Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With Paclitaxel

Leyland‐Jones, Brian; Gelmon, Karen A.; Ayoub, Jean-Pierre; Arnold, Andrew; Verma, S.; Dias, Reg; Ghahramani, Parviz

doi:10.1200/jco.2003.12.109

Cited by 273 publications

(118 citation statements)

References 20 publications

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“…The results of our study show that pharmacokinetics of cyclophosphamide, cisplatin, and BCNU, administered at high doses, are not altered in the presence of trastuzumab. Previous reports indicated that the pharmacokinetics of trastuzumab are not affected by the presence of chemotherapy drugs (46,47).…”

Section: Discussionmentioning

confidence: 99%

Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Nieto

Vredenburgh

Shpall

et al. 2004

Clinical Cancer Research

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Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2؉ advanced breast cancer.Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as >4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day ؊5), HDC (days ؊5 to ؊2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day ؉1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days ؉20 and ؉65.Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day ؊4, responsive to treatment.Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively.Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

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Section: Discussionmentioning

confidence: 99%

Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Nieto

Vredenburgh

Shpall

et al. 2004

Clinical Cancer Research

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“…This is particularly important, given the cardiotoxic side effects of trastuzumab seen in approximately 1.4% of patients receiving the drug as a single agent, 36,42,43 and even in higher percentages of patients receiving trastuzumab concomitantly with paclitaxel (13%) or anthracyclines (27%), 37 as well as the high cost of the drug. 44,45 HER2 IHC poses even greater challenges than does ER IHC, as both accurate as well as semi-quantitative assessment of the results of HER2 immunostaining are critical.…”

Section: Part 2: Human Epidermal Receptor Protein-2mentioning

confidence: 99%

Current issues in ER and HER2 testing by IHC in breast cancer

2008

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The presence of estrogen receptors (ERs), as detected by immunohistochemistry (IHC), is a weak prognostic marker of clinical outcome in breast cancer, but a strong predictive marker for response, for example, to tamoxifen-based therapy. As with all IHC markers, factors such as tissue fixation (both type and duration), the choice of antibody, and the threshold for interpretation of positive immunostaining can dramatically affect test accuracy and reproducibility. For example, optimal fixation for detection of ER requires at least 6-8 h in formalin, and the use of newer antibodies such as SP1 may identify additional patients who might benefit from hormonal therapy. Although the threshold for positivity may be as few as 1% of tumor cells showing nuclear signal, recent studies appear to demonstrate a dichotomization of ER IHC, with the vast majority of cases showing all positive or all negative results. This may be helpful in dictating the appropriateness of hormonal therapy, but quantification of ER by IHC, or other methods, may play a more important role in the future. Breast cancers with human epidermal receptor protein-2 (c-erbB-2; HER2) alterations are critical to identify because such tumors require unique treatment, including the use of targeted therapies such as trastuzumab. HER2 alterations at the DNA (amplification) and protein (overexpression) level usually occur in concert, and both fluorescence in situ hybridization (FISH) or IHC can be accurate methods to assess these alterations. However, recent studies have suggested that serious reproducibility issues exist in both FISH and IHC HER2 studies. To address this, a joint committee of both the American Society for Clinical Oncologists and the College of American Pathologists has promulgated new guidelines for HER2 testing. These include the following: (a) recommendations for tissue fixation for more than 6 and less than 48 h; (b) new scoring criteria, including a new threshold of 30% strong immunostaining for classification of 3 þ ; (c) introduction of the term 'equivocal' to characterize HER2 studies that are 2 þ by IHC and/or show HER2/chromosome 17 ratios of between 1.8 and 2.2 by FISH; (d) requirements for laboratories to validate HER2 assays, generally through the cross-testing of cases with another HER2 methodology, with laboratories required to attain 95% concordance for both positive and negative tests; (e) participation in HER2 proficiency testing.

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“…This is particularly important given the cardiotoxic side effects of trastuzumab seen in approximately 1.4% of patients receiving the drug as a single agent, 10,16,17 and in even higher percentages of patients receiving trastuzumab concomitantly with paclitaxel (13%) or anthracyclines (27%), 11 as well as the high cost of the drug. 18,19 Although a tight association between HER2 gene amplification and protein overexpression has been documented in breast cancers by western and northern blot analyses, 20 Press et al 21 have demonstrated that immunohistochemistry (IHC) on deparaffinized, formalin-fixed tissue can be quite variable in its ability to identify HER2-amplified tumors.…”

mentioning

confidence: 99%

High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system

Gown¹,

Goldstein²,

Barry³

et al. 2008

Modern Pathology

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The American Society of Clinical Oncologists and College of American Pathologists have recently released new guidelines for laboratory testing of HER2 status in breast cancer, which require high levels (95%) of concordance between immunohistochemistry positive (3 þ ) and fluorescence in situ hybridization-amplified cases, and between immunohistochemistry negative (0/1 þ ) and fluorescence in situ hybridization-nonamplified cases; these required levels of concordance are significantly higher than those found in most published studies. We tested the hypothesis that a modification of the HER2 immunohistochemistry scoring system could significantly improve immunohistochemistry and fluorescence in situ hybridization concordance. A total of 6604 breast cancer specimens were evaluated for HER2 status by both immunohistochemistry and fluorescence in situ hybridization using standard methodologies. Results were compared when the standard immunohistochemistry scoring system was replaced by a normalized scoring system in which the HER2 score was derived by subtracting the score on the non-neoplastic breast epithelium from that on the tumor cells. Among the 6604 tumors, using a non-normalized immunohistochemistry scoring system, 267/872 (30.6%) of the immunohistochemistry 3 þ cases proved to be fluorescence in situ hybridization nonamplified, whereas using the normalized scoring system only 30/562 (5.3%) of immunohistochemistry 3 þ cases proved to be 'false positive'. The concordance rate between immunohistochemistry 3 þ and fluorescence in situ hybridizationamplified cases using the normalized scoring method was 94.7%, whereas the concordance using the non-normalized method was only 69.4%. Extremely high concordance between immunohistochemistry and fluorescence in situ hybridization assessment of HER2 status in breast cancer is achievable, but to attain this high level of concordance, modification of the FDA-approved immunohistochemistry scoring system is required.

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Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With Paclitaxel

Cited by 273 publications

References 20 publications

Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Current issues in ER and HER2 testing by IHC in breast cancer

High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system

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