The breast epithelium has two major compartments, luminal and basal cells, that are established and maintained by poorly understood mechanisms. The p53 homolog, p63, is required for the formation of ...mammary buds, but its function in the breast after birth is unknown. We show that in primary human breast epithelial cells, maintenance of basal cell characteristics depends on continued expression of the p63 isoform, ΔNp63, which is expressed in the basal compartment. Forced expression of ΔNp63 in purified luminal cells confers a basal phenotype. Notch signaling downmodulates ΔNp63 expression and mimics ΔNp63 depletion, whereas forced expression of ΔNp63 partially counteracts the effects of Notch. Consistent with Notch activation specifying luminal cell fate in the mammary gland, Notch signaling activity is specifically detected in mice at sites of pubertal ductal morphogenesis where luminal cell fate is determined. Basal cells in which Notch signaling is active show decreased p63 expression. Both constitutive expression of ΔNp63 and ablation of Notch signaling are incompatible with luminal cell fate. Thus, the balance between basal and luminal cell compartments of the breast is regulated by antagonistic functions of ΔNp63 and Notch.
Background: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing ...after aromatase inhibitor (AI) treatment.
Patients and methods: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n = 70) with AI-responsive disease and group B (n = 20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (±3) days.
Results: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease SD for ≥24 weeks) in 28% (90% confidence interval CI 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B.
Conclusions: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.
Endometriosis is a common, hormone-dependent gynecologic disease. Undiagnosed in large proportion of women, managing therapies depend on the impact of quality of life and includes hormonal treatment ...and pelvic surgery. Less likely endometriosis can occur in post-menopausal women. Malignant transformation of endometriosis is a rare but well-described process, most of time occurring in the ovary, and justifies the practitioner not to underestimate this pathology. We present a case of a 61 year old woman with a symptomatic endometriotic pelvic mass, status post hysterectomy, with no history of endometriosis diagnosed beforehand.
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.
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.
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.
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.
Determination of the HER2/neu (HER2) status in breast carcinoma has become necessary for the selection of breast cancer patients for trastuzumab therapy. Amplification of the gene analysed by ...fluorescence in situ hybridisation (FISH) or overexpression of the protein determined by immunohistochemistry (IHC) are the two major methods to establish this status. A strong correlation has been previously demonstrated between these two methods. However, FISH is not always feasible in routine practice and weakly positive IHC tumours (2+) do not always correspond to a gene amplification. Our study was performed in order to evaluate the contribution of chromogenic in situ hybridisation (CISH), which enables detection of the gene copies through an immunoperoxidase reaction. CISH was performed in 79 breast carcinomas for which the HER2 status was previously determined by IHC and FISH. The results of IHC, FISH and CISH were compared for each tumour. CISH procedures were successful in 95% of our cases. Whatever the IHC results, we found a very good concordance (96%) between CISH and FISH. Our study confirms that CISH may be an alternative to FISH for the determination of the gene amplification status in 2+ tumours. Our results allow us to think that, in many laboratories, CISH may also be an excellent method to calibrate the IHC procedures or, as a quality control test, to check regularly that the IHC signal is in agreement with the gene status.
Abstract Background Lapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated ...patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1–2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial. Patients and methods Patients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21 days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m2 ). Results Twenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ⩾7 days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed. Conclusions Our recommended dose for phase II is lapatinib 1000 mg/day and docetaxel 100 mg/m2 with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250 mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250 mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.
Aims: HER2 protein is over‐expressed in 15–30% of breast carcinomas. Immunohistochemistry (IHC) is a common and inexpensive method able to specifically detect HER2 protein. However, lack of ...standardization of IHC has been considered responsible for discrepancies in HER2 status assessment performed by IHC and fluorescence in‐situ hybridization (FISH). This prompted us to perform a multicentric IHC calibration test to achieve a maximum accuracy of HER2‐IHC compared with HER2‐FISH taken as the reference method.
Methods and results: Twelve French laboratories participated in this study, including 119 cases of invasive breast carcinomas for which both fixed and frozen tissues were available. HER2 expression was determined in fixed tissues by individual in‐house IHC techniques, using either CB11 (Novocastra, Newcastle, UK) or A0485 (Dako, Glostrup, Denmark) anti‐HER2 antibodies. Two cut‐off values were used: 10% and 60% of immunostained cells. In 116 of the 119 cases, HER2 gene status could also be determined by FISH on frozen sections, performed in a single laboratory. Results were centralized and compared. When suboptimal concordance between IHC and FISH was observed, IHC was calibrated and a second run was performed. The specificity, sensitivity and accuracy of IHC compared with FISH were noted before and after calibration. Forty‐four out of 116 (38%) tumours showed HER2 gene amplification. Accuracy of IHC was complete in the first run for 6/12 laboratories. Calibration, necessary for the six others, relied mainly on the combination of a heat‐induced epitope retrieval step with an increase of dilution of the primary antibody. In the second run, HER2 over‐expression was found in 46 (40%) and 44 (38%) of the 116 cases, using 10% or 60% of stained cells as cut‐offs, respectively. The corresponding accuracy rates were 93% and 95%.
Conclusions: This study showed that a high accuracy of IHC could be obtained for the determination of HER2 status in all laboratories using their in‐house IHC technique, provided that a calibration process was performed. Antigen retrieval procedure, high dilutions of anti‐HER2 antibody and the use of specific controls were crucial for HER2‐IHC calibration. A 95% accuracy rate of IHC, using FISH as gold standard, was obtained by considering immunolabelling HER2‐IHC results as a continuous variable, and taking 60% invasive stained cells as the cut‐off for HER2 over‐expression.
Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human ...breast are unclear. Receptor activator of nuclear factor κB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR(+) breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention.
Highlights • Invasive lobular carcinomas (ILC) are specific and heterogeneous at a molecular level. • ILC does not have an indolent course compared to invasive ductal carcinoma. • Molecular subtypes ...of ILC could determine the risk of relapse. • Neoadjuvant chemotherapy in ILC can be beneficial. • Adjuvant letrozole seems to be more effective than tamoxifen in ILC.
Previous microarray studies on breast cancer identified multiple tumour classes, of which the most prominent, named luminal and basal, differ in expression of the oestrogen receptor alpha gene (ER). ...We report here the identification of a group of breast tumours with increased androgen signalling and a 'molecular apocrine' gene expression profile. Tumour samples from 49 patients with large operable or locally advanced breast cancers were tested on Affymetrix U133A gene expression microarrays. Principal components analysis and hierarchical clustering split the tumours into three groups: basal, luminal and a group we call molecular apocrine. All of the molecular apocrine tumours have strong apocrine features on histological examination (P=0.0002). The molecular apocrine group is androgen receptor (AR) positive and contains all of the ER-negative tumours outside the basal group. Kolmogorov-Smirnov testing indicates that oestrogen signalling is most active in the luminal group, and androgen signalling is most active in the molecular apocrine group. ERBB2 amplification is commoner in the molecular apocrine than the other groups. Genes that best split the three groups were identified by Wilcoxon test. Correlation of the average expression profile of these genes in our data with the expression profile of individual tumours in four published breast cancer studies suggest that molecular apocrine tumours represent 8-14% of tumours in these studies. Our data show that it is possible with microarray data to divide mammary tumour cells into three groups based on steroid receptor activity: luminal (ER+ AR+), basal (ER- AR-) and molecular apocrine (ER- AR+).
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