Emmanuelle Fourme

Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue for Refractory and Recurrent Primary CNS and Intraocular Lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire

PURPOSE The prognosis of relapsing primary CNS lymphoma (PCNSL) is poor. We report the results of a prospective multicenter trial of intensive chemotherapy followed by autologous hematopoietic stem-cell rescue (IC + HCR) in immunocompetent adult patients with PCNSL or intraocular lymphoma (IOL) after failure of high-dose methotrexate-based treatment. PATIENTS AND METHODS Salvage treatment consisted of two cycles of high-dose cytarabine and etoposide (CYVE). Intensive chemotherapy combined thiotepa, busulfan, and cyclophosphamide. Forty-three patients (median age, 52 years; range, 23 to 65 years) were included, with relapse (n = 22), refractory disease (n = 17), or a partial response to first-line treatment (n = 4). The response to CYVE was not assessable in three cases because of treatment-related death. Twenty patients (47%) were chemosensitive to CYVE: 15 of them proceeded to IC + HCR. IC + HCR was also administered to 12 patients who did not respond to CYVE. All but one of the 27 patients who underwent IC + HCR entered complete remission. RESULTS With a median follow-up of 36 months, the median overall survival was 18.3 months in the overall population, and 58.6 months among patients who completed IC + HCR. The respective median progression-free survival (PFS) times after IC + HCR were 11.6 and 41.1 months. The 2-year overall survival probability was 45% in the whole population and 69% among the 27 patients who received IC + HCR. The 2-year PFS probability was 43% among all the patients and 58% in the IC + HCR subpopulation. CONCLUSION IC + HCR is an effective treatment for refractory and recurrent PCNSL.

PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups

IntroductionPIK3CA is the oncogene showing the highest frequency of gain-of-function mutations in breast cancer, but the prognostic value of PIK3CA mutation status is controversial.MethodsWe investigated the prognostic significance of PIK3CA mutation status in a series of 452 patients with unilateral invasive primary breast cancer and known long-term outcome (median follow-up 10 years).ResultsPIK3CA mutations were identified in 151 tumors (33.4%). The frequency of PIK3CA mutations differed markedly according to hormone receptor (estrogen receptor alpha [ERα] and progesterone receptor [PR]) and ERBB2 status, ranging from 12.5% in the triple-negative subgroup (ER-/PR-/ERBB2-) to 41.1% in the HR+/ERBB2- subgroup. PIK3CA mutation was associated with significantly longer metastasis-free survival in the overall population (P = 0.0056), and especially in the PR-positive and ERBB2-positive subgroups. In Cox multivariate regression analysis, the prognostic significance of PIK3CA mutation status persisted only in the ERBB2-positive subgroup.ConclusionsThis study confirms the high prevalence of PIK3CA mutations in breast cancer. PIK3CA mutation is an emerging tumor marker which might become used in treatment-choosing process. The independent prognostic value of PIK3CA mutation status in ERBB2-positive breast cancer patients should be now confirmed in larger series of patients included in randomized prospective ERBB2-based clinical trials.

High and typical 18F-FDG bowel uptake in patients treated with metformin

PurposeThis prospective and bi-centric study was conducted in order to determine the impact of antidiabetic treatments (AD) on 18F-FDG bowel uptake in type 2 diabetic patients.MethodsFifty-five patients with previously diagnosed and treated type 2 diabetes mellitus (group 1) were divided in two subgroups: AD treatment including metformin (n=32; group 1a) and AD treatment excluding metformin (n=23; group 1b). The 95 patients without diabetes mellitus made up controls (group 2). 18F-FDG uptake in small intestine and colon was visually graded and semi-quantitatively measured using the maximum standardized uptake value.Results18F-FDG bowel uptake was significantly increased in AD patients (group 1) as compared to controls (group 2) (p<0.001). Bowel uptake was significantly higher in AD patients including metformin (group 1a) as compared to AD patients excluding metformin (group 1b) (p<0.01), whose bowel uptake was not significantly different from controls (group 2). A metformin treatment was predictive of an increased bowel uptake in the small intestine (odds ratio OR=16.9, p<0.0001) and in the colon (OR=95.3, p<0.0001), independently of the other factors considered in the multivariate analysis. Bowel uptake pattern in the patients treated with metformin was typically intense, diffuse and continuous along the bowel, strongly predominant in the colon, in both the digestive wall and lumen.ConclusionThis study emphasizes that metformin significantly increases 18F-FDG uptake in colon and, to a lesser extent, in small intestine. It raises the question of stopping metformin treatment before an 18F-FDG PET/CT scan is performed for intra-abdominal neoplasic lesion assessment.

18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging in the staging and prognosis of inflammatory breast cancer

To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC).

CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study

Introduction CDH1 predisposes primarily to diffuse gastric cancer (DGC). Multiple DGC cases in a family, DGC at a young age in an individual or the combination of DGC andlobular breast cancer (LBC) in an individual or a family define the hereditary DGC syndrome (HDGC), and testing for germline CDH1 mutations is warranted in HDGC. Methods and results We report all index cases from Ile-de-France in which a germline CDH1 mutation has been identified. Out of 18 cases, 7 do not fulfil the HDGC-defining criteria. Three of them are women who presented initially with bilateral LBC below age 50, without personal or family history of DGC, and who subsequently developed symptomatic DGC. Discussion Our series of CDH1 mutation carriers is the largest to date and demonstrates that LBC might be the first manifestation of HDGC. A personal or family history of multiple LBCs at a young age, even without DGC, should prompt CDH1 mutation screening. It is paramount to identify mutation carriers early, so that they can benefit from prophylactic gastrectomy before they develop symptomatic, highly lethal DGC. We recommend a revision of the HDGC-defining criteria and propose for consideration the name ‘Hereditary Diffuse Gastric and Lobular Breast Cancer’ instead of HDGC.

Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases

Background Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25-40%. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem cell rescue. We report the results of a large multicenter retrospective analysis of intensive chemotherapy followed by hematopoietic stem cell rescue in immunocompetent adult patients with primary central nervous system lymphoma or intraocular lymphoma after the failure of high-dose methotrexate-based treatment. Design and Methods Patients were included if they received intensive chemotherapy with a combination of thiotepa, busulfan and cyclophosphamide. Seventy-nine patients (median age 52.4 years, range 23-67 years) were identified. All of the patients except 5 received a salvage treatment after the failure of high-dose methotrexate. After salvage treatment and just before intensive chemotherapy followed by hematopoietic stem cell rescue, 32 patients were in complete response, 26 patients were in partial response, 2 patients had stable disease and 19 patients had progressive disease. Results With a median follow up of 56 months, the 5-year overall survival probability was 51% in the whole population and 62% among patients who were chemosensitive to the salvage treatment. The 5-year event-free survival probability was 37.8% in the whole population and 43.7% in the chemosensitive subpopulation. Neurocognitive assessments in a subset of patients suggest no evidence of intensive chemotherapy-induced neurocognitive decline. Conclusions Thiotepa, busulfan and cyclophosphamide-based intensive chemotherapy is an effective treatment for refractory and recurrent primary central nervous system lymphoma in chemosensitive patients up to 65 years of age. The role of intensive chemotherapy followed by hematopoietic stem cell rescue in chemorefractory patients needs to be more accurately defined.

DNA Repair Gene Expression and Risk of Locoregional Relapse in Breast Cancer Patients

PURPOSE Radiation therapy appears to kill cells mainly by inducing DNA double-strand breaks. We investigated whether the DNA repair gene expression status might influence the risk of locoregional recurrence (LRR) in breast cancer patients. METHODS AND MATERIALS We used a quantitative reverse transcriptase PCR-based approach to measure messenger RNA levels of 20 selected DNA repair genes in tumor samples from 97 breast cancer patients enrolled in a phase III trial (Centre René Huguenin cohort). Normalized mRNA levels were tested for an association with LRR-free survival (LRR-FS) and overall survival (OS). The findings were validated in comparison with those of an independent cohort (Netherlands Cancer Institute (NKI) cohort). Multivariate analysis encompassing known prognostic factors was used to assess the association between DNA repair gene expression and patient outcome. RESULTS RAD51 was the only gene associated with LRR in both cohorts. With a median follow-up of 126 months in the CRH cohort, the 5-year LRR-FS and OS rates were 100% and 95% in the 61 patients with low RAD51 expression, compared with 70% and 69% in the 36 patients with high RAD51 expression, respectively (p < 0.001). RAD51 overexpression was associated with a higher risk of LRR (hazard ratio [HR], 12.83; 95% confidence interval [CI], 3.6-45.6) and death (HR, 4.10; 95% CI, 1.7-9.7). RAD51 overexpression was also significantly associated with shorter LRR-FS and OS in the NKI cohort. CONCLUSIONS Overexpression of RAD51, a key component of the homologous DNA repair pathway, is associated with poor breast cancer outcome. This finding warrants prospective studies of RAD51 as a prognosticator and therapeutic target.

18F-FDG PET/CT to Predict Response to Neoadjuvant Chemotherapy and Prognosis in Inflammatory Breast Cancer

The aim of this prospective study was to assess the predictive value of 18F-FDG PET/CT imaging for pathologic response to neoadjuvant chemotherapy (NACT) and outcome in inflammatory breast cancer (IBC) patients. Methods: Twenty-three consecutive patients (51 y ± 12.7) with newly diagnosed IBC, assessed by PET/CT at baseline (PET1), after the third course of NACT (PET2), and before surgery (PET3), were included. The patients were divided into 2 groups according to pathologic response as assessed by the Sataloff classification: pathologic complete response for complete responders (stage TA and NA or NB) and non–pathologic complete response for noncomplete responders (not stage A for tumor or not stage NA or NB for lymph nodes). In addition to maximum standardized uptake value (SUVmax) measurements, a global breast metabolic tumor volume (MTV) was delineated using a semiautomatic segmentation method. Changes in SUVmax and MTV between PET1 and PET2 (ΔSUV1–2; ΔMTV1–2) and PET1 and PET3 (ΔSUV1–3; ΔMTV1–3) were measured. Results: Mean SUVmax on PET1, PET2, and PET3 did not statistically differ between the 2 pathologic response groups. On receiver-operating-characteristic analysis, a 72% cutoff for ΔSUV1–3 provided the best performance to predict residual disease, with sensitivity, specificity, and accuracy of 61%, 80%, and 65%, respectively. On univariate analysis, the 72% cutoff for ΔSUV1–3 was the best predictor of distant metastasis-free survival (P = 0.05). On multivariate analysis, the 72% cutoff for ΔSUV1–3 was an independent predictor of distant metastasis-free survival (P = 0.01). Conclusion: Our results emphasize the good predictive value of change in SUVmax between baseline and before surgery to assess pathologic response and survival in IBC patients undergoing NACT.

Cigarette smoking in women after BRCA1/2 genetic test disclosure: a 5-year follow-up study of the GENEPSO PS cohort

Purpose:This study aimed to measure patients’ smoking patterns for 5 years after BRCA1/2 test result disclosure.Methods:A national cohort consisting of 621 French cancer-free women from families with BRCA1/2 mutations (mean age (SD): 40.5 years (11.5 years)) were included from December 1999 to January 2006, before disclosure of genetic test results, and followed for 5 years. They completed self-administered questionnaires about their cigarette smoking behaviors before receiving their test results (baseline) and 6, 12, 24, and 60 months after disclosure. Multivariate statistical analyses of the changes in participants’ smoking behaviors were performed using a zero-inflated Poisson mixed model.Results:Baseline smoking was found to depend on age, educational level, marital status, alcohol consumption, body mass index, and cancer risk perception. The zero-inflated part of the model showed the occurrence of no significant changes in the percentage of smokers during the 5 years after disclosure of the BRCA1/2 test results; however, daily smoking among BRCA1/2 carriers decreased significantly compared with that of noncarriers (adjusted hazard ratio = 0.83; (95% confidence interval: 0.69–0.99); P = 0.04) after adjusting for baseline smoking behavior.Conclusion:It would be worth investigating the possibility of counseling women during the genetic testing process about the multiple risk factors involved in cancer, such as genetic and lifestyle factors.Genet Med 17 2, 117–124.

Doxorubin-based adjuvant chemotherapy for elderly patients with hormone receptors negative breast carcinoma: a French geriatric oncology group (GERICO) phase II multicentric program

 SARCOME 07 – (Communication Orale) : A FNCLCC French SARCOMA Group : GETO multicenter randomized phase II study of Gemcitabine (G) versus Gemcitabine and Docetaxel (G+D) in patients with metastatic or relapsed leimyosarcoma (LMS). F. Duffaud, B. Bui, N. Penel, A. Cioffi, N. Isambert, J.Y. Blay, D. Cupissol, M. Jimenez, A. Rey, P. Pautier ; La Timone University Hospital, Marseille, France ; Institut Bergonié, Bordeaux, France ; Centre Oscar Lambret, Lille, France ; Institut Gustave Roussy, Villejuif, France ; Centre Georges-François Leclerc, Dijon, France ; Hôpital Edouard Herriot, Lyon, France ; Centre Val d’Aurelle, Montpellier, France ; FNCLCC, Paris, France.