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ABSTRACT: Changes in serum human epidermal growth factor receptor 2 (HER2) levels associated with clinical outcomes, including objective response rate, progression-free survival (PFS), and overall survival have been reported in patients with metastatic breast cancer (MBC) receiving trastuzumab and chemotherapy. This study investigated whether baseline or changes in serum HER2 correlated with overall response rate (ORR) and/or PFS in patients with MBC receiving first-line lapatinib monotherapy.
The EGF20009 study investigated lapatinib monotherapy in 138 HER2-positive patients with MBC previously untreated for their metastatic disease. Serum was collected and assessed at baseline and every 4 weeks for 16 weeks after treatment initiation. Disease assessment was performed at weeks 8 and 12 and every 12 weeks thereafter. A ≥ 20% decrease or increase in serum HER2 was defined as a significant change.
Seventy-nine percent of patients had elevated baseline serum HER2. Baseline serum HER2 was associated with ORR (P = .043) but not PFS. Patients with a ≥ 20% decrease from baseline of serum HER2 at weeks 4, 8, 12, and 16 had a significantly increased ORR and prolonged PFS. Conversely, those with a ≥ 20% increase from baseline had a significantly lower ORR and shorter PFS.
Significant decreases in serum HER2 levels during the first 16 weeks of lapatinib monotherapy were associated with better clinical outcome (longer PFS and increased ORR) in HER2-positive MBC patients.
Cancer 03/2011; 117(21):5013-20. · 4.77 Impact Factor
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William K Oh,
Roberto Vargas,
Susanna Jacobus,
Kim Leitzel,
Meredith M Regan,
Peter Hamer,
Karen Pierce,
Sheryl Brown-Shimer, Walter Carney,
Suhail M Ali,
Philip W Kantoff,
Allan Lipton
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ABSTRACT: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has paradoxical multifunctional roles in tumorigenesis: inhibition of the catalytic activity of matrix metalloproteinases and apoptosis as well as promotion of angiogenesis and tumor growth. Elevated TIMP-1 levels have been associated with a poorer prognosis in multiple cancers.
Ethylenediaminetetraacetic acid plasma TIMP-1 was determined in 362 castration-resistant prostate cancer (PC) patients using a TIMP-1 enzyme-linked immunosorbent assay. All patients with castration-resistant PC and available plasma were identified from an institutional database. Overall survival was analyzed using the Kaplan-Meier method and Cox modeling on plasma TIMP-1 tertiles.
Patients were evaluated in pilot (n = 60) and primary (n = 302) sets. Median follow-up from diagnosis was 5.8 and 6.6 years, respectively. Median plasma TIMP-1 levels were 335 and 183 ng/mL in the pilot and primary sets, respectively. Overall survival was significantly shorter with each higher tertile of TIMP-1 in both datasets (P<.001). For the primary cohort, hazard ratio of (HR) death and median survival by plasma TIMP-1 tertile levels were: low, HR 1.0, 43 months; middle, HR 1.7, 27 months; high, HR 2.4, 19 months. In the primary set, significant covariates in the adjusted Cox regression model were: TIMP-1 level (mid or high vs low tertile), prostate-specific antigen (>20 vs ≤20 ng/mL), alkaline phosphatase (>102 vs ≤102 U/L), Eastern Cooperative Oncology Group performance status (1 + vs 0), and Gleason score (7 or 8 vs ≤6).
Elevated plasma TIMP-1 levels predicted decreased survival in metastatic castration-resistant PC patients, independent of known prognostic markers.
Cancer 02/2011; 117(3):517-25. · 4.77 Impact Factor
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Evangelos Terpos,
Meletios A Dimopoulos,
Vikas Shrivastava,
Kim Leitzel,
Dimitrios Christoulas,
Magdalini Migkou,
Maria Gavriatopoulou,
Konstantinos Anargyrou,
Peter Hamer,
Efstathios Kastritis, Walter Carney,
Allan Lipton
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ABSTRACT: Tissue inhibitor of metalloproteinase-1 (TIMP-1) was evaluated in the pre-treatment serum of 55 newly diagnosed patients with symptomatic myeloma. TIMP-1 was elevated in 47% of patients and correlated with lytic bone disease and increased bone resorption. Importantly, TIMP-1 correlated with ISS stage (p=0.005) and was an independent prognostic covariate for survival [HR: 1.003 (1-1.006), p=0.004] in these patients who were all treated with novel agents (bortezomib and/or IMiDs) during their disease course. Our study provides evidence that pre-treatment serum TIMP-1 is associated with advanced myeloma and suggests the further evaluation of this molecule to better determine its prognostic potential in MM.
Leukemia research 09/2009; 34(3):399-402. · 2.36 Impact Factor
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Allan Lipton,
Kim Leitzel,
Hilary A Chaudri-Ross,
Dean B Evans,
Suhail M Ali,
Laurence Demers,
Peter Hamer,
Sheryl Brown-Shimer,
Karen Pierce,
Victor Gaur, Walter Carney
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ABSTRACT: To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen.
Five hundred twenty-two patients estrogen receptor-positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay.
Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone.
Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.
Journal of Clinical Oncology 07/2008; 26(16):2653-8. · 18.37 Impact Factor
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ABSTRACT: Tissue inhibitors of metalloproteinase (TIMPs) have at least 2 different functions. They inhibit the catalytic activity of matrix metalloproteinases, and they act as growth factors.
Pretreatment ethylenediamine tetracetic acid plasma TIMP-1 was assayed from 251 patients who were enrolled in a Phase III, second-line, hormone therapy trial, and from a control group of 50 healthy, postmenopausal women by using the TIMP-1 enzyme-linked immunosorbent assay.
The plasma TIMP-1 levels from the postmenopausal control group (n = 50 women) were 201 +/- 86 ng/mL mean +/- standard deviation (range, 49-455 ng/mL). The upper limit of normal was defined as the mean +/- 2 standard deviations of the control group (373 ng/mL). Patient pretreatment plasma TIMP-1 levels ranged from 70 ng/mL to 982 ng/mL. Plasma TIMP-1 was elevated above the mean + 2 standard deviations of the control group (373 ng/mL) in 19 patients (7.6%). In univariate analysis, patients who had elevated versus normal plasma TIMP-1 levels had a reduced clinical benefit rate (CBR) (16% vs 42%; P = .03). The time to progression (TTP) (84 days vs 174 days; P < .0001) and overall survival (141 days vs 860 days; P = .0001) also were significantly shorter in patients who had elevated TIMP-1 levels. TTP and overall survival also were significantly shorter in patients who had higher TIMP-1 plasma levels when it was analyzed as a continuous variable. In multivariate analysis, elevated plasma TIMP-1 level remained a prognostic factor for reduced overall survival (P < .0001) along with elevated serum HER-2/neu (P < .0001) and the presence of visceral metastases (P = .008).
Elevated pretreatment plasma levels of TIMP-1 predicted a decreased response to second-line hormone therapy and reduced survival in women with metastatic breast cancer.
Cancer 05/2007; 109(10):1933-9. · 4.77 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor.
Pretreatment serum EGFR levels were quantified by using an enzyme-linked immunoadsorbent assay in a Phase III first-line trial of letrozole and tamoxifen and were correlated with patient outcomes.
Serum EGFR levels in a control group of 117 healthy, postmenopausal women measured 64.1 +/- 13.3 ng/mL (mean +/- standard deviation). Using a cutoff EGFR level of 44.1 ng/mL from the control group (5% nonparametric method), 53 of 535 patients (10%) had decreased serum levels of EGFR. Patients with decreased serum EGFR had no significant difference in objective response rate (ORR), clinical benefit rate (CBR), time to progression (TTP), or time to treatment failure (TTF); however, they did have significantly reduced survival compared with patients who had normal serum EGFR levels (median survival, 23.3 months vs. 30.9 months; P = .007). A combined analysis of pretreatment serum EGFR and HER-2 yielded no additional predictive information for ORR, CBR, TTP, or TTF compared to serum HER-2 alone. However, in the current analysis, a subgroup of patients who had decreased serum EGFR and normal serum HER-2 was identified (n = 39 of 535 patients; 7.3%) that had significantly reduced survival compared with patients who had normal serum levels of both EGFR and HER-2 (median survival, 23.5 months vs. 37.1 months; P = .005). In multivariate analysis, a decreased serum EGFR level remained a significant independent prognostic factor for decreased survival (hazards ratio, 1.58; P = .007).
In patients who had metastatic breast cancer, decreased serum EGFR/normal serum HER-2 predicted shorter survival compared with patients who had normal levels of serum EGFR/HER-2. This patient subgroup deserves further study to assess their response to and selection for anti-EGFR-directed therapies.
Cancer 12/2006; 107(10):2337-45. · 4.77 Impact Factor
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Allan Lipton,
Kim Leitzel,
Suhail M Ali,
Laurence Demers,
Harold A Harvey,
Hilary A Chaudri-Ross,
Dean Evans,
Raquel Lang,
Wolfgang Hackl,
Peter Hamer, Walter Carney
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ABSTRACT: Prolonged exposure of breast carcinoma cells in vitro to tamoxifen results in tamoxifen resistance. Tamoxifen-resistant cells express increased HER-2/neu mRNA and protein. The objective of this study was to determine whether patients with metastatic or locally advanced breast carcinoma who have negative serum HER-2/neu status at the initiation of first-line hormone therapy with letrozole or tamoxifen convert to positive serum HER-2/neu status at the time of disease progression and to determine whether serum HER-2/neu conversion to positive status is associated with response to therapy and overall survival.
Serum samples were obtained at baseline and at the time of disease progression from 240 patients who initially had negative serum HER-2/neu status (< 15 ng/mL). A manual microtiter, enzyme-linked immunosorbent assay that was specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to quantitate serum levels.
Among 240 patients, 61 patients (26%) converted from serum HER-2/neu negative to positive (> 15 ng/mL) at the time of disease progression. Thirty-two of 129 patients (25%) who were treated with tamoxifen and 29 of 111 patients (26%) who were treated with letrozole became converted to positive serum HER-2/neu status at the time of disease progression. The response rate and the time to disease progression on first-line hormone therapy were not affected by serum HER-2/neu conversion. The survival of patients who converted to positive serum HER-2/neu status was significantly shorter compared with the survival of patients who remained negative for serum HER-2/neu. A multivariate analysis revealed that conversion to positive serum HER-2/neu status was an independent prognostic variable for survival.
Conversion to positive serum HER-2/neu status occurred in approximately 25% of patients who received first-line hormone therapy. Conversion to serum HER-2/neu-positive status occurred with equal frequency in antiestrogen and aromatase-inhibitor therapy. The current results showed that serum conversion to HER-2/neu-positive status was an independent risk factor for decreased survival in patients with breast carcinoma.
Cancer 07/2005; 104(2):257-63. · 4.77 Impact Factor
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Walter Schippinger,
Peter Regitnig,
Thomas Bauernhofer,
Ferdinand Ploner,
Günter Hofmann,
Peter Krippl,
Martin Wehrschütz,
Sigurd Lax, Walter Carney,
Rainer Neumann,
Klaus-Dieter Wernecke,
Hellmut Samonigg
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ABSTRACT: The purpose of this study was to determine the impact of serum HER-2/neu level dynamics during the course of disease and treatment on the prognosis of patients with metastatic breast cancer. Two thousand and thirty-eight serum samples collected sequentially after disease relapse in 286 patients with metastatic breast cancer were measured by Bayer Immuno 1 trade mark assay retrospectively for serum HER-2/neu (cut-off level 15 ng/ml). One hundred and five patients (37%) presented with serum HER-2/neu continuously </=15 ng/ml after disease recurrence, 71 (25%) had continuously elevated levels and 110 patients (38%) had both non-elevated and elevated values in the course of metastatic breast cancer. Patients with continuously elevated serum HER-2/neu levels had a significantly poorer survival after disease recurrence compared to patients with continuously or temporarily non-elevated serum HER-2/neu values (log-rank test: p<0.001). Including the number of palliative antitumor therapies and therapy response in Cox regression analysis, serum HER-2/neu dynamics revealed to be an independent prognostic factor for survival. In conclusion, 63% of 286 patients with metastatic breast cancer demonstrated either continuously or temporarily elevated serum HER-2/neu levels. Decrease of elevated serum HER-2/neu to levels </=15 ng/ml and levels continuously </=15 ng/ml during the course of disease correlated significantly with longer survival.
Oncology Reports 07/2004; 11(6):1331-6. · 1.84 Impact Factor
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ABSTRACT: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes.
Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER(+)), ER(-)/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1.
Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis.
Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.
Clinical Chemistry 08/2002; 48(8):1314-20. · 7.91 Impact Factor
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ABSTRACT: To evaluate longitudinal variations of serum HER-2/neu extracellular domain (sHER-2) in metastatic breast cancer patients receiving combined trastuzumab treatment.
Thirty-three patients were monitored by serial sHER-2 ELISA (Oncogene Science). Results were compared to time to progression (TTP) and survival from treatment initiation. Non parametric statistical tests were used.
Median sHER-2 before first injection was 41.37 ng/ml (range 7.54-1597.00 ng/ml, n=32). Mean sHER-2 levels differed significantly between responders (n=20) and non responders (n=13) (p<0.0001). Median TTP (266 days, range 35-1000 days) was unrelated to clinico-biological variables at diagnosis or number and site of metastases before treatment. Patients with pre-treatment sHER-2 levels < or = 30 ng/ml (n=14) had a significantly longer TTP than the group with sHER-2 > 30 ng/ml (n=18) (p=0.0346) and sHER-2 levels were of prognostic value for overall survival from first injection (p=0.0150).
Our results show that monitoring serum HER-2/neu levels during metastatic breast cancer can provide a real time assessment of a woman's HER-2/neu status and can provide important information for therapeutic decisions.
Anticancer research 24(2C):1083-9. · 1.73 Impact Factor
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Raquel A Nunes,
Xiaochun Li,
Soonmo Peter Kang,
Harold Burstein,
Lisa Roberts, Walter Carney,
Kimberly Blackwell,
Paula Ryan,
Virginia Borges,
J Dirk Iglehart,
Paula Friedman,
Lyndsay N Harris
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ABSTRACT: The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2 positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.
The International journal of biological markers 24(1):1-10. · 1.48 Impact Factor
