Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer.

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 (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six 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.

Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact.

BACKGROUND: 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. PATIENTS AND METHODS: Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. 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. RESULTS: Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out 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. CONCLUSIONS: 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 a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC. CLINICAL TRIAL NUMBER: NCT00933517.

Intraoperative imprint cytology examination of sentinel lymph nodes after neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

Ovarian epithelial dysplasia after ovulation induction: time and dose effects.

BACKGROUND: Ovarian epithelial dysplasia was first described after prophylactic oophorectomies for genetic risk. Ovarian stimulation has been considered as a risk factor of ovarian cancer by Fathalla's incessant ovulation theory. In this study, we have investigated the risk of ovarian dysplasia after ovulation induction. METHODS: We reviewed 99 oophorectomies or cystectomies between 1990 and 2005 divided them into two groups: previous in vitro fertilization (n = 37) and a panel of fertile controls (n = 62). Eleven epithelial cytological and architectural features were defined and an ovarian epithelial dysplasia score was calculated to quantify the degree of ovarian epithelial abnormalities. RESULTS: All the ovaries were macroscopically non-cancerous except in two patients (one endometrioid cancer and one borderline tumour). The mean ovarian dysplasia score was significantly higher in the ovulation induction group than in the control group (7.64 versus 3.62, P = 0.0002). We also found a relationship between the number of ovulation-inducted cycles and the severity of ovarian dysplasia ('dose-effect') and a relationship between time after the end of ovulation induction (over 7 years) and the severity of ovarian dysplasia ('time-effect'). CONCLUSIONS: There is probably a relationship between ovarian epithelial dysplasia and either ovulation inducing drugs or infertility. By Fathalla's incessant ovulation theory, 'the dose effect and the time effect' of ovarian stimulation may explain ovarian dysplasia formation.

[Ovarian epithelial dysplasia: myth or reality? Review]. / Dysplasie épithéliale ovarienne: mythe ou réalité? Revue de la littérature.

Ovarian epithelial dysplasia has been described in the ovarian surface epithelium by histologic, morphometric and nuclear profile studies. It could represent a potential precursor of ovarian malignancy in patients with genetic risk of ovarian cancer, although its natural history and progression to carcinoma are unpredictable. Diagnosis and identification of ovarian dysplasia would certainly be useful to understand the early steps of ovarian carcinogenesis. However, dysplasia in relation with ovulation induction seems to have a different pattern. We report dysplasia definitions and the current clinical management.

Correlation between molecular metastases in sentinel lymph nodes of breast cancer patients and St Gallen risk category.

AIMS: To evaluate the clinical significance of tumour metastases detected using real-time reverse transcription-PCR (RT-PCR) in sentinel lymph nodes (SLN) of breast cancer patients. METHODS: Sixty-seven patients with T1-T2 primary breast cancer were included in a prospective study. SLN were analysed for the presence of metastatic tumour cells using standard histopathology staining, immunochemistry (IHC) and multimarker real-time RT-PCR assay for mammaglobin (MMG), carcinoembryonic antigen (CEA) and cytokeratin-19 (CK19) mRNA expression. Correlations between molecular metastases and traditional clinicopathological prognostic factors, including St Gallen risk categories were studied. RESULTS: Of the 67 patients, 15 (22.3%) had one or more pathology-positive SLN. Five (9.6%) pathology-negative SLN were positive by IHC and 19 (36.5%) by RT-PCR. Of note, RT-PCR analysis was also positive in all cases with pathology- or IHC-positive SLN. MMG was the most informative tumour marker in the panel. Molecularly detected metastases were significantly associated with intermediate St Gallen risk category (p=0.023). CONCLUSION: Molecular staging of SLN using real-time RT-PCR for early breast cancer could serve as a useful complement to standard clinicopathological risk factors. Studies with long-term follow-up are necessary to define the impact of molecular metastases on disease free survival and overall survival.

[Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis: role of gadolinium?]. / Dermopathie néphrogénique fibrosante traitée par photochimiothérapie extracorporelle: rôle du gadolinium?

BACKGROUND: Nephrogenic fibrosing dermopathy is a cutaneous and systemic sclerosis affecting patients with renal failure. CASE-REPORT: A 68-year-old man with renal insufficiency and on dialysis developed hardening of the skin and severe joint contractions. He had previously undergone angiography with gadolinium-containing contrast agents. A skin biopsy confirmed nephrogenic fibrosing dermopathy. The patient was treated by oral steroids followed by extracorporeal photopheresis. An improvement was seen after 12 cycles. DISCUSSION: Treatment of nephrogenic systemic fibrosis is not codified and is normally based on the methods used for other forms of systemic sclerosis. Six cases of patients showing improvement under extracorporeal photopheresis have been published. The physiopathology of the disease is unknown. Gadolinium could act as a triggering agent by attracting circulating fibrocytes in the dermis of patients. Medical authorities recommend avoidance of gadolinium in patients with advanced kidney failure unless strictly necessary.

[Anatomoclinical study of ovarian cancers in patients with history of hysterectomy for benign pathology]. / Étude anatomoclinique des cancers de l'ovaire chez les patientes aux antécédents d'hystérectomie pour pathologie bénigne.

OBJECTIVE: To establish the various anatomoclinical characteristics of ovarian cancer in patients with a history of hysterectomy for benign disease. METHODS: This is a comparative, retrospective, monocentric and descriptive study, carried out at the Centre of Jean-Perrin in patients with ovarian cancer between 2005 and 2014 and with a history of hysterectomy for benign disease. Each patient was paired with a non-hysterectomy patient with ovarian cancer. The two populations were matched 1 to 5, based on their age at diagnosis and their FIGO stage. RESULTS: During the period of the study, 249 patients were operated for de novo ovarian neoplasia, 43 patients had a history of hysterectomy (group 1) and 206 remaining patients represented the control group (group 2). There was no difference in overall survival and disease-free survival between the two subpopulations of patients (P=0.59 and P=0.38). On CT-scan assessment, the lymph node involvement risk was greater than 2.6 in the group of patients with hysterectomy (P=0.00038). Peritoneal Cancer Index scores of the two subgroups of populations were comparable, there were an average of 13.65 for group 1 versus 12.31 for group 2 (P=0.28). The rate of rectosigmoid resection was higher in group 1: 48.6% versus 32.9% in group 2 without any significant difference (P=0.07). Hundred and thirty-three patients undergone lumbar aortic lymphadenectomy, with node involvement found in 83% of patients in the hysterectomy group and 51% of patients in the control group (P=0.0053). CONCLUSION: Indication of lumbar aortic lymphadenectomy should be taken in better consideration in patients with history of inter-adnexial hysterectomy. These data must be thoroughly assessed with a prospective multicenter comparative study.

[Evaluation of stereotactic core biopsies of the breast with the 10-gauge Vacora® biopsy device: a review of 541 procedures]. / Évaluation des macrobiopsies mammaires stéréotaxiques par système Vacora® 10-gauge (541 procédures).

PURPOSE: To evaluate stereotactic core biopsies of the breast with the 10-gauge Vacora(®) biopsy device. PATIENTS AND METHODS: Retrospective study of 541 procedures in 502 patients performed between 2007 and 2009. RESULTS: The procedure failed in 2% of cases, non-complicated hematomas occurred in 5% of cases and unsightly scars in two cases. A clip was deployed in 70% of cases, successfully in 99% of cases. The procedure was well tolerated in 88% of cases. Core biopsies confirmed a benign lesion in 55% of cases, borderline lesions in 19% of cases and malignant lesions in 26% of cases with complementary surgery performed in 40% of cases. For surgical lesions, sensitivity, specificity, PPV and NPV were 89%, 100%, 100% and 84% respectively. Atypical ductal dysplasia was under-estimated in 8% of cases while DCIS was under-estimated in 14% of cases. After review of the mammograms, 3% of Bi-Rads 4 lesions were reclassified as Bi-Rads 3 lesions, all benign at core biopsy. Half of these results were from screening mammography programs. CONCLUSION: Results with the 10-gauge Vacora(®) biopsy device are similar to reports from the literature, mainly using the Mammotome system, with regards to tolerability and reliability for a lesser cost.

[Case report of a 2-year-old child with palpebral rhabdomyosarcoma]. / Rhabdomyosarcome palpébral chez un enfant âgé de deux ans.

Rhabdomyosarcoma is an extremely virulent rare tumor whose early diagnosis considerably improves survival and visual prognosis. We report the case of a 2-year-old child with levator palpebrae superioris muscle rhabdomyosarcoma revealed by a sudden and isolated blepharoptosis. Initially, clinical and imaging investigations did not show any abnormality but a painful tumor with some hematoma quickly developed, so the investigations were repeated. The CT-scan showed an extra-conal tumor that had developed at the superior part of the orbit. Histology confirmed the diagnosis of embryonic rhabdomyosarcoma. Because of its results, treatment consisting of chemotherapy associating ifosfamide, vincristine, actinomycin and orbital radiotherapy of 40 Gy with a local addition of 10 Gy were administrated with successful results after a 3-year-follow-up.

[Intraoperative determination of axillary node metastasis by RT-PCR]. / Utilisation d'une méthode PCR en temps réel pour l'étude des ganglions sentinelles dans les carcinomes mammaires : expérience des centres anticancéreux de Lille et de Clermont-Ferrand.

UNLABELLED: The intraoperative determination of axillary node micrometastasis according to the Rapid GeneSearch Breast Lymph Node (BLN) is based on RT-PCR (mRNA of mammaglobine and CK19) detects metastases > 0.2 mm. PATIENTS AND METHODS: Eighty-three pts between November 2007 and June 2008 were included (33 from Centre Jean-Perrin and 50 from Centre Oscar-Lambret). Lymph nodes were cut in 2 mm slices, and 1 out of 2 was examined with BLN; the others were examined by imprints then histological exam with immunohistochemistry. RESULTS: Forteen pts had micro- or macrometastasis. Seven were positive with intraoperative imprints including six macrometastasis and one micrometastasis; seven were positive with BLN and seven at histological exam with two cases of discordance. Sensitivity was 92%, specificity 98%. Positive predictive value 92%, and negative predictive value 98%. The median time for intraoperative determination was 40 minutes for 2 SLN. DISCUSSION: Half each lymph node is study by each method. This explains the discordances observed. Limit of BLN is the absence of CTI detection; however there is no consensus about the necessity of axillary clearance in such a case. CONCLUSION: In this series BLN reduces axillary clearance and improves comfort patients.

Comparison of dysplasia profiles in stimulated ovaries and in those with a genetic risk for ovarian cancer.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.