Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.

BACKGROUND: Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. PATIENTS AND METHODS: In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. RESULTS: Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). CONCLUSIONS: The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Prediction of axillary lymph node status in male breast carcinoma.

BACKGROUND: To evaluate whether predictive factors of axillary lymph node metastasis in female breast cancer (BC) are similar in male BC. PATIENTS AND METHODS: From January 1994 to May 2011, we recorded 80 non-metastatic male BC treated at Institut Curie (IC). We analysed the calibration and discrimination performance of two nomograms [IC, Memorian Sloan-Kettering Cancer Center (MSKCC)] originally designed to predict axillary lymph node metastases in female BC. RESULTS: About 55% and 24% of the tumours were pT1 and pT4, respectively. Nearly 46% demonstrated axillary lymph node metastasis. About 99% were oestrogen receptor positive and 94% HER2 negative. Lymph node status was the only significant prognostic factor of overall survival (P = 0.012). The area under curve (AUC) of IC and MSKCC nomograms were 0.66 (95% CI 0.54-0.79) and 0.64 (95% CI 0.52-0.76), respectively. The calibration of these two models was inadequate. CONCLUSIONS: Multi-variate models designed to predict axillary lymph node metastases for female BC were not effective in our male BC series. Our results may be explained by (i) small sample size (ii) different biological determinants influencing axillary metastasis in male BC compared with female BC.

[Merkel cell carcinoma revisited: a new example of viro-induced human tumour]. / Le carcinome à cellules de Merkel revisité : un nouvel exemple de tumeur humaine viro-induite.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin of poor outcome. A new type of virus, isolated in 2008, was found to be strongly associated with CCM. This virus, belonging to the family of polyomavirus, was called MCPyV for Merkel Carcinoma Polyomavirus. Recent data favour a causative role of MCPyV in oncogenesis. MCC represents thus a new model for the understanding of the mechanisms of oncogenesis. The distinct molecular viral signature in every case of MCC represents an original tool for the follow-up of the disease. New therapeutic perspectives are to be drawn using this model.

HPV ctDNA detection of high-risk HPV types during chemoradiotherapy for locally advanced cervical cancer.

BACKGROUND: Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC. METHODS: We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR. RESULTS: HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013). CONCLUSION: This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse.

Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer.

BACKGROUND: In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated with distant metastasis and locoregional recurrence. Our aim was to determine whether BM DTC detection could be related to specific locoregional dissemination of cancer cells, according to radiotherapy volumes. PATIENTS AND METHODS: The relationship between locoregional recurrence-free survival (LRFS) and DTC detection was evaluated according to the various locoregional volumes irradiated after surgery. RESULTS: BM DTCs were detected in 94 of 621 stage I-III breast cancer patients (15%) and were not associated with axillary node status. Eighteen patients (2.9%) experienced locoregional recurrence (median follow-up 56 months), of whom eight (44%) were initially BM DTC positive. BM DTC detection was the only prognostic factor for LRFS [P = 0.0005, odds ratio = 5.2 (2.0-13.1), multivariate analysis]. In BM DTC-positive patients, a longer LRFS was observed in those who were given adjuvant hormone therapy (P = 0.03) and radiotherapy to supraclavicular nodes (SCNs)/internal mammary nodes (IMNs) (P = 0.055) (multivariate analysis; interaction test: P = 0.028). CONCLUSIONS: The presence of DTC in BM may be associated with a different pattern of locoregional cancer cell dissemination and influences LRFS. The possible reseeding of the primary cancer area by DTC could be prevented by systemic hormone therapy but also by SCN/IMN irradiation.

RB1 and TP53 pathways in radiation-induced sarcomas.

The tumour suppressor genes, TP53 and RB1, and four genes involved in their regulation, INK4a, ARF, MDM2 and MDMX, were analysed in a series of 36 post-radiotherapy radiation-induced sarcomas. One-third of the tumours developed in patients carrying a germline mutation of RB1 that predisposed them to retinoblastoma and radiation-induced sarcomas. The genetic inactivation of RB1 and/or TP53 genes was frequently observed in these sarcomas. These inactivations were owing to an interplay between point mutations and losses of large chromosome segments. Radiation-induced somatic mutations were observed in TP53, but not in RB1 or in the four other genes, indicating an early role of TP53 in the radio-sarcomagenesis. RB1 and TP53 genes were biallelically coinactivated in all sarcomas developing in the context of the predisposition, indicating that both genes played a major role in the formation of these sarcomas. In the absence of predisposition, TP53 was biallelically inactivated in one-third of the sarcomas, whereas at least one allele of RB1 was wild type. In both genetic contexts, the TP53 pathway was inactivated by genetic lesions and not by the activation of the ARF/MDM2/MDMX pathway, as recently shown in retinoblastomas. Together, these findings highlight the intricate tissue- and aetiology-specific relationships between TP53 and RB1 pathways in tumorigenesis.

Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells.

BACKGROUND: At metastatic relapse, detection of circulating tumor cells (CTC) in peripheral blood is predictive of poor survival of breast cancer patients. Detection of disseminated tumor cells (DTC) in bone marrow (BM) is an independent prognostic factor in early breast cancer. We evaluated the prognostic value of DTC detection in the BM of metastatic breast cancer patients. MATERIALS AND METHODS: BM aspirates from 138 patients were screened for DTC with the pancytokeratin mAb A45-B/B3, according to the ISHAGE classification. One hundred and ten patients (80%) were enrolled before first-line treatment. Thirty-seven patients were simultaneously screened for CTC in the blood. RESULTS: DTC detection rate in the BM was 59%. DTC were associated with bone metastasis (P = 0.0001), but not with a poorer overall survival. Adverse significant prognostic factors were hormone receptor negativity (P = 0.0004) and more than one line of chemotherapy (P = 0.002). CTC detection in the subgroup of 37 metastatic patients was associated with shorter survival (P = 0.01). CONCLUSIONS: Detection of CTC but not BM DTC had a prognostic significance in stage IV breast cancer patients. CTC in blood are a more reliable and a less invasive tool to evaluate prognostic and monitor tumor response in this metastatic setting.

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors.

To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were co-amplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas.

BACKGROUND: The production of the cytokine interferon gamma (IFN gamma) by activated peripheral blood mononuclear cells may be reduced in patients with invasive cervical carcinoma. This study was designed to assess the prognostic value of intratumoral IFN gamma messenger RNA (mRNA) levels in such patients. METHODS: Biopsy specimens of primary cervical lesions were obtained from 27 patients with invasive squamous cell carcinoma before they received any therapy. Two prognostic groups were considered: 1) a group of 14 patients who had no apparent disease recurrence and who were alive 2 years after diagnosis (good-prognosis group) and 2) a group of 13 patients who had disease recurrence or died during the 2-year follow-up (poor-prognosis group). A competitive reverse transcription-polymerase chain reaction assay was used to measure levels of IFN gamma and beta actin mRNA. The expression of human leukocyte antigen (HLA) class II proteins (which is stimulated by IFN gamma) in tumor cells was studied by immunostaining. RESULTS: Tumor specimens from all 14 patients in the good-prognosis group contained more than 10(3) IFN gamma mRNA copies per 5 x 10(5) beta actin mRNA copies, whereas tumor specimens from only six of the 13 patients in the poor-prognosis group contained this level of IFN gamma mRNA (two-sided P = .006). No clear relationship was observed between levels of IFN gamma mRNA and T-cell or natural killer cell infiltration in tumors; however, a statistically significant association was observed between HLA class II expression on tumor cells and IFN gamma mRNA levels (two-sided P = .01). CONCLUSIONS: A subgroup of poor-prognosis cervical carcinoma patients who have low levels of intratumoral IFN gamma mRNA was identified.

[Radiation-induced sarcomas after breast cancer: experience of Institute Curie and review of literature]. / Sarcomes radio-induits après cancer du sein: expérience de l'institut Curie et revue de la littérature.

Adjuvant radiotherapy to the breast plays a significant role in preventing local failure in women treated for early stage breast cancer. This fact is supported by multiple clinical trials demonstrating that adjuvant radiotherapy decreases the risk of local recurrence and increases the rate of breast preservation, and actually the rules of adjuvant breast irradiation are clearly established. Sarcomas are a rare but recognized complication of radiation therapy for breast carcinoma, and are associated with poor prognosis. The first case of a bone sarcoma after radiation therapy of breast cancer was described by Beck in 1922. In 1948, Cahan et al. defined the criteria for diagnosis of radiation-induced sarcoma. Since then, some studies have reported the incidence of radiation-induced sarcoma after radiotherapy for different cancers. This article reports and discusses the incidence, management and treatment outcome of radiation-induced sarcomas occurring after radiotherapy for breast cancer in our institute. The incidence, histology, latency of appearance, genesis, their treatment and the prognostic factors of these rare tumors are discussed and the literature is reviewed.

Analysis of interleukin 6 gene expression in cervical neoplasia using a quantitative polymerase chain reaction assay: evidence for enhanced interleukin 6 gene expression in invasive carcinoma.

Interleukin 6 (IL-6) is a multifunctional cytokine which has recently been shown to act in vitro as a growth factor for cervical carcinoma cell lines. This prompted us to measure IL-6 gene expression using a new quantitative polymerase chain reaction assay in 13 invasive cervical cancers, 5 cases of cervical intraepithelial neoplasia, and 2 normal cervix. A significant increase in the expression of the IL-6 gene in invasive cervical carcinoma as compared to cervical intraepithelial neoplasia and normal cervix was demonstrated (P < 0.05). Unlike IL-6, the expression of other cytokine genes such as gamma-interferon was not correlated with any particular cervical histological lesion. Immunohistochemical analysis identified IL-6 protein only on stroma cells which, based on morphological criteria, most likely belong to the macrophage lineage. This was reinforced by the correlation observed between IL-6 gene expression and macrophage tumor infiltration (P < 0.007). No IL-6 immunostaining of cervical tumor cells was shown. Therefore this study confirms, in vivo, that IL-6 may play a role in the pathogenesis of carcinoma of the uterine cervix since its increased expression is associated with advanced neoplastic cervical lesions. In contrast to in vitro studies, the stromal origin of IL-6 suggests that this cytokine may modulate tumor cell proliferation by a paracrine rather than an autocrine mechanism.

Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice.

Interleukin (IL) 17 is a proinflammatory cytokine secreted mainly by activated human memory CD4 T cells that induces IL-6, IL-8, and nitric oxide. Because IL-6 and IL-8 have been implicated in the pathogenesis of cervical cancer, we investigated the action of IL-17 on human cervical tumor cell lines in vitro and in vivo. We showed that in vitro, IL-17 increases IL-6 and IL-8 secretion by cervical carcinoma cell lines at both protein and mRNA levels. No direct effect of IL-17 on in vitro proliferation of cervical tumor cell lines could be demonstrated. However, two cervical cell lines transfected with a cDNA encoding IL-17 exhibited a significant increase in tumor size as compared to the parent tumor when transplanted in nude mice. This enhanced tumor growth elicited by IL-17 was associated with increased expression of IL-6 and macrophage recruitment at the tumor site. A potential role of IL-17 in modulation of the human cervical tumor phenotype was also supported by its expression on the cervical tumor in patients with CD4 infiltration. IL-17 therefore behaves like a T-cell-specific cytokine with paradoxical tumor-promoting activity. This may partially explain previous reports concerning the deleterious effect of CD4 T cells in cancer.

Estrogen-Receptor, Progesterone-Receptor and HER2 Status Determination in Invasive Breast Cancer. Concordance between Immuno-Histochemistry and MapQuant™ Microarray Based Assay.

BACKGROUND: Hormone receptor status and HER2 status are of critical interest in determining the prognosis of breast cancer patients. Their status is routinely assessed by immunohistochemistry (IHC). However, it is subject to intra-laboratory and inter-laboratory variability. The aim of our study was to compare the estrogen receptor, progesterone receptor and HER2 status as determined by the MapQuant™ test to the routine immuno-histochemical tests in early stage invasive breast cancer in a large comprehensive cancer center. PATIENTS AND METHODS: We retrospectively studied 163 invasive early-stage breast carcinoma with standard IHC status. The genomic status was determined using the MapQuant™ test providing the genomic grade index. RESULTS: We found only 4 tumours out of 161 (2.5%) with discrepant IHC and genomic results concerning ER status. The concordance rate between the two methods was 97.5% and the Cohen's Kappa coefficient was 0.89. Comparison between the MapQuant™ PR status and the PR IHC status gave more discrepancies. The concordance rate between the two methods was 91.4% and the Cohen's Kappa coefficient was 0.74. The HER2 MapQuant™ test was classified as « undetermined ¼ in 2 out of 163 cases (1.2%). One HER2 IHC-negative tumour was found positive with a high HER2 MapQuant™ genomic score. The concordance rate between the two methods was 99.3% and the Cohen's Kappa coefficient was 0.86. CONCLUSION: Our results show that the MapQuant™ assay, based on mRNA expression assay, provides an objective and quantitative assessment of Estrogen receptor, Progesterone receptor and HER2 status in invasive breast cancer.

Human papillomavirus genotype as a major determinant of the course of cervical cancer.

PURPOSE: To determine whether the prognosis of invasive cancers of the uterine cervix is related to the type of human papillomavirus (HPV) associated with the tumor. PATIENTS AND METHODS: Two hundred ninety-seven patients with invasive cervical cancer were prospectively registered from 1986 to 1994. HPV typing was performed on DNA extracted from frozen tumor specimens by means of Southern blot hybridization (SBH) and polymerase chain reaction (PCR) techniques. The median follow-up was 38 months. RESULTS: HPV sequences were detected in 246 patients (83%): 150 patients had HPV16, 31 patients had HPV18, and 14 patients had one of the intermediate-oncogenic-risk HPV types (HPV31, 33, 35, 52, 58). In 51 patients, HPV type remained undetermined, and in 51 patients, no viral sequences were found. No significant associations were observed between virologic data and tumor stage or node status. The 5-year disease-free survival (DFS) rate was 100% for patients with intermediate-risk HPV-associated tumors, 58% for patients with HPV16-positive tumors, and 38% for patients with HPV18-positive tumors (P = .02). In multivariate analysis, patients with HPV18-associated tumors had a relative risk (RR) of death 2.4 times greater (95% confidence interval [CI], 1.29-4.59) than that for patients with HPV16, and 4.4 times greater (95% CI, 3.48-5.32) than that for patients with a tumor associated with a viral type different from HPV16/18. CONCLUSION: The prognosis for invasive cancers of the uterine cervix is dependent on the oncogenic potential of the associated HPV type. HPV typing may provide a prognostic indicator for individual patients and is of potential use in defining specific therapies against HPV-harboring tumor cells.

Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma.

PURPOSE: Several histologic grading systems have been validated in soft tissue sarcomas (STS), but no system is currently accepted worldwide. The National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems were examined comparatively in the same population of patients with STS to determine which system is the best prognosticator with regard to metastasis development and tumor mortality. PATIENTS AND METHODS: Four hundred ten adult patients with nonmetastatic STS were examined. Histologic grade was established according to the NCI and FNCLCC systems in each case. The prognostic value of both systems was examined using univariate and multivariate (Cox's model) analyses, and special attention was devoted to tumors with discordant grades. RESULTS: In univariate analysis, both the NCI and FNCLCC systems were of prognostic value to predict metastasis development and tumor mortality. In multivariate analysis, high-grade tumors, irrespective of the system used, size > or = 10 cm, and deep location were found to be independent prognostic factors for the advent of metastases. Tumor grade had a higher predictive value than size or depth, and higher prognostic weight was assigned to the FNCLCC grading system in Cox models. Grade discrepancies were observed in 34.6% of the cases. An increased number of grade 3 STS, a reduced number of grade 2 STS, and a better correlation with overall and metastasis-free survival within subpopulations with discordant grades were observed in favor of the FNCLCC system. CONCLUSION: The FNCLCC system showed slightly increased ability to predict distant metastasis development and tumor mortality. The use of this system to evaluate STS aggressiveness might be favored.

Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients.

PURPOSE: To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas (SS) and to confirm the usefulness of the French Federation of Cancer Centers (FNCLCC) grading system, the prognostic impact of which has been already proven in soft tissue sarcomas. PATIENTS AND METHODS: Data on 128 patients with nonmetastatic SS collected from a cooperative database by the FNCLCC Sarcoma Group between 1980 and 1994 were studied retrospectively. Immunohistochemistry was performed at diagnosis in 77 cases (61%). The tumors were classified as biphasic (n = 45), monophasic fibrous (n = 72), and poorly differentiated (n = 10) subtypes. Histologic grade was determined according to the FNCLCC method, and vascular invasion was assessed in every case. RESULTS: The 5-year disease-specific survival (DSS) rate for this series of patients with localized SS was 62.9% (+/- 9.6% [SD]) with a median follow-up time of 37 months (range, 8 to 141 months). In multivariate analysis, the adverse risk factors associated with decreased DSS were International Union Against Cancer/American Joint Committee on Cancer stage III/IVA disease, male sex, and truncal tumor locations. For metastasis-free survival (MFS), disease stage III/IVA, tumor necrosis, and monophasic subtypes were the major factors associated with a less favorable prognosis. Separately, when not using disease stage, tumor necrosis, and mitotic activity, histologic grade became the most significant prognostic factor for both DSS and MFS. In addition, larger tumors and older patients become associated with a significantly worse prognosis. Independent adverse risk factors for local recurrence-free survival included histologic grade 3 and truncal tumor location. CONCLUSION: These data confirm that not all SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach.

Wide metastatic spreading in infiltrating lobular carcinoma of the breast.

The aim of this study was to determine whether the metastatic potential of breast cancer could be related to phenotypic characteristics of the tumour. Therefore, we compared the metastatic patterns of invasive lobular (ILC) and ductal (IDC) carcinomas. In ILC, we also analysed this pattern according to the histological subtype of the primary and the E-cadherin (EC) expression level. Metastatic ILC cases (n=96) were retrospectively analysed and classified into classical, alveolar, solid, tubulo-lobular, signet ring cells or pleomorphic subtypes. Anatomical distribution of metastases was detailed for every patient and compared with that registered for IDC (n=2749). Immunostaining of EC (HECD1 antibody) was performed in 82 cases. Histologically, 78 of the 96 cases (81%) corresponded to classical ILC. The pleomorphic subtype was observed in 14 cases (15%), a rate that was higher than that expected. Others corresponded to alveolar (2 cases), signet ring cell (1 case) and solid (1 case) subtypes. EC was undetectable in 72/82 cases (88%). The rate of multiple metastases was higher in ILC (25.0%) than in IDC (15.8%) (P=0.016). Metastases were found more frequently in ILC than in IDC in the bone (P=0.02) and/or in various other sites (peritoneum, ovary, digestive tract, skin em leader ) (P<0.001). In ILC, no significant link was found between the localisation(s) of metastases, the histological subtype and the EC status in the primary. In conclusion, in breast carcinomas, the frequency of multiple metastasis was found to be higher in ILC than IDC. This fact may be related to the phenotypic trait of discohesive small cells which characterises ILC. EC loss, observed in most cases of ILC, may result in alterations in cell-cell adhesion and a preferential growth at metastatic sites. A high rate of pleomorphic tumours was observed in the group of metastatic ILC, but the pattern of metastatic site(s) was not related to the histological subtype of the primary.

Overexpression of nucleoside diphosphate kinase (Nm23) in solid tumours.

The product of the nm23-H1 gene, reported to be related to the metastatic potential of tumour cells, was recently identified as the nucleoside diphosphate (NDP) kinase A (Gilles et al., 1991, J Biol Chem, 266, 8784-8789). An analysis of the enzyme by activity measurement and immunological techniques using polyclonal antibodies raised against the NDP kinase A purified from human erythrocytes, was performed on 39 human tissue specimens. Markedly increased activity and higher level of the protein were observed in extracts of solid tumours as compared to the corresponding normal tissues (P less than 0.01). An intense immunolabelling of tumoral cells was observed in sections of the malignant tumours and of some but not all benign neoplasia. The staining is observed in noninvasive and invasive ductal breast carcinomas with or without lymph node involvement as well as in colon and cervix carcinomas and in a case of metastatic melanoma. Therefore, NDP kinase A level is increased in neoplastic tissues but no correlation with metastatic potential could be demonstrated.

ERBB2 overexpression in breast carcinomas: no positive correlation with complete pathological response to preoperative high-dose anthracycline-based chemotherapy.

The predictive value of ERBB2 amplification/expression to doxorubicin use is controversial. Preoperative chemotherapy, followed by the pathological assessment of tumour response to treatment provide optimal conditions for the evaluation of the predictive value of biological parameters. We report here data on the predictive value of ERBB2 in a series of 54 cases of breast cancer treated by preoperative high-dose anthracycline-based chemotherapy. Our series consisted of 26 women presenting an inflammatory breast cancer (IBC) and of 28 women with poor prognosis primary cancer (PPPC). Patients received a total of four cycles with doxorubicin (75 mg/m(2) for IBC or 70 mg/m(2) for PPPC) and cyclophosphamide (6 g/m(2) for IBC or 1400 mg/m(2) for PPPC), every 21 days. ERBB2 expression was determined by immunohistochemistry (clone CB11) performed on a tumour biopsy taken before chemotherapy. All patients underwent surgery as a second step of treatment, and the tumour response was assessed on pathological specimens. A complete pathological response was observed in 24 of the 54 cases (44%) (95% confidence interval (CI), 31-57). Pathological complete response was positively correlated with high histological grade (P=0. 02) and with the absence of oestrogen (P=0.003) or progesterone (P=0. 02) receptor expression. ERBB2 overexpression was found in 18 of the 54 cases (33%). A complete pathological response was observed in 33% of these cases (6/18). This figure was not significantly different from the 50% rate of complete response observed for tumours with no detectable ERBB2 expression (18/36). In this small series, ERBB2 overexpression was not a significant predictive marker of the pathological response to high-dose doxorubicin-based chemotherapy.