Weekly Trastuzumab and Paclitaxel Therapy for Metastatic Breast Cancer With Analysis of Efficacy by <i>HER2</i> Immunophenotype and Gene Amplification

Seidman, Andrew D.; Fornier, Monica; Esteva, Francisco J.; Tan, Lee K.; Kaptain, Stamatina; Bach, Ariadne M.; Panageas, Katherine S.; Arroyo, Crispinita D.; Valero, Vicente; Currie, Violante E.; Gilewski, Teresa; Theodoulou, Maria; Moynahan, Mary Ellen; Moasser, Mark M.; Sklarin, Nancy T.; Dickler, Maura N.; D’Andrea, Gabriella; Cristofanilli, Massimo; Rivera, Edgardo; Hortobágyi, Gabriel N.; Norton, Larry; Hudis, Clifford A.

doi:10.1200/jco.2001.19.10.2587

Cited by 513 publications

(310 citation statements)

References 25 publications

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“…Although this agent is only active in a minority (30%) of Her-2 þ tumors, treatments that enhance the activity of Herceptin should improve therapeutic outcome for a greater number of Her-2 þ patients. [5][6][7][8][9][10] In this study, we have used the novel approach of combining a gene drug (Ad-mda7) with the biological agent, Herceptin, and evaluated its antitumor effects against breast cancer cells. Preliminary results of this study have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7] In these studies, Herceptin has shown additive antitumor activity, and statistically significant survival benefit, and is now being integrated into the adjuvant and neoadjuvant setting. [5][6][7][8][9][10] Trastuzumab plus taxanes is the only combination indicated for the treatment of patients with MBC whose tumors overexpress Her-2 and as a single agent in women with Her-2-overexpressing MBCs resistant to chemotherapy. Although a subset of patients treated has shown cardiotoxicity, Herceptin is a generally well-tolerated drug and side effects that are commonly seen with chemotherapy are rarely observed.…”

Section: Introductionmentioning

confidence: 99%

“…Although a subset of patients treated has shown cardiotoxicity, Herceptin is a generally well-tolerated drug and side effects that are commonly seen with chemotherapy are rarely observed. [5][6][7][8][9][10][11][12][13][14] However, Herceptin shows activity in only 30% of Her-2 þ breast cancers -the reason why only a minority of tumors respond is not known.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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The melanoma differentiation-associated gene-7 (mda-7) is a member of the interleukin-10 cytokine family and a novel tumor suppressor gene. Adenoviral-mediated mda-7 (Ad-mda7) gene transfer has tumor-specific growth inhibitory and proapoptotic effects in a broad spectrum of cancer cells. In breast cancer cells, adenoviral-induced mda-7 expression triggers antiproliferative effects by downregulation of survival signals, such as Bcl-2 and Akt. The anti-human epidermal growth factor receptor-2 (Her-2) monoclonal antibody, Trastuzumab (Herceptin), increases the sensitivity of Her-2/neu-overexpressing breast cancer cells to chemotherapeutic agents and radiotherapy. In this study, we evaluate the effects of treatment with Ad-mda7 and Herceptin combination therapy in a panel of Her-2/neu-overexpressing cell lines, and in established tumors in nude mice. Compared to individual treatments, the combination of Ad-mda7 and Herceptin elicits supra-additive antitumor activity in Her-2/neuoverexpressing tumor cell lines: increased cell death, cell cycle block and apoptosis. The Ad-mda7 and Herceptin interaction was shown to be synergistic by isobologram analysis. Ad-mda7 does not alter cell surface Her-2/neu levels, but the combination of Ad-mda7 þ Herceptin results in increased expression of cell surface E-cadherin with concomitant translocation of b-catenin from the nucleus to the cell membrane. In vivo, the combination of Ad-mda7 and Herceptin showed significantly increased antitumor activity (Po0.003) against Her-2/neu-overexpressing tumors. These data suggest that the combination of Ad-mda7 with Herceptin may be a novel therapy for breast cancer patients whose tumors overexpress Her-2/neu. The observed synergistic effect may improve treatment options for otherwise poorly responsive, Her-2-positive, breast cancer patients. Cancer Gene Therapy (2006) 13, 958-968.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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“…In addition, the majority of patients who initially respond to Trastuzumab demonstrate disease progression within 1 year of treatment initiation. Combination of Trastuzumab with Paclitaxel (Seidman et al, 2001) or Docetaxel (Esteva et al, 2002) increase the response rate and overall survival.…”

Section: Naked Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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“…Targeting HER-2/neu with trastuzumab, a humanized anti HER-2/neu monoclonal antibody, inhibits the growth signals mediated by this oncogene [7]. Trastuzumab demonstrated moderate activity as single agent, but showed high activity in combination with chemotherapy as front-line therapy in HER-2/neu positive BC [8][9][10]. In a randomized trial of first-line therapy in HER-2/neu positive BC, the combination of trastuzumab with anthracyclines or taxanes significantly improved clinical outcome [11] and quality of life [12] as compared to chemotherapy alone.…”

Section: Introductionmentioning

confidence: 99%

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

Gasparini

Gion²,

Mariani³

et al. 2006

Breast Cancer Res Treat

129

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Background A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2. Patients and methods Among 124 patients randomized, 123 are assessable for toxicity and 118 for response. Patients received weekly paclitaxel single agent (80 mg/m 2 ) or combined with trastuzumab (4 mg/kg loading dose, then weekly 2 mg/kg). HER-2 overexpression was determined by immunohistochemistry (IHC). Patients with 2+/3+ IHC scores were eligible. IHC was compared with HER-2 serum extracellular domain (ECD). Results Patient characteristics were similar in the two arms. Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity. No patient developed cardiac toxicity. The combined treatment was statistically significant superior for overall response rate (ORR) (75% vs. 56.9%; P = 0.037), particularly in the subset of IHC 3+ patients (84.5% vs. 47.5%; P = 0.00050). A statistically significant better median time to progression was seen in the subgroup with IHC 3+ (369 vs. 272 days; P = 0.030) and visceral disease (301 vs. 183 days; P = 0.0080) treated with combination. Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR (P = 0.0035). Conclusion Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3+.

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Weekly Trastuzumab and Paclitaxel Therapy for Metastatic Breast Cancer With Analysis of Efficacy by HER2 Immunophenotype and Gene Amplification

Abstract: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.

Cited by 513 publications

References 25 publications

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Novel antibodies as anticancer agents

Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

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