Breast Neoplasms: Planet Earth

Shao ZM, Wu J, Shen ZZ, Nguyen M. · Department of Surgery, Cancer Hospital/Cancer Institute, Fu Dan University, Shanghai 200032, People's Republic of China. · Clin Cancer Res. · Pubmed #11489795 links to  free full text

Abstract: PURPOSE: Tumor-specific DNA has recently been detected in the plasma of lung, head and neck, breast, and colon cancer patients. Detection of tumor-specific genetic materials in cancer patients at sites distant from the tumor, such as in the blood, may provide a unique and valuable tumor marker for diagnosis and prognosis. EXPERIMENTAL DESIGN: The present investigation was aimed at determining the presence of p53 mutations in the peripheral blood of breast cancer patients and its prognostic value in these patients. RESULTS: In this study, we found that the mean concentration of plasma DNA in healthy women was 21 ng/ml, whereas in patients with breast cancer the mean concentration was 211 ng/ml (P < 0.01). p53 mutations were detected in the primary tumors of 46 of 126 (36.5%) breast cancer patients. Of these 46 patients, 30 (65.1%) were found to have p53 mutations in their plasma DNA. p53 mutations in plasma DNA were strongly correlated with clinical stage, tumor size, lymph node (LN) metastasis, and estrogen receptor status (P < 0.05). After a median follow-up of 29 months, univariate and multivariate analysis revealed that both primary tumor and plasma DNA p53 mutations were significant prognostic factors for both relapse-free and overall survival. Furthermore, we demonstrated that patients with both primary tumor and plasma p53 mutations have the worst survival. This outcome occurs in both LN-positive and LN-negative groups. Thirteen of the 22 (59%) patients with recurrence and/or metastasis later had detectable p53 mutations in their plasma DNA. CONCLUSIONS: Detection of p53 mutations in plasma DNA may be used as a prognostic factor and an early marker to indicate recurrence or distant metastasis.

Mansoor I. · Department of Histopathology, King Abdul Aziz University Hospital, Jeddah, Saudia Arabia. · J Pak Med Assoc. · Pubmed #11558215 No free full text.

Abstract: OBJECTIVE: To evaluate the outline and pattern of male and female breast diseases in Saudi Arabia. METHODS: The study consisted of 953 consecutive female breast biopsies and mastectomies. Information on these cases were retrieved from the records of the laboratory. Outline of breast lesions were tabulated and classified into inflammatory, benign and malignant lesions. RESULTS: Benign lesions comprised 55.24% of all lesions (mean age 31.7), most commonly reported being fibroadenoma 46.9%, fibrocystic disease 23.25% and fibroadenosis 14.5%. Malignant lesion comprised 31.5% of all lesions (mean age 49.19), most commonly reported being ductal carcinoma 80% and lobular carcinoma 5.5%. Inflammatory lesions comprised of 10.1% of all lesions (mean age 29.56), most commonly reported lesion being chronic mastitis 30% and ducectasia 17.6%. CONCLUSION: The rates for female breast diseases varied in different studies but benign fibroadenoma was the most common breast lesion followed by ductal carcinoma. The mean age for malignant lesions in seven different studies was 44.18 years.

Abou Zeid H, Al-Gahamdi A, Abdul-Hadi M. · Department of Anesthesiology, King Faisal University, King Fahd Hospital, Al-Khobar, Saudi Arabia. · Breast J. · Pubmed #12100113 No free full text.

Abstract: In a randomized, placebo-controlled, double-blind trial, we compared the efficacy of dolasetron, dexamethasone, and metoclopramide in a preventing postoperative nausea and vomiting in women undergoing breast surgery. Patients were allocated randomly to one of four groups (20 patients each): group A received 12.5 mg dolasetron, group B received 8 mg dexamethasone, group C received 20 mg metoclopramide, and group D received placebo intravenously. If patients complained of retching or vomiting or if patients demanded an antiemetic, 1.25 mg droperidol was administered intravenously. To quantify postoperative nausea and vomiting, the following score was used: 0 = no nausea, 1 = nausea, 2 = retching, 3 = single vomiting, 4 = multiple vomiting. Dolasetron and dexamethasone reduced the postoperative nausea and vomiting score significantly (p < 0.02 versus metoclopramide; p < 0.0001 versus placebo). Metoclopramide also reduced the postoperative nausea and vomiting score (p < 0.02 versus placebo). Fisher's exact test showed a significant reduction of vomiting in the dolasetron and dexamethasone groups compared with metoclopramide-treated patients (p < 0.007) and placebo-treated patients (p < 0.000006) and a significantly lower rate of nausea in comparison to the placebo group (p < 0.009). There were no significant differences between the metoclopramide and the placebo groups (using Fisher's exact test). The use of postoperative droperidol was significantly lower in both the dolasetron group (p < 0.04 versus metoclopramide; p < 0.0001 versus placebo) and dexamethasone group (p < 0.04 versus metoclopramide; p < 0.0001 versus placebo), as well as in the metoclopramide group (p < 0.02 versus placebo). Intravenous dolasetron and dexamethasone were equally effective and both are more effective than metoclopramide for preventing vomiting after breast surgery. Also both were significantly superior to either metoclopramide or placebo for postoperative nausea and vomiting and the need for droperidol rescue.

Stoica GE, Franke TF, Wellstein A, Czubayko F, List HJ, Reiter R, Morgan E, Martin MB, Stoica A. · Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA. · Mol Endocrinol. · Pubmed #12554767 links to  free full text

Abstract: Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.

Boér K, Láng I, Juhos E, Pintér T, Szántó J. · V. Department of Internal Medicine - Oncology, Szent Margit Hospital, Budapest, H-1032, Hungary. · Pathol Oncol Res. · Pubmed #14530809 links to  free full text

Abstract: The adjuvant chemotherapy of breast cancer changed in the past two decades. Docetaxel containing regimens are highly active in metastatic breast cancer. A logical approach was their incorporation into trials of early breast cancer adjuvant therapy. The authors present the Hungarian interim analysis and experience with the BCIRG 001 randomized, multicentric, phase III clinical trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) and FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients. The results are presented compared to the international data. Three Hungarian centers - Szt. Margit Hospital, Budapest, National Institute of Oncology, Budapest, Petz Aladár Hospital, Gyôr - participated in the international trial. Between June 1997 and June 1999, 61 patients with node positive breast cancer were enrolled in the study after the surgery. Thirty-four patients were randomized to TAC (75/50/500 mg/m2 6xq3wk) and 27 patients were randomized to FAC (500/50/500 mg/m2 6x q3wk) chemotherapy, with prospective stratification by node (1-3, 4+). Patients with hormone receptor positive tumors received tamoxifen for 5 years after the chemotherapy. Radiotherapy was performed after the 6th cycle of chemotherapy. 33 months of follow up was performed. In both arms the hematological toxicity was more frequent. The TAC group showed a higher incidence of neutropenia (76%) compared to the FAC (22%), as well as a higher incidence of febrile neutropenia (26 % versus none), without grade 3-4 infection and there was no cases of septic death. More grade 3-4 nausea and vomiting was observed in the FAC group. At three years follow up, results indicated improvement in disease-free survival (88% vs. 76%) in favour of TAC, and similar tendency was observed in the case of overall survival (97% vs. 88%). Based on the international data analysis TAC was superior to FAC chemotherapy, the results show statistically significant differences between the two arms. This benefit with TAC was seen regardless of hormone receptor status. Additional follow up data will evaluate the role of TAC in the adjuvant setting of early breast cancer treatment.

DeMichele A, Aplenc R, Botbyl J, Colligan T, Wray L, Klein-Cabral M, Foulkes A, Gimotty P, Glick J, Weber B, Stadtmauer E, Rebbeck TR. · Department of Biostatistics and Epidemiology, Abramson Cancer Center, PA, USA. · J Clin Oncol. · Pubmed #16110016 No free full text.

Abstract: PURPOSE: Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and glutathione S-transferases (GST), may predict treatment-related outcomes. PATIENTS AND METHODS: We examined CYP3A4*1B, CYP3A5*3, and deletions in GST mu (GSTM1) and theta (GSTT1), as well as a priori-defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS). RESULTS: Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio [HR] = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status. CONCLUSION: Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.

Glaros S, Atanaskova N, Zhao C, Skafar DF, Reddy KB. · Department of Pathology, Wayne State University School of Medicine, 540 East Canfield Avenue, and The Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201, USA. · Mol Endocrinol. · Pubmed #16455819 links to  free full text

Abstract: The antiestrogen tamoxifen has been widely used for decades as selective estrogen receptor (ER) modulator for ERalpha-positive breast tumors. Tamoxifen significantly reduces tumor recurrence by binding to the activation function-2 (AF-2) domain of the ER. Acquired resistance to tamoxifen in breast cancer patients is a serious therapeutic problem. Antiestrogen-resistant breast cancer often shows increased expression of the epidermal growth factor receptor (EGFR) family members, EGFR and ErbB2. In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ERalpha, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen. In contrast, transfection of activated MAPK kinase, an immediate upstream activator of MAPK (ERK 1 and 2) into MCF-7 cells leads to phosphorylation of Ser118 in the AF-1 domain of ERalpha, inhibition of ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of Tam, and maintenance of sensitivity to tamoxifen. Inhibition of AKT by short inhibitory RNA blocked Ser167 phosphorylation in ER and restored tamoxifen sensitivity. However, maximum sensitivity to tamoxifen was observed when both AKT and MAPK were inhibited. Taken together, these data demonstrate that different phosphorylation sites in the AF-1 domain of ERalpha regulate the agonistic and antagonistic actions of tamoxifen in human breast cancer cells.

Choi Y, Kim Y, Park SK, Shin HR, Yoo KY. · Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. · Breast Cancer. · Pubmed #16929120 links to  free full text

Abstract: BACKGROUND: Although breast cancer in women remains relatively rare in Korea, its incidence and mortality figures are increasing, consistent with the increasing risk observed in successive generations of Korean women. The aim of the current study was to examine time trends of breast-cancer mortality during the period 1984-2003 in Korea, assessing the importance of the effects of age, period and birth cohort as risk factors. METHODS: Data on the annual number of deaths due to female breast cancer and on female population statistics from 1984 to 2003 were obtained from the Korean National Statistical Office. A log-linear Poisson age-period-cohort model was used to estimate age, period and cohort effects. RESULTS: The trend of breast cancer mortality was explained by an age-cohort model based on goodness of fit, even though the significance of the cohort effect was marginal (p=0.08) after adjusting for age. The risk of breast cancer death was found to increase with age after adjusting for the cohort effect, and it was different from the cross-sectional age curve. Also, breast cancer mortality increased along with the birth cohort. CONCLUSIONS: Even though the cohort effect was found to have a marginally significant effect on breast cancer mortality, it is expected to be more significant in the future given the recent on-going changes in diet and reproductive behavior shown by Korean women.

Tamiolakis D, Papadopoulos N, Venizelos J, Lambropoulou M, Romanidis C, Petrakis G, Limberis V, Galazios G, Koutsougeras G, Simopoulos C. · Department of Cytology, Regional Hospital of Chania, Greece. · Onkologie. · Pubmed #16974114 No free full text.

Abstract: BACKGROUND: Imprint cytology may provide a fast and accurate method for intraoperative screening of sentinel lymph nodes, so a decision can be made regarding whether to perform axillary clearance during primary surgery. If the findings are negative, in many cases axillary dissection can be omitted. Patients and METHODS: 128 sentinel nodes from a cohort of 87 patients that had been identified using technetium-99m nanocolloid as a radioactive tracer and Patent blue dye were dissected for rapid Diff-Quick stained touch preparations. Intraoperative evaluation of sentinel node status by imprint cytology was correlated with histopathological results of permanent sections. Tumor-negative nodes in routine paraffin sections were further investigated with the employment of an anti-cytokeratin antibody. RESULTS: 36 of all sentinel nodes harbored metastases in the paraffin sections, of which 32 were identified by imprint cytology (sensitivity 88.8%). 3 sentinel nodes were positive by imprint cytology and negative by histopathology of the paraffin sections. Comparison of the results of the touch preparations with the final histopathology (hematoxylin-eosin and anticytokeratin antibody stains) demonstrated a sensitivity of 83.3% and a negative predictive value of 92.5%. The specificity and positive predictive value were 100% each. CONCLUSIONS: Touch imprint cytology is potentially useful for intraoperative evaluation of sentinel lymph nodes in breast cancer patients.