Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis.

Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.

Impact of serum HER2, TIMP-1, and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab).

BACKGROUND: The lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. METHODS: MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. RESULTS: Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05-0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00-01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01-0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. CONCLUSIONS: Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

Circulating HER2 Extracellular Domain: A Specific and Quantitative Biomarker of Prognostic Value in all Breast Cancer Patients?

The HER2 oncoprotein has emerged as an essential biomarker in the treatment of breast cancer patients. Once the primary breast cancer is removed, there is an increasing need to detect breast cancer recurrence as early as possible with the hope that earlier intervention with new anti-HER2 therapies will improve quality of life and increase overall survival. Numerous publications have shown that increasing blood levels of circulating HER2 is an early indicator of progression, particularly in HER2-positive patients and that the rise and fall parallels the clinical course of disease and independent of therapy. Many studies show that the HER2 status of the primary tumor may not fully and accurately reflect the HER2 status of recurrent cancer. Thus, elevated serum HER2 levels may be an early signal of the emergence of a HER2-positive metastatic tumor and therefore alert the physician to re-assess HER2 status using a tissue test.

Soluble human epidermal growth factor receptor 2 (HER2) levels in patients with HER2-positive breast cancer receiving chemotherapy with or without trastuzumab: results from North Central Cancer Treatment Group adjuvant trial N9831.

BACKGROUND: Increased soluble human epidermal growth factor receptor 2 (sHER2) is an indicator of a poor prognosis in HER2-positive metastatic breast cancer. In this study, the authors evaluated levels of sHER2 during treatment and at the time of disease recurrence in the adjuvant North Central Cancer Treatment Group N9831 clinical trial. METHODS: The objectives were to describe sHER2 levels during treatment and at the time of recurrence in patients who were randomized to treatment arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab), and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available from 2318 patients, serial samples were available from 105 patients, and recurrence samples were available from 124 patients. The cutoff sHER2 value for the assay was 15 ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank-sum tests, and Cox regression models. RESULTS: There were differences between groups in terms of age, menopausal status, and hormone receptor status. Within treatment arms A, B, and C, patients who had baseline sHER2 levels ≥15 ng/mL had worse disease-free survival than patients who had baseline sHER2 levels <15 ng/mL (arm A: hazard ratio, 1.81; P = .0014; arm B: hazard ratio, 2.08; P = .0015; arm C: hazard ratio, 1.96; P = .01). Among the 124 patients who experienced disease recurrence, sHER2 levels increased from baseline to the time of recurrence in arms A and B but remained unchanged in arm C. Patients who had recurrence sHER2 levels ≥15 ng/mL had a shorter survival after recurrence with a 3-year overall survival rate of 51% compared with 77% for those who had recurrence sHER2 levels <15 ng/mL (hazard ratio, 2.36; 95% confidence interval, 1.19-4.70; P = .01). CONCLUSIONS: In patients with early stage, HER2-positive breast cancer, a high baseline sHER2 level was identified as a prognostic marker associated with shorter disease-free survival, and a high sHER2 level at recurrence was predictive of shorter survival.

Microfluidics and circulating tumor cells.

Circulating tumor cells (CTCs) are shed from cancerous tumors, enter the circulatory system, and migrate to distant organs to form metastases that ultimately lead to the death of most patients with cancer. Identification and characterization of CTCs provides a means to study, monitor, and potentially interfere with the metastatic process. Isolation of CTCs from blood is challenging because CTCs are rare and possess characteristics that reflect the heterogeneity of cancers. Various methods have been developed to enrich CTCs from many millions of normal blood cells. Microfluidics offers an opportunity to create a next generation of superior CTC enrichment devices. This review focuses on various microfluidic approaches that have been applied to date to capture CTCs from the blood of patients with cancer.

Human epidermal growth factor receptor 2 (HER2) extracellular domain levels are associated with progression-free survival in patients with HER2-positive metastatic breast cancer receiving lapatinib monotherapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Elevated plasma TIMP-1 levels predicted decreased survival in metastatic castration-resistant PC patients, independent of known prognostic markers.

TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients.

BACKGROUND: Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear. METHODS: Patients with epithelial ovarian cancer who presented for primary surgery were included in this study. A total of 148 serum samples from 37 patients were analyzed. Samples were prospectively collected at 4 predefined time points: 1. before radical debulking surgery, 2. after surgery and before platinum/taxane based chemotherapy, 3. during chemotherapy, 4. after chemotherapy. Serum VEGF-165 and TIMP-1 as well as CA-125 were quantified by ELISA or ECLIA and correlation with response and long-term clinical outcome was analyzed. RESULTS: Serum levels of all markers changed substantially during first-line therapy. High CA-125 (p = 0.002), TIMP-1 (p = 0.007) and VEGF-165 (p = 0.02) after chemotherapy were associated with reduced overall survival. In addition, elevated CA-125 (p < 0.001) and VEGF-165 (p = 0.006) at this time point predicted poor progression-free survival. TIMP-1 and VEGF-165 were closely correlated at all time-points during therapy. CONCLUSIONS: TIMP-1 and VEGF serum levels changed significantly during first-line therapy of ovarian cancer patients and predicted prognosis. These findings support the role of angiogenesis in ovarian cancer progression and the use of antiangiogenic therapy.

Serum carbonic anhydrase IX during first-line therapy of ovarian cancer.

OBJECTIVE: Carbonic anhydrase IX (CAIX) is primarily involved in maintaining the extracellular pH. It is overexpressed in a variety of tumors including ovarian cancer. To evaluate the potential prognostic and predictive role of serum CAIX for therapy response in ovarian cancer, we analyzed longitudinal serum samples. METHODS: One hundred forty-eight serum samples from 37 patients with primary epithelial ovarian cancer were analyzed. Samples were prospectively collected at 4 time points: (1) before radical surgery, (2) after surgery and before platinum/taxane chemotherapy, (3) during chemotherapy, and (4) after chemotherapy. Serum CAIX was quantified by ELISA and expression in tumor tissue was verified by immunohistochemistry. Correlation with response and clinical outcome as well as the tumor marker CA-125 was analyzed. RESULTS: Serum concentration of CAIX ranged between 30 and 1687 pg/mL and showed no significant changes during first-line therapy (median level before and after surgery 204 and 198 pg/mL, during and after chemotherapy 175 and 181 pg/mL). There was no association between serum CAIX and progression-free or overall survival. CA-125 decreased significantly after surgery (median serum level before and after surgery 413 and 84 kU/L, p<0.001) and further during and after first-line chemotherapy (median serum levels 21 and 15 kU/L, p<0.001). No intermarker correlation was observed. CONCLUSIONS: CAIX is upregulated in ovarian cancer and serum CAIX could be a marker to stratify patients for therapy response. However, CAIX serum levels did not change significantly during first-line therapy and were not prognostically relevant. Based on the findings of the current study, CAIX cannot be recommended for therapy monitoring in this context.

High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents.

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.

Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy.

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.

Hidden HER-2/neu-positive breast cancer: how to maximize detection.

The HER-2/neu oncoprotein is an important cellular target for the development of a variety of targeted therapies for HER-2/neu-positive breast cancer. Methods for tumor analysis such as immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) are routinely used to determine the HER-2/neu status of patients with breast cancer and their eligibility for HER-2/neu-targeted therapies, such as trastuzumab (Herceptin) and lapatnib (Tykerb). In a January 2008 article in the Wall Street Journal, it was reported that breast cancer patients may be receiving the wrong treatments or no treatment because of errors in the laboratory tests (IHC/FISH) that are widely used to determine the HER-2/neu status of breast cancers. Numerous reports have demonstrated that 20 to 30% of patients with primary breast cancer have HER-2/neu positive tumors. However, several studies have also shown that up to 40% of patients who are designated HER-2/neu negative with primary tumor analysis by IHC/FISH are actually HER-2/neu positive when the corresponding metastatic tumor is also evaluated by IHC/FISH. Studies have also demonstrated that up to 40% of patients with breast cancer who have a HER-2/neu-negative primary tumor as determined by IHC/FISH can develop elevated levels (> 15 ng/ml) of the circulating HER-2/neu oncoprotein during metastasis. Therefore, elevated serum HER-2/neu levels can be used to alert physicians of the possible presence of HER-2/neu-positive breast cancer in patients who have been previously classified as HER-2/neu negative. Collectively, these studies identify a population of women designated HER-2/neu negative that could have HER-2/neu-positive breast cancer, but have not been eligible for targeted therapies such as trastuzumab and lapatinib. Women who are incorrectly classified as HER-2/neu negative, but are also ineligible for approved HER-2/neu-targeted therapies, may also not be considered for clinical trials of additional HER-2/neu therapies in development. Several studies have also demonstrated that serum HER-2/neu can be elevated in patients with early breast cancer, and up to 90% of patients with HER-2/neu-positive metastatic breast cancer can have elevated serum HER-2/neu levels. These studies have also revealed that the frequency of patients who have HER-2/neu-positive breast cancer is greater than indicated previously by IHC/FISH. Thus, the number of patients classified incorrectly as HER-2/neu negative could be substantially greater than recognized previously. This feature review presents a HER-2/neu testing algorithm that combines the serum HER-2/neu test result with IHC/FISH test results to maximize the identification of patients who are HER-2/neu positive and could be potential candidates for HER-2/neu-targeted therapies. The HER-2/neu situation also exemplifies that multiple diagnostic tools are required to correctly and accurately identify patients for targeted therapies--an important lesson as many new biomarkers are identified for the multitude of new targeted therapies in development for various forms of cancers.

Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer.

BACKGROUND: Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS: This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease >or=20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS: Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS: In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (>or=20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions.

Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer.

PURPOSE: To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

HER-2/neu diagnostics in breast cancer.

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed.

Circulating oncoproteins HER2/neu, EGFR and CAIX (MN) as novel cancer biomarkers.

Pharmaceutical companies have developed targeted therapies such as trastuzumab and lapatinib for human epidermal growth factor receptor (HER)2/neu-positive tumors, while others have developed antiepidermal growth factor receptor (EGFR) therapies, such as tarceva and erbitux for EGFR-positive tumors. A drug called rencarex is targeted to an oncoprotein designated carbonic anhydrase IX (CAIX), which is being evaluated in renal cell carcinoma patients. Based on these targeted therapeutic approaches, this review describes clinical research studies performed with enzyme-linked immunosorbent assays specific for the circulating oncoproteins, HER2/neu, EGFR and CAIX. These circulating biomarkers have the potential to be used in conjunction with the specific targeted therapies for patient selection, monitoring and management. With the variety of new therapeutic options, the major challenge ahead will be to select the appropriate therapy or combinations of therapies for each patient. Specific biomarker tests, either alone or in panels, will be needed at the appropriate time in the course of disease to ensure that patients receive the right drug at the right time. These tests will also be valuable in monitoring the efficacy of the targeted therapies. A circulating biomarker such as serum HER2/neu may be able to specifically identify patients with progressing HER2/neu-positive disease and provide the information needed by physicians to choose from the variety of HER2/neu-targeted therapies that will soon be available to cancer patients.

Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

On target? The challenge of integrating biomarker research in drug development. Interview with Walter Carney.

In spite of the current explosion of interest in biomarker research, industry seems to be struggling to incorporate these advances into drug development and healthcare delivery. Biomarkers in Medicine explored the issues with Dr Walter Carney, a pioneer in linking diagnostics with medicines to target therapies to stratified patient groups. Dr Carney and his colleagues were the first to discover the circulating human epidermal growth factor receptor (HER)2/neu oncoprotein in women with metastatic breast cancer. He has been granted numerous patents pertaining to the HER2/neu and ras oncoproteins, as well as having published extensively in this area. Dr Carney joined the DuPont Medical Products Department in 1982 where he held a variety of management positions in the Diagnostics Division. He was Vice President and General Manager of the Diagnostics and Research Products Division and in 1997 was appointed President of Oncogene Science. Dr Carney also held the position of Vice President of Proprietary Drug Development Programs for OSI Pharmaceuticals until Oncogene Science joined Bayer Diagnostics in late 1999. As part of Bayer HealthCare, Dr Carney continued as Head of the Oncogene Science business, which is a Center of Excellence for Oncology and is focused on the use of novel biomarker tests in linking diagnostics with pharmaceuticals. Oncogene Science is now part of the Global Siemens Medical Solutions Diagnostics, which is the first integrated diagnostics company and driving medical innovation by combining circulating biomarkers with imaging biomarkers.

Serum epidermal growth factor receptor/HER-2 predicts poor survival in patients with metastatic breast cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR, HER-1, and erbB1) is overexpressed in primary breast cancer and had been identified as a poor prognostic factor. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.