[Show abstract][Hide abstract] ABSTRACT: Triple negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the Epithelial Growth Factor Receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane based chemotherapy in patients with operable, stage II-III, TNBC.
Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for 8 cycles q.3 weeks combined with 4 cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks followed by 4 cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathological complete response (pCR) in evaluable patients was the main endpoint while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody.
Sixty patients were enrolled with 47 assessable for pathologic response. The pathological complete response (pCR) rates were 46.8% [95% CI: 32.5-61.1] and 55.3% [95% CI: 41.1-69.5] according respectively to Chevallier and Sataloff classifications. The complete clinical response rate (cCR) was 37.5%. Conservative surgery was performed in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR.
Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC.
[Show abstract][Hide abstract] ABSTRACT: Background:To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.Methods:This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH.Results:The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR.Conclusions:Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.British Journal of Cancer advance online publication 6 May 2014; doi:10.1038/bjc.2014.213 www.bjcancer.com.
British Journal of Cancer 05/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A subgroup of T1N0M0 breast cancer (BC) carries a high potential of relapse, and thus may require adjuvant systemic therapy (AST).
Retrospective analysis of all patients with T1 BC, who underwent surgery from January 1999 to December 2009 at 13 French sites. AST was not standardized.
Among 8100 women operated, 5423 had T1 tumors (708 T1a, 2208 T1b and 2508 T1c 11-15 mm). T1a differed significantly from T1b tumors with respect to several parameters (lower age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion), exhibiting a mix of favorable and poor prognosis factors. Overall survival was not different between T1a, b or c tumors but recurrence-free survival was significantly higher in T1b than in T1a tumors (P = 0.001). In multivariate analysis, tumor grade, hormone therapy and lymphovascular invasion were independent prognostic factors.
Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of AST (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 BC.
[Show abstract][Hide abstract] ABSTRACT: AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.Oncogene advance online publication, 18 November 2013; doi:10.1038/onc.2013.487.
[Show abstract][Hide abstract] ABSTRACT: These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) incidence and epidemiology In 2008, the estimated age-adjusted annual incidence of breast cancer in Europe (40 countries) was 88.4/100 000 and the mortality 24.3/100 000. The incidence increased after the introduction of mammography screening and continues to do so with the aging of the population. The most important risk factors include genetic predisposition, exposure to estrogens (endogenous and exogenous) and ionising radiation, low parity and history of atypical hyperplasia. The Western-style diet, obesity and consumption of alcohol also contribute to the rising incidence of breast cancer . There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35. The estimated prevalence of breast cancer in Europe in 2010 was 3 763 070 cases  and is increasing, both as a consequence of increased incidence and of improvements in treatment outcomes. In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups because of improved treatment and earlier detection . However, breast cancer is still the leading cause of cancer-related deaths in European women. Breast cancer in males is rare, contributing ∼1% of cases. The major risk factors include clinical disorders carrying hormonal imbalances, radiation exposure and, in particular, a positive family history and genetic predisposition . diagnosis and pathology/molecular biology Eighteen European countries have established national or regional population-based mammography screening programmes with the purpose of detecting breast cancers at a pre-clinical stage, in order to improve the chance of survival . The European Guidelines for quality assurance in breast cancer screening and diagnosis recommend standards and describe performance parameters and indicators that should be monitored in any screening programme . Biannual mammography screening has been shown to have the greatest effect on breast cancer mortality reduction in the age group of 50–69 years and mammography screening in this age group is recommended by the European Union and numerous countries , while the effect in women aged 40–49 years is disputed . There is no consensus about the exact effect of mammography screening on breast cancer mortality reduction, and the estimates reported vary. In a recent UK review of the randomised, controlled mammography trials, a 20% relative breast cancer mortality reduction was estimated in women invited to screening in the age group of 50–70 years , although the review stresses the importance of taking into account the risk of overdiagnosis and overtreatment as well as false-positive screening when balancing the benefits and harms of screening. Additionally, screening programmes carry the risk of false-negative results and consequently a false feeling of security among patients and doctors. In women with familial breast cancer with or without proven BRCA mutations, annual screening with magnetic resonance imaging (MRI) of the breast in combination with mammography can detect the disease at a more favourable stage compared with mammography screening alone (70% lower risk to be diagnosed with breast cancer stage II or higher). It is not known, however, whether breast cancer mortality is lowered . The diagnosis of breast cancer is based on clinical examination in combination with imaging, and confirmed by pathological assessment (Table 1). Clinical examination includes bimanual palpation of the breasts and locoregional lymph nodes and assessment for distant metastases (bones, liver, lungs and neurological examination in the case of symptoms). Imaging includes bilateral mammography and ultrasound of the breast and regional lymph nodes. The added value of ultrasound is well proven. An MRI of the breast is not
[Show abstract][Hide abstract] ABSTRACT: Our understanding of the early natural history of epithelial ovarian carcinoma is limited by the access to early lesions as the disease is very often diagnosed at advanced stages. The incessant ovulation theory from the last century that indicated the ovary as the site for the initiation of high-grade serous cancers is contrary to the newly emerging idea that ovarian cancer could arise from the distal fallopian tube. In view of the recent pathological and molecular studies, we propose to discuss the genesis of high-grade serous ovarian cancer.
Critical reviews in oncology/hematology 03/2013; · 5.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The sentinel lymph node (SN) status is a crucial parameter in the therapeutic approach to breast cancer. However, there is no consensus established yet with regards to the method of SN assessment. The SN assessment ex tempore determines its status during a surgical procedure, thus allowing complete axillary dissection in case of SN positivity. That analysis is not performed systematically and can be done by cytological, histological (frozen sections) or molecular methods (qRT-PCR). The methods differ in sensitivity; qRT-PCR seems to be the most sensitive. The definitive SN status is also assessable by various approaches, immunohistochemistry (IHC) being the preferred one. However, the primacy of IHC is challenged by molecular biology methods.
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer is the most lethal of the gynaecological malignancies because this « silent killer » is almost always diagnosed at an advanced stage. Precursor lesions have at least been discovered. This review will describe in details specific features of tubal and ovarian preinvasive lesions and the old and novel techniques that could be used for early detection of ovarian cancer.
Journal de Gynécologie Obstétrique et Biologie de la Reproduction 11/2012; · 0.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with trisomy 21, still called Down's syndrome (DS), present a particular tumoral profile compared to the general population with an increased incidence of leukaemia in the childhood and a low risk of solid cancer in the adulthood. DS children indeed present a 50-fold risk of developing a leukaemia compared to age-matched non-trisomic children and most of them develop a specific myelodysplasic disorder called transient myeloproliferative disorder. In spite of the low incidence of solid tumors, some are very rare as breast cancer, nephroblastoma, neuroblastoma and medulloblastoma, whereas the others remain more frequent as retinoblastoma, lymphoma and gonadal and extragonadal germ cell tumours. In this review, we present possible mechanisms which can favour, or on the contrary repress the formation and progression of tumours in DS patients, which are related to gene effect dosage of oncogenes or tumour repressors on chromosome 21, tumour angiogenesis, apoptosis and epithelial cell-stroma interactions.
[Show abstract][Hide abstract] ABSTRACT: Background
The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial.Patients and methodsThe five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS).ResultsExpected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases.Conclusions
In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.
[Show abstract][Hide abstract] ABSTRACT: EUSOMA (The European Society of Breast Cancer Specialists) is committed to writing recommendations on different topics of breast cancer care which can be easily adopted and used by health professionals dedicated to the care of patients with breast cancer in their daily practice. In 2011, EUSOMA identified the management of young women with breast cancer as one of the hot topics for which a consensus among European experts was needed. Therefore, the society recently organised a workshop to define such recommendations. Thirteen experts from the different disciplines met for two days to discuss the topic. This international and multidisciplinary panel thoroughly reviewed the literature in order to prepare evidence-based recommendations. During the meeting, two working groups were set up to discuss in detail diagnosis and loco-regional and systemic treatments, including both group aspects of psychology and sexuality. The conclusions reached by the working groups were then discussed in a plenary session to reach panel consensus. Whenever possible, a measure of the level of evidence (LoE) from 1 (the highest) to 4 (the lowest) degree, based on the methodology proposed by the US Agency for Healthcare Research and Quality (AHRQ), was assigned to each recommendation. The present manuscript presents the recommendations of this consensus group for the management of young women with breast cancer in daily clinical practice.
European journal of cancer (Oxford, England: 1990) 10/2012; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab).Patients and methodsKRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.ResultsSixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation.Conclusion
Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers.ClinicalTrials.gov IdentifierNCT00655499.
[Show abstract][Hide abstract] ABSTRACT: Triple-negative breast cancer (TNBC) is a heterogeneous disease diagnosed by immunohistochemistry and is characterised by tumours that do not express estrogen receptor (ER) or progesterone receptor (PR) at all, and do not overexpress human epidermal growth factor receptor 2 (HER2). Prototypical TNBC is aggressive in nature and associated with a poor prognosis, making the accurate diagnosis of the disease vitally important for ensuring optimal therapy for patients. Morphological and biological analyses can identify subtypes of TNBC, which can have different prognoses, and (in the case of the latter) may eventually be used to predict response to treatment. This mini-review focuses on clinically relevant issues in the diagnosis of TNBC, including the importance of adherence to international guidelines for the detection of ER/PR/HER2 status, and the relationship between TNBC and the overlapping (yet distinct) intrinsic subtype of 'basal-like' breast cancer. In addition, we review the potential use of emerging biomarkers as surrogates for molecular subtypes and as a means of identifying potential responders to new therapies.
[Show abstract][Hide abstract] ABSTRACT: The initial report from the Programme Action Concertée Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the sequential administration of docetaxel after FEC100 (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)) for patients with node-positive, operable breast cancer. We evaluate here the impact of this regimen at 8 years.
Between June 1997 and March 2000, a total of 1,999 patients (age <65) with localized, resectable, non-pretreated, unilateral breast cancer were randomly assigned to receive either standard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2) docetaxel (FEC-D), both given every 21 days. Radiotherapy was mandatory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients. Five-year DFS was the trial's main endpoint. Updated 8-year survival data are presented.
With a median follow-up of 92.8 months, 639 patients experienced at least one event. A total number of 383 deaths were registered. Eight-year DFS rates were 65.8% with FEC alone and 70.2% with FEC-D. OS rates at 8 years were 78% with FEC alone and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse and a 25% reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive, HER2-positive, and Ki67 ≥20% subpopulations.
Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years.
The Oncologist 05/2012; 17(7):900-9. · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. Patients and methods Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. Results Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. Conclusion FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.
Annals of Oncology 03/2012; 23(10):2552-61. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients.
Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand-binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes.
Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ≈ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used.
This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples.
Clinical Cancer Research 03/2012; 18(5):1313-22. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics.
Breast (Edinburgh, Scotland) 02/2012; 21(1):20-6. · 2.09 Impact Factor