Adjuvant Docetaxel or Vinorelbine with or without Trastuzumab for Breast Cancer

University of Helsinki, Helsinki, Uusimaa, Finland
New England Journal of Medicine (Impact Factor: 55.87). 02/2006; 354(8):809-20. DOI: 10.1056/NEJMoa053028
Source: PubMed

ABSTRACT We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment.
We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival.
Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure.
Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).

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    • "Enrichment designs have been widely discussed to establish treatment benefit in a selected (enriched) subpopulation [1] [2] [3] [4] [5] [6] [7] and are closely related to FDA's initiative on personalized medicine [8]. One purpose to select such enriched population is for better treatment response potential, for example the trastuzumab benefit on HER2+ breast cancer patients [9] [10] [11] [12]. "
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    ABSTRACT: Clinical trials can be enriched on subpopulations that may be more responsive to treatments to improve the chance of trial success. In 2012 FDA issued a draft guidance to facilitate enrichment design, where it pointed out the uncertainty on the subpopulation classification and on the treatment effect outside of the identified subpopulation. We consider a novel design strategy where the identified subpopulation (biomarker-positive) is augmented by some biomarker-negative patients. Specifically, after sufficiently powering biomarker-positive subpopulation we propose to enroll biomarker-negative patients, enough to assess the overall treatment benefit. We derive a weighted statistic for this assessment, correcting for the disproportionality of biomarker-positive and biomarker-negative subpopulations under enriched trial setting. Screening information is utilized for weight determination. This statistic is an unbiased estimate of the overall treatment effect as that in all-comer trials, and is the basis to power for the overall treatment effect. For analysis, testing will be first performed on biomarker-positive subpopulation; only if treatment benefit is established in this subpopulation will overall treatment effect be tested using the weighted statistic. This design approach differs from typical enrichment design or stratified all-comer design in that the former enrolls only biomarker-positive patients and the latter enrolls a regular all-comer population. It also differs from adaptive enrichment by maintaining the trial design and analysis priority on biomarker-positive subpopulation. Therefore the proposed approach not only warrants a high probability of trial success on biomarker-positive subpopulation, but also efficiently assesses the overall treatment effect in the presence of an uncertain treatment benefit among biomarker-negative patients. Copyright © 2015. Published by Elsevier Inc.
    Contemporary Clinical Trials 03/2015; 42. DOI:10.1016/j.cct.2015.02.010 · 1.94 Impact Factor
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    • "The approval was based on evidence of a significant prolongation in disease-free survival in women receiving trastuzumab and chemotherapy compared to those receiving chemotherapy alone. Table 2 shows five pivotal trials involving more than 10,000 women which demonstrated that one year of trastuzumab therapy provided significant clinical benefit [63–66]. These trials demonstrated that inclusion of trastuzumab produces roughly a 50% improvement in disease-free survival and 33% improvement in overall survival, regardless of the chemotherapy regimen or sequence of trastuzumab delivery. "
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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2.
    09/2014; 2014:852748. DOI:10.1155/2014/852748
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    • "Study material consisted of DNA and formalin-fixed, paraffin-embedded tissue samples from primary tumors of 1010 women with high-risk early breast cancer who participated in the adjuvant phase III FinHer trial (International Standard Ran- domised Controlled Trial number, ISRCTN76560285) [18]. The key inclusion criteria in the FinHer trial were histologically confirmed invasive breast cancer, age 65 or less, macroscopically complete surgery for breast cancer, presence of at least one positive axillary lymph node or a node-negative breast cancer with tumor diameter at least 20 mm and a negative immunostaining for progesterone steroid hormone receptors. "
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    ABSTRACT: A number of genetic variants have been linked to increased risk of breast cancer. Little is, however, known about the prognostic significance of hereditary factors. Here, we investigated the frequency and prognostic significance of two ERBB4 promoter region variants, -782G>T (rs62626348) and -815A>T (rs62626347), in a cohort of 1010 breast cancer patients. The frequency of nine previously described somatic ERBB4 kinase domain mutations was also analyzed. Clinical material used in the study consisted of samples from the phase III, adjuvant, FinHer breast cancer trial involving 1010 women. Tumor DNA samples were genotyped for ERBB4 variants and somatic mutations using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Paraffin-embedded tumor sections from all patients were immunohistochemically stained for ErbB4 expression. Association of ERBB4 genotype to distant disease-free survival (DDFS) was assessed using Kaplan-Meier and Cox regression analyses. Genotyping was successful for 91-93% of the 1010 samples. Frequencies observed for the ERBB4 variants were 2.5% and 1.3% for -782G>T and -815A>T, respectively. Variant -815A>T was significantly associated with poor survival (HR = 2.86 [95% CI 1.15-6.67], P = 0.017). In contrast, variant -782G>T was associated with well-differentiated cancer (P = 0.019). Two (0.2%) ERBB4 kinase domain mutations were found, both of which have previously been shown to be functional and promote cancer cell growth in vitro. These data present the germ-line ERBB4 variant -815A>T as a novel prognostic marker in high-risk early breast cancer and indicate the presence of rare but potentially oncogenic somatic ERBB4 mutations in breast cancer.
    PLoS ONE 07/2014; 9(7):e102388. DOI:10.1371/journal.pone.0102388 · 3.23 Impact Factor
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