Trastuzumab In HER2-positive Breast Cancer Research Articles

2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial

Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with ClinicalTrials.gov, number NCT00045032. We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85-1·14, p=0·86). Grade 3-4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3-4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67-0·86, p<0·0001) for disease-free survival and 0·76 (0·65-0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. F Hoffmann-La Roche (Roche).

Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model

Human epidermal growth factor receptor 2 (HER2)-targeted therapy by trastuzumab has become increasingly important for treating HER2-positive cancers, and trastuzumab emtansine (T-DM1) is expected to serve as an effective alternative to trastuzumab. Pertuzumab, a HER2 dimerization inhibitor, showed prolonged progression-free survival when used with trastuzumab for HER2-positive breast cancer. In this study, we investigated the effect of combining T-DM1 and pertuzumab on xenografted gastric tumors. T-DM1 as a single agent showed significant antitumor activity in all the three HER2-high expression tumor models tested (NCI-N87, SCH and 4-1ST) but was ineffective against two HER2-low expression tumors (SNU-16 and MKN-28). Using the T-DM1-sensitive NCI-N87 model, the combination efficacy of T-DM1 and pertuzumab was elucidated. The combination induced significant tumor regression, whereas T-DM1 or pertuzumab alone did not. In cultured NCI-N87 cells stimulated with epidermal growth factor (EGF) or heregulin-α, concomitant treatment of T-DM1 and pertuzumab significantly inhibited proliferation and increased caspase 3/7 activity compared to either agent alone. Only the combination significantly inhibited the phosphorylation of EGFR or HER3, and its downstream factor AKT. Suppressed HER3 phosphorylation by the combination was also seen in the NCI-N87 xenografted tumors. Compared to single agent treatments, the combination treatment significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) against NCI-N87 cells. These findings suggest that T-DM1 in combination with pertuzumab shows significant antitumor activity by increasing AKT signal inhibition and ADCC in HER2-positive gastric cancers.

Duration of trastuzumab for HER2-positive breast cancer

Duration of trastuzumab for HER2-positive breast cancer

The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Objective:Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be related to trastuzumab resistance in in vitro studies; however, this issue in clinical studies is controversial. Therefore, we conducted a meta-analysis to assess the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in HER2-positive breast cancer patients.Methods:A computerized search was performed through the PubMed database, the online proceedings of the American Society of Clinical Oncology Annual Meetings, the San Antonio Breast Cancer Symposium and the International St. Gallen Breast Cancer Conference. Ten eligible studies including 1889 cases were identified.Results:In HER2-positive locally advanced breast cancer patients, neither PTEN loss, PIK3CA mutation nor PI3K activation was associated with the response rate of trastuzumab-based neoadjuvant treatment (PTEN loss: RR = 0.687, 95% CI: 0.439–1.074, P = 0.099; PIK3CA mutation: RR = 1.114, 95% CI: 0.453–2.735, P = 0.814; PI3K activation: RR = 0.787, 95% CI: 0.417–1.484, P = 0.459; RR = 0.772, 95% CI: 0.387–1.539, P = 0.462). In HER2-positive early stage breast cancer patients, PTEN loss was not associated with the disease-free survival (DFS) rate of trastuzumab-based adjuvant treatment (HR = 1.096, 95% CI: 0.706–1.700, P = 0.684). In HER2-positive recurrent or metastatic breast cancer patients, PTEN loss was significantly correlated with poorer efficacy of trastuzumab-based salvage treatment (RR = 0.682, 95% CI: 0.550–0.846, P = 0.000).Conclusions:In HER2-positive recurrent or metastatic breast cancer patients PTEN loss might indicate resistance to trastuzumab-based salvage treatment. Due to the small sample size and the considerable heterogeneity in the chemotherapy treatment regimens, further research is needed to clarify the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in neoadjuvant and adjuvant settings.

501 Jab1/CSN5 as a Novel Target to Overcome the Resistance to Trastuzumab in Her2-positive Breast Cancer

501 Jab1/CSN5 as a Novel Target to Overcome the Resistance to Trastuzumab in Her2-positive Breast Cancer

Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023

This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer. Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle. The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58% of all patients. Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.

Outcomes of Women with Early-Stage Breast Cancer Receiving Adjuvant Trastuzumab

Large randomized trials assessing the benefit of adjuvant trastuzumab in early-stage breast cancer positive for the human epidermal growth factor receptor 2 (her2) have demonstrated a significant improvement in survival. The objective of the present study was to describe the outcomes of women who received adjuvant trastuzumab for her2-positive breast cancer in British Columbia since publicly funded population-based use was initiated in July 2005. Women from British Columbia, newly diagnosed with stage i-iii breast cancer between July 2004 and December 2006, who were positive for her2 overexpression by immunohistochemistry (3+) or amplification by fluorescence in situ hybridization (ratio ≥ 2.0) were included in the study. Data were collected from the prospectively assembled BC Cancer Agency Outcomes Unit, with cases linked to the provincial pharmacy data repository to determine the proportion of women who received adjuvant trastuzumab. Our retrospective study identified 703 her2-positive patients, of whom 480 (68%) received trastuzumab. In patients receiving trastuzumab, the 2-year relapse-free survival was 96.1% [95% confidence interval (CI): 93.6% to 97.7%] and the overall survival was 99.3% (95% CI: 97.9% to 99.8%). Among node-negative and -positive patients, the 2-year relapse-free survival was 97.8% and 94.8% respectively (p = 0.09) for the trastuzumab-treated group and 90.9% and 77.3% (p = 0.01) for the group not receiving trastuzumab (n = 223). Site of first distant metastasis was the central nervous system in 19.5% of the entire cohort and in 37.5% of patients treated with trastuzumab. This population-based analysis of adjuvant trastuzumab use among Canadian women demonstrates highly favorable outcomes at the 2-year follow-up.

Nine-weeks of adjuvant trastuzumab in HER2-positive breast cancer: A single center experience.

e11080 Background: Trastuzumab is an effective adjuvant targeted therapy in patients with HER-2 positive breast cancer. However, effect of this therapy on survival is not well described in literature. In this study, we aimed to show characteristics of patients treated with nine week trastuzumab therapy for breast cancer and survival analysis. Methods: We analyzed the data of 2.218 breast cancer patients treated and followed up in our medical oncology department. There were 165 patients treated with 9 weeks of adjuvant trastuzumab therapy in this cohort. Patients’ characteristics, prognostic factors, and survival data were analyzed by using SPSS 18.0 version. Results: The mean age of the patients at the time of diagnosis of breast cancer was 47.3 ± 10.0 years. Sixty two (37.6%) patients were postmenopausal, eighty two patients (49.7%) were premenopausal and twenty patients (12.1%) were peri-menopausal. Invasive ductal carcinoma was the most common pathological type and was observed in 87.9% of the patients. ER and PR was positive in 49.1% of the patients and 54.5 % of the patients, respectively. Percentage of stage of the patients was 10.9 in stage I, 21.1 in stage IIA, 17.6 in stage IIB, 21.2 in stage IIIA, 0.6 in stage IIIB, 23.6 in stage IIIC. Mean follow up time of the patients was 30.9 ± 13.4 months. Numbers of the patients with progression were eighteen (10.9%). Eight (4.8%) patients died due to disease progression. Two-year survival rate was 98.3%. Disease free, progression free and overall survival times could not be obtained due to inadequate number of events. Conclusions: The superiority of nine weeks of adjuvant trastuzumab therapy to standard one year regimen of adjuvant trastuzumab is not well described in literature. The studies comparing 9-weeks and one year of adjuvant trastuzumab use with large numbers of patients are needed to show which regimen is superior.

Reappraising antiangiogenic therapy for breast cancer

Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed.

The Clinical Utility of HER2-Targeted Therapy in the Neoadjuvant Setting: Recent Results From the San Antonio Breast Cancer Symposium

HER2-targeted therapies have demonstrated significant efficacy against HER2-positive (HER2+) breast cancer, with trastuzumab considered the standard of care in the adjuvant and metastatic settings. 1 Mariani G Fasolo A De Benedictis E et al. Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol. 2009; 6: 93-104 Crossref PubMed Scopus (67) Google Scholar Trastuzumab is also associated with significant efficacy in the neoadjuvant setting. The GeparQuattro study reported a pathologic complete response (pCR) rate in the breast of 32% for trastuzumab with neoadjuvant anthracycline/taxane-based chemotherapy in patients with operable or locally advanced HER2+ breast cancer. 2 Untch M Rezai M Loibl S et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010; 28: 2024-2031 Crossref PubMed Scopus (434) Google Scholar The phase III NOAH (Neoadjuvant Herceptin®) trial reported a significant improvement in 3-year event-free survival (71% vs. 56%; P = .013) and pCR in the breast (43% vs. 22%; P = .0007) with the addition of trastuzumab to neoadjuvant chemotherapy in patients with HER2+ locally advanced breast cancer. 3 Gianni L Eiermann W Semiglazov V et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010; 375: 377-384 Abstract Full Text Full Text PDF PubMed Scopus (974) Google Scholar

The art of prescribing trastuzumab for HER2-positive breast cancer

AbstractThe human epidermal growth factor receptor 2 (HER2) is overexpressed in HER2-positive breast cancer. This confers characteristics associated with an overall poor prognosis, with early metastases to major visceral sites and a relative resistance to chemotherapy. Trastuzumab is a humanised monoclonal therapeutic antibody that specifically targets HER2 receptor overexpressing breast cancer cells, inhibiting their growth and proliferation, and inducing their regression. It is licensed for metastatic and early HER2-positive breast cancer, determined by slide-based testing techniques. Trastuzumab dosing regimens are aimed at increasing its efficacy, while minimising its potentially undesirable effects which include cardiotoxicity and the development of resistance.

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

Reply to Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

Reply to Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

Cytologically proven axillary lymph node metastases are eradicated in patients receiving preoperative chemotherapy with concurrent trastuzumab for HER2‐positive breast cancer

The axillary pathologic complete response rate (pCR) and the effect of axillary pCR on disease-free survival (DFS) was determined in patients with HER2-positive breast cancer and biopsy-proven axillary lymph node metastases who were receiving concurrent trastuzumab and neoadjuvant chemotherapy. The use of neoadjuvant chemotherapy is reported to result in pCR in the breast and axilla in up to 25% of patients. Patients achieving a pCR have improved DFS and overall survival. To the authors' knowledge, the rate of eradication of biopsy-proven axillary lymph node metastases with trastuzumab-containing neoadjuvant chemotherapy regimens has not been previously reported. Records were reviewed of 109 consecutive patients with HER2-positive breast cancer and axillary metastases confirmed by ultrasound-guided fine-needle aspiration biopsy who received trastuzumab-containing neoadjuvant chemotherapy followed by breast surgery with complete axillary lymph node dissection. Survival was evaluated by the Kaplan-Meier method. Clinicopathologic factors and DFS were compared between patients with and without axillary pCR. Eighty-one patients (74%) achieved a pCR in the axilla. Axillary pCR was not associated with age, estrogen receptor status, grade, tumor size, initial N classification, or median number of lymph nodes removed. More patients with an axillary pCR also achieved a pCR in the breast (78% vs 25%; P < .001). At a median follow-up of 29.1 months, DFS was significantly greater in the axillary pCR group (P = .02). Trastuzumab-containing neoadjuvant chemotherapy appears to be effective in eradicating axillary lymph node metastases in the majority of patients treated. Patients who achieve an axillary pCR are reported to have improved DFS. The success of pCR with concurrent trastuzumab and chemotherapy in eradicating lymph node metastases has implications for surgical management of the axilla in these patients.

Association between pathologic complete response and survival in patients treated with sequential anthracyclines and concomitant taxanes and trastuzumab in HER2-positive breast cancer.

Abstract Abstract #3141 Background: We reported high pathologic complete response (pCR) rates in patients with AC-sensitive and AC-resistant breast cancer (BC) who received trastuzumab-based chemotherapy regimens (SABCS 2004-2007). Following standard chemotherapy, pCR in 33% patients with HER2-positive breast cancer (BC) predicts 5-year DFS of 94% compared to 69% in 67% of patients with residual disease (RD)-a 25% difference (MD Anderson data). However, a similar association of DFS with pCR following trastuzumab has yet to be demonstrated.&amp;#x2028; Material and Methods: A retrospective analysis of 40 patients with stage I-IIIC (6T4a-c, 9T4d, 8T3, 11T2, 6TX-1, 7 LN-negative, 33 LN-positive) HER2-positive (IHC2+ and FISH+ or IHC3+) BC treated preoperatively on and off institutional trials with trastuzumab-based regimens between 11/2002 and 10/2007 was conducted. Generally, patients received in vivo chemosensitivity-adjusted dose-dense doxorubicin and cyclophosphamide (2-4 cycles) followed by paclitaxel (cremophor or albumin-bound), carboplatin and trastuzumab for 12-16 weeks. Median age was 51 (range 26-71), and 16 (40%) had HR-positive BC. Postoperative treatment included radiation based on pretreatment stage, hormonal modulation for HR-positive BC, and additional trastuzumab was optional.&amp;#x2028; Results: Twenty-six (65%, 95% CI 48-79%) patients achieved pCR in breast and axilla. pCR rate was 30%, 67% and 90% (p=0.02) with increasing HER2 FISH ratio of 1-4 (n=10), &amp;gt;4 (n=18), and &amp;gt;7 (n=10), respectively. pCR was demonstrated in 50% HR-positive and in 75% HR-negative BC (p=0.17). DFS and OS of 40 patients at a median follow-up of 28 months (range 2-56) of live patients is 88% (95% CI: 73-96) and 93% (95% CI: 80-98). DFS was 95% for patients who achieved pCR and 69% for patients with RD (Hazard ratio 0.12; 95% CI: 0.02 to 0.72, p=0.022). Age, grade, tumor size, preoperative lymph node and hormone receptor status were not prognostically significant in this small series. DFS was 94% for HER2+/HR+ and 83% for HER2+/HR- BC. Of the 5 relapses, 3 patients had inflammatory (2 had brain relapse as first site), one IIIB and one IIB BC.&amp;#x2028; Discussion: This is the first demonstration of statistically significant difference in DFS of 95% in 65% achieving pCR versus 69% in 35% with RD treated preoperatively with trastuzumab-taxanes following anthracyclines. The strength of association between pCR and DFS is same as that following non-trastuzumab chemotherapy. In contrast, the 2-3 times higher pCR following trastuzumab is associated with a higher DFS of 88% for overall HER+ BC despite inclusion of inflammatory and locally advanced BC, and compares favorably with adjuvant trastuzumab studies of operable BC. The association between pCR and longer-term outcome also underscores the adequacy of in vivo chemosensitivity-adjusted 12-16 weeks (short course) of trastuzumab-taxanes combination sequenced following 2-4 cycles of anthracyclines in the neoadjuvant setting. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3141.

Phase II Southwest Oncology Group study of docetaxel and vinorelbine plus filgrastim with weekly trastuzumab for HER2-positive, stage IV breast cancer

1033 Background: The taxane, docetaxel (DOC), and the vinca alkaloid, vinorelbine (VNR), have significant activity in combination as first line chemotherapy for HER2-negative, stage IV breast cancer (BC). Preclinical studies suggest potential synergy between these two classes of anti-tubulin drugs. Each agent has significant activity when combined with trastuzumab in HER2-positive BC. This study evaluates both agents together with trastuzumab as first-line chemotherapy for stage IV disease. Methods: Patients (pts) with HER2-positive, metastatic BC were eligible. Pts may have received prior adjuvant chemotherapy that did not include DOC or VNR. DOC (60 mg/m2) on day 1 and VNR (27.5 mg/m2) on days 8 and 15 were given intravenously each 21-day cycle. Trastuzumab was administered concurrently (standard weekly schedule), with filgrastim days 2–21. The primary endpoint was overall survival (OS) at 1-year, with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. The planned sample size was 90 pts, sufficient to estimate 1-year OS within 11% at α=0.05 (2-sided). Results: Due to slow accrual, the study was closed with a total of 76 pts registered between 2/03 and 12/06. The OS analysis includes 71 eligible pts with available data. One-year OS is 94% (95% CI 88%-100%) with a median OS of 39 months (95% CI 29–41). One-year PFS is 70% (95% CI 59%-80%) with median PFS of 19 months (95% CI 14–28). Of 63 pts with measurable disease, there were 45 (71%) CR+PRs (95% CI 59–82%). Six pts remain on treatment, with the most common reasons for discontinuation being progression (n=17) and adverse events (n=16). Of 67 pts evaluable for toxicity, 14 (21%) had a grade 4 event and 20 (30%) had a grade 3 event as the highest adverse event. Neutropenia was the predominant G 4 event. The most common G 3/4 non-hematologic toxicities were fatigue (10%) and hyperglycemia (7%). No G 5 toxicity was reported. Conclusions: The combination of docetaxel, vinorelbine, and trastuzumab is very active as first-line chemotherapy in HER2-positive, stage IV breast cancer and has the best survival rate published to date in this population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology, GlaxoSmithKline, sanofi-aventis Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Roche, sanofi-aventis

Predictors of response to primary systemic therapy (PST) with docetaxel and trastuzumab in HER2-positive breast cancer

11100 Background: The purpose of this study was to assess the relationship between estrogen receptor (ER) status, amplification of HER-2, and tumor response to PST with docetaxel and trastuzumab in breast cancers positive for HER-2 by immunohistochemistry (IHC). Long-term disease-free survival data are also reported. Methods: Eligible patients were those with T2 or T3 tumors and overexpression of HER-2 via IHC. Docetaxel 100 mg/sq m q. 3 weeks × 4 with growth factor support and weekly trastuzumab × 12 were given before surgery. The Miller-Payne system was used to define pathologic responses (PR) in the excision specimen (0, 1, 2 - no/minimal response; 3 - 4 partial response, pPR; 5 - complete response, pCR). Adjuvant therapy was given at the discretion of the treating oncologist. Results: Of 22 enrolled patients, 19 were assessable. 17 of the 19 subjects had subsequent FISH confirmation of HER-2 status. Six subjects (31%) had a pCR. Of these, 5 had strong amplification of HER-2 and 5 had tumors that were ER-negative. A pPR occurred in an additional 2 subjects (10%). Of the 11 subjects who had no or minimal PR (Miller-Payne 0 - 2), 8 were found to have no amplification for HER-2 and 9 had tumors that were ER-positive. Postoperative (adjuvant) chemotherapy was given to 17 patients. All 12 patients with ER-positive tumors received adjuvant hormonal therapy. Three patients had an asymptomatic decline in left ventricular ejection fraction (LVEF) of 10 - 15% after anthracycline containing chemotherapy, and one had symptomatic non-ischemic cardiomyopathy of unclear etiology 4 years after completion of study therapy and an anthracycline. With a median follow up of 56 months, all 19 participants are alive and disease-free. Conclusion: PST with a 12-week course of trastuzumab and docetaxel is safe and effective, produces a substantial pCR rate, and may result in excellent long-term recurrence-free and overall survival. The subset of patients with tumors that were IHC-positive, but FISH-negative for HER-2, and ER-positive had minimal or no response to therapy, highlighting the importance of identifying patients most likely to respond to trastuzumab-based regimens. [Table: see text]

‘Simply stunning’ – trastuzumab in HER2-positive breast cancer

Human epidermal growth factor receptor-2 (HER-2)-positive metastatic breast cancer is a more aggressive disease than HER-2-negative metastatic breast cancer. The initial Phase III trial with the HER-2 antibody, trastuzumab, in this cancer suggested that, although trastuzumab was beneficial, cardiac adverse events would prevent it from being widely used. Recently trials suggest that, with close monitoring of left ventricular ejection fraction, trastuzumab can be used concurrently or sequentially with the standard adjuvant treatment of HER-2-positive metastatic breast cancer with good benefit. Therefore, with appropriate regimens, trastuzumab will be able to be used routinely in the treatment of HER-2-positive metastatic breast cancer.