HER2 and Response to Paclitaxel in Node-Positive Breast Cancer

Duke University, Durham, North Carolina, United States
New England Journal of Medicine (Impact Factor: 54.42). 10/2007; 357(15):1496-506. DOI: 10.1056/NEJMoa071167
Source: PubMed

ABSTRACT 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.

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    • "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. "
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    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.
    Cancer Treatment Reviews 12/2014; 41(2). DOI:10.1016/j.ctrv.2014.12.005 · 6.47 Impact Factor
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    • "This observation should be attributed to the incorporation of taxanes (both docetaxel and paclitaxel), which was the main difference between the two regimens; whether this effect represents a greater sensitivity of CTCs to taxanes or it is an additive effect of the chemotherapy agents is unknown. This observation is in agreement with several recent clinical data indicating the superiority of taxane-containing regimens in the adjuvant setting and could be explained by the fact that incorporation of taxanes in the adjuvant treatment is more pronounced in patients with HER2-positive tumours (Hayes et al, 2007; Ellis et al, 2009). Several studies have shown that CTCs express HER2/c-neu (Wulfing et al, 2010) irrespectively of the HER2 status of the primary tumours (Pestrin et al, 2009). "
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    ABSTRACT: Background: To determine the effect of adjuvant taxane-free and taxane-based chemotherapy regimens on the elimination of circulating tumour cells (CTCs) in patients with early breast cancer. Methods: The presence of CK-19 mRNA-positive CTCs in the peripheral blood was evaluated before and after chemotherapy, using a real-time RT–PCR assay, in a historical comparison of two cohorts of women with stage I–III breast cancer treated with adjuvant taxane-free (N=211; FE75C or E75C) and taxane-based (N=334; T/E75C or T/E75) chemotherapy. Results: Taxane-based chemotherapy resulted in a higher incidence of CTCs' elimination than taxane-free regimens since 49.7% (74 of 149) and 33.0% (29 of 88) of patients with detectable CTCs before chemotherapy, respectively, turned negative post-chemotherapy (P=0.015). Patients treated with taxane-free regimens had a significantly lower disease-free survival (DFS) (P=0.035) than patients treated with taxane-based regimens; this difference was observed in patients with but not without detectable CTCs before chemotherapy (P=0.018 and P=0.481, respectively). The incidence of deaths was significantly higher in the taxane-free cohort of patients with but not without detectable CTCs before chemotherapy compared with that of the taxane-based cohort (P=0.002). Multivariate analysis revealed that the chemotherapy regimen was significantly associated with prolonged DFS (HR: 2.00; 95% CI=1.20–3.34). Conclusion: Elimination of CK-19 mRNA-positive CTCs during adjuvant chemotherapy seems to be an efficacy indicator of treatment and is associated with a favourable clinical outcome of patients with detectable CTCs before chemotherapy.
    British Journal of Cancer 01/2013; 108(3). DOI:10.1038/bjc.2012.597 · 4.82 Impact Factor
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    • "Despite initial reports that TNBC might not ben - efit from taxanes , the addition of paclitaxel to AC ( doxorubicin , cyclophosphamide ) was associated with increased disease - free survival ( DFS ) rates ( p = 0 . 002 ) in patients with TNBC [ Hayes et al . 2007 ] . This benefit has also been confirmed by other groups both in node - positive and node - negative TNBC patients [ Hugh et al . 2009 ; Martin et al . 2010 ; Roche et al . 2006 ] ."
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    ABSTRACT: The so-called triple-negative breast cancer, as defined by tumors that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression, has generated growing interest in recent years despite representing less than 20% of all breast cancers. These tumors constitute an important clinical challenge, as they do not respond to endocrine treatment and other targeted therapies. As a group they harbor an aggressive clinical phenotype with early development of visceral metastases and a poor long-term prognosis. While chemotherapy remains effective in triple-negative disease, research continues to further identify potential new targets based on phenotypical and molecular characteristics of these tumors. In this respect, the presence of a higher expression of different biomarkers including epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and Akt activation has led to a proliferation of clinical trials assessing the role of inhibitors to these pathways in triple-negative tumors. Moreover, the described overlap between triple-negative and basal-like tumors, and the similarities with tumors arising in the BRCA1 mutation carriers has offered potential therapeutic avenues for patients with these cancers including poly (ADP-ribose) polymerase inhibitors and a focus on a higher sensitivity to alkylating chemotherapy agents. Results from these trials have shown some benefit in small subgroups of patients, even in single-agent therapy, which reflects the heterogeneity of triple-negative breast cancer and highlights the need for a further subclassification of these types of tumors for better prognosis identification and treatment individualization.
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