Discordant results obtained for different methods of HER-2/neu testing in breast cancer--a question of standardization, automation and timing

BACKGROUND: HER-2/neu positivity is required for the selection of stage IV breast cancer patients for trastuzumab therapy. We compared the results of the recommended immunohistochemistry (IHC) evaluation with the automated ACIS IHC system and with fluorescence in situ hybridization (FISH). These HER-2/neu tissue results were correlated with the serum HER-2/neu (sHER-2/neu) levels at the time of metastatic spread. PATIENTS AND METHODS: A total of 61 IHC slides from 30 patients were stained using the HercepTest. HER-2/neu gene amplification was determined using the Ventana FISH assay. sHER-2/neu levels were measured with the Oncogene Science" ELISA kit. The concordance of HER-2/neu results was determined using the concordance index Kappa (kappa). RESULTS: The best concordance between any IHC and FISH was found for the automated ACIS system (88.5%, kappa=0.68, category "good"). The comparison between the manual interpretations and the automated IHC was categorized as "very good" (95.1%, kappa=0.85). The median sHER-2/neu level of FISH positive patients was significantly higher (67 ng/mL) than that of FISH negative patients (17 ng/mL, p=0.018). The increase in HER-2/neu positivity comparing tissue to stage IV serum was statistically significant (p=0.001). CONCLUSIONS: The concordance between conventional IHC and computerized analysis was very good. The number of patients with stage IV breast cancer with an elevated sHER-2/neu level was much higher than HER-2/neu positivity in tissue. This discrepancy is only partially explained by the influence of tumor load. Patients with an elevated sHER-2/neu level and no tissue overexpression should be considered for retesting of tissue or a new biopsy.     

Prognostic value of cytokeratin 19 fragment (CYFRA 21-1) and cytokeratin-positive cells in bone marrow samples of breast cancer patients

The aim of this study was to investigate the relationship between the detection of micrometastatic cells by immunocytochemistry (ICC) with an anticytokeratin antibody and cytokeratin fragment (CYFRA 21-1) expression detected by an immunofluorescent assay in bone marrow of breast cancer patients. Micrometastatic CK+ cells were screened with a pancytokeratin antibody A45 B/B3 from bone marrow aspiration samples of 102 breast cancer patients (65 primary tumors, 10 local recurrences and 27 distant metastases). CYFRA 21-1 levels were assessed in bone marrow supernatant of these patients before collection of the mononucleated interface cells on a Ficoll-Hypaque density gradient and in 20 control patients. CYFRA 21-1 and CK+ cell detection by ICC were both correlated with clinical stage. CYFRA 21-1 was significantly elevated in patients with micrometastatic disease detected by ICC: 4.77 ng/mL (+/- 10.87 SD) versus 1.00 ng/mL (+/-1.36 SD) in patients with negative ICC (p=0.01). In univariate analysis, a CYFRA 21-1 value > or =1 ng/mL and the presence of CK+ cells were associated with a poorer survival for patients with stage I to III breast cancer (n=65). On multivariate analysis, only pathological nodal status and presence of CK+ cells in bone marrow were independent prognostic factors for overall survival. In conclusion, in this series CYFRA 21-1 was correlated with detection of CK+ cells by ICC in bone marrow, but cannot replace ICC. The presence of CK+ cells in bone marrow remains a strong independent prognostic factor in primary breast cancer.     

Clinical significance of cathepsin D concentration in tumor cytosol of primary breast cancer

BACKGROUND: Cathepsin D is the proteolytic enzyme most frequently implicated as a prognostic factor in primary breast cancer. In the present study we evaluated by means of an immunoradiometric assay the tumor content of this protease in primary breast cancer, its relationship with tumor-related clinical and pathological parameters, and its prognostic significance in a large series of breast cancer patients. METHOD: The study comprised 1033 women with histologically established invasive breast cancer. Cathepsin D was measured in cytosol samples by means of an immunoradiometric assay to determine the total amount of cathepsin D (52 kDa, 48 kDa and 34 kDa). Evaluation of relapse-free survival and cause-specific survival was performed in the group of 1003 patients without evidence of metastasis at the time of initial diagnosis. The median follow-up of the patients who were free of recurrence was 54 months. RESULTS: Cathepsin D levels showed a wide range among the studied tumors (n = 1033; median (range) 41 (0.9-2504) pmol/mg protein). Statistical analysis showed that the median cathepsin D levels were considerably higher in large tumors (T2-4) than in smaller ones (T1) (p = 0.017), as well as in node-positive than in node-negative tumors (p = 0.004). Cathepsin D levels were also higher in ductal tumors than in the other histological types (p = 0.001), as well as in moderately or poorly differentiated tumors (p < 0.001). Likewise, the median value of the protease was significantly higher in ER or PgR-positive tumors than in hormone receptor-negative ones (p = 0.011 and p = 0.004, respectively), as well as in aneuploid tumors than in diploid tumors (p = 0.029). Multivariate analysis demonstrated that elevated cathepsin D levels (> 59 pmol/mg protein) were notably associated with a shorter cause-specific survival in the whole group of patients with breast cancer, as well as in the subgroup of node-positive patients (p < 0.05). CONCLUSIONS: This study suggests that elevated intratumoral cathepsin D levels may identify a subset of node-positive breast cancer patients showing a high probability of earlier death.     

Chromosomal imbalances are associated with metastasis-free survival in breast cancer patients.

Multiple chromosomal imbalances have been identified in breast cancer using comparative genomic hybridization (CGH). Their association with the primary tumors' potential for building distant metastases is unknown. In this study we have investigated 39 invasive breast carcinomas with a mean follow-up period of 99 months (max. 193 months) by CGH to determine the prognostic value of chromosomal gains and losses.The mean number of chromosomal imbalances per tumor was 6.5+/-0.7 (range 2 to 18). The most frequent alterations identified in more than 1/3 of cases were gains on chromosomes 11q13, 12q24, 16, 17, and 20q, and losses on 2q and 13q. A significantly different frequency of chromosomal aberrations (p相似文献   

Prognostic value of pS2 protein and receptors for epidermal growth factor (EGF-R), Insulin-like growth factor-1 (IGF-1-R) and somatostatin (SS-R) in patients with breast and ovarian cancer

The prognostic value of EGF-R, IGF-1-R and SS-R, and of cytosolic estrogen-regulated pS2 protein, was studied in patients (pts) with primary breast and advanced ovarian cancer. Ovarian cancer tissues were negative for pS2 (by immunoradiometric assay) IGF-1-R and EGF-R contents (by ligand binding assay, LBA) were of no or moderate prognostic value for breast cancer pts (n = 214). For advanced ovarian cancer pts, EGF-R content determined by LBA (n = 55) showed no prognostic value, whereas EGF-R status (n = 55) determined by immunohistochemistry (MoAb 2E9) signiificantly correlated with progression of disease (P < 0.05). In breast cancer pts, both SS-R and pS2 showed no association with tumor size, nodal status and grade. For pS2 the best cut-off level with respect to relapse-free (RFS) and overall survival (OS) was found to be 11 ng/mg protein. Both SS-R (1 g% SS-R+, n = 135; P < 0.04) and pS2 (27% pS2+, n = 197; P < 0.001), which were mainly positive in ER+ tumors, were of prognostic value, especially within the subgroups with ER+/PgR+ tumors. Also within N+ and No pts the 5-yr RFS and OS showed a difference between pS2+ and pS2- (33 and 54% for N+, and 31 and 13% difference for No pts). In summary, SS-R and pS2 are valuable pronosticators in breast cancer pts, and prognostic significance of EGF-R in ovarian cancer pts needs further study.     

Insulin-like growth factor II (IGF-II) immunohistochemistry in breast cancer: relationship with the most important morphological and biochemical prognostic parameters

Recent in situ hybridization experiments have shown a high content of IGF-II mRNA in breast cancer stroma. The aim of this study was to examine the relationship between IGF-II protein expression and several prognostic parameters in 75 infiltrating ductal carcinomas (IDC) of the breast. Tissue sections were evaluated for proliferative activity, IGF-II protein, ER, PgR, p53, and p21 expression using immunohistochemical procedures. The degree of stromal proliferation was assessed. Menopausal status, axillary lymph node involvement and nuclear grade were known. Thirty-five patients (44.3%) were premenopausal and 47 (62.6%) had lymph node metastases. Marked stromal proliferation was found in 34 (45.3%) specimens and high nuclear grade in 20 (26.5%). Eighteen tumors (24%) showed no IGF-II immunostaining. In the positive cases, IGF-II was detected both in the tumor stroma and in the cytoplasm of epithelial cancer cells: a high IGF-II content was found in 12 specimens (16.0%), a low content in 14 (18.7%) and a moderate content in 31 (41.3%). Twenty-four tumors (32.0%) showed high proliferative activity. Both ER and PgR were expressed in the nucleus of cancer cells: 49 tumors (65.3%) were ER positive (ER+) and 34 (45.3%) PgR positive (PgR+). p21 protein was detected in 37 tumors (49.6%) and p53 in 12 (16%). IGF-II protein was not correlated with menopausal status, lymph node metastases, nuclear grade, proliferative activity, ER or p53. In contrast, IGF-II correlated strongly with stromal proliferation (p=0.008), PgR (p=0.03) and p21 (p=0.01). This study demonstrates that in IDC of the breast IGF-II protein is expressed in the epithelium and stroma of the majority of tumors and is correlated with stromal amount, PgR and p21 expression. These preliminary results indicate that IGF-II expression in breast cancer is connected with two important regulators of breast cancer growth and differentiation.     

Are 90K/MAC-2BP serum levels correlated with poor prognosis in HCC patients? Preliminary results

In this study we assessed the prognostic significance of 90K/MAC-2BP serum levels in a group of 40 hepatocellular carcinoma patients. This glycoprotein is a new, interesting serum marker that reflects the immune reaction of the host against certain viral infections and tumors such as breast, ovarian and pancreatic cancer. Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world. AFP is currently the most useful marker for HCC, in spite of its poor diagnostic sensitivity. In this study 40 cirrhotic HCC patients were enrolled. The prevalence of viral hepatic infections in this group was 73% for HCV, 8% for HBV, and 8% for both viruses. Thirteen percent of the patients showed non-virus-related liver damage. 90K serum levels were assayed by an ELISA kit and AFP levels by a chemiluminescent enzyme immunometric system. The overall survival curves were estimated by the Kaplan-Meier method, taking into account age, sex, 90K and AFP serum levels. Statistical analysis showed a highly significant influence on overall survival of age below 70 years and 90K serum levels below the cutoff of 14 ng/mL. Serum AFP (< or = 20 ng/mL) had positive prognostic value only when it was associated with 90K levels (p < 0.02, log-rank).     

Parallel assessment of circulatory cell-free DNA by PCR and nucleosomes by ELISA in breast tumors

OBJECTIVES: In order to assess the potential biomolecules for breast cancer, we analyzed in parallel the levels of cell-free glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cell-free nucleosomes in serum samples from patients with benign and malignant breast tumors. The levels of cell-free DNA obtained by quantitative PCR were compared with those obtained by enzyme-linked immunosorbent assay (ELISA). METHODS: Twenty-three patients with benign breast tumors, 27 patients with breast cancer, and 32 age-matched healthy women were recruited. The amounts of serum nucleosomes were analyzed by ELISA and the levels of cell-free GAPDH were measured by real-time quantitative PCR. The correlation between nucleosome and cell-free GAPDH levels was examined using the Spearman rank test. RESULTS: The levels of cell-free GAPDH were significantly higher in the serum samples of patients with benign and malignant breast tumors than in those of the control group (median 37,966 GE/mL, range 3,802-130,104 versus 11,770 GE/mL, range 2,198-73,522, p=0.035 and median 40,698 GE/mL, range 3,644-192,482 versus 11,770 GE/mL range 2,198-73,522, p=0.001). The concentration of cell-free GAPDH correlated significantly with the quantities of nucleosomes in serum samples (r=0.451, p=0.000). There was, however, no significant difference between healthy individuals and women with benign breast tumors or breast cancer in terms of nucleosomes determined by ELISA. CONCLUSION: Our data suggest that the cell-free serum GAPDH DNA assayed by quantitative PCR is a better biomarker than nucleosomes assayed by ELISA in patients with breast tumors.     

Quantitative assessment of HER-2/neu protein concentration in breast cancer by enzyme-linked immunosorbent assay

PURPOSE: The HER-2/neu protein (p185) has become a promising target for antibody therapy in breast cancer. We tested the feasibility of a quantitative approach for HER-2/neu testing based on the analysis of tumor tissue extracts by an enzyme-linked immunosorbent assay (ELISA). EXPERIMENTAL DESIGN: Tumor tissue extracts of primary human breast cancers (n=124) were prepared using a triton-based buffer. HER-2/neu concentration was quantified by ELISA. Paraffin-embedded tissue sections of the same tumors were analyzed by immunohistochemical staining applying the monoclonal HER-2/neu antibody TAB 250 (n=124) and by chromogenic in situ hybridization (CISH) (n=73). RESULTS: Concentrations of p185 in tissue extracts determined by ELISA varied from 1 to 927 ng per mg protein with a median of 25 ng/mg protein, whereas normal breast tissue showed values from 0.4 to 5.5 ng/mg with a median of 2.2 ng/mg (p<0.0001, Mann-Whitney U test). A significant correlation between p185 concentration and immunohistochemical staining was observed (p<0.0001, Kruskal-Wallis test). In addition, p185 concentration measured by ELISA was correlated with the degree of HER-2/neu gene amplification determined by CISH. HER-2/neu-amplified tumors had significantly higher p185 concentrations (median value 181 ng/mg protein) than non-amplified tumors (median value 20 ng/mg; p<0.0001, Mann-Whitney U test). CONCLUSIONS: ELISA-based measurement of HER-2/neu protein concentration in breast cancer tissue extracts is feasible and provides quantitative results for p185 protein concentrations that correlate closely with HER-2/neu immunoscore and gene amplification.     

Cytosolic levels of an estrogen-induced breast cancer-associated peptide (TFF1/pS2) in colorectal cancer: clinical significance and relationship with steroid receptors

BACKGROUND: The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA in MCF-7 breast cancer cells and is also expressed by colorectal carcinomas. The objective of this work was to evaluate the cytosolic TFF1 content in colorectal carcinomas, its possible relationship with estrogen and progesterone receptors as well as with clinicopathological tumor parameters, and its potential prognostic significance. METHODS: Cytosolic TFF1 levels were examined by immunoradiometric assay in 178 patients with resectable colorectal cancer. The mean follow-up period was 32 months. RESULTS: There was a wide variability of cytosolic TFF1 levels in tumor-surrounding mucosa samples (0.09-42.5 ng/mg protein) as well as in tumors (0.01-270 ng/mg protein). Comparison of paired mucosa and carcinoma samples showed significantly higher TFF1 levels in tumors (mean: 17.1 ng/mg protein) than in mucosa samples (10 ng/mg protein) (p = 0.027). TFF1 levels were significantly higher in mucosa samples surrounding distal colon and rectal tumors (p = 0.0001) and in tumor samples obtained from older patients (p = 0.007). However, there were no significant differences in tumor TFF1 levels with respect to clinicopathological parameters such as the patient's sex, tumor location, stage, histological grade, ploidy, S-phase, or tumor estrogen and progesterone receptors. In addition, there was no significant relationship between tumor TFF1 levels and disease outcome. CONCLUSIONS:TFF1 may play an as yet undetermined role in the tumorigenesis of colorectal carcinomas. However, cytosolic levels of TFF1 do not seem to have any prognostic significance in colorectal carcinomas.     

A serological marker of the N-terminal neoepitope generated during LOXL2 maturation is elevated in patients with cancer or idiopathic pulmonary fibrosis

ObjectivesLysyl oxidase like 2 (LOXL2) is associated with poor prognosis in idiopathic pulmonary disease (IPF) and cancer. We developed an Enzyme-linked immunosorbent assay (ELISA) targeting the LOXL2 neo-epitope generated through the release of the signal peptide during LOXL2 maturation.Design and methodsAn ELISA targeting the N-terminal site of the human LOXL2 was developed including technical optimization and validation steps. Serum LOXL2 was measured in patients with breast, colorectal, lung, ovarian, pancreatic and prostate cancer, melanoma, IPF and in healthy controls (n = 16).ResultsA technically robust and specific assay was developed. LOXL2 was detectable in serum from healthy controls and showed reactivity towards recombinant LOXL2. Compared to controls, LOXL2 levels were significantly (p < 0.001–0.05) elevated in serum from patients with breast, colerectal, lung, ovarian and pancreatic cancer (mean range: 49–84 ng/mL), but not in prostate cancer (mean: 36 ng/mL) and malignant melanoma patients (41 ng/mL). Serum LOXL2 was elevated in IPF patients compared to healthy controls (mean: 76.5 vs 46.8 ng/mL; p > 0.001)ConclusionsA specific ELISA towards the N-terminal neo-epitope site in LOXL2 was developed which detected significantly elevated serum levels from patients with above-mentioned cancer types or IPF compared to healthy controls.     

Vascular endothelial growth factor (VEGF) and other common tissue prognostic indicators in breast cancer: a case-control study

VEGF is a specific mitogen and survival factor for endothelial cells and a key promoter of angiogenesis in physiological and pathological conditions. Nevertheless, VEGF tissue evaluation in cancer patients as a prognostic factor compared to the conventional histological and biological parameters is still controversial. In this case-control study, tissue VEGF was retrospectively determined by immunohistochemistry and related to T, N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 in 129 breast cancer patients. Seventy-four of these patients had developed distant metastases postoperatively. The remaining 55 patients had remained disease-free >10 years after surgery. In 17 (13%) of the 129 patients (six with distant metastases and eleven disease-free) tissue and plasma VEGF were concomitantly evaluated. In univariate analysis no significant differences in VEGF and tumor size were found between metastatic and disease-free patients, whereas there were significant differences in N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 (p ranging from 0.001 to 0.0001). In multivariate analysis VEGF showed less significance than N, ER, c-erbB-2, MIB-1 and cyclin D1 (p = 0.012, p = 0.007, p = 0.005, p = 0.005, p = 0.002 and p = 0.001, respectively). VEGF was a significant unfavorable prognostic indicator only in the N+ subset (p = 0.015), while ER (p = 0.05 and p = 0.021) and MIB-1 (p = 0.031 and p = 0.022) were significant in both the N+ and N- subgroups. In multivariate analysis in the 74 metastatic cases VEGF did not show any significance in relation to disease-free interval and overall survival from the time of mastectomy and from the time of relapse, whereas N and PgR did (p ranging from 0.018 to 0.001). In conclusion, tissue VEGF does not seem a suitable candidate to replace conventional histological and other common biological prognostic factors in breast cancer.     

Prognostic value of plasminogen activator inhibitors in breast cancer

The prognosis of cancer is primarily dependent on its potential to invade and metastasize. Data from both preclinical and clinical studies strongly suggest that serine proteases, as well as their inhibitors and receptor, play a central role in the processes leading to metastasis. We therefore investigated the prognostic value of plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2) and the combination of both inhibitors in 332 patients with operable breast cancer. PAI-1 and PAI-2 content was measured in the primary tumor cytosols using an enzyme-linked immunosorbent assay. For PAI-1 the median value (3.9 ng/mg protein) was used as cutoff, while the optimized cutoff for PAI-2 (6.5 ng/mg protein) was obtained using the log-rank statistic. After a median follow-up of 46 months 96 (29%) patients relapsed. In univariate analysis patients with a high PAI-1 or a low PAI-2 content had an increased risk of relapse. The difference was statistically significant for PAI-1 (p<0.0001) and almost statistically significant for PAI-2 (p=0.057). Stage, tumor size, differentiation grade, lymph node status and hormone receptor status also showed significant univariate impact on disease-free survival (DFS). In multivariate analysis (Cox model) PAI-1 (p<0.0001, RR=2.78), PAI-2 (p=0.0075, RR=2.17), UICC stage (p=0.0014, RR=2.2), differentiation grade (p=0.0097, RR=1.91) and nodal status (p<0.0001, RR=2.9) retained their significance. When both inhibitors were combined the worst prognosis was observed in patients with simultaneous high PAI-1 and low PAI-2 levels, whereas low PAI-1 in combination with high PAI-2 values indicated a very favorable prognosis. In conclusion, our study showed that both PAI-1 and PAI-2 had independent prognostic value in breast cancer. Combination of both inhibitors further improved the differentiation of patients with respect to prognosis.     

Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.     

Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer

The present study on the prognostic and predictive value of serine proteases was conducted in 460 early breast cancer patients mostly treated with some kind of adjuvant systemic therapy: 156 received chemotherapy, 141 hormone therapy and 111 a combination of both. Already in univariate analysis PAI-1 was the only proteolytic factor with a significant impact on DFS, which was retained in multivariate analysis (p = 0.020); PAI-2 showed borderline significance in univariate analysis (p = 0.0503) and uPA did not present as a significant prognostic factor for DFS in our patient series. In a separate univariate analysis of DFS on patient subgroups defined by adjuvant systemic therapy, a higher risk of relapse associated with higher uPA and PAI-1 levels was found in the subgroup of patients who did not receive any treatment; this difference did not reach the level of significance, probably due to the small number (n = 52) of patients in this group (HR 1.37; p = 0.71 and HR 2.14; p = 0.321, respectively). A higher risk of relapse was also found in the subgroup of patients treated with adjuvant chemotherapy (HR 1.44; p = 0.381 and HR 2.48; p = 0.003, respectively). In contrast, the bad prognostic impact of high uPA and PAI-1 levels was lost in the subgroup of patients treated with adjuvant hormone therapy (HR 0.79; p = 0.693 and HR 0.26; p = 0.204, respectively). The same observations were made for the uPA/PAI-1 combination. Our study confirmed the prognostic value of serine proteases in early breast cancer. In addition, it pointed to a possible predictive value of these tumor markers for response to adjuvant hormone therapy with tamoxifen, which should be confirmed in further studies.     

Prognostic value of S-phase fraction in 920 breast cancer patients: focus on T1N0 status

The aim of this study was to reexamine the prognostic role of tumor cell kinetics measured by S-phase fraction (SPF) and to establish its clinically relevant threshold values. SPF was determined by flow cytometry in a group of 920 consecutive breast cancer patients, all followed at our institute for 10 years (1988 to 1998). Mean age was 60.5 years (27-89 years). Median follow-up was 63 months (3-150 months). All patients had initial surgical treatment. SPF quartiles were: Q1=3.08%, median value = 5.98%, Q3=10.22%. A significant difference in overall specific survival was obtained between two populations divided by a cutoff at Q1 (p < 0.0001). A multifactorial analysis including SPF and known prognostic factors such as tumor size, node status, histological grade, ER and PR status was performed using the Cox model in a population of 719 patients: univariate analysis showed that each of these factors had significant influence on overall survival. Multivariate analysis selected three of them, ranked by decreasing order of hazard ratio (HR) value: SPF (HR: 3.88, p < 0.001), tumor size (HR: 2.49, p < 0.001) and nodal status (HR: 2.28, p < 0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (< 2 cm) and in axillary node-negative patients.     

Upregulation of IGF-1R Expression during Neoadjuvant Therapy Predicts Poor Outcome in Breast Cancer Patients

IntroductionThe insulin-like growth factor 1 receptor (IGF-1R) may be involved in the development of resistance against conventional cancer treatment. The aim of this study was to assess whether IGF-1R expression of breast tumors changes during neoadjuvant therapy and to study whether these changes were associated with survival.MethodsParaffin embedded tumor tissue was collected from pretreatment biopsies and surgical resections of 62 breast cancer patients who were treated with neoadjuvant chemotherapy or endocrine therapy. IGF-1R expression was determined immunohistochemically and compared before and after treatment.ResultsHigh membranous IGF-1R expression at diagnosis correlated significantly with ER positivity, low tumor stage (stage I/II) and longer overall survival (p < 0.05). After neoadjuvant treatment, membranous IGF-1R expression remained the same in 41 (65%) tumors, was upregulated in 11 (18%) tumors and downregulated in 11 (18%) tumors. Changes in membranous IGF-1R expression were associated with overall survival (log-rank test: p = 0.013, multivariate cox-regression: p = 0.086). Mean overall survival time for upregulation, no change, and downregulation in IGF-1R expression was 3.0 ± 0.5 years, 7.3 ± 1.0 years and 15.0 ± 1.8 years, respectively. Changes in other parameters were not significantly associated with survival.ConclusionNeoadjuvant therapy can induce changes in IGF-1R expression. Upregulation of IGF-1R expression after neoadjuvant treatment is a poor prognostic factor in breast cancer patients, providing a rationale for incorporating anti-IGF-1R drugs in the management of these patients.     

Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study

Background

Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive. It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity.

Methods and Findings

In case-control and case-series analyses, we examined serum concentrations of 25-hydroxyvitamin D (25OHD) in relation to breast cancer prognostic characteristics, including histologic grade, estrogen receptor (ER), and molecular subtypes defined by ER, progesterone receptor (PR) and HER2, among 579 women with incident breast cancer and 574 controls matched on age and time of blood draw enrolled in the Roswell Park Cancer Institute from 2003 to 2008. We found that breast cancer cases had significantly lower 25OHD concentrations than controls (adjusted mean, 22.8 versus 26.2 ng/mL, p<0.001). Among premenopausal women, 25OHD concentrations were lower in those with high- versus low-grade tumors, and ER negative versus ER positive tumors (p≤0.03). Levels were lowest among women with triple-negative cancer (17.5 ng/mL), significantly different from those with luminal A cancer (24.5 ng/mL, p = 0.002). In case-control analyses, premenopausal women with 25OHD concentrations above the median had significantly lower odds of having triple-negative cancer (OR = 0.21, 95% CI = 0.08–0.53) than those with levels below the median; and every 10 ng/mL increase in serum 25OHD concentrations was associated with a 64% lower odds of having triple-negative cancer (OR = 0.36, 95% CI = 0.22–0.56). The differential associations by tumor subtypes among premenopausal women were confirmed in case-series analyses.

Conclusion

In our analyses, higher serum levels of 25OHD were associated with reduced risk of breast cancer, with associations strongest for high grade, ER negative or triple negative cancers in premenopausal women. With further confirmation in large prospective studies, these findings could warrant vitamin D supplementation for reducing breast cancer risk, particularly those with poor prognostic characteristics among premenopausal women.     

DNA cytophotometric analysis of breast cancer. Follow-up for 10 years.

Forty-four cases of newly diagnosed invasive ductal breast cancer were studied by static cytometry at the time of diagnosis and were followed for 10 years to determine if the survival rate correlated with the nuclear DNA measurements. In 22 cases the stem line was in the 2c range, in 15 cases in the 3c range and in 7 cases in the 4c range. Thirty-four percent (n = 15) of the patients died of metastases during the first five years, 11% (n = 5) died of metastases between 5 and 10 years, and 55% (n = 24) survived for > 10 years without metastases. No correlation between increased tumor cell proliferation and recurrence of tumors could be found. In this study all patients with diploid tumors, tumor size T1 and negative lymph node status survived for > 10 years. In the presence of node metastasis (T1N1M0) all patients (n = 4) having tumors with the stem line in the 2c range survived for 5 years but only 2/4 for > 10 years. The percentage of patients surviving for 10 years showed no significant differences between the groups: in the 2c range, 59% (13/22); in the 3c range, 53% (8/15); and in the 4c range, 43% (3/7). The small number of cases does not allow definitive statistical conclusions, although the logistic regression analyses showed that stem line, pT and pN were the important prognostic factors for five-year survival. However, only pT and especially pN were of prognostic value for 10-year survival.