Weeks Of Trastuzumab Research Articles

Results of Chemotherapy Alone, with Sequential or Concurrent Addition of 52 Weeks of Trastuzumab in the NCCTG N9831 HER2-Positive Adjuvant Breast Cancer Trial.

Abstract Background: N9831 is the only randomized phase III trial comparing safety and efficacy of the addition of trastuzumab (H) to doxorubicin and cyclophosphamide then paclitaxel (Arm A: AC→T) either following (Arm B: AC→T→H) or starting concurrently with paclitaxel (Arm C: AC→T+H→H) for women with resected Stage I-III invasive HER2+ breast cancer. The 3 yr cumulative incidence of NYHA class III or IV congestive heart failure or sudden cardiac death was previously reported: 3.3% in Arm C, 2.8% in Arm B (Perez EA, et al. JCO 2008). The comparison of AC→T to AC→T+H→H was reported in a joint analysis of N9831 and NSABP B-31 in 2005 and updated in 2007, demonstrating a 52% reduction in risk of a disease event (Romond E et al., NEJM 2005; Perez EA, et al. ASCO 2007).Materials and Methods: Primary endpoint is disease-free survival (DFS). At the second planned interim analysis of Arm A vs. Arm B, the O’Brien-Fleming boundary (OFB) was crossed. NCCTG Independent Data Safety Monitoring Committee approved the release of these data as well as the data pertaining to Arm B vs. Arm C due to slow pace of events [expected 647 events in 4 yr follow-up period (f/u) vs. actual 334 events in 4.5 yr f/u]. Shortly thereafter, there were sufficient events to perform the first planned interim analysis of B vs. C. We present the results of each of these pairwise comparisons taking into account the potential for crossover to Arm C after the release of the joint analysis findings in 2005.Results: From 5/2000 to 4/2005, 2448 eligible women were enrolled for the Arm A (n=1087) vs. Arm B (n=1097) comparison. Median f/u is 5.5 yrs. with 386 events. The addition of trastuzumab sequentially to AC→T significantly improved DFS, univariately [HR(Arm B/Arm A)=0.70, 95% CI: 57-86%, logrank p=0.0005] and after adjusting for age, tumor size, number of positive nodes, and ER [PPH: HRadj=0.67 (95% CI: 0.55-0.82)]. 5 yr DFS was increased from 72% with AC→T to 80% with AC→T →H.From 5/2000 to 4/2005, 1903 eligible women were enrolled for the Arm B (n=954) vs. Arm C (n=949) comparison. Median f/u is 5.3 yrs. with 312 events. The log-rank p-value testing whether DFS differs with respect to starting time of trastuzumab was 0.019. [Not crossing pre-specified OFB for statistical significance]. After adjusting for tumor size, number of positive nodes, and ER, HRadj(Arm C/Arm B)=0.75 (95% CI: 0.60-0.94)]. 5 yr DFS was increased from 80% with AC→T →H to 84% for AC→T+H →H.Conclusions: DFS is significantly improved with the addition of 52 weeks of H (sequentially or concurrently) to AC→ T. There is a statistically significant 33% reduction in the risk of an event with the sequential addition of H following AC→T. There is a strong trend for a 25% reduction in the risk of an event with starting H concurrently with T relative to sequentially after T. Therefore, based on a positive risk/benefit ratio, we recommend that trastuzumab be incorporated in a concurrent fashion with T chemotherapy.Acknowledgements: NIH CA25224, Breast Cancer Research Foundation, Genentech. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 80. NOTE: This abstract was accepted for presentation at the Symposium after the Abstract Book went to press.

5081 Triple combination of 3-weekly trastuzumab (T) plus oral vinorelbine (VNR) and capecitabine (CAP) as first-line treatment in HER2-positive metastatic breast cancer (MBC): an active and well-tolerated regimen that allows patient compliance

5081 Triple combination of 3-weekly trastuzumab (T) plus oral vinorelbine (VNR) and capecitabine (CAP) as first-line treatment in HER2-positive metastatic breast cancer (MBC): an active and well-tolerated regimen that allows patient compliance

S41 Targeting HER2 in the adjuvant setting: Dealing with new standards and open questions

not received. S41 Targeting HER2 in the adjuvant setting: Dealing with new standards and open questions I.E. Smith1. 1Medicine, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom The HER2 gene is amplified and the receptor overexpressed in around 20% of women with early breast cancer, and this is associated with an adverse prognosis. Trastuzumab (Herceptin), a humanised monoclonal antibody targeted against the external domain of the HER2 receptor, has been shown to have major clinical benefit in all stages of HER2 positive breast cancer including in particular as adjuvant therapy for early disease. The 2007 St Gallen guidelines recommended that trastuzumab should be considered as standard treatment concurrently with or sequentially after chemotherapy in patients with HER2 positive disease which is IHC (immunohistochemistry) 3+ or FISH positive except in those with a primary tumour less than 1 cm and no axillary node involvement. Important unanswered questions remain however. Concurrent or sequential therapy: Three major trials (NSABPB-31; NCCTG N9831 and BCIRG006) have shown significant survival benefit with concurrent trastuzumab given with a taxane chemotherapy following anthracycline treatment. A further major trial (HERA) has shown similar survival benefit with sequential trastuzumab given after standard adjuvant chemotherapy, but another smaller trial of sequential trastuzumab (PACS004) also given after chemotherapy has failed to show benefit. Results from the N9831 trial comparing concurrent with sequential treatment are awaited. Duration of treatment: All the major trials have empirically used one year of adjuvant trastuzumab. The HERA trial is also comparing 2 v.1 year and results are awaited. A much smaller trial (FinHER) has shown similar efficacy gains with a mere 9 weeks of trastuzumab given concurrently with chemotherapy, suggesting that much shorter treatment may be as effective. The role of anthracyclines: Adjuvant trastuzumab after anthracyclines is associated with a small but significant increase in the risk of cardiotoxicity. Results from the BCIRG 006 trial suggest that a non-anthracycline regimen of docetaxel and carboplatin with trastuzumab achieves similar efficacy to anthracycline-containing regimens but without an increase in cardiotoxicity. Standardised measurement of HER2: ASCO and the College of American Pathologists recently convened an expert panel which concluded that around 20% of current HER2 testing may be inaccurate and proposed recommendations for standardised central testing in accredited laboratories with defined proficiency testing requirements. A positive HER2 result should be defined as IHC staining of 3+ (uniform intense membrane staining of greater than 30% of invasive tumour cells) or a fluorescent in situ hybridisation (FISH) result of more than 6 HER2 gene copies per nucleus or a FISH ratio of more than 2.2. ‘Low-risk’ HER2: So called low-risk T1, N0 HER2+ve breast cancers were largely excluded from the major adjuvant trastuzumab trials but data are accumulating that these have significant risk of relapse, even including <1 cm tumours. It is likely that trastuzumab with chemotherapy would also be of benefit in these circumstances; the role of adjuvant trastuzumab alone is plausible here but no direct data are available. New anti-HER2 targeted therapies: These are rapidly becoming available including lapatinib, an oral small molecule dual HER1/HER2tyrosine kinase inhibitor with significant clinical activity in metastatic breast cancer after trastuzumab. Adjuvant single agent lapatinib is being assessed in patients with trastuzumab-naive HER2 positive breast cancer in continuing remission following adjuvant chemotherapy in the TEACH trial. In addition, adjuvant lapatinib and chemotherapy is being compared directly with trastuzumab, or the 2 agents sequentially, or in combination, in the ALTTO trial. S42 Adjuvant therapy of triple negative breast cancer E.A. Perez. Jacksonville, USA Abstract not received.not received. S43 Review of new targeted drugs: Crawling towards the adjuvant

PI3 kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancer (LABC).

Abstract Abstract #34 Background: Activating mutations of PI3 kinase (PIK3CA) and PTEN loss may be associated with trastuzumab resistance. Trastuzumab, a HER2 humanized monoclonal antibody, and lapatinib, an EGFR/HER2 tyrosine kinase inhibitor are both established treatments. Greater understanding of the cellular response to trastuzumab or lapatinib is needed to tailor targeted therapy for individual patients and identify those less likely to benefit. Material and Methods: We performed two sequential neoadjuvant clinical trials in HER-2 overexpressing LABC: 40 patients received weekly trastuzumab at standard doses given initially as a single agent for the first 3 weeks, then in combination with 3-weekly docetaxel for 12 weeks (T), while 49 patients received lapatinib as a single agent (1,500 mg daily, orally) for 6weeks then the combination of 3-weekly trastuzumab/docetaxel for 12 weeks, before primary surgery (L). Sequential core biopsies of the primary breast tumors were taken at initial, weeks 1 and 3 after the first dose of trastuzumab, and at initial, weeks 2, 4, and 6 after lapatinib. Apoptosis, Ki67 proliferation rate, and PTEN were assessed by immunohistochemistry. Low PTEN was defined as Allred score of &amp;lt;3. Genomic DNA (10-100ng) was sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) and an ABI 3730 automated capillary sequencer. Two sample and paired sample comparisons were performed using nonparametric tests. Results: There was a significant decrease in clinical tumor size after three weeks of trastuzumab (n=35, median=-20%), and six weeks of lapatinib (n=49, median=-74%) compared to pre-therapy (p&amp;lt;0.001). At surgery, pathologic complete response was observed in 38% in patients on upfront T and 70% patient on L. There was a significant increase in apoptosis (median=3.5% to 4.7%, p=0.006) within one week after trastuzumab, with no significant change in Ki67 at any of the time point. Lapatinib was associated with a no significant increase in apoptosis but a significant decrease in Ki67 at week 2, 4, and 6 of therapy (p&amp;lt;0.001). Cases with low PTEN or PIK3CA mutations were significantly less likely to have a pathologic complete response to T (p&amp;lt;0.005). Howver, low PTEN or PIK3CA mutations was not significantly associated with pathologic resistance to L. Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 34.

Estimating recurrences prevented from using trastuzumab in adjuvant breast cancer in the United States.

Abstract Abstract #2107 Introduction: Trastuzumab was recently approved for adjuvant use in HER2+ breast cancer. Adjuvant treatment should result in a reduction in recurrences, but this has not been estimated from a US population perspective. Methods: We estimated the number of HER2+ breast cancers in the US in 2005 using SEER data. Because HER2 status is not available in SEER, the number of HER2+ patients was estimated using the known relationship between HER2 status and both estrogen receptor (ER) and progesterone receptor (PR) status. Patients with no ER or PR results were assumed to have no HER2 testing. HER2+ proportions for remaining ER+/PR+, ER+/PR-, ER-/PR+ and ER-/PR- patients were estimated from published data and applied to patients diagnosed in the 17 SEER registries. The resulting rates were applied to the 2005 US female population counts. Estimated HER2+ patient counts were stratified by nodal status (+/-), and age (30-50, 50-70, and &amp;gt;70 years). Patients with significant underlying cardiovascular (CV) disease were assumed not to use trastuzumab. Underlying recurrence rates were pooled across studies that compared doxorubicin and cyclophosphamide followed by a taxane (AC-T) versus the same regimen plus 52 weeks of trastuzumab (AC-TH). Rates were stratified by nodal status. The relative risk of recurrence with trastuzumab (0.53) was assumed to be constant across subgroups based on published data, and assumed to persist for 5 years. One study (NSABP B-31) estimated the proportion experiencing a CV event (primarily defined as ejection fraction decline below threshold or dyspnea with normal activity) based on 5-year follow-up. Probabilistic model inputs were used to reflect the likelihood of possible values where possible. The results were run using 5,000 replications and reported as the mean and middle 95% of the distribution using @Risk (Palisade Corp., Ithaca, NY). Results: The model estimated that there are approximately 28,500 (95% interval 26,400 to 31,500) patients who could be diagnosed with HER2+ breast cancer in one year in the US, 6,128 (95% interval 4,292 to 8,600) of whom will have a recurrence within 5 years, and up to 2,619 of whom (95% interval 1,506 to 3,701) who could be prevented from disease recurrence with trastuzumab use. The number of patients who might experience a CV event is approximately 941 (95% interval 510 to 1,395) giving a ratio of 2.7 recurrences prevented for every CV event (95% interval 1.4 to 5.6). Conclusion: Trastuzumab is capable of preventing at least 2,600 recurrences within 5 years after its initial year of use. Its most clinically important side effect, a CV event, is likely to appear once for every 2.7 recurrences that are prevented, although many cases are asymptomatic and reversible. Extrapolated over 20 years, targeting HER2+ tumors in the adjuvant setting could prevent as many as 50,000 HER2+ patients from recurrence with important clinical, humanistic and economic consequences for patients, physicians and payors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2107.

Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab (H)

LBA513 Background: Trastuzumab (H) has been shown to improve survival in HER2 positive, node-positive breast cancer patients when combined with paclitaxel following AC (Romond NEJM 2005:353;1673–1684). Cardiac dysfunction is the major toxicity associated with this regimen. Methods: NSABP B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node- positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on MUGA scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by a panel of cardiologists to determine whether criteria were met for a cardiac event (CE), defined as NYHA class III or IV CHF or possible/probable cardiac death. Among patients with normal post-AC LVEF who began post-AC treatment, 10 of 872 (1.3%) control patients subsequently had confirmed CEs (9 CHFs and 1 cardiac death) compared with 35 of 932 (3.9%) trastuzumab-treated patients (35 CHFs and no cardiac deaths). The difference in cumulative incidence at 5 years was 2.7%. Risk factors for CHF were age 50 (5.2–5.3%), requirement for hypertension medication (7.7%), and post AC-LVEF values of 50–54% (13.0%). Conclusion: Administering trastuzumab with paclitaxel after AC increases incidence of CHF. Risk factors for increased risk of cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy. No significant financial relationships to disclose.

Safety and efficacy of combined trastuzumab and CMF therapy in women with metastatic breast cancer: EORTC protocol 10995

1040 Background: Safety and efficacy of classical CMF combined with 3-weekly Trastuzumab (T), followed by T alone in metastatic breast cancer (MBC). Methods: Patients (pts) with previously treated MBC were enrolled into a Phase II study of T (4 mg/kg then by 2 mg/kg) IV weekly plus CMF, Bonadonna regimen, for a maximum of 8 cycles (cy), followed by T alone (6 mg/kg) IV 3 weekly. Entry criteria included HER2 overexpression, limited anthracycline (A) exposure, normal baseline LVEF and measurable disease (RECIST). Cardiac endpoints were defined as: symptomatic CHF or LVEF drop by ≥ 15% from baseline or to ≥ 5% below lower limit. Results: The trial was closed to recruitment in January 2006, 12 pts are still on treatment. Seventy one pts were entered with a median age of 54 (range 31–75). Forty-one pts had prior CT (32 A), of which 26 adjuvant, 6 MBC, and 9 both adjuvant and MBC. Median PS was 0, 52 pts had visceral disease with a median interval from diagnosis to first relapse of 33.4 months (mo). Out of 70 pts receiving T+CMF (33 pts with 8 cy), 42 continued with T alone for a median duration of 7 cy. Eleven pts discontinued treatment for toxicity (9 on T+CMF, 2 on T alone). To date, the overall response rate is 55% (31/56 pts): 55% (23/42) 1st line; 57% (8/14) 2nd line. An independent review of responses is on-going. Median time to response was 2 mo, median duration of response was 8.3 mo and the median progression free survival was 9.2 mo. The most common grade 3–4 toxicity was neutropenia (53 %). Fourteen pts had cardiac toxicities, one NYHA grade 2 CHF, 6 pts with a drop in LVEF of 15% from baseline after a median of 3 mo of treatment, 9 pts with a drop in LVEF of 5% below LLN, after a median of 8 mo of treatment. The other toxicities included one grade 3 arrhythmia, two grade 3 hypertension, one grade 2 SVT, one grade 3 thrombosis, and one grade 2 dyspnea. One pt previously exposed to A had NYHA grade 4 CHF one year after treatment discontinuation. Conclusions: Combination of T+CMF regimen is feasible treatment for HER2+ MBC patients. The safety profile was acceptable, with cardiac toxicity and neutropenia within previously reported range. Drops in LVEF were mostly asymptomatic irrespective of previous exposure to A. Preliminary response data confirm good efficacy of CMF+T in MBC patients. [Table: see text]

Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy

Aims:To investigate the correlation between centrally assessed human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) results and response to treatment of patients with...

Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial

BackgroundAfter two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks.MethodsPatients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization), PS ≤2, normal left-ventricular ejection fraction (LVEF) and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m2) was given on days 1&8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg) every 21 days). A single-stage phase 2 design, with p0 = 0.45, p1 = 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients.ResultsFrom Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31–81). Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8–66.2); 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3–12.3), median overall survival 22.7 months (95% CI 19.5-NA). Fifteen patients (30%) developed brain metastases at a median time of 12 months (range 1–25). There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46%) had grade 3–4 neutropenia, 2 (4%) grade 3 anemia, 4 (8%) febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF.ConclusionAlthough lower than in initial studies, activity of 3-weekly trastuzumab plus vinorelbine fell within the range of results reported with weekly schedules. Toxicity was prevalently manageable. This combination is safe and active for metastatic breast cancer patients who received adjuvant taxanes with anthracyclines.

Assessment of Cardiac Dysfunction in a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel, With or Without Trastuzumab As Adjuvant Therapy in Node-Positive, Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: NSABP B-31

Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines. National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms. Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.

Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer

We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831. Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)

Phase II Study of Efficacy, Safety, and Pharmacokinetics of Trastuzumab Monotherapy Administered on a 3-Weekly Schedule

This phase II study investigated the efficacy, safety, and pharmacokinetics of trastuzumab monotherapy given as first-line treatment once every 3 weeks (3-weekly) in women with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Patients with previously untreated HER2-positive MBC received a loading dose of trastuzumab, 8 mg/kg intravenously (IV) and then 6 mg/kg IV at 3-week intervals until disease progression or patient withdrawal. In total, 105 patients received a median of five cycles of therapy (range, 1 to 35+). The overall response rate was 19% (23% in patients with measurable centrally confirmed immunohistochemistry [IHC] 3+ and/or fluorescence in situ hybridization [FISH] -positive disease) and clinical benefit rate (complete and partial responses plus stable disease for at least 6 months) was 33% (36% in patients with measurable centrally confirmed IHC 3+ and/or FISH-positive disease). Median time to progression was 3.4 months (range, 0.6 to 23.6 months). The most common treatment-related adverse events were rigors, pyrexia, headache, nausea, and fatigue. Median baseline left ventricular ejection fraction was 63%; this did not significantly change over the course of the study. The average exposure to trastuzumab observed in this study was similar to that in previous studies of the weekly regimen. However, as expected, mean trough trastuzumab concentrations were lower and peak levels were higher with 3-weekly trastuzumab compared with weekly treatments. Administering higher doses on a 3-weekly schedule did not compromise the efficacy and safety of trastuzumab in women with HER2-positive MBC, and average exposure was similar to that observed with weekly therapy. Three-weekly trastuzumab may represent a convenient alternative to weekly administration.

Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers

Greater understanding of the cellular response in trastuzumab-treated patients will provide insight into the clinical management of patients. We performed a neoadjuvant trial in 35 patients with locally advanced HER-2/neu overexpressing breast cancers who received weekly trastuzumab given as a single agent for the first 3 weeks, followed by a combination of trastuzumab and docetaxel for 12 weeks before surgery. Sequential core biopsies were taken at baseline and within weeks 1 and 3 after the first dose of trastuzumab. Clinical response to trastuzumab was assessed by tumor measurements on day 22 before chemotherapy. Core biopsies were assessed by immunohistochemistry for cell cycle and proliferation (Ki67, p27, phosphorylated [p] -MAPK), apoptosis and survival (apoptotic index, p-Akt), epidermal growth factor receptor, and total and p-HER-2. There was early tumor regression with a median decrease of -20.0% (range. 0% to 60.4%) after only 3 weeks of trastuzumab, and eight patients (23%) had a partial response. Consistent with the clinical regressions, apoptosis was significantly induced (median increase from 3.5% to 4.7%; P = .006) within week 1, a 35% increase above baseline. No significant change in epidermal growth factor receptor score was observed in week 1, without changes in total or p-HER-2 expression. Tumors with high baseline Ki67 were less likely to respond (P = .02). In primary breast cancers, trastuzumab substantially induces apoptosis, providing a molecular explanation for both its therapeutic efficacy and its successful combination with cytotoxic chemotherapy.

Optimizing treatment of HER2-positive metastatic breast cancer

The primary goal of therapy for metastatic breast cancer is to improve the outcome for patients. Ideally, this should be achieved with minimal short-term side effects and without long-term irreversible toxicity. Trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) is proven to be efficacious in women with metastatic breast cancer who have HER2-positive disease. Data from pivotal clinical trials and postmarketing surveillance in women with metastatic breast cancer confirm that trastuzumab is also well tolerated with a low incidence of conventional chemotherapeutic side effects. Severe adverse events are confined to serious infusion-related reactions and cardiac issues, which are infrequent and readily managed. Patients at risk of these severe events can be identified before starting trastuzumab therapy. Ideally, treatment should also be convenient for the patient. This can be achieved through less frequent dosing. A 3-weekly trastuzumab schedule, with higher individual loading and maintenance doses than the conventional weekly schedule, has been investigated. This has similar efficacy, tolerability, and pharmacokinetics (exposure) to the weekly regimen, providing a convenient schedule.

Favourable pharmacokinetics of 3-weekly trastuzumab

Favourable pharmacokinetics of 3-weekly trastuzumab