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Jeffrey S Ross

Publications and source records attributed to Jeffrey S Ross.

At least 19 recordsLinked to original sources
PubMed2026

Molecularly Guided Therapy Versus Continued Chemotherapy in Unfavorable Cancer of Unknown Primary: Updated Efficacy and Safety From the Randomized, Phase II CUPISCO Study.

CUPISCO (ClinicalTrials.gov identifier: NCT03498521) demonstrated longer progression-free survival (PFS) with comprehensive genomic profiling (CGP) and subsequent molecularly guided therapies (MGTs), versus standard platinum-based chemotherapy, in patients with previously untreated, unfavorable cancer of unknown primary (CUP) who reached disease control after induction chemotherapy (three cycles). We report efficacy and safety after >1 year of additional follow-up. Eligible patients were randomly assigned (3:1) to MGT (investigator-chosen after discussion in a molecular tumor board) or three further cycles of chemotherapy. The primary end point was PFS. Secondary end points included overall survival (OS) and safety. At data cutoff (December 6, 2024), 436 patients were randomly assigned (326 to MGT; 110 to chemotherapy). Median follow-up was 37.0 months (range, 0.0-67.8). Updated median PFS was 6.1 months (95% CI, 4.7 to 6.5) with MGT and 4.4 months (95% CI, 4.2 to 6.4) with chemotherapy (hazard ratio [HR], 0.75 [95% CI, 0.59 to 0.95]; P = .017); median OS was 15.2 months (95% CI, 13.9 to 18.4) and 12.8 months (95% CI, 9.8 to 15.4), respectively (HR, 0.79 [95% CI, 0.61 to 1.02]; P = .0689). No new safety signals were identified. These updated results aligned with the primary analysis, demonstrating the benefit of CGP with subsequent MGT and highlighting the importance of incorporating CGP at initial diagnosis to guide treatment decisions for patients with unfavorable CUP.

Journal Article↗
PubMed2026

C-Terminal Truncation and Fusion Partner Determine Oncogenicity of FGFR3.

UNLABELLED: Genomic alterations affecting components of the fibroblast growth factor (FGF) signaling axis can trigger aberrant pathway activation and tumor development. Genomic truncation of the FGF receptor 2 (FGFR2) exon 18 (E18) disrupts the FGFR2 carboxy (C)-terminal tail, acting as a potent driver alteration across multiple tumor types. In this study, we analyzed human oncogenomic datasets to reveal that E18 truncations are similarly prevalent in FGFR3, an FGFR2 paralog. FGFR3 E18 truncations primarily occur due to rearrangements (RE) that involve transforming acidic coiled-coil-containing protein 3 (TACC3), resulting in FGFR3ΔE18-TACC3 gene fusions. In contrast to E18-truncated FGFR2, functional in vitro and in vivo examination of Fgfr3 variants demonstrated that the truncation of Fgfr3 E18 is insufficient to promote oncogenic activity in cell lines or in the lungs and mammary glands of mice. Only the combination of an Fgfr3 E18 truncation with a RE partner gene that encodes a receptor-dimerizing domain resulted in the development of tumors, which were sensitive to FGFR inhibition. Overall, these findings suggest that patients with cancers that are positive for rearranged FGFR3, resulting in E18 truncation and a fusion to dimerizing partners, should be considered for FGFR-targeted therapies. SIGNIFICANCE: FGFR3, unlike its paralog FGFR2, requires both a C-terminal truncation and fusion to a partner gene that retains the expression of a dimerizing domain to effectively drive oncogenic signaling and tumorigenesis.

Receptor, Fibroblast Growth Factor, Type 3↗
PubMed2006

Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.

BACKGROUND: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy. METHODS: Drug cytotoxicity, both individually and together, and drug effects on p27 localization and NF-kappaB activation were investigated on four breast cancer cell lines: SKBR-3 (HER-2+++), MDA-MB-453 (HER-2++), HER-2-transfected MCF-7 (HER-2+++), and MCF-7 (HER-2-). RESULTS: Bortezomib induced apoptosis in HER-2-positive and HER-2-negative breast cancer cells in a dose- and time-dependent manner. Together, these drugs induced apoptosis of HER-2++/+++ cells at low concentrations, which had no effect when used alone, indicating there was a synergistic effect. Sequential treatment (trastuzumab then bortezomib) induced either necrosis or apoptosis, depending on the trastuzumab preincubation time. Susceptibility to bortezomib alone and the drug combination correlated with NF-kappaB activity and p27 localization. CONCLUSIONS: The addition of bortezomib to trastuzumab increases the effect of trastuzumab in HER-2+++/++ cell lines in a synergistic way. This effect likely results from the ability of these two drugs to target the NF-kappaB and p27 pathways. The potential clinical application of this drug combination is under current evaluation by our group in a phase 1 clinical trial.

Antibodies, Monoclonal↗
PubMed2006

Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.

PURPOSE: To investigate whether nuclear factor kappaB (NF-kappaB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-kappaB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-kappaB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. EXPERIMENTAL DESIGN: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-kappaB inhibitor PS-1145 (an inhibitor of IkappaB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-kappaB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. RESULTS: PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival. CONCLUSIONS: Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.

Aged↗
PubMed2006

Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.

PURPOSE: We developed a multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its predictive accuracy on independent cases. PATIENTS AND METHODS: One hundred thirty-three patients with stage I-III breast cancer were included. Pretreatment gene expression profiling was performed with oligonecleotide microarrays on fine-needle aspiration specimens. We developed predictors of pCR from 82 cases and assessed accuracy on 51 independent cases. RESULTS: Overall pCR rate was 26% in both cohorts. In the training set, 56 probes were identified as differentially expressed between pCR versus residual disease, at a false discovery rate of 1%. We examined the performance of 780 distinct classifiers (set of genes + prediction algorithm) in full cross-validation. Many predictors performed equally well. A nominally best 30-probe set Diagonal Linear Discriminant Analysis classifier was selected for independent validation. It showed significantly higher sensitivity (92% v 61%) than a clinical predictor including age, grade, and estrogen receptor status. The negative predictive value (96% v 86%) and area under the curve (0.877 v 0.811) were nominally better but not statistically significant. The combination of genomic and clinical information yielded a predictor not significantly different from the genomic predictor alone. In 31 samples, RNA was hybridized in replicate with resulting predictions that were 97% concordant. CONCLUSION: A 30-probe set pharmacogenomic predictor predicted pCR to T/FAC chemotherapy with high sensitivity and negative predictive value. This test correctly identified all but one of the patients who achieved pCR (12 of 13 patients) and all but one of those who were predicted to have residual disease had residual cancer (27 of 28 patients).

Adult↗
PubMed2006

Differential cellular and molecular effects of bortezomib, a proteasome inhibitor, in human breast cancer cells.

The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3'-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.

Boronic Acids↗
PubMed2006

A quantitative reverse transcriptase-polymerase chain reaction assay to identify metastatic carcinoma tissue of origin.

Identifying the primary site in patients with metastatic carcinoma of unknown primary origin can enable more specific therapeutic regimens and may prolong survival. Twenty-three putative tissue-specific markers for lung, colon, pancreatic, breast, prostate, and ovarian carcinomas were nominated by querying a gene expression profile database and by performing a literature search. Ten of these marker candidates were then selected based on validation by reverse transcriptase-polymerase chain reaction (RT-PCR) on 205 formalin-fixed, paraffin-embedded metastatic carcinoma specimens originating from these six and from other cancer types. Next, we optimized the RNA isolation and quantitative RT-PCR methods for these 10 markers and applied the quantitative RT-PCR assay to a set of 260 metastatic tumors. We then built a gene-based algorithm that predicted the tissue of origin of metastatic carcinomas with an overall leave-one-out cross-validation accuracy of 78%. Lastly, our assay demonstrated an accuracy of 76% when tested on an independent set of 48 metastatic samples, 37 of which were either a known primary or initially presented as carcinoma of unknown primary but were subsequently resolved.

Algorithms↗
PubMed2005

Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma.

BACKGROUND: Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2). Nonsmall cell lung carcinoma (NSCLC) overexpresses HER-2 protein in approximately 20% of cases. In the current study, the authors combined trastuzumab with weekly taxanes in an attempt to improve outcomes over standard chemotherapy in patients with advanced NSCLC. METHODS: The primary objective was to determine whether docetaxel plus trastuzumab or paclitaxel plus trastuzumab was the superior regimen based on response and toxicity, and to determine whether either regimen was appropriate for further testing in a randomized Phase III trial. After stratification based on the results of HER-2 immunohistochemistry, chemotherapy-naive patients were randomized to receive trastuzumab plus docetaxel or trastuzumab plus paclitaxel. The study was designed so patients with or without HER-2 overexpression would be distributed equally between the study arms. RESULTS: Immunohistochemistry for HER-2 protein expression was attempted for 182 pathologic samples from 169 patients. Twenty-eight of the 179 evaluable samples (16%) revealed 2+ or 3+ staining. The objective response rate was 23% (7 of 30 patients) in the patients treated with docetaxel plus trastuzumab and 32% (11 of 34 patients) in the patients treated with paclitaxel plus trastuzumab (P=0.76, Wilcoxon test). No difference was noted in the median survival (16 mos vs. 14 mos) or 1-year survival (57% vs. 55%) (P=0.998). Toxicities were mild in both treatment arms. No difference with regard to response rates or survival was noted between HER-2-positive (2+ or 3+) and HER-2-negative (0-1+) patients. CONCLUSIONS: The expression of HER-2 protein in patients with advanced NSCLC in this study was found to be similar to that reported in previous series. The response rates and toxicities for patients treated with docetaxel and trasuzumab or paclitaxel and trasuzumab were not significantly different, though survival in both arms was better than expected. HER-2 expression status did not appear to affect outcomes for this uniform group of patients who were treated in a comparable fashion. Because of the infrequency of HER-2 overexpression, and the absence of improved outcomes in patients with NSCLC who were treated with trastuzumab plus chemotherapy in other studies, neither regimen tested will be advanced to a Phase III trial.

Antibodies, Monoclonal↗
PubMed2005

Fluid in the flute: Reversible hydromyelia.

Non-communicating syrinx formation in association with demyelinating disease has been reported in approximately 50 patients. It has been unknown whether this is a permanent or potentially reversible phenomenon. We report a patient with acute transverse myelitis who developed a syrinx that resolved within 6 months. Mechanisms of syrinx formation in demyelinating disease are discussed.

Humans↗
PubMed2005

Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.

PURPOSE: We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk. METHODS: Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays. RESULTS: Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit. CONCLUSION: Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.

Adult↗
PubMed2005

Breast cancer molecular subtypes respond differently to preoperative chemotherapy.

PURPOSE: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like, normal-like, and erbB2+ subgroups were identified and were shown to have different prognoses. The goal of this research was to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy. EXPERIMENTAL DESIGN: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the previously reported "breast intrinsic" gene set was used for hierarchical clustering and multidimensional scaling to assign molecular class. RESULTS: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% [95% confidence interval (95% CI), 24-68] and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade. None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+ group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor-negative subtypes. CONCLUSIONS: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.

Adult↗
PubMed2005

Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer.

Breast cancers show variable sensitivity to paclitaxel. There is no diagnostic test to identify tumors that are sensitive to this drug. We used U133A chips to identify genes that are associated with pathologic complete response (pCR) to preoperative paclitaxel-containing chemotherapy in stage I-III breast cancer (n = 82). Tau was the most differentially expressed gene. Tumors with pCR had significantly lower (P < 0.3 x 10(-5)) mRNA expression. Tissue arrays from 122 independent but similarly treated patients were used for validation by immunohistochemistry. Seventy-four percent of pCR cases were tau protein negative; the odds ratio for pCR was 3.7 (95% confidence interval, 1.6-8.6; P = 0.0013). In multivariate analysis, nuclear grade (P < 0.01), age <50 (P = 0.03), and tau-negative status (P = 0.04) were independent predictors of pCR. Small interfering RNA experiments were performed to examine whether down-regulation of tau increases sensitivity to chemotherapy in vitro. Down-regulation of tau increased sensitivity of breast cancer cells to paclitaxel but not to epirubicin. Tubulin polymerization assay was used to assess whether tau modulates binding of paclitaxel to tubulin. Preincubation of tubulin with tau resulted in decreased paclitaxel binding and reduced paclitaxel-induced microtubule polymerization. These data suggest that low tau expression renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression may be used as a marker to select patients for paclitaxel therapy. Inhibition of tau function might be exploited as a therapeutic strategy to increase sensitivity to paclitaxel.

Biomarkers↗
PubMed2005

Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy.

PURPOSE: Women with advanced epithelial ovarian cancer are routinely treated with platinum-paclitaxel chemotherapy following cytoreductive surgery, yet only approximately 20% achieve long-term disease-free survival. We hypothesized that differences in gene expression before treatment could distinguish patients with short versus long time to recurrence after administration of platinum-paclitaxel combination chemotherapy. EXPERIMENTAL DESIGN: To test this hypothesis, gene expression profiling of 79 primary surgically resected tumors from women with advanced-stage, high-grade epithelial ovarian cancer was done using cDNA microarrays containing 30,721 genes. Supervised learning algorithms were applied in an effort to develop a binary classifier that could discriminate women at risk for early (< or =21 months) versus late (>21 months) relapse after initial chemotherapy. RESULTS: A 14-gene predictive model was developed using a set of training samples (n = 51) and subsequently tested using an independent set of test samples (n = 28). This model correctly predicted the outcome of 24 of the 28 test samples (86% accuracy) with 95% positive predictive value for early relapse. CONCLUSIONS: Predictive markers for early recurrence can be identified for platinum-paclitaxel combination chemotherapy in primary ovarian carcinoma. The proposed 14-gene model requires further validation.

Adult↗
PubMed2005

Antibody-based therapeutics: focus on prostate cancer.

The recent clinical and commercial success of anti-cancer antibodies such as rituximab, trastuzumab, cetuximab and bevacizumab has continued to foster great interest in antibody-based therapeutics for the treatment of both hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies which, in contrast with traditional cytotoxic small molecule drugs, target tumor cells and have a lower impact on non-malignant by-stander organs, the potential increases in efficacy associated with conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drugs clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. A significant number of cell surface proteins, glycoproteins, receptors, enzymes and peptides have been discovered that have become targets for the treatment of advanced hormone-refractory prostate cancer. A variety of naked antibodies and antibody conjugates have currently progressed through preclinical development and are in early or more advanced stages of clinical development. Clinicians, scientists and prostate cancer patients are all keenly interested to learn whether these agents when administered alone or in combination with other hormonal-based and cytotoxic therapies will show lasting benefit for sufferers of this common disease.

Antibodies, Monoclonal↗
PubMed2005

Smad4 protein expression correlates with grade, stage, and DNA ploidy in prostatic adenocarcinomas.

The tumor suppressor gene Smad4 (DPC4) has been localized to chromosome 18q21.1 and is a member of the Smad family that mediates the transforming growth factor beta signaling pathway suppressing epithelial cell growth. However, variable expression of this protein has been reported, with a loss in some cancers and increased expression in others. Given both the variability and lack of consensus reported regarding Smad4 expression in prostate cancer, we assessed Smad4 immunoreactivity in prostatic adenocarcinomas (PACs). Formalin-fixed, paraffin-embedded tissue sections from 133 PACs were immunostained by a manual method using indirect biotin streptavidin horseradish peroxidase and diaminobenzidine detection using a monoclonal mouse antihuman Smad4 antibody (sc-7966; Santa Cruz Biotechnology Inc, Santa Cruz, Calif). Nuclear immunoreactivity and cytoplasmic immunoreactivity were each semiquantitatively scored based on intensity and percentage of positive cells. Deoxyribonucelic acid ploidy was determined on Feulgen-stained tissue sections by static image analysis. Results were correlated with morphological and prognostic variables. Variable nuclear and cytoplasmic Smad4 positivity was noted in the adjacent benign glands in all cases. Of 133 PACs, 64 (48%) featured increased nuclear and 68 (51%) featured increased cytoplasmic protein expression. Nuclear Smad4 overexpression correlated with tumor grade (P = .02), stage (P = .04), and DNA ploidy (P = .04). Cytoplasmic overexpression correlated with tumor grade (P = .04) and DNA ploidy (P = .04) while showing a trend for correlation with tumor stage (P = .08). Neither nuclear nor cytoplasmic Smad4 overexpression correlated with postsurgical biochemical disease recurrence. Smad4 protein expression persists in PACs compared with benign glands, with both nuclear and cytoplasmic overexpression correlating with prognostic variables indicative of aggressive tumor behavior. Given the significant reported variability of Smad4 in several different cancers, further studies in prostate and other tumors are warranted to elucidate its role in tumorigenesis.

Adenocarcinoma↗
PubMed2005

Breast cancer biomarkers.

Substantial progress has been made over the past three decades in our understanding of the epidemiology, clinical course and basic biology of breast cancer. This chapter considers the existing ancillary tests and emerging molecular markers in breast cancer prognosis assessment and the prediction of response of breast cancer to treatment of the disease.

Biomarkers, Tumor↗
PubMed2005

Comparison of the predictive accuracy of DNA array-based multigene classifiers across cDNA arrays and Affymetrix GeneChips.

We examined how well differentially expressed genes and multigene outcome classifiers retain their class-discriminating values when tested on data generated by different transcriptional profiling platforms. RNA from 33 stage I-III breast cancers was hybridized to both Affymetrix GeneChip and Millennium Pharmaceuticals cDNA arrays. Only 30% of all corresponding gene expression measurements on the two platforms had Pearson correlation coefficient r >or= 0.7 when UniGene was used to match probes. There was substantial variation in correlation between different Affymetrix probe sets matched to the same cDNA probe. When cDNA and Affymetrix probes were matched by basic local alignment tool (BLAST) sequence identity, the correlation increased substantially. We identified 182 genes in the Affymetrix and 45 in the cDNA data (including 17 common genes) that accurately separated 91% of cases in supervised hierarchical clustering in each data set. Cross-platform testing of these informative genes resulted in lower clustering accuracy of 45 and 79%, respectively. Several sets of accurate five-gene classifiers were developed on each platform using linear discriminant analysis. The best 100 classifiers showed average misclassification error rate of 2% on the original data that rose to 19.5% when tested on data from the other platform. Random five-gene classifiers showed misclassification error rate of 33%. We conclude that multigene predictors optimized for one platform lose accuracy when applied to data from another platform due to missing genes and sequence differences in probes that result in differing measurements for the same gene.

Adult↗