HER2 Metastatic Breast Cancer Research Articles

SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC).

510 Background: Mutations in PIK3CA, the gene encoding the p110a subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus antiestrogens. Methods: We conducted a phase Ib trial of letrozole (2.5 mg/d) with the pan-PI3K inhibitor BKM120 in post-menopausal patients (pts) with ER+/HER2 MBC. BKM120 (100 mg/d) was given continuously (Arm A) or intermittently (5 on/2 off days; Arm B). Upon toxicity, BKM120 was reduced to 80 and 60 mg/d. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. FDG-PET was done at baseline and at 2 weeks in all pts in Arm A. Results: Fifty-one pts were accrued; 49 had progressed on an AI previously. Median age was 56 years (range 34-77); 95% had bone and 70% visceral metastases. Toxicities and outcomes are summarized in the table. The only DLT* in Arm A and B were transaminitis and depression, respectively; both at 100 mg. Over 50% of Arm A pts had >25% reduction in their peak SUV at the 2-week FDG-PET. Pts who did not exhibit a metabolic response by FDG-PET progressed rapidly on therapy. Three pts in Arm A had a PI3K mutation; one of them has had stable disease on treatment for >12 months. Conclusions: The combination of letrozole/ BKM120 is safe in pts with AI-refractory ER+/HER2 MBC. Arm B is ongoing and will be updated at the meeting. All tumor biopsies will be analyzed for PI3K pathway alterations. FDG-PET at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition in most patients. Its value in predicting treatment response remains to be determined. [Table: see text] [Table: see text]

Metronomic cyclophosphamide and capecitabine combined with lapatinib in heavily pretreated metastatic breast cancer (MBC) HER2-positive patients.

e11071 Background: Current therapeutic goals for MBC, as an incurable disease, are symptoms and prolonged disease control together with good quality of life. Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. We evaluated the efficacy and tolerability of the combination of anti-angiogenetic activity of metronomic chemotherapy with a tyrosine kinase inhibitor such as lapatinib in heavily pre-treated MBC HER-2 positive patients. Methods: Metastatic breast cancer patients HER-2 positive with CEA or Ca15.3 elevated, measurable disease, prior systemic therapy (chemotherapy and/or hormonal therapy) for advanced disease, ECOG performance status < 1 and life expectancy longer than 3 months. MBC patients were treated with metronomic oral capecitabine (1500 mg daily) and cyclophosphamide (50 mg daily) plus lapatinib (1250 mg daily). The treatment was given until disease progression or unacceptable toxicity. Primary objective was time to progression (TTP) and safety. Results: Tenpatients were included. Median age was 56 years old (range 46-76). Median number of previous chemotherapy lines was 5 (range 2-10). Median time to tumor progression was 4 months (2-7). No complete response was observed. Six out of ten patients (60%) with pre-existing only bone metastases achieved a stable disease and/or partial response and are still on treatment after 6 month of therapy. At the same time 100% of these patients exhibited reduction of serum marker concentrations to normal range. No grade 3-4 toxicity was reported. There was no decline in cardiac function. Hematological and gastro-intestinal toxicity was well tolerated (G1-2). No reduction of dose was needed. Conclusions: The treatment appears to be an effective and less toxic option in heavily pretreated MBC patients. Of note is the observed activity in patients with exclusive bone metastases. Monitoring of CEA and Ca15.3 during the first two months of treatment appears to provide a sensitive and economical means of identifying those patients who are responding to the therapy. Therefore, the combination of lapatinib with metronomic chemotherapy should be explored in advance for osseous MBC.

Assessment of trastuzumab use in adjuvant therapy

BackgroundTrastuzumab is indicated for the treatment of patients overexpressing HER2 in metastatic breast cancer and HER-positive early breast cancer.PurposeThis study aimed to evaluate the use of trastuzumab in an adjuvant...

Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series

Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations.

Cisplatin, gencitabine, and lapatinib in patients with HER2-positive metastatic breast cancer: An experience in routine clinical practice.

e11005 Background: The treatment of metastatic breast cancer HER-2 + is based on the use of chemotherapy plus trastuzumab in the first line and the use of lapatinib and capecitabine after trastuzumab progression. There is little evidence of the use of lapatinib with chemotherapy other than capecitabine. On the other hand, data about the best possible therapy after trastuzumab and lapatinib’s progression is limited, given that seems advisable to keep blocked the HER-2 pathway. Methods: We treated 19 patients diagnosed with metastatic breast cancer that had previously been treated with chemotherapy and trastuzumab and/or lapatinib and capecitabine, with cisplatinum 25 mg/m2 IV days 1 and 8, gemcitabine 1000 mg/m2 IV days 1 and 8 cycles each 21 days more daily oral lapatinib 1000 mg continuously. The primary endpoint was progression-free survival (PFS). Secondary efficacy endpoint was clinical benefit rate, defined as complete response, partial response and stable disease. Results: We administered a median of 5 cycles of treatment with cisplatinum-gemcitabine and lapatinib, range 1-12. Three patients continued treatment in December 2010. The median follow-up is 7 months, range 1-12 months. Patients received a median of 2 previous lines of chemotherapy for metastatic breast cancer, range 1-7, two patients didn't receive trastuzumab due to decreased FEVI and brain metastases disease at the moment of diagnosis, 12 patients recieved lapatinib previously, 6 patients had brain metastases. Median PFS was 4 months, range 1-12 months. CBR 44% (4 partial response and 4 stable disease). Five patients died. There were a total of 14 events of hematologic toxicity G3-4, (6 in one patient), 2 episodes of diarrhea G3-4, 1 event G3-4 of hepatic toxicity, and 1 event of mucositis G3-4. Conclusions: The schedule cisplatin-gemcitabine-lapatinib, 25 mg and 1000 mg/m2 days 1 and 8 every 21 and 1000 mg IV continuous oral, may be a reasonable therapeutic option in patients with metastatic breast cancer HER-2 + previously treated with chemotherapy and trastuzumab plus lapatinib plus capecitabine.

Abstract P6-11-12: A Novel Capecitabine Schedule (7 on — 7 off) Is Feasible with Lapatinib for Patients with HER2-Positive Metastatic Breast Cancer Refractory to Trastuzumab

Abstract Background Capecitabine (C) administered for 14 days followed by a 7 day rest (14—7) in combination with lapatinib (L) improved TTP in patients (pts) with HER2(+) metastatic breast cancer (MBC) that progressed following trastuzumab (T). Our mathematical modeling of C dosing predicted 7 days of therapy followed by 7 days of rest (7—7) to maximize efficacy and minimize drug-related toxicity. In xenograph models, C (7—7) was better tolerated than C (14—7) at higher doses and led to improved survival. We established the maximum tolerated dose of C (7—7) to be 2,000 mg twice daily and have studied C (7—7) in combination with targeted therapies. We now report the results of C (7—7) with L in pts with trastuzumab-refractory HER2(+) MBC. Methods Eligible pts had measurable, HER2(+) MBC with progression following T. HER2(+) is defined as 3+ on IHC or FISH-amplified. Pts had normal LVEF by MUGA, ECOG performance status (PS) ≥2, and <3 chemotherapy regimens (CRx) for MBC (no prior fluoropyrimidine). Therapy was C (2,000 mg orally twice daily, 7—7) with L (1,250 mg orally daily); cycle length was 4 weeks. Pts were evaluated for toxicity every 4 weeks and for LVEF by MUGA every 12 weeks. Response was assessed every 12 weeks. Primary endpoint was response rate (RR). Secondary endpoints included toxicity by NCI CTCv3, stable disease (SD) > 6 months, and progression free survival (PFS). Using a Simon optimal 2-stage design, with alpha 10% and power 90% to discriminate between RR 10% and 25%, 21 pts were planned for the 1st stage. If >2 pts responded, then 29 additional pts were to have been enrolled to 2nd stage. If >7/50 pts responded, C (7—7) with L would be considered worthy of further study. Results As of 6/14/10, 22 pts were enrolled on study with the following characteristics: median (med) age 55 years (42-72), med PS 0 (0-2), ER/PR(+) 12, HER2(+) 22, med LVEF 64% (51-70%). Sites of MBC include viscera 16, brain 3. Prior therapy includes 8 pts with adjuvant anthracycline and taxane exposure, 4 pts with adjuvant T, 18 pts with metastatic T, and a med of 1 CRx for MBC. After a med of 5 cycles (1-16), 18 patients are evaluable for response: 0 CR, 3 PR, 6 SD >6 months, 9 SD <6 months. Med PFS is 36 weeks (95% CI 23-not reached). Four pts are too early for response assessment. Nine pts remain on treatment. One pt experienced grade (gr) 4 treatment-related anemia and had refused supportive erythropoietin. Treatment-related gr 2 or 3 toxicities in >10% of patients include: hand-foot syndrome (gr 3: 5%, gr2: 41%), diarrhea (gr 3: 0%, gr 2: 23%), elevated AST/ALT or bilirubin (gr 3: 0%, gr 2: 18%). There have been no declines in LVEF. Conclusion Due to slower than expected accrual and an anticipated randomized, phase III trial comparing C (7—7) with C (14—7), we closed this study to further accrual. However, our data suggests that C (7—7) with lapatinib is active, well-tolerated, feasible and associated with mild gastrointestinal toxicity in pts with trastuzumab-refractory, HER2(+) MBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-12.

Underuse of Anthracyclines in Women with HER-2+ Advanced Breast Cancer

Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)-2(+) metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi-institutional database containing the treatment history of 450 patients who received at least one trastuzumab-based regimen for HER-2(+) metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline-based therapy after failure with the first trastuzumab-based regimen in eligible patients. Three-hundred twenty-one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab-based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab-based therapy for HER-2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab-refractory disease. A role for these compounds should be redefined in this patient subset.

Phase II Evaluation of a Novel Capecitabine Schedule in Combination with Lapatinib for Patients with HER2-Positive Metastatic Breast Cancer Refractory to Trastuzumab.

Abstract BackgroundCapecitabine (C) administered for 14 days followed by a 7 day rest (14—7) in combination with lapatinib (L) improved TTP in patients with HER2(+) metastatic breast cancer (MBC) that progressed following trastuzumab (T). We applied mathematical methods to C dosing which predicted 7 days of treatment (Tx) followed by 7 days of rest (7—7) to be optimal. In animal models, C(7—7) was better tolerated than C(14—7) at higher doses and led to improved survival. A phase I study in patients (pts) with MBC concluded the MTD of C(7—7) is 2,000mg BID. To optimize the combination of C+L, we are testing C(7—7) + L.MethodsEligible pts have measurable, HER2(+) MBC with progression following trastuzumab. HER2(+)=3+ or FISH-amplified. Pts have normal LVEF by MUGA, ECOG performance status (PS) ≤2 and normal organ function. Prior therapy is limited to <3 chemotherapy (CRx) regimens for MBC; prior fluoropyrimidine is not permitted. Tx = C (2,000mg orally BID, 7—7) plus L (1,250mg orally daily). Cycle length=4 weeks (wks). Pts were evaluated for toxicity every 4 wks, for response every 12 wks and for LVEF by MUGA every 12 wks. Primary endpoint: Response Rate. Secondary endpoints: toxicity by NCI CTCv3, stable disease (SD)>6 months and PFS. Using a Simon optimal 2-stage design, with alpha 10% and power 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the 1st stage. If >2 patients respond, 29 additional pts will be enrolled. If >7/40 pts respond, then C(7—7) + L will be considered worthy of further study.ResultsAs of 5/28/09, 12 pts are enrolled; 6 are evaluable for response. Median (med) age 61 years (41-71), med ECOG PS 0 (0-2), ER/PR(+) 5, HER2(+) 12. Sites of MBC: Viscera 5, Brain 2. Med LVEF 64% (51-71%). Prior Tx: Adjuvant: CRx (7), hormone Tx (3), T (4); MBC: CRx (6), hormone Tx (4), T (8). After a med of 3 cycles (1-8), 6 pts are evaluable for response: CR 0, PR 1, SD>6mo 2, SD<6 mo 3. Five pts are too early for response assessment; 1 pt discontinued Tx during 1st cycle for palliative radiation without documented progression. There were no treatment-related grade 4/5 events or unexpected toxicity. Tx-related Grade (Gr) 2 or 3 toxicity in >10% of pts includes: hand-foot syndrome (Gr 3: 8%, Gr 2: 17%) and diarrhea (Gr 2: 17%). There were no declines in LVEF.ConclusionCapecitabine (7—7) plus lapatinib appears well-tolerated and demonstrates activity in pts with HER2(+) MBC that has progressed following trastuzumab based therapy. Additional efficacy and safety data is expected prior to this meeting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5113.

First-line trastuzumab utilization: Patterns of care and progression in the community setting

e12009 Background: This study describes patterns of care and outcomes in metastatic breast cancer (MBC) patients treated with trastuzumab (T) within the US Oncology network. Methods: This retrospective study utilized data from US Oncology's iKnowMed EMR system. HER-2 (+) MBC patients who initiated a first-line regimen containing T between January 1, 2006 and July 31, 2007, were identified. Patients were divided into three treatment cohorts: A) those who discontinued T prior to disease progression; B) those who continued T following discontinuation of chemotherapy prior to progression; and C) those who received T monotherapy. Patients were followed through October 31, 2008, to measure treatment duration and observe progression (as defined as escalation to second-line therapy). The Kaplan Meier method/log-rank test were used to estimate and compare progression free survival (PFS) across cohorts. Results: We identified 139 patients receiving first-line therapy including T. The median age was 58 years and 84 patients were ER and/or PR (+). The top 5 chemotherapy regimens included T plus: paclitaxel (n = 14); docetaxel (n = 14); vinorelbine (n = 14); carboplatin/paclitaxel (n = 12); carboplatin/docetaxel (n = 7 pts). Twenty-one (15%) patients were in cohort A, 55 (40%) were in cohort B, and 63 (45%) were in cohort C. Overall, the median duration of first-line T use was 281 days (mean = 287; range = 1–862). Following the initiation of first-line therapy, a total of 56 (40%) patients progressed (median follow up = 15 months). Following progression, 22 (39%) patients received second-line regimens containing T. The overall median PFS was 17.4 months (mean = 18.6). Patients in cohort A (n = 15) had significantly shorter PFS versus patients in cohort B/C (median 3.9 and 19.6 months, respectively; p < 0.001). Conclusions: In this observational study within the outpatient community setting, persistent first-line T use for MBC was associated with delayed disease progression. Future research should evaluate the causal relationship of this association. In addition, a more comprehensive evaluation should be conducted of therapies prescribed concomitant to T for patients treated with T “monotherapy.” [Table: see text]

Safety of a novel capecitabine dosing schedule when combined with lapatinib in patients with HER2-positive metastatic breast cancer refractory to trastuzumab

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) <2 and normal organ function. <3 prior chemotherapy (CRx) regimens are permitted. Prior fluoropyrimidine is excluded. Therapy (tx) consists of C (2,000 mg BID, 7 - 7) and L (1,250 mg, daily). Cycle length = 4 wk. Pts are evaluated for toxicity q4 weeks (wk), for response q12wk; LVEF by MUGA q12wk. Primary endpoint: response rate (RR). Secondary endpoints: toxicity, stable disease >6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD<6 mo = 1. Conclusions: Capecitabine (7 - 7) + lapatinib appears well tolerated compared to C(14 - 7)+L (Geyer et al). Additional safety and efficacy data is anticipated prior to this meeting. [Table: see text]

Trastuzumab and Vinorelbine as Highly Effective and Safe Therapy for HER-2-Overexpressing Metastatic Breast Cancer. A Single Institution Experience

Trastuzumab-based therapy has improved survival of women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. From September 2002 to July 2006, 45 women with metastatic breast cancer HER2 3+, or 2+ and positive for HER2 gene amplification, were enrolled in the study and received a combination therapy with vinorelbine, 25 mg/m2 weeks 1 and 2, plus trastuzumab, 4 mg/kg loading dose and then 2 mg/kg weekly, in a three weeks cycle. Eligibility criteria included measurable disease and a baseline ejection fraction > or = 50%. Forty-two percent of the patients were not pretreated, whereas 58% had received a previous chemotherapy regimen for metastatic disease, including anthracyclines and/or taxanes (47%), and trastuzumab plus taxol (11%). We observed 14 (31%) complete responses and 21 (47%) partial responses, with an overall response rate of 78%. Stable disease > 6 months was assessed for 5 (11%) patients with a clinical benefit of 89%. Five (11%) patients progressed. With a median follow-up of 11 months, median time to progression was 9 months and median duration of response was 7.6 months for complete remissions and 4 months for partial remissions. Median survival was 29 months. In spite of a smaller dose intensity of vinorelbine than previously reported, the regimen evaluated was notably effective in terms of response rate, time to progression and survival, with very mild toxicity.

Capecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3–05)

1025 Background: There is uncertainty, if trastuzumab treatment should be continued beyond progression (TBP). Methods: Patients (pts) with HER-2 positive, locally advanced or metastatic breast cancer that progressed during treatment with trastuzumab with or without adjuvant and/or 1st-line metastatic chemotherapy were prospectively randomized to capecitabine (X; 2,500 mg/m² on days 1–14, q21) or X plus continuation of trastuzumab (XH; 6 mg/kg, q3w). The primary end point was TTP. With registration of lapatinib, the slowly accruing trial was closed prematurely. Results: Between 01/04 and 05/07 156 pts (X=78; XH=78) were randomized and stratified according to pre-treatment: taxane/trastuzumab as 1st-line therapy (111 pts), taxanes/trastuzumab as adjuvant therapy (3 pts), trastuzumab alone or without taxanes as 1st-line treatment (42 pts). 75 (48.1%) pts were pre-treated with anthracyclines. 119 (76.3%) showed visceral metastasis. Current analysis (median follow-up 11.8 months) revealed a progression-free survival of 5.6 months with 53 events for X and 8.5 months with 48 events for XH (HR=0.71). Brain metastases were observed in 4 (X) and 7 (XH) pts. Overall survival was 19.9 months with 31 events for X and 20.3 months with 26 events in XH (HR=0.79). Crude response rates were 24.6% (X) and 49.1% (XH) and primary progressions were observed in 26.3% (X) and 16% (XH) of patients. Grade III/IV toxicities were (%X/%XH): neutropenia (3.3/6.3), febrile neutropenia (0/0), vomiting (6.0/1.6), diarrhea (20.9/14.8), mucositis (3.0/1.6), hand-foot syndrome (23.9/31.1), nail changes (0/4.9), sensory neuropathy (4.5/3.3), fatigue (6.0/4.9), allergic (3.0/3.3), and cardiac (2.9/4.9). No therapy-related death occurred. Conclusions: Preliminary results of the TBP study suggest a higher efficacy but similar toxicity for continuing trastuzumab beyond trastuzumab progression when 2nd-line chemotherapy with capecitabine is initiated. Final efficacy analysis will be performed in March 2008. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Roche Roche

Trastuzumab

Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours. In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) co-positive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone. Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone. There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial. In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.

Paclitaxel (P), pegylated liposomal doxorubicin (PLD) and trastuzumab as 1st-line chemotherapy (chemo) in HER2/neu-positive (+) metastatic breast cancer (MBC)

10663 Background: Addition of trastuzumab (Herceptin, H) to successive neoadjuvant taxane+anthracycline-based chemo in patients (pts) with HER-2 (+) breast cancer significantly increases the pathological complete response (CR) rates. PLD has considerably less cardiotoxicity compared to parent drug. The aim of the study was to evaluate the activity and safety of combining H with PLD and P as 1st-line chemo in HER-2 (+) MBC pts. Methods: Inclusion criteria were: histologically confirmed MBC or relapsed after adjuvant chemo, ≥1 measurable lesion, adequate organ function, ECOG-PS 0–1, left ventricular ejection fraction (LVEF) by MUGA ≥55% (reevaluated after cycles 3 and 6). HER-2 positivity was determined by IHC and confirmed with CISH. Chemo was administered as follows: H 6mg/kg (8mg/kg-1st cycle) infused over 90min, PLD 35mg/m2 over 1hr, and P 175mg/m2 over 3hrs on day 1, with prophylactic G-CSF, recycled every 3 weeks. In responders, H was administered as consolidation (6mg/kg/3wks) until disease progression. Results: From 10/2003–10/2005, 19 female HER-2 positive MBC pts were enrolled. Median age: 68 (range, 42–78). Metastatic sites were: lung 6, liver 1, bone 3, lymph nodes 11, soft tissue 5 [median: 2 (range, 1–4)]. Pts received a median of 6 (range, 1–8) for a total of 102 cycles. PLD was started at 35 mg/m2, but in pts with grade 3 hand-foot syndrome (HFS) dose was reduced by 25% (6 pts), or the drug was omitted for 1 cycle (1 pt). 17 pts completed 3–6 cycles and were evaluable for response, all treated patients were evaluable for toxicity. Response rates (RR) were 71%; CR 41%, PR 30%, SD 29%, with no PD. Two pts rendered operable had pCR. Toxicities were: HFS; grade 4: 1, grade 3: 6 (overall 37%), grade 3–4 neutropenia: 4, grade 3 anemia: 1, grade 3–4 mucositis: 2, and grade 2 alopecia: 19. Neither significant LVEF decline, nor symptomatic cardiac event was observed. It is too early to provide data on response duration, TTP, and OS, and these will be available at the meeting. Conclusions: H+P+PLD as 1st-line chemo in HER-2(+) MBC pts is a very active and well tolerated regimen with no significant morbidity/mortality. HFS was the most relevant toxicity. The study is ongoing. No significant financial relationships to disclose.

A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer

Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting. We have conducted a meta-analysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer. Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method. Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results. HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.

The role of serum HER2 as an alternative to fluorescence in situ hybridization for HER2 in metastatic breast cancer

681 Background: Measuring HER2 is required for the selection of metastatic breast cancer (MBC) patients for trastuzumab therapy. Since the guideline was widely accepted that recommended initial testing of tissue samples by immunohistochemistry (IHC), acceptance of 0/1+ as negative, 3+ as positive and further testing by fluorescent in situ hybridization (FISH) just in 2+ IHC, FISH study is particulary important in IHC 2+ cases to predict therapeutic response of trastuzumab therapy. Recently serum HER2 has been studied to be a complement to IHC or FISH, however, the association between serum HER2 level and HER2 gene amplification was not fully known. This study aimed to evaluate the relationship between serum HER2 level and FISH for HER2 to know whether serum HER2 can be used as an alternative to FISH for HER2 in HER2 overexpressing MBC. Methods: The HER2 overexpression was determined by IHC using polyclonal rabbit anti-human c-erbB-2 oncoprotein (Code A0485; DAKO Corp, CA, USA), and FISH analysis was performed using the PathVysion HER-2 DNA Probe Kit (Vysis, Downers Grove, IL, USA) on tissue from 126 MBC patients between Feb 2002 and Nov 2004. Serum HER2 was measured by immunoassay using Bayer ADVIA Centaur. Statistical analysis was performed using Mann-Whitney test and optimal serum HER2 values for differentiation between FISH+ (amplification) and FISH- (non-amplification) determined by receiver operating characteristics curve (ROC) analysis. Results: A total of 126 patients with HER2 overexpressing MBC with median age of 51 years included. IHC was 2+ and 3+ in 65 (52%) and 61 (48%) tumors, respectively and HER2 amplification by FISH was observed in 28% of IHC 2+ (16/58) and 100% of IHC3+ tumors (2/2). Serum HER2 levels showed significant difference at 30.6 ± 76.90 and 639.6 ± 1797.5 μg/L (mean ± SD, P = 0.01) in FISH- vs. FISH+ groups, but it was not significantly different in IHC 2+ vs. IHC 3+ groups (P = 0.54). ROC analysis showed 95% specificity at 100 μg/L with 78% positive predictive value. Conclusions: Serum HER2 may be a useful marker to predict HER2 gene amplification specifically in HER2 2+ by IHC with optimal value at 100 μg/L with 95% specificity and 78% positive predictive value. No significant financial relationships to disclose.

Trastuzumab (T) and docetaxel (D) for the treatment of HER2 metastatic breast cancer (MBC): A literature based (LB) and individual patient data (IPD) meta-analysis (MA) of phase II trial

706 Background: Phase II studies of T with D have demonstrated encouraging response rates in women with HER2/neu overexpressing (HER2+) MBC. Because there are no studies comparing this combination to the efficacy of the well-studied combination of Paclitaxel (P) and T, we undertook a MA to obtain a summary estimate of the response rate and toxicity, and to derive aggregate measures of other efficacy parameters. Methods: The project was designed in 2 phases: An LBMA and an IPDMA. Studies were included in the LBMA if they were prospective clinical trials of D + T in women with HER2+ MBC containing ≥ 10 patients. Studies were identified by an electronic literature search of 8 medical databases (Medline and Premedline, Embase, Cancerlit, CINAHL, Biological Abstracts, HealthStar, ACP Journal Club, and Cochrane Database of Systematic Reviews) for the years 1966–2002 using the following criteria; “trastuzuamab”, “herceptin”, “docetaxel” and “taxotere”. This was supplemented by hand searches of abstracts from proceedings of the European Society of Medical Oncology, American Society for Clinical Oncology and San Antonio Breast Cancer meetings for the years 1995 - 2002. Summary estimates of the objective response rates (OR) (intent to treat) were obtained using methods described by Laird and Mosteller (Int J Technol Assess in Health Care 6:5–30, 1990) for random effects adjustment.Results: 7 phase II trials with a total of 165 patients were identified. The overall estimated response rate was 60% (95% CI 52%–68%). Major grade 3/4 toxicities are presented. The IPDMA is currently underway and is to be completed in the spring of 2004. Conclusions: Results of the LBMA and IPDMA will be presented and their clinical implication discussed in light of known outcome with P + T and subsequent clinical implications. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Roche Canada

Trastuzumab (T) and docetaxel (D) for the treatment of HER2 metastatic breast cancer (MBC): A literature based (LB) and individual patient data (IPD) meta-analysis (MA) of phase II trial

706 Background: Phase II studies of T with D have demonstrated encouraging response rates in women with HER2/neu overexpressing (HER2+) MBC. Because there are no studies comparing this combination to the efficacy of the well-studied combination of Paclitaxel (P) and T, we undertook a MA to obtain a summary estimate of the response rate and toxicity, and to derive aggregate measures of other efficacy parameters. Methods: The project was designed in 2 phases: An LBMA and an IPDMA. Studies were included in the LBMA if they were prospective clinical trials of D + T in women with HER2+ MBC containing ≥ 10 patients. Studies were identified by an electronic literature search of 8 medical databases (Medline and Premedline, Embase, Cancerlit, CINAHL, Biological Abstracts, HealthStar, ACP Journal Club, and Cochrane Database of Systematic Reviews) for the years 1966–2002 using the following criteria; “trastuzuamab”, “herceptin”, “docetaxel” and “taxotere”. This was supplemented by hand searches of abstracts from proceedings of the European Society of Medical Oncology, American Society for Clinical Oncology and San Antonio Breast Cancer meetings for the years 1995 - 2002. Summary estimates of the objective response rates (OR) (intent to treat) were obtained using methods described by Laird and Mosteller (Int J Technol Assess in Health Care 6:5–30, 1990) for random effects adjustment.Results: 7 phase II trials with a total of 165 patients were identified. The overall estimated response rate was 60% (95% CI 52%–68%). Major grade 3/4 toxicities are presented. The IPDMA is currently underway and is to be completed in the spring of 2004. Conclusions: Results of the LBMA and IPDMA will be presented and their clinical implication discussed in light of known outcome with P + T and subsequent clinical implications. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Roche Canada

Chemotherapy and herceptin for HER2(+) metastatic breast cancer: the best drug?

Chemotherapy and herceptin for HER2(+) metastatic breast cancer: the best drug?