Smith I, Procter M, Gelber RD et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial. Lancet 369: 29-36

Dana-Farber Cancer Institute, Boston, Massachusetts, United States
The Lancet (Impact Factor: 45.22). 02/2007; 369(9555):29-36. DOI: 10.1016/S0140-6736(07)60028-2
Source: PubMed


Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study.
HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11.
97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001).
Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

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    • "Gene amplification or protein overexpression of the human epidermal growth factor receptor type 2 (HER2) has been reported in w20% of invasive breast cancer (BC) and is usually associated with worse prognosis (Slamon et al., 1987, 1989). The monoclonal antibody trastuzumab has dramatically increased survival in patients with HER2-overexpressing metastatic disease (Hudis, 2007; Slamon et al., 2001) and has often proved curative when used in combination with chemotherapy in the adjuvant setting (Joensuu et al., 2006; Piccart- Gebhart et al., 2005; Romond et al., 2005; Smith et al., 2007). "
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    ABSTRACT: Introduction: Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. Methods: Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. Results: Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. Conclusion: Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy.
    Full-text · Article · Sep 2015 · Molecular oncology
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    • "There are many candidates of targeting ligands, such as folate (Yoo and Park, 2004), aptamers (Gu et al., 2008), and antibodies (Wartlick et al., 2004). Herceptin 1 (Trastuzumab, Genentech) is a humanized antibody which specifically binds to Human Epidermal growth factor Receptor 2 (HER2/neu) and has been approved by FDA for the treatment of HER2-positive (HER2+) early-stage breast cancer and metastatic breast cancer (Hudis, 2007; Piccart-Gebhart et al., 2005; Smith et al., 2007). In addition, Herceptin and its fragments have also been conjugated to various drug carriers for active targeting against HER2 overexpressed breast cancer cells (Kim et al., 2011; Kirpotin et al., 2006; Zhao et al., 2012). "
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    ABSTRACT: A dual functional nano-scaled drug carrier, comprising of a targeting ligand and pH sensitivity, has been made in order to increase the specificity and efficacy of the drug delivery system. The nanoparticles are made of a tri-block copolymer, poly(D,L lactide-co-glycolide) (PLGA)-b-poly(L-histidine) (PHis)-b-polyethylene glycol (PEG), via nano-precipitation. To provide the nanoparticle feature of endolysosomal escape and pH sensitivity, poly(L-histidine) was chosen as a proton sponge polymer. Herceptin, which specifically binds to HER2 antigen, was conjugated to the nanoparticles through click chemistry. The nanoparticles were characterized via dynamic light scattering (DLS) and transmission electron microscopy (TEM). Both methods showed the sizes of about 100nm with a uniform size distribution. The pH sensitivity was assessed by drug releases and size changes at different pH conditions. As pH decreased from 7.4 to 5.2, the drug release rate accelerated and the size significantly increased. During in vitro tests against human breast cancer cell lines, MCF-7 and SK-BR-3 showed significantly increased uptake for Herceptin-conjugated nanoparticles, as compared to non-targeted nanoparticles. Herceptin-conjugated pH-sensitive nanoparticles showed the highest therapeutic effect, and thus validated the efficacy of a combined approach of pH sensitivity and active targeting. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Apr 2015 · International Journal of Pharmaceutics
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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.
    Full-text · Article · Mar 2015 · Contemporary Clinical Trials
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