Zinc-alpha2-glycoprotein: a new biomarker of breast cancer?

BACKGROUND/AIM: Obesity increases the risk of breast cancer. It is established that adipocyte secretions, i.e. adipokines, may play a role in mammary carcinogenesis. We have shown that two major adipokines, leptin and adiponectin, were expressed in mammary adenocarcinoma. PATIENTS AND METHODS: Here, we evaluated zinc-alpha2-glycoprotein (ZAG) expression in tumor (n=55) and healthy (n=6) breast tissue by immunohistochemistry and examined whether it was correlated with that of major adipokines, usual tumor biomarkers (sex steroids receptors, i.e. estrogen (ER) and progesterone; Ki-67; cErb2), or apoptosis markers (Bcl2 and Bax). RESULTS: ZAG expression was detected in ductal carcinoma and normal epithelial adjacent tissue but not in normal tissue of healthy women. In cancer tissue, its expression was correlated positively to leptin receptor and negatively to adiponectin receptor and ER. CONCLUSION: These preliminary results suggest both a relationship between ZAG expression and pathways involving adipokines or estrogen and that ZAG may be a potential breast cancer biomarker.

Anti-melanoma efficacy of internal radionuclide therapy in relation to melanin target distribution.

Targeted internal radionuclide therapy (TRT) could be an efficient, specific way to treat disseminated melanoma. Based on a previous pharmacomodulation study, we selected a quinoxaline-derived molecule (ICF01012) for its melanin specificity and kinetic properties suitable for TRT. Here, we determined the efficacy of [(131)I]ICF01012 radiotherapy in vitro and in vivo in relation to melanogenesis using human melanoma models. [(125)I]ICF01012 uptake was first assessed in relation to melanin content. We found that melanin distribution in different models was representative of pathology seen in human tumours: melanin content was high in the extracellular space of SKMel3 tumours, and accumulated primarily in melanophages in M4Beu tumours. Targeted [(131)I]ICF01012 radiotherapy had a strong anti-tumoural efficacy in pigmented versus unpigmented tumours, regardless of target distribution and content. This study supports the use of melanin targeting with (131)I-labelled iodoquinoxaline for effective treatment of melanoma.

[Intraoperative determination of axillary node metastasis by RT-PCR]. / Utilisation d'une méthode PCR en temps réel pour l'étude des ganglions sentinelles dans les carcinomes mammaires : expérience des centres anticancéreux de Lille et de Clermont-Ferrand.

UNLABELLED: The intraoperative determination of axillary node micrometastasis according to the Rapid GeneSearch Breast Lymph Node (BLN) is based on RT-PCR (mRNA of mammaglobine and CK19) detects metastases > 0.2 mm. PATIENTS AND METHODS: Eighty-three pts between November 2007 and June 2008 were included (33 from Centre Jean-Perrin and 50 from Centre Oscar-Lambret). Lymph nodes were cut in 2 mm slices, and 1 out of 2 was examined with BLN; the others were examined by imprints then histological exam with immunohistochemistry. RESULTS: Forteen pts had micro- or macrometastasis. Seven were positive with intraoperative imprints including six macrometastasis and one micrometastasis; seven were positive with BLN and seven at histological exam with two cases of discordance. Sensitivity was 92%, specificity 98%. Positive predictive value 92%, and negative predictive value 98%. The median time for intraoperative determination was 40 minutes for 2 SLN. DISCUSSION: Half each lymph node is study by each method. This explains the discordances observed. Limit of BLN is the absence of CTI detection; however there is no consensus about the necessity of axillary clearance in such a case. CONCLUSION: In this series BLN reduces axillary clearance and improves comfort patients.

Comparison of dysplasia profiles in stimulated ovaries and in those with a genetic risk for ovarian cancer.

AIM: Ovarian epithelial dysplasia (OED) was first described after prophylactic oophorectomy for genetic risk of ovarian cancer. In light of Fathalla's incessant ovulation theory, this study was set up to describe the presence of ovarian abnormalities (dysplasia) after ovulation induction and to compare dysplasia profiles in stimulated and genetic risk ovaries. METHODS: One-hundred and twenty-four patients who had undergone salpingo-oophorectomies or ovarian cystectomies between 1990 and 2005 were reviewed. They were divided into three groups: (1) previous in vitro fertilisation (n=35); (2) prophylactic oophorectomies for genetic risk (n=27) and (3) fertile non-cancerous controls (n=62). Eleven cytological and architectural epithelial features were defined and a dysplasia score was calculated to quantify ovarian epithelial abnormalities. RESULTS: Mean dysplasia score was significantly higher in the genetic risk and stimulated ovary groups than in controls (9.55 versus 3.62, p<0.0001; 7.51 versus 3.62, p<0.0002, respectively). Cytological and architectural abnormalities were more frequent in the genetic risk group, while the profile of abnormalities was different in the genetic risk and stimulated groups. CONCLUSIONS: These findings support a possible relationship between OED and the use of ovulation-stimulating drugs. The increased dysplasia score in stimulated and genetic risk ovaries might be consistent with progression towards neoplastic transformation, and may justify the use of the term dysplasia or intraepithelial ovarian neoplasia. The observation of dysplasia in the stimulated group may differentiate women at risk. Conversely, the fact that the dysplasia profile after stimulation differs from that in genetic risk ovaries suggests that ovarian stimulation may predispose to a different evolution.

Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies.

Obesity is a risk factor for breast cancer development. A recent hypothesis suggests that the adipokines, adiponectin and leptin, are involved in breast cancer development. This prompted us to investigate the role of adiponectin and leptin in mammary carcinogenesis. Adiponectin receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rt, representing all the isoforms of Ob-R) proteins were detected by immunohistochemistry in in situ ductal carcinoma, invasive ductal malignancy, and healthy adjacent tissue. In addition, mRNA expression of adiponectin, AdipoR1, AdipoR2, leptin, Ob-Rt, and Ob-Rl (the long isoform of Ob-R) was observed in MCF-7 breast cancer cells. Interestingly, leptin mRNA expression was 34.7-fold higher than adiponectin mRNA expression in the MCF-7 cell line. Moreover, adiponectin (10 microg/ml) tended to decrease the mRNA expression of leptin (-36%) and Ob-Rl (-28%) and significantly decreased Ob-Rt mRNA level (-26%). In contrast, leptin treatment (1 microg/ml) significantly decreased AdipoR1 mRNA (-23%). Adiponectin treatment (10 microg/ml) inhibited the proliferation of MCF-7 cells, whereas leptin (1 microg/ml) stimulated the growth of cancer cells. In addition, adiponectin inhibited leptin-induced cell proliferation (both 1 microg/ml). Using microarray analysis, we found that adiponectin reduced the mRNA levels of genes involved in cell cycle regulation (mitogen-activated protein kinase 3 and ATM), apoptosis (BAG1, BAG3, and TP53), and potential diagnosis/prognosis markers (ACADS, CYP19A1, DEGS1, and EVL), whereas leptin induced progesterone receptor mRNA expression. In conclusion, the current study indicates an interaction of leptin- and adiponectin-signaling pathways in MCF-7 cancer cells whose proliferation is stimulated by leptin and suppressed by adiponectin.

Ovarian epithelial dysplasia after ovulation induction: time and dose effects.

BACKGROUND: Ovarian epithelial dysplasia was first described after prophylactic oophorectomies for genetic risk. Ovarian stimulation has been considered as a risk factor of ovarian cancer by Fathalla's incessant ovulation theory. In this study, we have investigated the risk of ovarian dysplasia after ovulation induction. METHODS: We reviewed 99 oophorectomies or cystectomies between 1990 and 2005 divided them into two groups: previous in vitro fertilization (n = 37) and a panel of fertile controls (n = 62). Eleven epithelial cytological and architectural features were defined and an ovarian epithelial dysplasia score was calculated to quantify the degree of ovarian epithelial abnormalities. RESULTS: All the ovaries were macroscopically non-cancerous except in two patients (one endometrioid cancer and one borderline tumour). The mean ovarian dysplasia score was significantly higher in the ovulation induction group than in the control group (7.64 versus 3.62, P = 0.0002). We also found a relationship between the number of ovulation-inducted cycles and the severity of ovarian dysplasia ('dose-effect') and a relationship between time after the end of ovulation induction (over 7 years) and the severity of ovarian dysplasia ('time-effect'). CONCLUSIONS: There is probably a relationship between ovarian epithelial dysplasia and either ovulation inducing drugs or infertility. By Fathalla's incessant ovulation theory, 'the dose effect and the time effect' of ovarian stimulation may explain ovarian dysplasia formation.

[Ovarian epithelial dysplasia: myth or reality? Review]. / Dysplasie épithéliale ovarienne: mythe ou réalité? Revue de la littérature.

Ovarian epithelial dysplasia has been described in the ovarian surface epithelium by histologic, morphometric and nuclear profile studies. It could represent a potential precursor of ovarian malignancy in patients with genetic risk of ovarian cancer, although its natural history and progression to carcinoma are unpredictable. Diagnosis and identification of ovarian dysplasia would certainly be useful to understand the early steps of ovarian carcinogenesis. However, dysplasia in relation with ovulation induction seems to have a different pattern. We report dysplasia definitions and the current clinical management.

[Ductal carcinoma in situ of the breast with microinvasion. Role of sentinel lymph node biopsy]. / Cancer canalaire in situ du sein avec micro-invasion. Place du ganglion sentinelle.

OBJECTIVES: To investigate the role of sentinel lymph node biopsy for microinvasive ductal carcinoma in situ of the breast. PATIENTS AND METHODS: From January 2001 to January 2006, lymphatic mapping was performed using radiocolloid and/or blue dye technique. Full axillary lymph node dissection was accomplished systematically in 10 instances at the beginning of the study, and furthermore when the sentinel node was involved (macrometastatic or micrometastatic disease). RESULTS: Identification rate was 98% (40/41), the unsuccessful procedure occurred after incisional biopsy for diagnosis. The number of sentinel nodes removed was 2 in average (1-5). Sentinel node involvement was found in 10% of cases (4/40): 1 sentinel node macrometastasis pN1, 2 sentinel node micrometastases determined by hematoxylin and eosin staining pN1 (mi), 1 sentinel node micrometastasis detected only by immunohistochemical staining pN0 (mi). DISCUSSION AND CONCLUSION: Sentinel lymph node sampling should not be currently applied for management of every ductal carcinoma in situ of the breast but a selective utilization is proposed in documented high risk subset of patients according to clinical, mammographic, and histologic features obtained by percutaneous biopsies. Ductal carcinoma in situ (DCIS) with proved or suspected microinvasion could be scheduled for sentinel node procedure a fortiori in cases undergoing mastectomy because of extensive DCIS before the occurrence of disturbances of lymphatic drainage induced by surgical breast dissection.

[Micrometastatic disease and residual axillary disease. Breast cancer as an example Alct]. / Maladie micrométastatique et maladie résiduelle axillaire. Exemple du cancer du sein.

The knowledge of the axillary involvement is a major prognosis factor for breast cancer and an important parameter for treatment decision. Nevertheless, two recent current medical situations have occurred in breast cancer, changing our management. First, with the development of mass screening and sentinel lymph nodes biopsies, we have to take treatment decisions based upon minimal lymph node involvement, with a clinical significance still poorly understood. Second, for the large tumors, potentially with lymph node involvement, we have to deal with tumor and lymph node under staging, after induction chemotherapy. We have to learn how to evaluate accurately those new parameters to treat the best way our patients.

[Is there still a place for extemporaneous exam in breast cancer?]. / Existe-t-il encore une place pour l'examen extemporané dans le cancer du sein?

OBJECTIVE: The rise of preoperative diagnosis thanks to new methods of micro and macrobiopsy and the development of sentinel lymph node have dramatically modified the surgical management of patients with breast tumor. The purpose of this study is to know if extemporaneous exams still have a place in the management of breast cancer. PATIENTS AND METHODS: Retrospective study which compares the qualitiative evolution of frozen sections in breast tumor at Jean-Perrin center before the practice of percutaneous strereotaxic biopsy and after the training of sentinel lymph node operative biopsy. RESULTS: The results were in favour of a different distribution of anatomocytopathological activity with a decrease of frozen section in breast tumor and an increase of cytological imprints on sentinel nodes. DISCUSSION AND CONCLUSION: The interest of histologic preoperative diagnosis and the failure of consensus in the sentinel lymph node just leave a restrictive position to frozen section in breast cancer.