[Show abstract][Hide abstract] ABSTRACT: Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, stage II-III TNBC. Therapy consisted of weekly cetuximab (1(st) infusion: 400 mg/m(2) , then 250 mg/m(2) ) combined with 6 cycles of docetaxel (T: 100 mg/m(2) ) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy. This article is protected by copyright. All rights reserved.
Full-text · Article · Dec 2015 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
This work takes place in the "cartilage targeting strategy", consisting in using the quaternary ammonium (QA) function as a vector to proteoglycans (PGs) of extracellular matrix (ECM). The objective was to demonstrate that QA could address gadolinium based small rigid platforms (SRP) to PG-rich tumors. SRP were functionalized with QA, radiolabeled with (111)Indium and evaluated for biodistribution in vivo, respectively to non functionalized SRP, in two experimental models: (i) the HEMCSS human xenograft model; (ii) the Swarm rat chondrosarcoma (SRC) orthotopic model. The contribution of cellular uptake to tumoral accumulation of nano-objects was also determined from in vitro binding. In the SRC model expressing a highly and homogeneously distributed PG content, tumor accumulation and retention of SRP@QA were increased by 40% as compared to non-functionalized SRP. When considering the radiosensitizing potential of gadolinium based SRP, these results provide hopes for the radiobiological approach of highly resistant tumor such as chondrosarcoma.
From the clinical editor:
In this study, gadolinium-based complexing DOTA-surfaced small polysiloxane nanoparticles were functionalized with quaternary ammonium derivatives that target the extracellular matrix of chondrosarcoma. The authors demonstrate in a rat model that the use of these constructs results in a 40% increase of tumor accumulation and retention compared to non-functionalized (and otherwise same) platforms. Similar approaches would be welcome additions to the clinical armamentarium addressing chondrosarcoma.
No preview · Article · Jun 2014 · Nanomedicine Nanotechnology Biology and Medicine
[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.
Full-text · Article · May 2014 · Annals of Oncology
[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: Oncology research, and particularly breast pathology, is undergoing a revolution with the advent of molecular signatures. These tools are complementary to the classical clinicopathological parameters commonly used in routine. The intrinsic signature brings, via a new taxonomy of breast cancer, a fresh look at the tumor beyond the histopathological type, grade and classic parameters of the tumor burden. Other prognostic signatures are Mammaprint®, Oncotype Dx®, and MapQant Dx®. Some of these signatures are available for formalin-fixed paraffin-embedded tissues opening the door for an use in routine setting. However, pathological evaluation is still cornerstone for the optimal management of patients with breast cancer, with the back up of molecular signatures particularly for Hormone receptor positive, HER2 negative patients. Furthermore, true predictive signature are highly awaited.
[Show abstract][Hide abstract] ABSTRACT: Intraoperative imprint cytology (IC) is one of several accurate, proven methods to detect tumor cells in sentinel lymph nodes (SLN) from patients with operable breast cancer. In patients treated with neoadjuvant chemotherapy (NAC), studies have demonstrated the feasibility and accuracy of SLN biopsy procedure. We evaluated the validity of IC for SLN testing in patients after NAC.
Patients with infiltrating breast carcinoma receiving NAC (n = 132) were studied prospectively. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. SLN were evaluated using IC in 80 of 132 patients (60%). The results of IC in the adjuvant setting (100 patients) were used for comparison.
SLN metastases were correctly identified using IC in 58 of 80 (72%) patients. False negative results were observed in 21 patients. The sensitivity of IC testing was 38.2% and specificity 97.8%. The positive and negative predictive values (PPV and NPV) were 92.9% and 68.2%, respectively. In univariate analysis and multivariate logistic regression analysis, patients with micrometastases or isolated tumor cells in SLN have 2.3 times higher risk of a false negative IC result than patients with macrometastases in SLN (P = .00021; relative risk [RR] = 2.3; 95% confidence interval, 1.37-3.85). The non-NAC group, which contained fewer micrometastatic cases, showed better sensitivity (47.4%) and NPV (88.9%).
NAC does not seem to influence the accuracy and sensitivity of IC. Variations in sensitivity are related to the proportion of cases with micrometastases and ITC, as it was also shown in chemonaive patients.
No preview · Article · Feb 2010 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Sentinel lymph node (SLN) biopsy is the most used practice in breast cancer, in absence of clinical or radiological evidence of node metastasis for stage T0, T1 and T2 until 3cm tumours. About 20,000 patients each year could benefit from a SLN biopsy in France. Nevertheless, the mean rate of second surgical procedure is of 10 to 17%. Two techniques (OSNA® et GeneSearch™) are actually available in France. Their principle is based upon an intraoperative diagnosis of the presence or absence of metastasis in the SLN, using a rapid, quantitative, accurate molecular assay. The literature shows that those tests have the advantage of being more sensitive (frequently greater than 95%) than the classical techniques of frozen section diagnosis. The concordance with histopathological examination is high too (>90%). For some of the patients, these techniques avoid a second surgery, reduce the cost of the management and shorten the initiation of treatment. In the future, this approach could become a standard.
No preview · Article · Jan 2010 · Medecine Nucleaire
[Show abstract][Hide abstract] ABSTRACT: Ovarian epithelial dysplasia (OED) was first described after prophylactic oophorectomy for genetic risk of ovarian cancer. In light of Fathalla's incessant ovulation theory, this study was set up to describe the presence of ovarian abnormalities (dysplasia) after ovulation induction and to compare dysplasia profiles in stimulated and genetic risk ovaries.
One-hundred and twenty-four patients who had undergone salpingo-oophorectomies or ovarian cystectomies between 1990 and 2005 were reviewed. They were divided into three groups: (1) previous in vitro fertilisation (n=35); (2) prophylactic oophorectomies for genetic risk (n=27) and (3) fertile non-cancerous controls (n=62). Eleven cytological and architectural epithelial features were defined and a dysplasia score was calculated to quantify ovarian epithelial abnormalities.
Mean dysplasia score was significantly higher in the genetic risk and stimulated ovary groups than in controls (9.55 versus 3.62, p<0.0001; 7.51 versus 3.62, p<0.0002, respectively). Cytological and architectural abnormalities were more frequent in the genetic risk group, while the profile of abnormalities was different in the genetic risk and stimulated groups.
These findings support a possible relationship between OED and the use of ovulation-stimulating drugs. The increased dysplasia score in stimulated and genetic risk ovaries might be consistent with progression towards neoplastic transformation, and may justify the use of the term dysplasia or intraepithelial ovarian neoplasia. The observation of dysplasia in the stimulated group may differentiate women at risk. Conversely, the fact that the dysplasia profile after stimulation differs from that in genetic risk ovaries suggests that ovarian stimulation may predispose to a different evolution.
Full-text · Article · Oct 2009 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Le traitement conservateur est actuellement la référence dans la prise en charge des cancers du sein de stades I et II. L’obtention
de marges saines est un facteur primordial pour la diminution du taux de récidives locales. Elle ne fait l’objet d’aucun consensus
tant pour la technique d’évaluation des berges chirurgicales que pour la valeur seuil limite d’une marge d’exérèse de sécurité.
Diverses approches ont été évaluées dans la littérature, depuis la prise en charge macroscopique de la pièce à sa réception
par le pathologiste à l’emploi de méthodes cytologiques et histologiques d’évaluation des berges. De telles pratiques sont
évidemment à replacer dans un contexte radioclinique et doivent faire l’objet d’une collaboration étroite entre les différents
spécialistes. Les perspectives sont une amélioration de l’évaluation des limites et/ou des marges tumorales à l’aide de techniques
de médecine nucléaire, et/ou de biologie moléculaire afin de diminuer le nombre de reprises chirurgicales.
Conservative surgery is the actual gold standard for the management of low-stages (i.e. I and II) breast cancers. The completion
of clearmargins isaprerequisite for a complete local treatment and a decrease of local recurrences. Atight collaboration between
pathologists and surgeons is mandatory. There is no consensus for the definition of the cut of a clear margin. Different management
processes have been reported through the literature, ranging fromgrossmanagement to cytologic or histopathologic methods for
margin evaluation. Such approaches have to be correlated to the clinical and radiological setting. They have to be performed
in line with tumor characteristics, and treatment plans. The perspectives are a better evaluation of surgical margins using
nuclear medicine or molecular biology tools to decrease the number of second surgical procedures.