecitabine was well tolerated in patients with metastatic breast cancer, but the RR was not better than was seen in a prior study of single agent capecitabine. Correlative studies to explore c-kit, PDGFR, and estrogen receptor expression and response are in progress. No significant financial relationships to disclose.

Objective Response to Chemotherapy As a Potential Surrogate End Point of Survival in Metastatic Breast Cancer Patients

To assess the validity of objective response to chemotherapy as a surrogate end point for survival in metastatic breast cancer. We carried out a meta-analysis on individual data from 2,126 metastatic breast cancer patients who were enrolled onto 10 randomized trials comparing standard versus intensified epirubicin-containing chemotherapy. The intensified chemotherapy was associated with a significantly higher tumor response rate compared with standard chemotherapy (pooled odds ratio for nonresponse, 0.60; 95% CI, 0.51 to 0.72). The intensified regimens also led to better (although not significant) survival (pooled odds ratio, 0.94; 95% CI, 0.86 to 1.04; P = .22). Tumor response was a highly significant predictor of survival (P < .0001). When tumor response was introduced in the Cox model, the hazard ratio in favor of experimental treatment changed from 0.94 to 1.005 (95% CI, 0.91 to 1.11; P = .92), indicating that no residual effect of the experimental treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of intensified epirubicin was a result of the increase in response rate. The median survival time of patients with complete response and partial response was 28.8 months (95% CI, 25.4 to 45.3 months) and 21.3 months (95% CI, 19.2 to 22.4 months), respectively; whereas, the median survival time of patients with no response was 14.6 months (95% CI, 13.9 to 15.4 months). These results support the hypothesis that the achievement of an objective response to chemotherapy in metastatic breast cancer is associated with a true survival benefit. The potential role of objective response as a surrogate end point for survival in chemotherapy trials of metastatic breast cancer warrants further investigation.