Angela Ruggiero

A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer

Purpose: Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting. We have conducted a meta-analysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 in metastatic breast cancer. Experimental Design: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method. Results: Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results. Conclusions: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.

TRANSFECTION WITH A CRIPTO ANTI-SENSE PLASMID SUPPRESSES ENDOGENOUS CRIPTO EXPRESSION AND INHIBITS TRANSFORMATION IN A HUMAN EMBRYONAL CARCINOMA CELL LINE

CRIPTO is a member of the epidermal growth factor (EGF) gene family originally isolated from undifferentiated human NTERA2 clone D1 (NT2D1) multipotent embryonal carcinoma cells. Retinoic acid (RA) treatment of NT2D1 cells leads to a neuronal differentiation program and to concomitant loss of CRIPTO mRNA expression. To assess the role of CRIPTO in the control of NT2D1 cell growth or differentiation, these cells were treated with 3 anti‐sense oligodeoxynucleotides complementary to the 5′ end of the human CRIPTO mRNA. A dose‐dependent inhibition of monolayer and soft agar growth was observed with each of these CRIPTO anti‐sense oligodeoxynucleotides but not with a control oligodeoxynucleotide of random sequence or with the 3 corresponding CRIPTO sense oligodeoxynucleotides. In addition, NT2D1 cells were transfected with a recombinant expression vector containing a 918‐bp coding fragment of the human CRIPTO cDNA in the 3′ to 5′ orientation. NT2D1 CRIPTO anti‐sense transfectants exhibited a significantly reduced endogenous CRIPTO mRNA and protein, a 4‐to 5‐fold decrease in growth rate in monolayer and a 50–70% reduction in cloning efficiency in soft agar as compared with NT2D1 parental cells or with NT2D1 cells transfected with a plasmid containing the neomycin‐resistance gene alone (NT2D1 neo cells). Finally, we examined the expression of immunophenotypic markers that are modulated during the differentiation of NT2D1 cells following RA treatment. The globoseries stage‐specific embryonic antigen‐3 recognized by the monoclonal antibody (MAb) SSEA‐3 was expressed in 60% of undifferentiated parental NT2D1 or NT2D1 neo cells and in only 20% of NT2D1 CRIPTO anti‐sense transfectants, whereas it was down‐regulated in all cell lines following RA treatment. A neuroectodermal antigen recognized by the A2B5 MAb, which was not expressed in parental NT2D1, in NT2D1 neo or in CRIPTO anti‐sense NT2D1 cells, was induced by RA treatment in all cell lines. Taken together, our results show that inhibition of endogenous CRIPTO expression in human embryonal carcinoma cells interferes with both transformation and differentiation.

Pilomatrix carcinoma. A case report with immunohistochemical findings, flow cytometric comparison with benign pilomatrixoma and review of the literature.

We report a case of pilomatrix carcinoma in a 42 year old woman. The patient presented a rapidly growing 4-cm subcutaneous mass in the right preauricular area. She was free of recurrence 24 months after surgery. Immunoreactivity was studied for cytokeratins, epithelial membrane antigen, S-100 protein, blood group antigens, Leu-M1, β-2-microglobulin, vimentin, neuron-specific-enolase and cellular binding for peanut agglutinin. Squamous cells were reactive for cytokeratin AE1/3, epithelial membrane antigen, blood group antigens B and H, and peanut agglutinin. Basaloid cells were focally reactive for cytokeratin AE1/3 and epithelial membrane antigen. Flow cytometry revealed a euploid DNA content and a high proliferative rate of the pilomatrix carcinoma and in benign pilomatrixoma studied for comparison. The pathological diagnosis must be based on histomorphological criteria.

CHEMOTHERAPY WITH MITOMYCIN C AND VINBLASTINE IN PRETREATED METASTATIC BREAST CANCER

Aims In February 1986 we began a study to test the activity of mitomycin C (12 mg/m2) plus vinblastine (6 mg/m2) on day 1 of a 28-day cycle (MV) as second or third-line chemotherapy for metastatic breast cancer patients. Methods As of February 1988 the study was stopped after 26 patients had been enrolled. The median age of the patients was 54 years (range 35-78); all patients were progressive from chemotherapy; 15 (57.7 %) patients were treated as second and 11 (42.3 %) as third line; 19 (73.1 %) patients had received anthracyclines as first (13 patients) or second-line (6 patients) chemotherapy; 18 (69.2 %) patients had visceral Involvement; 7 (26.9 %) had one metastatic site, 11 (42.3 %) two sites, 6 (23.1 %) three sites and 2 (7.7 %) four sites. Results Overall, 86 cycles were administered, with a median number of 3 cycles per patient. Toxicity was mild; hematologic side effects required discontinuation of treatment in 3 cases. Vomiting occurred in 3 (11.5 %) patients, nausea in 5 (19.2 %). Moderate neurologic toxicity was recorded in 6 (23 %) patients. No complete and 3 partial responses were observed. The objective response rate was 11.5 % (exact 95 % confidence interval, 2.4-30.1). Responses occurred independently of disease-free interval, dominant metastatic site, response to previous chemotherapy, previous anthracycline and line of treatment; all responses were recorded in patients under 50 years of age. Kaplan-Meier estimated median time to progression and overall survival were 13 and 40 weeks, respectively. Conclusion The MV regimen was well tolerated but showed little activity in pretreated metastatic breast cancer.

DNA flow cytometry in patients undergoing liver transplantation for hepatocellular carcinoma

Abstract  The purpose of the study was to analyse patterns of DNA content in hepatocellular carcinomas (HCC) submitted to orthotopic liver transplantation (OLT). Paraffin‐embedded archival material from 15 patients (ten men, five women, mean age 51 ± 1.78 years) transplanted in St‐Roch Hospital between 1988 and 1991 was available for laboratory evaluation by flow cytometry. Five out of 15 were incidental HCC. The analysis was performed by a FACSscan flow cy‐tometer coupled to a Hewlett‐Packard computer. The cellular DNA content was defined as diploid or aneuploid in the presence of a single (DNA index of 1) or two distinct (DNA index different from 1) / peaks, respectively. All incidental HCC (five patients) were diploid, the tumour size was 1.2 ± 0.2 cm, the number of nodules was 1.4 ± 0.24 and the mortality rate was 40 %. No death in the incidental HCC group was related to neoplastic recurrence. In the remaining ten patients transplanted for HCC, we observed 50 % diploid tumours, the tumour size was 5.2 ± 1.55 cm and the number of nodules was 2.7 ± 0.56. In this group six patients died of neoplastic recurrence (two were diploid and four aneuploid). The diameter of the neoplasm in diploid patients who died of neoplastic recurrence was over 5 cm and the number of nodules was over three. Moreover, in aneuploid patients who died of neoplastic recurrence, the diameter of the neoplasm was less than 5 cm in three cases and the number of nodules was less than three in two patients. This study indicates that incidental HCC may be a less aggressive malignancy and may have a better prognosis. In this group, no patient recurred after OLT and all tumours were diploid. Aneuploidy, tumour size (> 5 cm) and number of lesions (> 3) are prognostic indicators for neoplastic recurrence in patients transplanted for hepatocellular carcinoma.