Trastuzumab In HER2-positive Patients Research Articles

Abstract PO2-16-12: Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival

Abstract Introduction: Breast cancer is the most common malignancy among women in Brazil and worldwide. Neoadjuvant chemotherapy (NAC) has been increasingly used for the treatment of breast cancer conditions ranging from locally advanced tumors to early-stage triple-negative and HER-2 positive tumors. Nowadays only 5% of breast cancer patients are enrolled in clinical trials. Real-world data is important to evaluate how clinical trial treatments behave in the real world with all the heterogeneous patient characteristics of those treated differently from the homogeneity of clinical trials. Objectives: To evaluate the rates of pathological complete response (pCR) in patients undergoing neoadjuvant chemotherapy (NAC) for the treatment of breast cancer (BC) To examine the differences in pathological complete response (pCR) rates between HER-2 positive breast cancer patients with and without trastuzumab treatment, and between triple-negative breast cancer (TNBC) patients with and without platinum-based treatment, Additionally, we aim to assess the impact of pCR on overall survival (OS) and disease-free survival (DFS) using real-world data (RWD). Methods: This was a retrospective, multicentric cohort study, that included female patients over 18 years of age, with a diagnosis of non-metastatic breast cancer undergoing NAC. As an exploratory real-world data study, no confirmatory hypothesis was established, so no corrections for multiple comparisons were necessary. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method calculated at five years. Additionally, we conducted a multivariate analysis to identify significant associations with pathologic complete response (pCR) and overall survival (OS). We employed a forest plot to visually represent these associations Results: From 2011 to 2020, 1,891 patients were included in the study, and 421 (22,3%) achieved pCR (ypT0 ypN0) and considering the presence of residual in situ carcinoma (DCIS) the pCR was seen in 467 patients (23,5) without significant difference (p=0,567) . The pCR rate varied between the subtypes: luminal A 17,0%, luminal B 21,3%, luminal HER2 23,0%, TNBC 22,5% and HER2 28,5% (p = 0,057). The type of neoadjuvant chemotherapy (NAC) regimen was correlated with pathological complete response (pCR). Among HER2-positive patients, those who received Trastuzumab had a significantly higher rate of pCR compared to those who did not receive it (p < 0.0001). Similarly, in patients with TNBC, those who underwent treatment with platinum-based regimens also showed higher rates of pCR (p < 0.0001). There were 694 deaths, and the 5-year OS rate was 62.9%. OS was also grouped according to pCR status, and pCR OS rate was 88,3% and non-pCR 58.1% significant difference observed (p < 0.0001). Five-year DFS of pCR was 92.2% and non-pCR 64.3% (p < 0.0001). Conclusion: this real-world data study evaluated the rates of pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The results revealed varying pCR rates among different breast cancer subtypes, with HER2-positive and triple-negative subtypes showing higher rates. The use of Trastuzumab in HER2-positive patients and platinum-based regimens in triple-negative patients correlated with significantly higher pCR rates. Furthermore, achieving pCR was associated with improved overall survival (OS) and disease-free survival (DFS). These findings emphasize the importance of considering individual tumor characteristics and tailoring treatment strategies for breast cancer patients to optimize outcomes. Clinicopathological characteristics of patients AJCC, American Joint Committee on Cancer; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; TNBC triple negative breast cancer. NAC schemas and correlation with pCR. AC-T, doxorubicin + cyclophosphamide – taxane; AC-TPlatinum, doxorubicin + cyclophosphamide – taxane+carboplatin; AC-TH, doxorubicin + cyclophosphamide – taxane+herceptin. Citation Format: Marcelo Antonini, Andre Mattar, Fernanda Grace Bauk Richter, Gabriel Pannain, Andressa Amorim, Marina Diogenes, Odair Ferraro, Luiz Gebrim, Reginaldo Coelho Lopes, Juliana Real. Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-12.

Treatment patterns and outcomes in older women with early breast cancer: a population-based cohort study in China

BackgroundDespite the proportion of elderly breast cancer patients has been consistently increasing, the optimal treatment modalities for this population have not been well explored. We summarized the treatment outcomes of these patients in our hospital.MethodsOlder patients with early breast cancer were identified from the Breast Cancer Information Management System at West China Hospital, Sichuan University (2000–2019). We compared tumor characteristics and treatment outcomes between the older group (65–74 years old) and the elderly group (≥75 years old). The Kaplan-Meier and Cox regression analysis were conducted to determine significant prognostic factors.ResultsIn total, 1094 patients were included. The median follow-up time for this cohort was 59 months. The majority of patients underwent surgery and benefited from surgical treatment. Elderly group patients were less likely to receive adjuvant chemotherapy or postmastectomy radiotherapy (PMRT) compared to the older group. However, adjuvant chemotherapy was associated with improved overall survival (OS) (hazard ratio [HR] 0.521, 95% confidence interval [CI] 0.284–0.955, P = 0.035). Subgroup analysis revealed that patients with grade III disease best benefited from adjuvant chemotherapy. PMRT offered a significant improvement in local disease control, but not in OS. Furthermore, endocrine therapy improved the OS of HR-positive patients (HR 0.440, 95%CI 0.261–0.741, P = 0.002), especially for cases aged 65–74 years. Also, receipt of trastuzumab in HER2-positive patients was associated with better OS (HR 0.168, 95%CI 0.029–0.958, P = 0.045).ConclusionsOur findings suggest that surgery, adjuvant chemotherapy, endocrine and targeted therapy are associated with improved OS in older breast cancer patients. Moreover, clinicopathological characteristics should be comprehensively considered when making treatment decisions for these patients.

Combination of trastuzumab and taxane-containing intensified chemotherapy in first-line treatment of HER2-positive advanced gastric cancer.

Taxane-containing combinations are recommended for the first-line therapy of advanced gastric cancer. It is not known which chemotherapy regimen is the best with trastuzumab for HER2-positive patients. The aim of this study was to compare taxane-containing intensified chemotherapy versus standard chemotherapy in combination with trastuzumab in the first-line treatment of HER2-positive advanced gastric adenocarcinoma. This study is a retrospective multicenter study of the Turkish Oncology Group. A total of 130 HER2-positive patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma being given chemotherapy plus trastuzumab as the first-line treatment were included from 16 different oncology centers. Trastuzumab combination with intensified chemotherapy including taxane or standard chemotherapy was compared in terms of progression-free survival (PFS), overall survival (OS), and toxicity. There were 108 patients in the standard and 22 patients in the intensified chemotherapy group. PFS of the standard and intensified group were 5.6 months (95% confidence interval [CI] 4.8-6.4) and 5.3 months (95% CI 2.6-8), respectively (p = 0.70). OS of the standard and intensified group were 11.1 months (95% CI 8.3-13.9) and 15.2 months (95% CI 12.7-17.7), respectively (p = 0.03). Repeated analysis excluding patients given any previous therapy revealed similar results. The intensified group had more fever and febrile neutropenia. Trastuzumab combination with intensified chemotherapy provides better OS in first-line treatment of HER2-positive advanced gastric cancer. Further large-scale studies should be performed in HER2-positive patients.

<p>Trastuzumab treatment after progression in HER2-positive metastatic breast cancer following relapse of trastuzumab-based regimens: a meta-analysis</p>

Background: This meta-analysis assessed the safety and effectiveness of retreatment with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (HER2+MBC).Materials and methods: Randomized controlled trials (RCTs) and cohort studies that compared the clinical outcomes of continuation and termination of trastuzumab treatment in HER2+MBC after failure of trastuzumab-based regimens were analyzed. Pooled estimates of time to progression (TTP) survival, overall survival (OS), the incidence of adverse events and central nervous system (CNS) perturbations were determined.Results: Four RCTs and six cohort studies with 2,409 patients were identified. The continuation of trastuzumab presented a statistical significance in prolonging TTP (HR 0.88; 95% CI: 0.82–0.94; P<0.000) and OS (HR 0.87; 95% CI: 0.82–0.93; P<0.000). Furthermore, retreatment with trastuzumab did not add to the risk of cardiac events (relative risk, 2.48; 95% CI: 0.86–7.15) or the incidence of CNS metastasis (P=0.83).Conclusion: Our findings confirm the clinical benefits and safety of retreatment therapy with trastuzumab for HER2-positive patients with metastatic cancer of the breast that had progressed during trastuzumab-based treatment regimens.

Neoadjuvant chemotherapy in breast cancer: a dose-dense schedule in real life and putative role of PIK3CA mutations.

BackgroundDose-dense chemotherapy is one of the treatments of choice for neoadjuvant therapy in breast cancer (BC). Activating mutations in PIK3CA gene predict worse response to neoadjuvant chemotherapy for HER2-positive patients, while their role is less clearly defined for HER2-negative tumors.MethodsWe conducted a phase I/II study of neoadjuvant, sequential, dose-dense anthracycline/taxane chemotherapy, plus trastuzumab in HER2-positive patients and investigated the correlation of pre-treatment PIK3CA mutation status with pathologic complete response (pCR) and long-term outcome in a real-life setting.Resultswe established a dose-dense docetaxel recommended dose of 60 mg/m2 and 65 mg/m2, with or without trastuzumab, respectively, according to HER2-status, following dose-dense epirubicin-cyclophosphamide (90/600 mg/m2), every 2 weeks. The overall pCR rate was 21.4%; median disease-free survival (DFS) was 52 months and median overall survival (OS) was not yet reached. PIK3CA mutation status was not significantly associated with the pCR rate: 18% for both mutated and wild-type patients. The pCR rate was: 25% in the mutated and 24% in the wild-type (p 0.560) cohort of the HER2-positive subgroup; 33% both in the mutant and wild-type cohort of the triple-negative subgroup; no pCR neither in the mutant nor in the wild-type cohort of the HR-positive/HER2-negative subgroup. Among the HER2-positive population, a trend toward worse DFS was observed in case of mutation, as opposed to the triple negative population.ConclusionsThis study proposes an effective and safe neoadjuvant dose-dense anthracycline/taxane schedule and suggests that PIK3CA mutation analysis can be usefully performed in real-life clinical practice.

Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in HER2-positive patients with metastatic gastric cancer.

HER2-overexpression in tumor tissue is observed in 6 to 23% of advanced gastric cancer (GC) cases, and trastuzumab is an active molecular drug for these patients. There are no data available on whether serum levels of ligands are associated with the response and resistance to trastuzumab in HER2-positive patients with metastatic GC. HER2 screening of 502 patients with advanced gastric cancer was performed in our institution. Among these patients, 84 patients (16.8%) were diagnosed as HER2-positive, and those who were treated with trastuzumab and met the inclusion criteria were enrolled in the present study. Serum levels of ligands that affect the HER2 signal pathway were measured by an enzyme-linked immunosorbent assay. Forty-six HER2-positive patients were enrolled in this study, and 26 patients (56.5%) achieved a partial response to treatment with trastuzumab. Among several ligands, the serum level of hepatocyte growth factor (HGF) was significantly lower in responders compared with that in non-responders (p = 0.014). Multivariate analyses showed that a high level of serum HGF was a poor prognostic factor for overall survival (OS) compared with low levels of HGF (adjusted HR: 3.857, 95% CI: 1.309–11.361, p = 0.014). Among 25 patients without initial disease progression on the treatment with trastuzumab, the mean value of serum HGF at disease progression was significantly higher than that at pre-treatment (p = 0.041). As novel findings, our study indicated that serum level of HGF was associated with tumor shrinkage and time to progression of trastuzumab in HER2-positive patients with metastatic GC.

1813 Interaction of TP53 mutations with trastuzumab in HER2-positive patients with operable breast cancer

1813 Interaction of TP53 mutations with trastuzumab in HER2-positive patients with operable breast cancer

Abstract P3-09-07: Prognostic value of immunophenotypically defined subtypes in patients treated with dose-dense sequential adjuvant chemotherapy in the trastuzumab era. A Hellenic Cooperative Oncology Group study

Abstract Background-Aim: The aim of the present study was to explore the efficacy of dose-dense sequential adjuvant chemotherapy followed by trastuzumab in HER2-positive patients according to the immunohistochemically (IHC) defined subtypes. Patients and methods: A total of 771 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples, prospectively collected from 990 eligible patients with high-risk N0 or N1 operable breast cancer participating in a phase III trial (HE10/05), were centrally assessed in tissue microarrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5) and EGFR. All cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low, N=382, 49.5%); luminal B (ER/PgR-positive, HER2-negative, Ki67high, N=136, 17.6%); luminal-HER2 (ER/PgR-positive, HER2-positive, N=125, 16.2%); HER2-enriched (ER-negative, PgR-negative, HER2-positive, N=63, 8.2%); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative, N=65, 8.4%); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive, N=53, 6.9%). Results: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) and overall survival (OS) rates for the total patient population were 88.3% and 96.0%, respectively. The 3-year DFS rates for luminal A, luminal B, luminal-HER2, HER2-enriched, TNBC and BCP patients were 91.1%, 88.2%, 86.4%, 93.7%, 87.7%, and 89.4%, respectively, while the corresponding 3-year OS rates were 95.8%, 95.6%, 97.6%, 95.2%, 95.4%, and 95.0%, respectively. No significant differences were detected for either 3-year DFS or OS in the immunohistochemically defined subtypes, except a trend for significantly worse DFS in patients with luminal-HER2 tumors compared to patients with HER2-enriched tumors (log-rank, p=0.069). Conclusions: In the post-trastuzumab era, at a relatively short follow-up, the luminal-HER2 patients show a trend for worse DFS compared to patients with HER2-enriched tumors treated with dose-dense sequential adjuvant chemotherapy followed by trastuzumab. No other significant differences were detected, with follow-up however being continued. Citation Format: George Fountzilas, Eleni Timotheadou, Georgia Gourgioti, Petroula Arapantoni-Dadioti, Sotiris Lakis, Anna Batistatou, Triantafyllia Koletsa, Olympia Tzaida, Mattheos Bobos, Alexandra Papoudou-Bai, Eleftheria Tsolaki, Sofia Chrisafi, Elena Fountzilas, Ioannis Efstratiou, Helen Gogas, Flora Zagouri, Dimitrios Pectasides. Prognostic value of immunophenotypically defined subtypes in patients treated with dose-dense sequential adjuvant chemotherapy in the trastuzumab era. A Hellenic Cooperative Oncology Group study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-07.

Analysis of neoadjuvant therapies in breast cancer with respect to pathological complete response, disease‐free survival and overall survival: 15 years follow‐up data from Kuwait

Optimizing neoadjuvant chemotherapy regimens is essential for achieving maximal pathological complete response (pCR) in patients with breast cancer. pCR is usually considered as a surrogate marker for survival. The aim of this study was to analyze pCR with respect to various neoadjuvant regimens and its effect on survival. This retrospective analysis included 377 patients with stages II and III breast cancer treated between 1998 and 2009 with neoadjuvant chemotherapy. Neoadjuvant regimens were analyzed with respect to pCR, disease-free survival (DFS) and overall survival (OS). The median age of our population was 50 years with the majority being premenopausal and locally advanced. The overall pCR rate was 13.7% with higher rates seen in patients receiving combination of anthracyclines and taxanes (14.2%). The practice of sandwiching surgery and chemotherapy was inferior to true neoadjuvant chemotherapy of eight cycles. Addition of trastuzumab to Her2 positive patients resulted in higher pCR rates (P = 0.006). Achievement of pCR with neoadjuvant chemotherapy resulted in significantly higher DFS and OS. pCR is associated with better survival in breast cancer patients receiving neoadjuvant chemotherapy. Initial anthracycline-based chemotherapy followed by non-cross-resistant taxane-based chemotherapy along with the addition of trastuzumab in Her2 positive patients might be the optimal neoadjuvant regimen in breast cancer patients.

TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab

To determine rates of pathologic complete response (pCR) and near-complete response (npCR) in operable early-stage breast cancer using neoadjuvant capecitabine plus docetaxel, with or without trastuzumab, and investigate biomarkers of pathologic response. Women with operable early-stage breast cancer were enrolled in a multicenter study of neoadjuvant therapy for four 21-day cycles with capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2) if human epidermal growth factor receptor 2 (HER2)-negative, and additionally, a standard trastuzumab dose if HER2-positive. Primary endpoint was rate of pCR and npCR. Secondary endpoints were potential associations between response and TP53 mutational analysis using the AmpliChip TP53 assay or immunohistochemical (IHC) staining, and genomic subtyping using the PAM50 assay. In patients who completed treatment and surgery, pCR and npCR rates were 15.8% in patients with HER2-negative and 50% in patients with HER2-positive tumors. Stratified by genomic subtype, patients of HER2-enriched subtype had the best response (72.2%), and luminal A (9.1%) and B (4.8%) subtypes, the poorest. Of 147 patients tested for TP53 mutations using the AmpliChip assay, 78 variants were detected; 55 were missense. Response rate among TP53-mutated patients was 30%, significantly higher than TP53 wild-type patients (10%; P = 0.0032). Concordance between AmpliChip mutation status versus TP53 IHC staining was 65%, with AmpliChip status predictive of response and IHC status not predictive. Capecitabine plus docetaxel in HER2-negative, and with trastuzumab in HER2-positive patients, provided a good response rate with four cycles of non-anthracycline-containing therapy. TP53 mutational analysis and genomic subtyping were predictive.

Abstract P2-02-11: Evaluation of Tumor Response Using 3T Breast MRI Following Neoadjuvant Albumin-Bound Paclitaxel and Carboplatin with Bevacizumab or Trastuzumab

Abstract PURPOSE: MRI is known as the most accurate imaging modality for evaluating the extent of residual disease following neoadjuvant chemotherapy (NAC). Although in general breast MRI is done at 1.5T, 3T can provide a better signal-to-noise ratio and may be more sensitive to detect residual disease. In this study the diagnostic performance of 3T MRI for NAC response was investigated. METHODS AND MATERIALS: In a period of 30 months, 42 NAC patients (29-83 y/o, mean 50 y/o) who received at least three MRI scans before, during and after therapy, and had surgery after completing NAC were analyzed in this study. The NAC protocol included albumin-bound paclitaxel, carboplatin and trastuzumab for HER-2 positive patients (N= 15), or bevacizumab for HER-2 negative patients (N=27). Some patients received doxorubicin and cyclophosphamide, bi-weekly for 4 cycles, as clinically indicated. Twenty-eight lesions were mass types and 14 showed non-mass-like enhancements. The residual tumor size was determined using the RECIST criteria, by measuring the longest dimension shown on MRI. When there was no enhancement (or, with a faint enhancement equal to the background normal tissue enhancement), the case was determined as complete clinical response (CCR). Pathological complete response (pCR) was defined as no residual invasive cancer cells, with or without DCIS. In cases with residual invasive cancer, the pathological size was determined as the longest dimension, either the longest dimension on H&amp;E-stained slide or from the number of blocks (each 5 mm) where the malignant invasive tumor was detected, whichever was greater. For residual tumor showing as scattered cancer cells/nests, the longest dimension was estimated from the involved blocks. RESULTS: MRI diagnosed 12 complete clinical response and 30 cases with residual cancers. In pathological examination, 12 were pCR (29%). Overall, comparing MRI diagnosis to pCR diagnosis, there were 27 true positive, 9 true negative, 3 false negative, and 3 false positive. The three false positive cases all had residual DCIS-so although MRI did not predict pCR it correctly diagnosed residual DCIS. The three false negative cases were all non-mass lesions, in which pathology showed scattered small cancer foci in 3, 14, and 14 cm areas, respectively. The sensitivity, specificity, and accuracy of MRI were 90%, 75%, and 86%. Overall, the correlation between MRI and pathologic size was higher for mass lesions than for non-mass-like lesions (r=0.80 vs. r=0.67), and similar between Her-2 positive and negative lesions (r=0.82 vs. r=0.84). The discrepancy between MRI and pathological size was larger for non-mass lesions than for mass lesions (0.6-14 cm vs. 0-3 cm). CONCLUSIONS: Similar to 1.5T, high resolution 3T MRI has limitations for the non-mass-like lesions that break into small foci and scattered cells. This might be due to that small tumor foci have lowered angiogenic activity, limiting MR contrast agent uptake, thus lowering the detection rate. For mass lesions, MR residual tumor size was highly correlated with pathological size. Understanding the accuracy and limitations of 3T MRI for NAC patients may aid in designing an improved NAC protocol and a better surgical planning. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-11.

A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-stage breast cancer

nab-Paclitaxel has shown favorable efficacy and toxicity profiles compared to other taxanes in the treatment of metastatic breast cancer. In this pilot trial, we evaluated a nab-paclitaxel-containing adjuvant regimen in patients with early stage breast cancer. Patients with node-positive or high-risk node-negative early-stage breast cancer were eligible following completion of standard primary therapy. All the patients received four cycles, at 21-day intervals, of nab-paclitaxel (100 mg/m(2) IV days 1, 8, and 15) and cyclophosphamide (600 mg/m(2) IV day 1). HER2-positive patients also received trastuzumab 8 mg/kg IV on cycle 1 day 1, followed by 6 mg/kg every 21 days for a total of 52 weeks. The purpose of this trial was to evaluate feasibility and toxicity of this nab-paclitaxel-containing adjuvant regimen. 62 patients were treated between 2/08 and 11/08. The majority of the patients (87%) were HER2-negative. This adjuvant regimen was well tolerated, and full doses of all agents were administered in >90% of cycles. Grade 3/4 neutropenia occurred in 53% of the patients; however, only one episode of febrile neutropenia occurred in a total of 249 cycles administered. Other grade 3/4 adverse events occurred in less than 5% of patients. After short follow-up, all the patients remain alive and disease-free. The combination of nab-paclitaxel and cyclophosphamide, with or without trastuzumab, is feasible and well tolerated in patients with early stage breast cancer. Further investigation of the role of nab-paclitaxel in adjuvant breast cancer therapy is indicated, but definitive evaluation will require randomized phase III trials.

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.

Improved Prognosis by Trastuzumab of Women With HER2-Positive Breast Cancer Compared With Those With HER2-Negative Disease

TO THE EDITOR: We have read with great interest the article by Dawood et al, and we think that the findings reported by the authors deserve some comments. Between June 2000 and January 2004, we consecutively enrolled 68 women with metastatic breast cancer: 33 patients received vinorelbine alone, while 35 patients were given trastuzumab plus vinorelbine according to human epidermal growth factor receptor-2 (HER2) expression determined by immunohistochemistry. This was formally a phase II study, which demonstrated that women with HER2-overexpressing metastatic breast cancer when treated with trastuzumab and vinorelbine had a better prognosis than those with HER2-negative disease treated with vinorelbine alone. In our study, the vast majority of patients received chemotherapy for metastatic disease. No one had previously received vinorelbine and only three women with HER2-positive disease had previously received trastuzumab for metastatic disease. Thus, by our findings, we provocatively suggested that the assumption that HER2positive tumors have a worse prognosis could be no longer valid when treated with trastuzumab. In fact, with the use of trastuzumab, women with HER2-positive disease appeared to do far better than did patients with HER2-negative tumors, exhibiting consistently higher rates of response, longer time to progression, and improved overall survival. Given that HER2-positive breast cancer is being treated as a distinct clinical entity, we cannot include women with HER2-positive breast cancer in trials recruiting patients regardless of HER2 status. Our study was criticized because it lacked a randomization plan. But, because in HER2-positive tumors chemotherapy alone as first-line treatment has been replaced with a combination of chemotherapy and trastuzumab, a trial without trastuzumab in HER2-positive patients with breast cancer would be ethically inappropriate. Thus, a prospective comparison between patients treated for HER2-positive disease and women treated for HER2-negative breast cancer can be formally performed only as a phase II study, in which consecutively enrolled patients with metastatic breast cancer are treated with chemotherapy with or without trastuzumab, according to HER2 status. Decades of randomized clinical trials on the first-line treatment of metastatic breast cancer have never been able to show so remarkable differences in time to progression and overall survival as the three fundamental randomized trials comparing chemotherapy with chemotherapy plus trastuzumab in women with HER2overexpressing metastatic breast cancer have been able to do. The merit of the study by Dawood et al is to have retrospectively compared the prognosis of three groups of patients: women with metastatic HER2-positive breast cancer with and without the addition of trastuzumab with women with HER2-negative disease. We agree with the authors that trastuzumab has not only beneficially changed the natural history of HER2-positive breast cancer, but it has also improved the prognostic outcomes of women with HER2overexpressing tumors beyond those of women with HER2negative disease.

Circulating tumor cells (CTCs) detection in a randomized phase II trial of neoadjuvant chemotherapy for large operable and locally advanced breast cancer (REMAGUS 02): Preliminary results

10637 Background: The presence of CTCs in blood from metastatic breast cancer patients before first line chemotherapy and persistence of CTCs after initiation of treatment, are predictive of shorter overall survival (Cristofanilli M; et al, 2005, J Clin Oncol 23:1420–1430). CTCs could be used as a surrogate marker. The aim of this study was to determine if CTC were present in the blood of patients who received neoadjuvant chemotherapy (CT) for large operable and locally advanced breast cancer, before initiation of CT (preCT) and at the end of CT before surgery (postCT). Methods: 7.5 ml of blood were obtained on CellSave tube from patients included in an ongoing randomized phase II trial. All patients received 4 cycles of Epirubicin-Cyclophosphamide every 3 weeks followed by 4 cycles of docetaxel associated with or not trastuzumab for HER2 positive patients and with or not celecoxib for HER2 negative patients. CTCs were immunomagnetically separated and fluorescently stained with the CellSearch kit. Cells were classified using the CellSpotter Analyzer as CTCs if they stained positive for DAPI (nuclear dye), and cytokeratin 8, 18 and 19, and if they stained negative for the leucocyte-specific antibody CD45. Results: From 10/2004 to 12/2005, preCT blood samples were obtained in 60 patients, analyzed in 56 for technical reasons. At least one CTC was detected in 15/56 (27%, CI 95%: 15.5–38.5%), 1 to 17 cells per sample (median 1.5). With a threshold of 2 cells, 8/56 (14%, CI 95%: 5–23%) patients were classified positive. At time of analysis, pre CT and post CT samples from the same patient were available for 19 patients. Six had &gt;1 CTC/sample before CT (31.5%) and only one (1/6, 17%) remained positive after CT. Thirteen were negative for CTC before CT and 2/13 (15%) became positive after CT, with only one cell per sample. Conclusions: CTCs can be detected in blood of patients with large operable or locally advanced breast cancer before initiation of neoadjuvant CT and can be monitored during treatment. Longer follow-up and a larger number of patients are expected before correlating these data with tumor response and survival. No significant financial relationships to disclose.

Ongoing trials with trastuzumab in metastatic breast cancer

Following the pivotal clinical trials of trastuzumab (Herceptin), further phase II and III studies have been initiated. Preliminary results from a phase II, dose-response study of single-agent trastuzumab in 113 HER2-positive metastatic breast cancer patients without prior chemotherapy for stage IV disease have shown that the overall response rate was 23% (six complete responses and 20 partial responses), with similar results using both standard- and high-dose regimens of trastuzumab. Another phase II study of trastuzumab plus paclitaxel, both given weekly, in 63 HER2-positive and -negative patients with metastatic breast cancer produced an overall response rate of 62% in HER2-positive and 44% in HER2-negative patients. A further phase II study is underway to investigate the combination of trastuzumab plus docetaxel in 30 HER2-positive patients with metastatic breast cancer. Finally, a number of European studies are at an advanced stage of planning or are about to start patient recruitment. These include docetaxel +/- trastuzumab, aromatase inhibitor +/- trastuzumab, CMF (cyclophosphamide, methotrexate, 5-fluorouracil) +/- trastuzumab, vinorelbine + trastuzumab, all in HER2-positive patients, and epirubicin-cyclophosphamide (EC) + trastuzumab in HER2-positive patients vs. EC alone in HER2-negative patients. The results from these trials should be available over the next one to two years.