HER2 and Response to Paclitaxel in Node-Positive Breast Cancer

Duke University, Durham, North Carolina, United States
New England Journal of Medicine (Impact Factor: 55.87). 10/2007; 357(15):1496-506. DOI: 10.1056/NEJMoa071167
Source: PubMed


The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both.
We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed.
No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor-positive cancers.
The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor-positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide.

Download full-text


Available from: Matthew J Ellis, Sep 15, 2015
  • Source
    • "Conversely, HER-2 positive/HR negative tumors relapse more commonly within the first 5 years. Moreover, sites of relapse are different, since bone and soft tissue are more common in ER positive disease, conversely, visceral sites are more frequently observed in ER negative subset, and sensitivity to some chemotherapy drugs, i.e. paclitaxel, may be different between the two subsets [57] [58] [59]. A recent evaluation of 1187 early breast cancers compared disease characteristics among different groups according to HR and HER-2 status. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is a heterogeneous disease, and within the HER-2 positive subtype this is highly exemplified by the presence of substantial phenotypical and clinical heterogeneity, mostly related to hormonal receptor’s (HR) expression. It is well known how HER-2 positivity is commonly associated with a more aggressive tumor phenotype and decrease overall survival and, moreover, with a reduced benefit from endocrine treatment. Preclinical studies corroborate the role played by functional crosstalks between HER-2 and estrogen receptor (ER) signaling in endocrine resistance and, more recently, the activation of ER signaling is emerging as a possible mechanism of resistance to HER-2 blocking agents. Indeed, HER-2 positive breast cancer heterogeneity has been suggested to underlie the variability of response not only to endocrine treatments, but also to HER-2 blocking agents. Among HER-2 positive tumors, HR status probably defines two distinct sutypes, with dissimilar clinical behaviour and different sensitivity to anticancer agents. The triple positive subtype, namely, ER/PgR/Her-2 positive tumors, could be considered the subset which most closely resembles the HER-2 negative/HR positive tumors, with substantial differences in biology and clinical outcome. We argue on whether in this subgroup the “standard” treatment may be considered, in selected cases, i.e., small tumors, low tumor burden, high expression of both hormonal receptors, an overtreatment. This article review the existing literature on biologic and clinical data concerning the HER-2/ER/PgR positive tumors, in an attempt to better define the HER-2 subtypes and to optimize the use of HER-2 targeted agents, chemotherapy and endocrine treatments in the various subsets.
    Full-text · Article · Dec 2014 · Cancer Treatment Reviews
  • Source
    • "It is difficult to define the chemotherapy benefit on the treatment of HER2-negative breast cancer, however, recent reports on the clinical benefit of adding 3-weeks treatment with taxanes to anthracycline-based postoperative chemotherapy in HER2-negative patients have indicated little or no benefit from taxanes.29 Our CDK1-based method of assessing SAC functionality may be useful for identifying which subset of patients with HER2-negative breast cancer actually would benefit from postoperative chemotherapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Taxanes are among the drugs most commonly used for preoperative chemotherapy for breast cancer. Taxanes induce mitotic arrest and subsequent apoptosis. The spindle-assembly checkpoint (SAC) is known to be activated during mitosis, along with cyclin-dependent kinase-1 (CDK1), and is required for taxane-induced cell death. We hypothesized that CDK1 activity predicts response to taxane-containing chemotherapy. This study included breast cancer patients who received preoperative chemotherapy— taxane-containing treatment followed by anthracycline-based treatment—and then underwent surgery. Before starting taxane-containing chemotherapy, patients underwent fine-needle aspiration biopsy, and the biopsy samples were incubated in paclitaxel solution to measure CDK activity. Clinical were evaluated after taxane therapy, and pathological resposes were evaluated after completion of all preoperative chemotherapy. Thirty five patients were eligible for analysis of clinical response to taxane-containing therapy. Twenty-six patients had taxane-sensitive and 9 taxane-resistant tumors. Using a cut-off of CDK activity determined by the ROC analysis, patients were classified into SAC function and dysfunction groups. Univariate logistic regression analysis with clinicopathologic parameters showed that only CDK-based SAC functionality was significantly correlated with clinical response (P =0.017). No significant correlation was observed between SAC functionality and pathologic response. CDK-based SAC functionality significantly predicted clinical response (P =.0072, overall agreement = 71.4%), and this is a unique mechanism-based marker for predicting taxane chemosensitivity. Further, large prospective study is needed to determine CDK-based SAC functionality could be developed as a predictive biomarker.
    Full-text · Article · Nov 2013 · Journal of Cancer
  • Source
    • "With no confirmed single oncogenic driver, TNBC is not amenable to treatment with currently approved targeted approaches, such as trastuzumab or endocrine therapy, making chemotherapy treatment the main systemic treatment option. Evidence from studies of taxane-based chemotherapy regimens have indicated that patients with TNBC derive greater benefit from regimens that include a taxane than those that do not [6-8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral PARP inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients who had received <=1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for 3 weeks per 4-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade >=2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). 19 patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade >=3) and four in cohort 2 (two grade >=3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26--100%) in cohort 1 and 73% (29--100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca;, NCT00707707).
    Full-text · Article · Sep 2013 · Breast cancer research: BCR
Show more