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Showing papers on "Pertuzumab published in 2005"


Journal ArticleDOI
TL;DR: Tastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer.
Abstract: Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...

5,200 citations


Journal ArticleDOI
TL;DR: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer.
Abstract: background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)

4,815 citations


Journal ArticleDOI
TL;DR: Tastuzumab combined with docetaxel is superior to docetAXel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity.
Abstract: Purpose This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (MBC). Patients and Methods Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen mor...

1,503 citations


Journal ArticleDOI
TL;DR: It is shown that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells, suggesting that the IGF-IR/HER-2 heterodimer contributes to trastzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastudumab.
Abstract: The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.

718 citations


Journal ArticleDOI
TL;DR: It is demonstrated that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.
Abstract: Purpose Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. Patients and Methods Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. Results Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab w...

404 citations


Journal ArticleDOI
TL;DR: Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression.
Abstract: In many solid tumors, overexpression of human epidermal growth factor receptors (e.g., HER1/EGFR and HER2) correlates with poor prognosis. Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor. Pertuzumab (Omnitarg), a novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization of HER2 with other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor growth inhibition. We evaluated whether inhibition of both mechanisms is superior to monotherapy in tumor cell lines expressing different HER levels. Human non-small cell lung cancer (NSCLC) cells (Calu-3: HER1/EGFR 0+, HER2 3+; QG56: HER1/EGFR 2-3+, HER2 0+) and breast cancer cells (KPL-4: HER1/EGFR 2-3+, HER2 3+) were implanted into BALB/c nu/nu mice and severe combined immunodeficient beige mice, respectively. Tumor-bearing mice (n = 12 or 15 per group) were treated with vehicle (Captisol or buffer), erlotinib (orally, 50 mg/kg/d), pertuzumab (i.p. 6 mg/kg/wk with a 2-fold loading dose), or erlotinib and pertuzumab for 20 (QG56), 27 (KPL-4), or 49 (Calu-3) days. Drug monotherapy had antitumor activity in all models. Tumor volume treatment-to-control ratios (TCR) with erlotinib were 0.36 (Calu-3), 0.79 (QG56), and 0.51 (KPL-4). Pertuzumab TCR values were 0.42, 0.51, and 0.64 in Calu-3, QG56, and KPL-4 models, respectively. Combination treatment resulted in additive (QG56: TCR 0.39; KPL-4: TCR 0.38) or greater than additive (Calu-3: TCR 0.12) antitumor activity. Serum tumor markers for NSCLC (Cyfra 21.1) and breast cancer (soluble HER2) were markedly inhibited by combination treatment (80-97% in Calu-3 and QG56; 92% in KPL-4), correlating with decreased tumor volume. Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression. A combination of these HER-targeted agents resulted in additive or greater than additive antitumor activity.

120 citations


Journal ArticleDOI
TL;DR: Pertuzumab was efficiently labelled with 177Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo and is of interest for further studies aimed at radionuclide therapy.
Abstract: The new antibody pertuzumab (Omnitarg) targets the dimerisation subdomain of HER-2. The purpose of this study was to analyse whether pertuzumab retains HER-2 targeting capacity after labelling with the therapeutically interesting beta emitter 177Lu and to make initial characterisations in vitro and in vivo. Pertuzumab was conjugated with isothiocyanate-benzyl-CHX-A″-DTPA and chelated to 177Lu. Immunoreactivity, affinity, cellular retention and internalisation were analysed using SKOV-3 cells. The affinity of non-radioactive pertuzumab was measured using a surface plasmon resonance biosensor. In vivo targeting and specific binding were assessed in Balb/c (nu/nu) mice carrying SKOV-3 xenografts. The biodistribution of 177Lu was determined 1, 3 and 7 days after [177Lu]pertuzumab administration. Gamma camera images were taken after 3 days. The immunoreactivity of [177Lu]pertuzumab was 85.8±1.3%. The affinity of non-radioactive pertuzumab was 1.8±1.1 nM, and that of [177Lu]pertuzumab, 4.1±0.7 nM. The cellular retention after 5 h pre-incubation was 90±2% at 20 h. The targeting was HER-2 specific both in vitro and in vivo, since excess amounts of non-labelled antibody inhibited the uptake of labelled antibody (p<0.0001 and p<0.01, respectively). The biodistribution and gamma camera images of 177Lu showed extensive tumour uptake. Normal tissues had a surprisingly low uptake. Pertuzumab was efficiently labelled with 177Lu and showed good intracellular retention and HER-2 specific binding both in vitro and in vivo. The gamma camera images and the biodistribution study gave excellent tumour targeting results. Thus, [177Lu]pertuzumab is of interest for further studies aimed at radionuclide therapy.

69 citations


Patent
06 Dec 2005
TL;DR: A method for selecting patients for therapy with a HER inhibitor, such as pertuzumab, based on gene expression analysis is described in this article, and a method for assessing HER phosphorylation or activation in a biological sample via gene expression analyses is also described.
Abstract: A method for selecting patients for therapy with a HER inhibitor, such as pertuzumab, based on gene expression analysis is described. A method for assessing HER phosphorylation or activation in a biological sample via gene expression analysis is also described.

47 citations


Journal ArticleDOI
TL;DR: A new class of targeted therapeutics known as HER-dimerization inhibitors (HDI) blocks ligand-associated heterodimerization of HER2 with other HER kinase family members, thereby inhibiting intracellular signaling.
Abstract: 3068 Background: P is the 1st of a new class of targeted therapeutics known as HER-dimerization inhibitors (HDI). It blocks ligand-associated heterodimerization of HER2 with other HER kinase family members, thereby inhibiting intracellular signaling. Preclinical activity of P in breast cancer has been shown to be independent of the HER2 expression level. In this study the primary endpoint was response rate according to RECIST. Secondary endpoints were: rate of stable disease (SD), toxicity profile, pharmacokinetics (PK). Methods: 79 pts in total were randomized to receive P every 3 weeks as an IV infusion either at 420 mg with a loading dose of 840 mg (arm A) or at 1050 mg (arm B). Selection criteria were: progressing MBC with low HER2 expression, anthracycline pretreatment, ≤ 2 chemotherapy regimens for MBC and LVEF ≥ 50%. Results: Out of 79 recruited pts, 78 were included in the intent to treat population. In arm A 2 partial responses (PR) and 18 SD were observed in 41 pts. In arm B 14 SD were observed ...

41 citations


Journal Article
TL;DR: The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer and another therapeutic antibody, 2C4 (PertuzumAB, Omnitarg), is currently under clinical evaluation.
Abstract: Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer. Next to risk-adapted strategies using conventional chemo- and/or endocrine therapies, antibody therapy has become an additional option. The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer. Patients with HER2/neu protein overexpression as assessed by immunohistochemistry (IHC) and/or gene amplification as assessed by fluorescence in-situ hybridization (FISH) in their tumors respond well to palliative trastuzumab therapy, either as single agent or in combination with chemotherapy. New combinations with endocrine therapy are currently being evaluated in clinical trials. Trastuzumab therapy is generally well-tolerated. So far, considerable cardiotoxicity was seen only in combination with doxorubicin. Thus, extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners. Clinical trials looking at early trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) setting are still open for recruitment in Germany. Since only about those 25 % of breast cancers which are HER2/neu-positive are eligible for trastuzumab, novel targeted therapeutics for the remaining HER2/neu-negative tumors are needed. Another therapeutic antibody, 2C4 (Pertuzumab, Omnitarg), is currently under clinical evaluation. It binds to a different epitope on HER2/neu than trastuzumab and inhibits heterodimerization with other HER receptors. Phase I data showed that 2C4 is well tolerated and clinically active.

31 citations


Journal ArticleDOI
TL;DR: Pertuzumab, a humanized HER2 antibody, represents a new class of targeted agents that inhibit dimerization of HER2 with EGFR, HER3 and HER4, and inhibit signaling through MAP and PI3 kinases and has demonstrated safety and activity in several tumors including ovarian cancer.
Abstract: 5051 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs) that inhibit dimerization of HER2 with EGFR, HER3 and...


Journal ArticleDOI
TL;DR: The primary endpoint in this study was PSA (prostate specific antigen) response rate (RR) at 24 weeks after start of single agent P.
Abstract: 4609 Background: P is the 1st of a new class of targeted therapeutics known as HER-dimerization inhibitors (HDI). P is a human monoclonal antibody that blocks ligand-associated heterodimerization o...

Journal ArticleDOI
TL;DR: Pertuzumab PK data from four phase II studies showed that a linear 2-compartment model best described the concentration-time profile of the drug in ovarian and breast cancer studies.
Abstract: 2532 Background: Pertuzumab, a humanized HER2-targeted antibody, represents the first in a new class of targeted therapeutic agents known as HER2 dimerization inhibitors (HDIs). Pertuzumab blocks ligand-associated HER2 dimerization with HER kinase family members (EGFR, HER3, HER4), thereby inhibiting intracellular signaling through MAP and PI3 kinases. Pertuzumab is currently being evaluated in phase II studies as a single-agent in ovarian, breast, prostate, and lung cancers. Interim pertuzumab PK data from the phase II studies is presented. Methods: Pertuzumab was administered once every 3 weeks (q3 week) as an IV infusion at a fixed dose of either 420 mg following an initial 840 mg loading dose (LD), or 1050 mg with no LD. PK data from four phase II studies were pooled for analysis by both descriptive and population PK (PopPK) modeling Methods: Results: PopPK modeling of the data from ovarian and breast cancer studies showed that a linear 2-compartment model best described the concentration-time profile...

Journal ArticleDOI
TL;DR: Pertuzumab, a humanized HER2 antibody, inhibits dimerization of HER2 with other HER kinase family members (EGFR, HER3 and HER4), thereby inhibiting signaling through MAP and PI...
Abstract: 4624 Background: Pertuzumab (P), a humanized HER2 antibody, inhibits dimerization of HER2 with other HER kinase family members (EGFR, HER3 and HER4), thereby inhibiting signaling through MAP and PI...

Journal ArticleDOI
TL;DR: P represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs) and blocks ligand-associated heterodimerization of HER2 with other HER-ki...
Abstract: 3166 Background: P represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). It blocks ligand-associated heterodimerization of HER2 with other HER-ki...

Journal ArticleDOI
C. Ng1, B. L. Lum1, S. Kelsey1, V. Hersberger‐Gimenez1, D.E. Allison1 
TL;DR: Pertuzumab (rhuMAb 2C4), a humanized IgG1 monoclonal antibody, is a novel HER2 dimerization inhibitor (HDI) being evaluated in the clinic for a variety of solid tumors.
Abstract: Background Pertuzumab (rhuMAb 2C4), a humanized IgG1 monoclonal antibody, is a novel HER2 dimerization inhibitor (HDI) being evaluated in the clinic for a variety of solid tumors. Objective To develop a POP PK model for pertuzumab, evaluate predictive covariates, and examine the variability of steady-state trough concentrations after fixed (FBD), or body weight-based dosing (WBD). Methods Pertuzumab was administered by IV infusion (q3 week) either as a weight-based dose (0.5–15 mg/kg) or a fixed dose (420 mg or 1050 mg). PK data from one Phase Ia and two Phase II trials (Ovarian and Breast), comprising of 153 patients and 1458 concentration-time points, were pooled for this analysis using NONMEM with the FOCE interaction method. Patient weights ranged from 45.0–150.6 kg. Results A linear 2-compartment model best described the data. Body weight, serum albumin, and alkaline phosphatase were significant covariates affecting clearance (CL). Weight only explained 8.3% of inter-patient variability for CL. Evaluation of the final POP PK model using a posterior predictive check showed good performance. Simulations showed that the percentages of predicted steady-state trough concentrations below 20 mcg/mL were similar between FBD and WBD, with WBD reducing the population variability by only 6.2%. Conclusion Although humanized antibodies are typically dosed by weight, our analyses demonstrate the feasibility of administrating pertuzumab using a fixed dose in patients with ovarian and breast cancers. Clinical Pharmacology & Therapeutics (2005) 77, P33–P33; doi: 10.1016/j.clpt.2004.12.019

Patent
05 Dec 2005
TL;DR: In this article, a pharmaceutical composition, comprising at least one compound of formula (I), in combination with capecitabine, trastuzumab, pertuzumabol, cisplatin or irinotecan for simultaneous, sequential or separate administration in the treatment of cancer is presented.
Abstract: The present invention is directed to a pharmaceutical composition, comprising at least one compound of formula (I), in combination with capecitabine, trastuzumab, pertuzumab, cisplatin or irinotecan for simultaneous, sequential or separate administration in the treatment of cancer.

Journal Article
TL;DR: A robust xenograft model was established by surgically inoculating cells into the gonadal fat pad of beige nude mice bearing supplemental estrogen, and transplanting the GonFP tumors into the MamFP, with and without exogenous estrogen supplementation, and showed a consistent and reliable tumor take rate.
Abstract: 1086 HER2/ErbB2 overexpression is known to play a key role in tumorigenesis and metastasis of breast adenocarcinomas. Breast cancer patients whose tumors overexpress HER2 are candidates for treatment with Herceptin®. The breast adenocarcinoma line, MDA-MB-175, expresses HER2 at the 1+ level (∼ 100,000 HER2 receptors/cell) in vitro. Previous studies with this cell line indicate that gamma-heregulin functions as an autocrine growth factor signaling through the HER3-HER2 complex. In vitro treatment of MDA-MB-175 cells with the anti-HER2 antibody, pertuzumab (2C4/OmnitargTM), significantly disrupts proliferation due to the fact that this antibody interrupts ligand-dependent formation of HER2-HER3 heterodimer complexes. Attempts to establish a tumor model with this line have proven difficult, since tumors do not grow when cells are inoculated subcutaneously or into the mammary fat pad (MamFP). Through a series of technical approaches, we established a robust xenograft model by surgically inoculating these cells into the gonadal fat pad (GonFP) of beige nude mice bearing supplemental estrogen. To refine this model, we then began transplanting the GonFP tumors into the MamFP, with and without exogenous estrogen supplementation, and showed a consistent and reliable tumor take rate. Histologically, the tumors from the GonFP and the MamFP are not morphologically different. Surprisingly, HER2 expression was quantitatively different for these two tumor cell lines. Immunohistochemistry analysis revealed that the GonFP tumors increased slightly in HER2 expression to 2+, whereas tumors from the MamFP were now 3+ for HER2 expression. These tumors were characterized further with respect to HER receptors and ligands as well as establishing the estrogen receptor (ER) status of the xenografts compared to the original cell line. Both tumors are strongly ER positive in a very small percentage of tumor cells (

Journal Article
TL;DR: Different markers of HER2 activation are expressed at different levels in primary breast cancer and there is a clear trend toward increased activation signals in lymph node metastases.
Abstract: 1893 Numerous studies have shown that overexpression of the human epidermal growth factor receptor type 2 (HER2/erbB2) is associated with poor prognosis of breast cancer. HER2 overexpression is now used as a diagnostic marker to select patients for antibody therapy with trastuzumab. In addition, HER2 may play an important role in tumor growth even when not overexpressed: being the preferred dimerization partner for other HER family members it can effectively boost anti-apoptotic and proliferation-stimulating signaling by growth-factor-activated receptors like HER1/EGFR and HER3. Pertuzumab is the first in a new class of targeted therapeutic agents known as HER dimerization inhibitors (HDIs) and is currently undergoing clinical testing in several phase II trials (Franklin et al., 2004). Previous studies using human tumor xenografts grown on nude mice indicated that the presence of HER2-containing heterodimers (HER2hd) correlated with response to pertuzumab treatment (Bossenmaier et al., 2004). These results suggest assessing patient tumors for possible indicators of HER2 activation that, in future studies, could be evaluated as response prediction markers. Here we investigated 15 freshly resected mammary tumors from untreated patients by immunohistochemistry, immunoprecipitation (IP) and Western blotting (WB) techniques. In particular, expression of HER family receptors, HER2 phosphorylation (pHER2) and HER2hd were assayed. From 5 patients, axillary lymph node metastases were available for analyses and comparison with the respective primary tumors. Our results confirm that IP/WB is a sensitive method to detect and quantify HER-family receptor proteins and HER2hd in nearly all patient tumor lysates. Receptor mRNA was compared to the respective protein expression and the presence of HER2hd complexes. Furthermore, the co-presence of HER2hd and pHER2, both of which would indicate activated HER2, was not always observed and was not predicted by receptor expression. In a subset of 5 patients, 3 lymph node metastases showed higher HER2 expression, increased HER2hd and elevated pHER2 compared to the respective primary tumors. Only one of the primary tumors indicated enhanced HER2 activation compared to the lymph node metastasis from the same patient at time of surgery. In conclusion, different markers of HER2 activation are expressed at different levels in primary breast cancer and there is a clear trend toward increased activation signals in lymph node metastases. The presence of HER2hd does not perfectly correlate with pHER2 and HER2 protein expression. The parameter most reliably predicting response to HER2-targeting therapies remains to be determined in future clinical trials.

Journal Article
Simon P. Langdon1, Peter Mullen1, Max Hasmann1, David Cameron1, John Smyth1 
TL;DR: Data indicate that a subset of ovarian cancer cell lines in which NRG1β induces HER2 phosphorylation at Tyr877 are sensitive to pertuzumab, a new class of targeted therapeutic agents known as HER dimerisation inhibitors (HDIs).
Abstract: Proc Amer Assoc Cancer Res, Volume 46, 2005 5064 The humanised monoclonal antibody pertuzumab (Omnitarg, rhuMAb 2C4), directed against the extracellular domain of HER2/erbB2, is the first in a new class of targeted therapeutic agents known as HER dimerisation inhibitors (HDIs). In a phase I study it has shown clinical activity in ovarian cancer (Agus et al., Proc ASCO, 771, 2003) but the determinants of sensitivity remain undefined. This study sought to identify indicators of sensitivity to pertuzumab in a panel of 13 ovarian cancer cell lines. They were treated with TGFα (activator of EGF receptor / HER1) or NRG1β (activator of HER3 and HER4) (1nM) with or without pertuzumab (100 nM) for 72h and cell proliferation assessed by the SRB assay. The PE01, 41M, PE06, PE04, CAOV3 and OVCAR3 cell lines were the most responsive to NRG1β while the OVCAR4, 59M, PEA2 and SKOV-3 cell lines showed no growth change. In general, the growth responses to NRG1β and TGFα were similar (r = 0.83 ; Pearson). The magnitude of NRG-driven growth stimulation was significantly associated with the fold-increase in ERK-2 activation (p=0.019; Pearson) but not Akt stimulation (p =0.99; Pearson). Addition of 100nM pertuzumab to cells being stimulated by 1nM NRG1β produced varying degrees of growth inhibition in all cell lines that were stimulated by NRG1β. In certain cell lines e.g. PE06 and PE04, the NRG1β stimulation was completely reversed, while in most cell lines it typically produced a 40-60% reversal. Although addition of 100nM pertuzumab to cells being stimulated by 1nM TGFα also produced complete growth inhibition in the PE04, PE06 and PE01 lines, in contrast to its general inhibitory effect in NRG1β-stimulated cells, it was ineffective in the remaining cell lines (possibly as a result of EGFR homodimerisation, thereby bypassing HER2). Investigation of signaling using phospho-specific antibodies in 7 cell lines (3 sensitive and 4 resistant to pertuzumab) indicated that in the 3 pertuzumab-responsive cell lines, NRG1β increased phosphorylation at Tyr877 of HER2 which was reversed by pertuzumab. In the 4 resistant cell lines, NRG1β alone did not increase Tyr877 phosphorylation, whilst addition of pertuzumab increased the signal. NRG1β also stimulated phosphorylation of HER2 Tyr1023 and Tyr1248 in some sensitive cell lines which was not reversed by pertuzumab. In cell lines growth stimulated by NRG1β, addition of pertuzumab reduced activation of both ERK-2 and AKT. These data indicate that a subset of ovarian cancer cell lines in which NRG1β induces HER2 phosphorylation at Tyr877 are sensitive to pertuzumab. Whether this marker holds potential for identifying patients benefiting from pertuzumab treatment remains to be tested in the clinic.

Book ChapterDOI
01 Jan 2005
TL;DR: The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (mAb) for cancer therapy and the humanized antibody trastuzumab (Herceptin™) has antitumor activity against HER2-overexpressing breast tumors.
Abstract: The HER family is composed of four receptors, HER1 to HER4, is dysregulated, and/or shows abnormal signaling activity in a broad range of human tumors. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (mAb) for cancer therapy. In particular, the humanized antibody trastuzumab (Herceptin™) has antitumor activity against HER2-overexpressing breast tumors and is widely used for the treatment of women with HER2-overexpressing breast cancers. However, trastuzumab activity relies on the presence of HER2 overexpression and it is not active against tumors that express moderate or normal levels of HER2.