Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of <i>HER2</i>-Overexpressing Metastatic Breast Cancer

Vogel, Charles L.; Cobleigh, Melody A.; Tripathy, Debu; Gutheil, John; Harris, Lyndsay N.; Fehrenbacher, Louis; Slamon, Dennis J.; Murphy, Maureen; Novotny, William; Burchmore, Michael; Shak, Steven; Stewart, Stanford J.; Press, Michael F.

doi:10.1200/jco.2002.20.3.719

Cited by 1,905 publications

(630 citation statements)

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“…However, the use of trastuzumab is limited by low response rates (11-26%; Cobleigh et al, 1999;Vogel et al, 2002) and the development of drug resistance within 12 months (Slamon et al, 2001). Therefore, trastuzumab has been combined with paclitaxel (Seidman et al, 2001;Slamon et al, 2001), cisplatin (Pegram et al, 1998), docetaxel , and vinorelbine (Burstein et al, 2001) to improve its potency.…”

Section: Discussionmentioning

confidence: 99%

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

et al. 2003

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The retinoid N-(4-hydroxyphenyl)retinamide (4-HPR also known as fenretinide) is a potent inducer of apoptosis in breast cancer cells. We observed a 4.5-fold reduction in 4-HPR-mediated apoptosis in MCF-7 breast cancer cells transfected with HER2/neu (MCF-7/HER2) as compared with the parental MCF-7 (MCF-7/WT) cells. Blocking HER2/neu with trastuzumab (Herceptin TM ) led to a sixfold increase in 4-HPR-induced apoptosis in HER2/neuoverexpressing cells. These data indicate that HER2/neu reduces the sensitivity of breast cancer cells to 4-HPR. We showed previously that nitric oxide (NO) is essential for 4-HPR to induce apoptosis in breast cancer cells. The inhibitory effects of the 4-HPR and trastuzumab combination correlated with the amount of NO produced in HER2/neu-overexpressing cells. When a NO synthase (NOS) inhibitor was used to block NO production, decreased apoptosis by the 4-HPR and trastuzumab combination was observed. Furthermore, 4-HPRmediated NOSII expression was lower in MCF-7/HER2 than MCF-7/WT cells, but was increased by trastuzumab in HER2/neu-overexpressing cells. Here we report the novel findings that HER2/neu reduces the ability of 4-HPR to induce apoptosis in breast cancer cells, and that one mechanism by which HER2/neu increases the resistance of breast cancer cells to 4-HPR is by decreasing NOSII-mediated NO production.

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Section: Discussionmentioning

confidence: 99%

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

et al. 2003

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“…A critical parameter governing the clinical efficacy of anticancer Abs is the expression level of target antigen. Indeed, clinical trials of trastuzumab have been limited to patients showing a moderate (2ϩ) to strong (3ϩ) level of Her2 overexpression by immunohistochemistry (22), reflecting Ϸ500,000 and 2,300,000 receptors per cell respectively (23). To explore the cytotoxic capacity of our Fc variants at different antigen expression levels, ADCC was measured for WT and variant trastuzumab Abs against four different cell lines expressing amplified to low levels of Her2 (Fig.…”

Section: Designed Fc Variants Mediate Enhanced Adcc Across a Range Ofmentioning

confidence: 99%

Engineered antibody Fc variants with enhanced effector function

Lazar

Dang²,

Karki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

712

583

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Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fc␥ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fc␥ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.antibody-dependent cell-mediated cytotoxicity ͉ Fc␥R ͉ protein engineering ͉ cancer

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“…Combination of FAS Inhibitor Cerulenin and Anti-p185 HER2 Ab Trastuzumab Synergistically Decreases Cell Viability. Trastuzumab (Herceptin) is a recombinant humanized anti-HER2 monoclonal Ab directed at the p185 HER2 ectodomain that is active against HER2-overexpressing cancer cells (29)(30)(31). However, not all HER2-overexpressing tumors respond to treatment with trastuzumab, and its clinical benefit is limited by the occurrence of resistance (32)(33)(34).…”

Section: Pharmacological and Sirna-mediated Inhibition Of Fas Differementioning

confidence: 99%

Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

Menendez

Vellón

Mehmi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

324

275

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Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185 HER2 oncoprotein expression and tyrosinekinase activity in breast and ovarian HER2 overexpressors. Similarly, p185 HER2 expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequencespecific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185 HER2 was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185 HER2 . The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185 HER2 trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185 HER2 was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.trastuzumab ͉ small interfereing RNA ͉ chemotherapy ͉ lipogenesis ͉ Herceptin T he biosynthetic enzyme fatty acid synthase (FAS) is the major enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids, and it functions normally in cells with high lipid metabolism. Under normal physiological conditions, any FAS increase is tightly regulated by a number of environmental, hormonal, and nutritional signals (1, 2). However, human tissue studies have demonstrated that infiltrating carcinomas of the breast constitutively express high levels of FAS compared to nontransformed human epithelial tissue (3-8). Furthermore, increased levels of FAS accompany the development of in situ carcinoma of the breast, suggesting a potential link between increased expression and increased risk of breast cancer development (9). Remarkably, overexpression and hyperactivity of FAS is associated with more aggressive breast and ovarian cancers (3-8, 10). The early and nearly universal up-regulation of FAS in many human cancers and its association with poor clinical outcome both strengthen the hypothesis that FAS is involved in the development, maintenance, and enhancement of the malignant...

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Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer

Abstract: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Cited by 1,905 publications

References 9 publications

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

HER2/neu reduces the apoptotic effects of N-(4-hydroxyphenyl)retinamide (4-HPR) in breast cancer cells by decreasing nitric oxide production

Engineered antibody Fc variants with enhanced effector function

Inhibition of fatty acid synthase (FAS) suppressesHER2/neu(erbB-2) oncogene overexpression in cancer cells

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