Results of Two Open-Label, Multicenter Phase II Studies of Docetaxel, Platinum Salts, and Trastuzumab in HER2-Positive Advanced Breast Cancer

Pegram, Mark D.; Pieńkowski, Tadeusz; Northfelt, Donald W.; Eiermann, W.; Patel, Ravi; Fumoleau, P.; Quan, E.; Crown, John; Toppmeyer, Deborah; Smylie, Michael; Riva, A.; Blitz, Sandra; Press, Michael F.; Reese, David; Lindsay, Mary Ann; Slamon, Dennis J.

doi:10.1093/jnci/djh133

Cited by 257 publications

(139 citation statements)

References 54 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…Pegram et al [26] reported the results of two phase II studies (BCIRG101 and UCLA-ORN) that evaluated triplets of trastuzumab, docetaxel and cisplatin or carboplatin. In both the studies an interesting response rate was obtained (ORR:79% BCIRG101; ORR:58% UCLA-ORN, respectively).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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+.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…The humanized monoclonal antibody, trastuzumab (Herceptin), has been shown to improve survival in both adjuvant and advanced settings of breast cancer (12). Several studies in vitro and in vivo have shown that both additive and synergistic effects occur when trastuzumab is combined with chemotherapeutic agents (13)(14)(15)(16)(17). The synergistic effects of combining trastuzumab with cisplatin, carboplatin, and paclitaxel have been shown in several breast cancer cell lines (18,19).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Boone

Bhosle

Tilby

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

HER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations.

show abstract

“…[36][37][38][39], this approach holds promise for increasing both response rate and duration relative to trastuzumab, and may expand the spectrum of antitumor activity of trastuzumab given alone or in combination with other antitumor strategies such as other cytotoxic agents (carboplatin, docetaxel; refs. [40][41][42][43], and/or antiangiogenic drugs (e.g., bevacizumab; anti-VEGF antibody, thrombospondin-1; refs. [44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy

Shin¹,

Cho²,

Merchan³

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody-murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human endostatin fusion proteins by fusing either wildtype or a mutant human endostatin (huEndo-P125A) to the 3' end of a humanized anti-HER2 IgG3 antibody. Antitumor efficacy was examined in murine and human breast tumor models. HuEndo-P125A antibody fusion protein (aHER2-huEndo-

show abstract

Results of Two Open-Label, Multicenter Phase II Studies of Docetaxel, Platinum Salts, and Trastuzumab in HER2-Positive Advanced Breast Cancer

Abstract: Combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2. The BCIRG is conducting ongoing randomized studies of the three-drug combination in both the metastatic and adjuvant settings.

Cited by 257 publications

References 54 publications

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

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

Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy

Contact Info

Product

Resources

About