Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types.

Due to activation of fibroblast into cancer-associated fibroblasts, there is often an increased deposition of extracellular matrix and fibrillar collagens, e.g. type III collagen, in the tumor microenvironment (TME) that leads to tumor fibrosis (desmoplasia). Tumor fibrosis is closely associated with treatment response and poor prognosis for patients with solid tumors. To assure that the best possible treatment option is provided for patients, there is medical need for identifying patients with high (or low) fibrotic activity in the TME. Measuring unique collagen fragments such as the pro-peptides released into the bloodstream during fibrillar collagen deposition in the TME can provide a non-invasive measure of the fibrotic activity. Based on data from 8 previously published cohorts, this review provides insight into the prognostic value of quantifying tumor fibrosis by measuring the pro-peptide of type III collagen in serum of a total of 1692 patients with different solid tumor types and discusses the importance of tumor fibrosis for understanding prognosis and for potentially guiding future drug development efforts that aim at overcoming the poor outcome associated with a fibrotic TME.

Higher serum PD-L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial.

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts.

Increased extracellular matrix (ECM) formation and matrix metalloprotease (MMP)-mediated ECM degradation are parts of tumorgenesis and generates collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in serum with outcomes in two independent metastatic breast cancer (MBC) cohorts. ELISAs were used to measure C1M (MMP-generated type I collagen fragment), C3M (MMP-generated type III collagen fragment), C4M (MMP-generated type IV collagen fragment), and PRO-C3 (pro-peptide of type III collagen) in pretreatment serum from a phase 3 randomized clinical trial of second-line hormone therapy (HR+, n = 148), and a first-line trastuzumab-treated cohort (HER2+, n = 55). All sites of metastases were included. The collagen fragments were evaluated by Cox-regression analysis for their association with time-to-progression (TTP) and overall survival (OS). In the HR+ cohort, higher C1M and C3M levels (75th percentile cut-off) were associated with shorter TTP; all fragments were associated with shorter OS. In the HER2+ cohort, higher levels of all fragments were associated with shorter TTP; higher PRO-C3 was associated with shorter OS. In multivariate analysis of the HR+ trial for OS, higher levels of all fragments were significant for reduced OS when added separately (C1M HR = 2.1, p < 0.001; C3M HR = 1.8, p = 0.028; C4M HR = 1.8, p = 0.018; PRO-C3 HR = 1.8, p = 0.017); none other clinical covariates were significant. In conclusion, collagen fragments quantified in pretreatment serum was associated with shorter TTP and OS in two independent MBC cohorts receiving systemic therapy. If validated, quantification of ECM remodeling in serum has potential as prognostic and/or predictive biomarkers in MBC.

Osteoporosis therapy and outcomes for postmenopausal patients with hormone receptor-positive breast cancer: NCIC CTG MA.27.

BACKGROUND: Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes. METHODS: The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05. RESULTS: Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31). CONCLUSIONS: Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society.

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.

N-Telopeptide of Type I Collagen Long-Term Dynamics in Breast Cancer Patients With Bone Metastases: Clinical Outcomes and Influence of Extraskeletal Metastases.

BACKGROUND: Markers of bone metabolism, such as N-telopeptide of type I collagen (NTX), have been demonstrated to be prognostic in previous trials of breast cancer (BC) patients with bone metastases (BMs). In the present study, we tested the survival effect of the NTX response to zoledronic acid (ZA) at 3 and 12 months in a contemporaneous cohort of BC patients with BMs and evaluated the influence of extraskeletal metastatic disease on NTX variation. PATIENTS AND METHODS: The present study was a prospective cohort study of consecutive BC patients diagnosed and treated at a single center. Patients presenting with de novo radiological evidence of BMs who started monthly intravenous ZA were included. Urinary NTX was measured at baseline and 1, 3, 6, 9, and 12 months after ZA introduction. RESULTS: Overall, 71 patients were enrolled, 32 with BMs and 39 with BMs plus extraskeletal metastases. The proportion of patients with elevated NTX at baseline and 3 and 12 months was 49.3%, 26.6%, and 34.2%, respectively. The variables associated with survival included age at diagnosis, tumor estrogen receptor status, and NTX at 3 and 12 months. Multivariate analysis showed that, in addition to age at diagnosis, only the 3-month NTX level was significantly associated with survival. Patients with BMs plus extraskeletal metastases had an erratic NTX variation pattern, unrelated to survival. CONCLUSION: In the present contemporaneous cohort of BC patients with BMs, the NTX response at 3 months was strongly associated with survival. Furthermore, an early response to ZA was strongly associated with long-term NTX control. Finally, patients with BMs plus extraskeletal metastases had an erratic NTX variation. IMPLICATIONS FOR PRACTICE: The present study showed that when accommodating recent therapy innovations and longer patient survival, the N-telopeptide (NTX) variation at 3 months is strongly associated with survival. In this setting, in addition to a few other clinicopathological features, NTX is a powerful prognostic marker. Moreover, early NTX correction associates with persistently normal NTX. This might identify a subgroup of patients with a good prognosis who are eligible for premature zoledronic acid (ZA) de-escalation. Finally, patients with bone plus extraskeletal metastases showed an erratic variation of NTX, raising concerns that a single ZA regimen might not fit all patients. Future trials should test its effect according to the presence of extraskeletal involvement.

Antiresorptive therapy in the management of cancer treatment-induced bone loss.

Cancer treatment-induced bone loss treatment has an important role to prevent bone loss-related events like fracture, significant morbidity, mortality, disfigurement and loss of self-esteem, and health-care expenditure. Numerous factors, including treatment regimens and bone metastasis, increase the risk of osteoporosis or local bone destruction in most breast and prostate cancer patients. Cytotoxic chemotherapies, radiation, and hormonal therapies can lead to premature menopause and decrease bone mineral density. Over 60 % of breast cancer patients within 1 year of beginning postoperative adjuvant chemotherapy experience ovarian failure. Also, ovarian ablation and aromatase inhibitors used to treat breast cancer and orchiectomy and androgen deprivation therapy (ADT; to treat prostate cancer) cause substantial bone loss. In this article, we will focus mainly on antiresorptive therapy in the management of cancer treatment-induced bone loss (CTIBL). An understanding of CTIBL is critical for determining how to assess the risk and identify which patients may benefit from preventive therapy.

HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer.

Trastuzumab is effective in the treatment of HER2/neu over-expressing breast cancer, but not all patients benefit from it. In vitro data suggest a role for HER3 in the initiation of signaling activity involving the AKT­mTOR pathway leading to trastuzumab insensitivity. We sought to investigate the potential of HER3 alone and in the context of p95HER2 (p95), a trastuzumab resistance marker, as biomarkers of trastuzumab escape. Using the VeraTag® assay platform, we developed a dual antibody proximity-based assay for the precise quantitation of HER3 total protein (H3T) from formalin-fixed paraffin-embedded (FFPE) breast tumors. We then measured H3T in 89 patients with metastatic breast cancer treated with trastuzumab-based therapy, and correlated the results with progression-free survival and overall survival using Kaplan­Meier and decision tree analyses that also included HER2 total (H2T) and p95 expression levels. Within the sub-population of patients that over-expressed HER2, high levels of HER3 and/or p95 protein expression were significantly associated with poor clinical outcomes on trastuzumab-based therapy. Based on quantitative H3T, p95, and H2T measurements, multiple subtypes of HER2-positive breast cancer were identified that differ in their outcome following trastuzumab therapy. These data suggest that HER3 and p95 are informative biomarkers of clinical outcomes on trastuzumab therapy, and that multiple subtypes of HER2-positive breast cancer may be defined by quantitative measurements of H3T, p95, and H2T.

Impact of genetic targets on prostate cancer therapy.

Given the global incidence of prostate cancer and its sociological impact, it remains a challenging disease to clinicians and researchers alike. In the last few years several new drugs have been added to the armamentarium of prostate cancer therapy and offers survival benefit to patients with prostate cancer. However, effective drugs are still needed that offer extended survival benefit and alter the natural history of the disease. Recent efforts have focused on better understanding the underlying biology and genetic heterogeneity of the disease and identified novel targets that can be utilized for drug development and therapeutics in the future. In this review we present an overview of the genetic landscape of prostate cancer, novel targets in the prostate cancer therapy and the results of key clinical trials of these novel drugs.

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.

Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics.

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

Phase II trial of gemcitabine, irinotecan, and celecoxib in patients with advanced pancreatic cancer.

GOALS AND BACKGROUND: Cyclooxygenase-2 (COX-2) has been shown to be expressed in a variety of tumors including pancreatic cancer. The combination of gemcitabine and irinotecan is active in pancreatic cancer. The purpose of this study is to determine the toxicity and response rate to the addition of the selective oral COX-2 inhibitor, celecoxib, to gemcitabine and irinotecan in patients with inoperable pancreatic cancer. STUDY: Twenty-one patients with previously untreated inoperable pancreatic cancer were entered on this trial. Seven patients had localized disease, 8 had metastatic disease, and 6 patients were inevaluable. RESULTS: Twenty percent of the patients had a partial response and 80% of the patients had a stable response with a median response rate of 9 months. The median overall survival was 18 months with 80% of the patients achieving 1-year survival and 20% achieving 2-year survival. Using the FACT-PA scale to measure the quality of life (QOL), 13 of the 15 patients reported an improvement in their QOL and 2 patients reported no change. The median CA19-9 levels for the 13 patients with measurable CA19-9 values, decreased by 71% by cycle 2. Adverse events were acceptable and included neutropenia, thrombocytopenia, nausea, fatigue, and anemia. CONCLUSIONS: The combination of gemcitabine, irinotecan, and celecoxib is an active therapy for inoperable pancreatic cancer. A marked reduction in CA19-9 is observed in all evaluable patients by cycle 2. Toxicity is tolerable and a majority of patients reported a decrease in pain and a significant improvement in their QOL.

Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01-1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06-1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049-0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33-3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34-0.80). When adjusting for CA19-9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09-2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.

Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease.

To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.

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.

Serum osteoprotegerin levels in healthy controls and cancer patients.

PURPOSE: Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor receptor superfamily. In vitro, OPG blocks osteoclastogenesis in a dose-dependent manner. Serum OPG levels were assayed in cancer patients and healthy control subjects using an ELISA. RESULTS: OPG levels in healthy controls were significantly higher in sera (0.17 ng/ml) than in plasma (0.14 ng/ml). OPG levels did not differ by age in either control group. Serum was available from patients with solid tumors (n = 145), hematological malignancies (n = 111), benign hematological disorders (n = 35), and rheumatologic diseases (n = 60). When adjusted for age and sex, there was no significant OPG elevation in the sera of patients with solid tumors compared with controls (0.2 versus 0.18 ng/ml). When analyzed by site of primary malignancy within the solid tumor patient group, serum OPG elevations were observed only in patients with colorectal cancer (0.29 ng/ml; P < 0.0001) and pancreatic cancer (0.35 ng/ml; P < 0.0001). When analyzed by site of metastasis within the solid tumor patient group, significant elevations in serum OPG were observed only in patients with liver metastases (0.29 ng/ml) and soft tissue metastases (0.21 ng/ml) but not in patients with bone or lung metastases. Within the hematological malignancy group, serum levels of OPG were significantly lower in patients with multiple myeloma (0.12 ng/ml) but were elevated in patients with Hodgkin's disease (0.29 ng/ml) and Non-Hodgkin's Lymphoma (0.24 ng/ml; P = 0.048). CONCLUSIONS: Although some patients with malignancy have significant elevations of circulating OPG, these concentrations do not approach the level that would be expected to suppress osteoclast function.

Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon carcinomas detected by RT-PCR.

The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors. An RT-PCR assay was used to detect EGFR mRNA in the blood of 43 patients with pancreatic, lung (NSCLC), colon, and renal carcinomas. After an initial serum tube was drawn to clear the line of detached epithelial cells, a 3 ml sample of EDTA-anticoagulated blood was collected from each cancer patient and healthy control. Total RNA was isolated from each sample and from cancer cell lines. After reverse transcription using specific priming, outer and nested primers for EGFR were employed for cDNA amplification. RNA integrity was confirmed with RT-PCR amplification using beta2-microglobulin primers. PCR products were electrophoresed on agarose gels containing ethidium bromide and visualized. The assay was validated using Southern blotting and was capable of detecting a lower limit of 100 fg of total RNA from the A431 cell line. EGFR-positive cells were detected in 3/10 (30%) non-small cell lung cancer patients, 2/11 (18%) pancreatic cancer patients, and 2/16 (12.5%) colon cancer patients, but in 0/6 (0%) patients with renal carcinoma (16% of solid tumor patients overall). All 23 healthy controls were negative. This study is the first to apply RT-PCR for the detection of EGFR mRNA in the peripheral blood of patients with pancreatic and renal carcinomas, and it lends further support for the use of EGFR mRNA as a marker of CTCs in the blood of patients with certain types of solid tumors.

Monitoring the circulating levels of the HER2/neu oncoprotein in breast cancer.

The HER2/neu oncoprotein is a major target for the development of new cancer therapies and is similar to the estrogen receptor, which guides hormone therapy. The HER2/neu status is used to guide therapy decisions in patients with HER2/neu-overexpressing breast cancer tumors. The HER2/neu oncogene, or c-erbB-2, encodes a transmembrane receptor protein that is expressed on normal epithelial cells and can be overexpressed in breast cancer cells. Studies have shown that the extracellular domain (ECD) of the HER2/neu oncoprotein is released from the cell and can be measured in the circulation of women with breast cancer. Enzyme-linked immunosorbent assay methods used to measure the circulating HER2/neu ECD have shown that the prevalence of elevated ECD levels is approximately 18.1% in women with primary breast cancer and approximately 45.6% in women with metastatic breast cancer (MBC). Many studies have monitored the circulating ECD levels after surgery and indicate that increasing ECD levels can indicate recurrence of breast cancer earlier than clinical diagnosis. Studies in women with MBC showed that serial changes in circulating HER2/neu ECD levels paralleled the clinical course of disease, regardless of the treatment regimen. Several studies identified a subgroup of patients with MBC who had HER2/neu-negative disease by tissue testing but developed elevated ECD levels with MBC. In contrast to tissue testing, which is a one-time event, monitoring the circulating levels of the HER2/neu ECD in patients with breast cancer provides a real-time assessment of the HER2/neu status and provides important information for managing the therapy of patients with MBC.

Would screening for lung cancer benefit 75- to 84-year-old residents of the United States?

BACKGROUND: The National Lung Screening Trial demonstrated that screening for lung cancer improved overall survival (OS) and reduced lung cancer mortality in the 55- to 74-year-old age group by increasing the proportion of cancers detected at an early stage. Because of the increasing life expectancy of the American population, we investigated whether screening for lung cancer might benefit men and women aged 75-84 years. MATERIALS/METHODS: Rates of non-small cell lung cancer (NSCLC) from 2000 to 2009 were calculated in both younger and older age groups using the surveillance epidemiology and end reporting database. OS and lung cancer-specific survival (LCSS) in patients with Stage I NSCLC diagnosed from 2004 to 2009 were analyzed to determine the effects of age and treatment. RESULTS: The per capita incidence of NSCLC decreased in the 55-74 cohort, but increased in the 75-84 cohort over the study period. Crude lung cancer death rates in the two age groups who had no specific treatment were 39.5 and 44.9%, respectively. These rates fell in both age groups when increasingly aggressive treatment was used. Rates of OS and LCSS improved significantly with increasingly aggressive treatment in the 75-84 age group. The survival benefits of increasingly aggressive treatment in 75- to 84-year-old females did not differ from their counterparts in the younger cohort. CONCLUSION: Screening for lung cancer might be of benefit to individuals at increased risk of lung cancer in the 75-84 age group. The survival benefits of aggressive therapy are similar in females between 55-74 and 75-84 years old.