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Frédérique Penault-Llorca

Publications and source records attributed to Frédérique Penault-Llorca.

At least 19 recordsLinked to original sources
PubMed2006

High inter-observer agreement in immunohistochemical evaluation of HER-2/neu expression in breast cancer: a multicentre GEFPICS study.

The accurate determination of HER-2 in invasive breast cancer has become a critical issue, particularly in the context of the results of recent trastuzumab (Herceptin((R))) adjuvant trials. This multicentre study evaluated inter-observer reproducibility in interpretation of HER-2 immunostains performed in different laboratories according to their in-house technique. A total of 74 HER-2 immunostains were evaluated by 16 pathologists and by a central review committee. As determined by central review, the HER-2 score was 0 in 33 cases (44%), 1+ in 10 cases (13%), 2+ in 9 cases (12%) and 3+ in 23 cases (31%). The overall kappa value was good (kappa=0.75). Agreement was excellent for the 0/1+ group (kappa=0.85) and for the 3+ group (kappa=0.82). As expected, the score 2+ group showed poor agreement (kappa=0.38). A quality assurance process showed that ring studies and adherence to national guidelines greatly improve inter-observer reproducibility.

Adult↗
PubMed2006

Assessment of epidermal growth factor receptor (EGFR) expression in primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray.

Metastatic colorectal carcinomas (CRC) resistant to chemotherapy may benefit from targeting monoclonal therapy cetuximab when they express the epidermal growth factor receptor (EGFR). Because of its clinical implications, we studied EGFR expression by immunohistochemistry on tissue sections of primary CRC (n=32) and their related metastases (n=53). A tissue microarray (TMA) was generated from the same paraffin blocks to determine whether this technique could be used for EGFR screening in CRC. On tissue sections, 84% of the primary CRC and 94% of the metastases were EGFR-positive. When matched, they showed a concordant EGFR-positive status in 78% of the cases. Moreover, staining intensity and extent of EGFR-positive cells in the primary CRC correlated with those observed in the synchronous metastases. On TMA, 65% of the primary CRC, 66% of the metastases, and 43% of the matched primary CRC metastases were EGFR-positive. There was no concordant EGFR status between the primary and the metastatic sites. A strong discrepancy of EGFR status was noted between TMA and tissue sections. In conclusion, EGFR expression measured in tissue sections from primary CRC and their related metastases was found to be similar and frequent, but it was significantly underestimated by the TMA technique.

Adenocarcinoma↗
PubMed2006

Involvement of the multidrug resistance transporters in cisplatin-induced neuropathy in rats. Comparison with the chronic constriction injury model and monoarthritic rats.

It has recently been suggested that P-glycoprotein is involved in the genesis and the treatment of the neurotoxic adverse events of anticancer drugs, including vincristine. A lower activity of P-glycoprotein in the peripheral nervous system (PNS) than in the central nervous system could contribute to the neurotoxicity of vincristine. Vincristine treatment is responsible for the induction of multidrug resistance (MDR) gene expression and transporter activity, with deleterious consequences, including a potential decrease in the efficiency of opioid analgesics, antidepressants or antiepileptics. Concerning cisplatin, which is also a strong neurotoxic drug but only an multidrug resistance protein 2 (MRP2) substrate, the same assumption could be suggested for MRP2 nervous function. The aim of this study was to assess MDR gene and protein activity in a rat model of cisplatin-induced neuropathy compared with different peripheral nerve injury models, i.e. mononeuropathy and inflammatory pain (monoarthritis). First, in cisplatin-induced neuropathy, this study demonstrated low MRP2 gene expression in dorsal root ganglia compared with the brain and spinal cord, which could contribute to the strong neurotoxicity of cisplatin in the PNS and particularly the dorsal root ganglia. Thus, gene expression increased in cisplatin-induced neuropathy but decreased in mononeuropathy and remained unchanged in monoarthritis models. Transporter activity of nervous tissues increased in the cisplatin-induced neuropathy, mononeuropathy and monoarthritis to different intensities (3.7-, 1.8- and 1.8-fold, respectively). The development of a MDR in the cisplatin-induced neuropathy is a striking difference with mononeuropathy and monoarthritis models, and characterizes the neuropathies induced by this anticancer drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.

Adult↗
PubMed2006

Randomized Phase II study comparing paclitaxel and carboplatin versus mitoxantrone in patients with hormone-refractory prostate cancer.

OBJECTIVES: Mitoxantrone/prednisone was the 2002 palliative reference treatment for hormone-refractory prostate cancer (HRPC). Paclitaxel and carboplatin has demonstrated antitumor activity in HRPC. The therapeutic benefit of such treatment was compared with that of mitoxantrone. METHODS: A randomized Phase II study was conducted that included 40 patients with HRPC who had not undergone chemotherapy. Patients in arm A received paclitaxel (175 mg/m2 every 3-week cycle) and carboplatin (area under the curve of 5 every 3-week cycle). Patients in arm B received mitoxantrone (12 mg/m2 every 3-week cycle). All the patients treated were receiving low-dose prednisone. The primary endpoint was the prostate-specific antigen response. RESULTS: The prostate-specific antigen response to paclitaxel and carboplatin was significantly greater (40% [95% confidence interval 18.5% to 61.5%] versus 10% [95% confidence interval 1% to 32%], P = 0.031) and more durable (8.6 versus 2 months, P = 0.015) than the response to mitoxantrone. A tendency was noted for patients with measurable disease who were receiving paclitaxel and carboplatin to have a somewhat greater objective response rate than those who received mitoxantrone (23% [95% confidence interval 5.3% to 55%] versus no objective response, P = 0.060). The median overall survival was 14.5 months for the paclitaxel and carboplatin arm compared with 11.1 months for the mitoxantrone arm. The group given paclitaxel and carboplatin had significantly greater rates of sensitive neuropathy (50% versus 0%, P = 0.00026). CONCLUSIONS: The 3-week regimen of paclitaxel and carboplatin induced a greater and more durable prostate-specific antigen response than did mitoxantrone for HRPC treatment. The major additive toxicity induced was peripheral neuropathy due to paclitaxel. Investigations with paclitaxel and carboplatin regimens merit large Phase III studies.

Aged↗
PubMed2006

Cost-effectiveness analysis of strategies for HER2 testing of breast cancer patients in France.

OBJECTIVES: A cost-effectiveness analysis was conducted comparing diagnostic strategies for determining the HER2 status of invasive breast carcinomas, as an indication for trastuzumab at metastatic relapse. METHODS: A decision tree compared five strategies distinguished by (i) the use of immunohistochemical (IHC) and/or fluorescent in situ hybridization (FISH) techniques, and (ii) the test schedule (at initial diagnosis or metastatic relapse). Most cost and effectiveness data came from a French multicentric study of 2,045 patients from eight hospitals. We were not able to select final criteria for trastuzumab effectiveness, because published data rely on IHC techniques not used in France (i.e., HercepTest). We, therefore, selected two intermediate criteria for inappropriate treatment at relapse, that is, patients with HER2-amplified tumors not receiving trastuzumab (Criterion 1) and HER2-nonamplified tumors improperly treated with trastuzumab (Criterion 2). Sensitivity analyses were then performed to assess the robustness of the results to (i) discount rate, (ii) cost of FISH, and (iii) tissue fixation technique. RESULTS: The strategy using IHC at diagnosis was dominated by the four other strategies. Among these approaches, the only efficient strategy for both criteria was IHC used alone at metastatic relapse; strategies using FISH, or IHC followed by FISH on IHC2+ cases were efficient for Criterion 1, whereas IHC followed by FISH on IHC2+ and 3+ cases was efficient for Criterion 2. CONCLUSIONS: Determining HER2 status at diagnosis, as an indication for trastuzumab at metastatic relapse, incurs substantial incremental costs, which do not appear to be justified. No other strategy can be excluded at first.

Antibodies, Monoclonal↗
PubMed2006

Sequential addition of an anthracycline-based regimen to docetaxel as neoadjuvant chemotherapy in patients with operable breast cancer.

BACKGROUND: The objective of this phase II study was to attempt to maximize response and survival in patients with bulky, operable breast cancer by combining sequential neoadjuvant docetaxel to a semi-intensive anthracycline-based regimen. PATIENTS AND METHODS: Eligible patients (N = 53) were included to receive 4 cycles of docetaxel, followed by a maximum of 4 cycles of TNCF (THP [theprubican]-doxorubicin/vinorelbine/cyclophosphamide/5-fluorouracil) every 21 days before definitive surgery and radiation therapy. RESULTS: After a median number of 4 cycles of docetaxel and 2 cycles of TNCF, the overall clinical response rate was 81.1%, including a 13.2% complete remission rate and only 2 incidences of progressive disease. Breast conservation was achieved in 87% of patients. According to Chevallier classification, a pathologic complete response in breast and axilla was confirmed in 6 patients (11.3%) and in 9 patients (17%) using the Sataloff's classification. The important myelosuppression observed in this trial was expected but limited by the prophylactic use of growth factors. After a median follow-up of 40.4 months, only 5 recurrences were documented, with a median time to first recurrence of 12.8 months. CONCLUSION: Despite disappointing results of this trial for pathologic complete response rate, possibly because of the order of drug administration, clinical response, breast conservation, and survival were optimized.

Adolescent↗
PubMed2006

[New entities in pathological classification and new therapeutic options in renal cell carcinoma].

Therapy for renal cell carcinoma has made considerable progress in the past few years. The aims of this review are to update the pathological classification of this tumor and discuss predictive factors for tumor response and survival in the case of metastasis as well as the place of immunotherapy with interleukine-2 and/or interferon alpha . Furthermore, we will review new therapeutic options and current results on allogeneic stem cell transplantation with non-myeloablative conditioning and HLA genoidentical donors. Finally, we will present targeted therapy (antiangiogenic drugs and tyrosine kinase inhibitors) with the mechanisms of action, efficacy and appropriate use in the treatment of metastatic renal cell carcinoma.

Angiogenesis Inhibitors↗
PubMed2006

[Sentinel lymph node biopsy for breast cancer after neoadjuvant chemotherapy: influence of nodal status before treatment].

OBJECTIVES: To determine feasibility and accuracy of SLN biopsy in locally advanced breast cancer treated by neoadjuvant chemotherapy. MATERIALS AND METHODS: From April 2001 to December 2004, a prospective series was constituted of 74 women with invasive breast carcinoma T1T2T3N0N1 receiving neoadjuvant chemotherapy. The SLN located was removed using subdermal periareolar injection of radiolabelled nanocolloid and axillary lymph node dissection was systematically performed. RESULTS: A SLN was identified in 68/74 (92%) patients. It was metastatic in 30/68 cases (44%). The false negative (FN) rate was 14% (5/35). In the subgroup of 42 patients clinically N(0) before chemotherapy, accuracy was 100 %, and FN rate 0%, in the 32 N1, accuracy was 83%, and FN rate 25%. CONCLUSIONS: SLN biopsy using a single subdermal injection of radiolabelled nanocolloid in patients with a breast cancer treated by neoadjuvant chemotherapy is technically feasible and appears to be highly accurate in the subgroup of patients with a clinically negative axilla breast cancer before treatment.

Adult↗
PubMed2006

[Place of anatomopathology in evaluation of response to neoadjuvant chemotherapy. Prognostic and predictive markers: example of breast cancer].

The pathologist plays a key role in the optimal management of patients receiving an induction or a neoadjuvant chemotherapy. The evaluation of the pre-treatment biopsy helps to establish key patient-management parameters such as tumor type, SBR grade and immunohistochemical parameters. This evaluation provides predictive parameters with regards to drug response such as hormonal status, proliferation factors and overexpression of Her-2. The evaluation of the post-treatment tumour residue helps to determine tumour response to treatment and prognosis, as well as to adjust adjuvant regimens. It is essential to standardize these histopathological procedures.

Biomarkers, Tumor↗
PubMed2006

Is there an immunohistochemical technique definitively valid in epidermal growth factor receptor assessment?

Immunohistochemistry (IHC) is required for the selection of patients for a monoclonal antibody based targeted treatment with C225 (Erbitux). To validate the usefulness of IHC, the confirmation of assays and scoring systems are mandatory. In an attempt to standardize the immunohistochemical detection of the epidermal growth factor receptor (EGFR), we retrospectively evaluated three commercially available EGFR kits or antibodies and analyzed the discrepancies between the tests in terms of the percentage of positive cells, intensity, cut-off value and fixatives. We extracted 232 paraffin-embedded samples from a metastatic colorectal cancer clinical trial. For all the cases, EGFR expression was assessed with the FDA approved Dako EGFR pharmaDx kit, the Zymed EGFR kit and the Ventana EGFR 3C6 antibody. Different cut-off values were tested, and the intensity was scored 0, 1+, 2+, 3+ following Dako's recommendations. The percentage of positive cases varied from 93 to 75% with a cut-off of value 1% of positive cells, from 80 to 61% with a cut-off of 5% positive cells and from 72% to 48% with a cut-off value of 10%. Both Ventana and Zymed tests were more sensitive than the Dako test (Ventana >Dako; p<10(-7), Zymed >Dako; p=2.10(-6)). No difference was noted between Ventana and Zymed tests (p=0.75). A high concordance was observed for the 3 tests for the evaluation of high intensities. The use of a scoring system combining the percentage of positive cells and intensity was not useful for Zymed and Ventana as the intensity of staining is correlated to the percentage of positive cells: Ventana (p<10(-6)) and Zymed (p<10(-5)). No interaction with staining was identified for any of the fixatives, or with the nature of samples received (i.e. slides vs blocks, biopsies vs surgical specimens). Our data showed a higher percentage of positive cells detected by Ventana and Zymed tests, whatever the cut-off value for positivity. No scoring system showed, to date, its accuracy, and more studies have to be conducted with an evaluation of the response to cetuximab, possibly with a correlation with FISH amplification in colorectal carcinoma.

Adenocarcinoma↗
PubMed2005

Typical medullary breast carcinomas have a basal/myoepithelial phenotype.

Medullary breast cancer (MBC) is a rare, diagnostically difficult, pathological subtype. Despite being high grade, it has a good prognosis. MBC patients have an excess of BRCA1 germ-line mutation and reliable identification of MBC could help to identify patients at risk of carrying germline BRCA1 mutations or in whom chemotherapy could be avoided. The aim of this study was therefore to improve diagnosis by establishing an MBC protein expression profile using immunohistochemistry (IHC) on tissue-microarrays (TMA). Using a series of 779 breast carcinomas ('EC' set), diagnosed initially as MBC, a double-reading session was carried out by several pathologists on all of the histological material to establish the diagnosis as firmly as possible using a 'medullary score'. Only MBCs with high scores, i.e. typical MBC (TMBC) (n=44) and non-TMBC grade III with no or low scores (n=160), were included in the IHC study. To validate the results obtained on this first set, a control series of TMBC (n=17) and non-MBC grade III cases (n=140) ('IPC' set) was studied. The expression of 18 proteins was studied in the 61 TMBCs and 300 grade III cases from the two sets. The global intra-observer concordance of the first reading for the diagnosis of TMBC was 94%, with almost perfect kappa (kappa) of 0.815. TMBC was characterized by a high degree of basal/myoepithelial differentiation. In multivariate analysis with logistic regression, TMBC was defined by the association of P-cadherin (R=2.29), MIB1 > 50 (R=3.80), ERBB2 negativity (R=2.24) and p53 positivity (RR=1.45).

Breast Neoplasms↗
PubMed2005

High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Pathological and clinical response of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel as neoadjuvant treatment in patients with operable breast cancer.

This phase II study investigated the efficacy and tolerability of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel (VEP protocol) in women with stage II/III operable breast cancer. Patients (n = 50) were treated with six cycles of VEP according to the following schedule: vinorelbine (Navelbine); Pierre Fabre, Boulogne, France; http://www.pierre-fabre.com) 20 mg/m2, epirubicin (Farmorubicin; Pharmacia, New York, NY; http://www.pnu.com) 35 mg/m2 given on days 1 and 8, paclitaxel (Taxol; Bristol-Myers Squibb, New York, NY; http://www.bmsoncology.com) 175 mg/m2 given on day 9, and G-CSF 5 mg/kg/day given on days 10-20 of a 21-day cycle, followed by surgery and radiotherapy. After six cycles of VEP, the pathological response rate (pCR) in breast was confirmed in six patients (12%; 95% confidence interval [CI]: 3-21)) using Chevallier's classification and in nine patients (18%; 95% CI: 7.4-28.6) using Sataloff's classification. The clinical response rate was 42% (95% CI: 28.3-55.7), including 26% complete responses. Breast conservation was achieved in 68% of patients. After a median follow-up of 48 months (range, 34-62 months), 16 relapses were observed. The overall and disease-free survivals at 5 years were 54.1% (95% CI: 40.3-67.9) and 38% (95% CI: 24.1-51.9), respectively. The principal toxicities of VEP were grade 3/4 neutropenia observed in 30% of patients and grade 3 anemia observed in 12% of patients. There was no case of severe cardiac toxicity, thrombocytopenia, or any other serious adverse events. In conclusion, whereas this regimen was relatively well tolerated, it appears inferior to other regimens and its use is not recommended.

Adult↗
PubMed2005

[EGFR expression in colorectal cancer and role in tumorigenesis].

Epithelial growth factor receptor (EGFR) appears as a key element in colorectal carcinogenesis. It displays high levels of expression. Its activation induces cell proliferation, angiogenesis, cell mobility and inhibition of apoptosis. EGFR inhibitors such as monoclonal antibodies or small molecules tyrosine kinase inhibitors have been developed. For EGFR, the diversity of the activation means (amplification, mutation, enhanced transcription, ligands...) leads to technical caveats. Pathologists are involved in the selection of patients for a monoclonal antibody based targeted treatment, Erbitux (cetuximab), and numerous standardization efforts are provided. No consensus has been reached, to date, for a scoring system for immunohistochemistry. No correlation has been found so far between EGFR level of expression and response to cetuximab. Whether and how the EGFR status has to be tested for the selection of patients is a non answered question. The selection of the "right patient for the right treatment" might be through the evaluation of other putative markers involved in resistance. EGFR testing may be required before targeted treatment. An exciting endpoint might be the functional and dynamic evaluation of EGFR and downstream proteins for patients, before and during treatment.

Colorectal Neoplasms↗
PubMed2004

[Classification of preinvasive breast and carcinoma in situ: doubts, controversies, and proposal for new categorizations].

As a consequence of increased screening mammography, preinvasive breast lesions represent a growing percentage of breast pathology diagnoses. Intraductal epithelial proliferations of the breast are, at present, classified into three groups: usual epithelial hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. The boundary between those two last entities is not clearly defined on a morphological point of view although the clinical management is different. Columnar atypical lesions or flat atypical hyperplasia, frequently observed near microcalcifications, are not homogeneously managed. Lobular lesions are classified under the category of lobular neoplasia which avoid interobserver variability. Molecular biology data and immunoprofiles isolate different lobular phenotypes and link them to invasive cancer. The different systems of classifications of those different entities, the most recent molecular biology datas, controversies and consensus are described in this manuscript.

Breast↗
PubMed2004

[Assessment of HER2 status in breast cancer].

HER2-positive status is the sole criterion for identifying patients with breast cancer for Herceptin (trastuzumab) therapy. Accurate assessment of HER2 status is essential to ensure that all patients who may benefit from Herceptin are correctly identified. There are several assays available to determine HER2 status: the most common in routine clinical practice are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The pros and cons of those two tests and the other upcoming methods for assessing HER2 status (with a focus on chromogenic in situ hybridization CISH recently approved by European Commission) are described in this manuscript. The importance of adhesion to quality assurance programs is underlined. Finally, the different national testing guidelines are discussed.

Antibodies, Monoclonal↗