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Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Background Neoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population. Methods This was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early “metabolic responders” (mR) when the decrease of SUVmax was higher than 40%, and “metabolic non-responders” (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS). Results Tumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10− 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease. Conclusions FDG-PET/CT imaging could become a “surrogate marker” to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC.

Background Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). Methods This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. Results In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)). Conclusions Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

Purpose For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we explored the role of dual time point [18F]FLT-PET for discriminating benign from malignant tissues. Methods Before any treatment, 85 womens with de novo unifocal breast cancer underwent three PET acquisitions at 33.94 ± 8.01 min (PET30), 61.45 ± 8.30 min (PET60), and 81.06 ± 12.12 min (PET80) after [18F]FLT injection. Semiquantitative analyses of [18F]FLT uptake (SUV) were carried out on tumors, liver, bone marrow (4th thoracic vertebra (T4) and humeral head), descending thoracic aorta, muscle (deltoid), and contralateral normal breast. Repeated measures ANOVA tests and Tukey’s posttests were used to compare SUVmax of each site at the three time points. Results There was a significant increase in SUVmax over time for breast lesions (5.58 ± 3.80; 5.97 ± 4.56; 6.19 ± 4.42; p < 0.0001) (m ± SD for PET30, PET60, and PET80, respectively), and bone marrow (for T4, 8.21 ± 3.17, 9.64 ± 3.66, 10.85 ± 3.63, p < 0.0001; for humeral head, 3.36 ± 1.79, 3.87 ± 1.89, 4.39 ± 2.00, p < 0.0001). A significant decrease in SUVmax over time was observed for liver (6.79 ± 2.03; 6.24 ± 1.99; 5.57 ± 1.74; p < 0.0001), muscle (0.95 ± 0.28; 0.93 ± 0.29; 0.86 ± 0.20; p < 0.027), and aorta (1.18 ± 0.34; 1.01 ± 0.32; 0.97 ± 0.30; p < 0.0001). No significant difference was observed for SUVmax in contralateral breast (0.8364 ± 0.40; 0.78 ± 0.38; 0.80 ± 0.35). Conclusion [18F]FLT-SUVmax increased between 30 and 80 min only in proliferating tissues. This could be helpful for discriminating between residual tumor and scar tissue.

Purpose For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we explored the role of dual time point [18F]FLT-PET for discriminating benign from malignant tissues. Methods Before any treatment, 85 womens with de novo unifocal breast cancer underwent three PET acquisitions at 33.94 ± 8.01 min (PET30), 61.45 ± 8.30 min (PET60), and 81.06 ± 12.12 min (PET80) after [18F]FLT injection. Semiquantitative analyses of [18F]FLT uptake (SUV) were carried out on tumors, liver, bone marrow (4th thoracic vertebra (T4) and humeral head), descending thoracic aorta, muscle (deltoid), and contralateral normal breast. Repeated measures ANOVA tests and Tukey’s posttests were used to compare SUVmax of each site at the three time points. Results There was a significant increase in SUVmax over time for breast lesions (5.58 ± 3.80; 5.97 ± 4.56; 6.19 ± 4.42; p < 0.0001) (m ± SD for PET30, PET60, and PET80, respectively), and bone marrow (for T4, 8.21 ± 3.17, 9.64 ± 3.66, 10.85 ± 3.63, p < 0.0001; for humeral head, 3.36 ± 1.79, 3.87 ± 1.89, 4.39 ± 2.00, p < 0.0001). A significant decrease in SUVmax over time was observed for liver (6.79 ± 2.03; 6.24 ± 1.99; 5.57 ± 1.74; p < 0.0001), muscle (0.95 ± 0.28; 0.93 ± 0.29; 0.86 ± 0.20; p < 0.027), and aorta (1.18 ± 0.34; 1.01 ± 0.32; 0.97 ± 0.30; p < 0.0001). No significant difference was observed for SUVmax in contralateral breast (0.8364 ± 0.40; 0.78 ± 0.38; 0.80 ± 0.35). Conclusion [18F]FLT-SUVmax increased between 30 and 80 min only in proliferating tissues. This could be helpful for discriminating between residual tumor and scar tissue.

In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France.

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.

Metastatic breast cancer (MBC) is the leading non hematologic cause of leptomeningeal metastases (LM), associated with a poor prognosis. Amongst breast cancer (BC) subtypes, HER2+ tumors present a high LM incidence. Intravenous (IV) trastuzumab (T) has improved survival of MBC patients but better control of central nervous system (CNS) disease is needed. The main physiopathological hypothesis for intracranial recurrences is the low level of T in cerebrospinal fluid (CSF) due to his high molecular weight (148kD). Intraventricular (via Ommaya port) or intrathecal (IT) T administration would permit LM progression control through high therapeutic T concentrations in the CSF. This prospective trial, sponsored by Institut Curie, was the first Phase I-II study to investigate the safety and efficacy of IT T administration for HER2+ LM in BC. The final results of the Phase I cohort are reported herein. Methods: LM diagnosis was based on either CSF with HER2+ cytology or clinical/MRI imagings of meningitis. Adequate organs functions for all patients were required. The T IT (or via Ommaya port) injections were given on weekly basis during 8 weeks. We used a Fibonacci dose escalation design, 4 dose levels (DL) (30-150mg). The objectives of this phase I were to investigate the maximum tolerated dose (MTD) and the recommend dose (DR) of T. A pharmacokinetic (PK) data analysis was performed. We targeted a concentration in the CSF close to the residual serum concentration (30µg/mL) achieved with standard IV schedule. Results: Starting May 2011, 19 patients were included, with 16 evaluable for toxicity (three had not received the treatment) treated in 4 DL (30-150mg). Twelve patients were evaluable for PK and 210 samples T concentrations available (103 in the LCR and 107 in the serum). The MTD was not reached and the treatment appears to have been well tolerated by the patients. Neither Grade ≥3 toxicity nor neurological toxicity related to IT T was observed. The T target-concentration in the CSF was reached at DL4 and the recommended T dose for the Phase II trial is 150 mg. Five patients have experimented a evident clinical benefit and received more than 8 weekly injections with an average of 23 [12-40]. Extended data on clinical outcome and PK will be presented. Conclusion: Intraventricular or IT injections appears to be safe at the dose of 150 mg and possibly effective. The Phase II study will investigate the efficacy of the recommended dose on neurological progression-free survival at 2 months in 19 patients. This trial was performed with Roche funding. Citation Format: Maya Gutierrez, Emmanuelle Mouret Fourme, Emilie Le Rhun, Olivier Tredan, Veronique Dieras, Patricia Tresca, Fawzia Mefti, Isabelle Turbiez, Sophie Taillibert, Céline Desvignes, Gilles Paintaud. Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-17.

Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

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.

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.

Tumor hypoxia is a hallmark of malignant tumors, and is a major factor in the resistance to anti-cancer therapies, particularly radiotherapy. Indeed, tumor blood flow often fluctuates, and thus the oxygen supply is often reduced, thereby inducing tumor hypoxia. We decided to explore whether post-occlusive reactive hyperemia, a physiological reaction known to occur in normal tissues, could be induced through a malignant tumor, basal cell carcinoma (BCC), in which angiogenesis occurs, as in all malignant tumors. Skin blood flow was measured in twelve patients with BCC, using Laser Speckle Contrast Imaging to determine BCC perfusion after three minutes of vascular occlusion, induced by limb tourniquet for limb tumors (4 BCC), and/or by clamping the pedicle of a skin flap with the BCC at its center, for other tumor locations (12 BCC). We demonstrated for the first time that post-occlusive reactive hyperemia occurs in malignant tumors in humans. BCC perfusion curves were similar to those of healthy skin, characterized by a peak of hyperemia after reperfusion followed by a progressive return to the pre-occlusion perfusion level. Induction of post-occlusive reactive hyperemia in malignant tumors is therefore a novel investigational approach that could lead to a new adjuvant tool to increase the efficacy of chemotherapy and radiotherapy, respectively through the synchronized temporary increase of tumor perfusion and oxygenation.

BACKGROUND: To prospectively assess fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging and prognosis value in patients with suspected inflammatory breast cancer (IBC). METHODS: Sixty-two women (mean age 50.7 ± 11.4 years) presenting with unilateral inflammatory breast tumors (59 invasive carcinomas; 3 mastitis) underwent a PET/CT scan before biopsy. RESULTS: PET/CT scan was positive for the primary malignant tumor in 100% and false positive in 2 of 3 benign mastitis. In 59 IBC patients, FDG nodal foci were detected in axillary (90%; n = 53) and extra-axillary areas (56%; n = 33) ipsilateral to the cancer. Compared with clinical examination, the axillary lymph node status by PET/CT was upstaged and downstaged in 35 and 5 patients, respectively. In 7 of 9 N0 patients, the axillary lymph node positivity on PET/CT was correct, as revealed by pathological postsurgery assessment (not available in the 2 remaining patients). The nodal foci were compared with preoperative fine needle aspiration and/or pathological postchemotherapy findings available in 44 patients and corresponded to 38 true positive, 4 false-negative, and 2 false-positive cases. In 18 of 59 IBC patients (31%), distant lesions were found. On the basis of a univariate analysis of the first enrolled patients (n = 42), among 28 patients who showed intense tumoral uptake (standard uptake valuemax>5), the 11 patients with distant lesions had a worse prognosis than the 17 patients without distant lesions (P = .04). CONCLUSIONS: FDG-PET/CT imaging provides additional invaluable information regarding nodal status or distant metastases in IBC patients and should be considered in the initial staging. It seems also that some prognostic information can be derived from FDG uptake characteristics. Cancer 2009. © 2009 American Cancer Society.

Objectives. The aim of this prospective study was to evaluate the impact of integrated PET-CT on treatment management in ovarian carcinoma recurrence suspicion because of increased CA-125. Methods. Twenty-nine patients (mean age=61 years), initially treated for ovarian carcinoma (FIGO stage I n =2, stage II n =3, stage III n =21 and stage IV n =3), presenting with increased CA-125 (mean=160 IU/ml, range 33–1930), underwent subsequently a CT and a PET-CT scans. The recurrence was acknowledged by the referring physicians for all patients. The impact of PET-CT on patient's management was evaluated by comparing the therapeutic decision mentioned respectively on the pre and post PET-CT questionnaires filled in by the oncologists. Results. The CT scan was positive in 22/29 patients (76%) and negative in 7/29 patients (24%). The PET-CT scan was positive in 27/29 patients (93%) and negative in 2/29 (7%) patients. Five out of the seven patients with a negative CT scan had a positive PET-CT scan. In comparison to CT scan alone, the PET-CT scan modified the disease distribution for 16 patients (55%; p n =11), more limited disease ( n =4), and different localizations ( n =1). The assessment of pre and post PET-CT questionnaires showed a statistically significant change in the decision making for 10 patients (34%, p Conclusion. This questionnaire-based study showed that PET-CT imaging allows a better restaging than CT and induces a change in clinical management in over one third of patients with suspected ovarian carcinoma recurrence on increased CA-125.

Resume Les lesions frontieres dont l’incidence croit avec l’extension du depistage organise, constituent cette frange de la pathologie situee entre les lesions strictement benignes et malignes et dont les limites apparaissent souvent floues. Elles regroupent differentes entites, neoplasie lobulaire, hyperplasie canalaire atypique a laquelle se sont ajoutees les lesions cylindriques atypiques. Leur definition est basee sur le risque relatif de developper ulterieurement un cancer du sein. Elles soulevent de multiples problemes. D’abord, leur identification diagnostique necessite de la part du pathologiste une technique histologique parfaite tant pour les biopsies guidees par imagerie que pour les resections chirurgicales. L’application stricte des criteres microscopiques doit assurer une reproductibilite satisfaisante. Ensuite, leur prise en charge doit etre fonction du type de prelevement, provenant d’une biopsie guidee par imagerie conduisant generalement a une exerese complete de la lesion et le prelevement provenant d’une resection chirurgicale. Enfin, la recherche s’applique a mieux definir les limites de chaque entite, a en preciser le plus precisement le niveau de risque pour adapter au mieux la prise en charge et a terme, trouver de nouvelles lesions selon le type de cancer et de patiente.

RESUME L’allongement de la duree moyenne de la vie (esperance de vie) contribue a l’augmentation de l’incidence et de la polyvalence des cancers. La poursuite de leur depistage aux âges avances de la vie doit pourtant prendre en consideration des objections de differentes natures : la prise en compte de la qualite de vie, le progres des traitements curatifs, le cout en terme de Sante publique de plus en plus eleve du depistage, au fur et a mesure qu’il s’adresse a des sujets plus âges, sans oublier la judiciarisation dans l’exercice de la medecine. Ainsi se pose la question du depistage des cancers au-dela de l’âge generalement requis pour en faire l’objet. Le medecin generaliste ou specialiste est de plus en plus souvent confronte a un dilemme : negliger un cancer debutant ou surmedicaliser inutilement une personne plus ou moins fragile. Une solution ne peut etre proposee qu’en tenant compte de l’esperance de vie et des desirs de chaque patient auquel les avantages et les inconvenients de chaque attitude devront etre soigneusement exposes. Seuls seront abordes ici les problemes du depistage de cancers, du sein, du colon-rectum et de la prostate.

In France, women carrying BRCA1/2 mutation, at an identified high risk of breast cancer are recommended to undergo breast MRI screening. That screening does not however prevent the risk of developing a breast cancer. The only alternative to breast cancer screening available in France is surgical prevention by prophylactic mastectomy. An interesting option for women who wish to reduce their breast cancer risk, but are unready for prophylactic mastectomy is a preventive hormonal treatment by aromatase inhibitors, or selective estrogens receptor modulators (SERMs). Reliable clinical trials show the efficiency of tamoxifen, raloxifen, exemestane, and anastrozole especially, in reducing breast cancer incidence by 33%, 34%, 65% and 53% respectively. This article tries to sum up the main published trials of breast cancer prevention with hormonal treatment, and presents the latest American and English clinical guidelines concerning hormonal prevention for women at high risk of breast cancer, and starts thinking about the possibilities of hormonoprevention, especially among women carrying a BRCA1/2 mutation in France.

International audience; 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.

Malgre une incidence croissante du cancer du sein dans la population âgee, les donnees specifiques prospectives concernant sa prise en charge apres 70 ans, tout particulierement pour les indications de chimiotherapie adjuvante, sont rares dans la litterature, genant l’application de recommandations standards etablies essentiellement chez les sujets plus jeunes. La plupart des donnees derivent d’essais multicentriques ayant etendu l’âge limite superieur d’inclusion a 65 ou 70 ans. Un seul essai multicentrique, francais, a specifiquement abordele role d’une chimiotherapie adjuvante a base d’anthracyclines ajoutee au tamoxifene chez le sujet de plus de 65 ans. Pourtant plusieurs revues retrospectives de groupes cooperateurs internationaux semblent demontrer lemâme beneefice potentiel d’une chimiotherapie adjuvante chez les sujets âges que chez les sujets plus jeunes, sous reserve d’une vigilance accrue a l’egard des effets secondaires. Avec l’aide ajustee d’echelles specifiques geriatriques, les cliniciens doivent apprendre a integrer benefice absolu, esperance de vie et tolerance, trois volets essentiels pour abandonner la discrimination ancienne reposant sur l’âge, inadaptee a l’evolution de nos moyens et pratiques.

e12592 Background: During last decade, therapeutic arsenal has expanded for metastatic breast cancer (mBC), but few data are available about mTNBC, a poor prognosis subtype. In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data. This base represents a great opportunity to update the outcomes and the treatment practice patterns of this population. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All pts who initiated treatment for mBC between 01-Jan-2008 and 31-Dec-2014 were selected. The primary objective of this study was to assess overall survival (OS) of mTNBC pts. TNBC status was defined as ER and PR < 10% in both primary and metastatic disease, as well as the absence of overexpression or amplification of HER2. The secondary objectives were to describe the characteristics of this population, clinical management (duration and sequence of treatments) and to evaluate the prognostic value of several clinical factors (age, distant disease free interval, location and number of metastatic sites) Results: Among 16703 pts in the ESME-mBC database, 2368 (14%) had mTNBC. Median OS over this time period was 14.8 months (95% CI 14-15.6). Median age at diagnosis of mBC was 57 years. For the pts who relapsed, median metastasis free interval was 24 months, while 25.5% of the pts were de novo metastatic. 61% of the pts presented visceral metastasis and 12% had cerebral metastasis as first metastatic site. The pattern of metastatic involvement (visceral and cerebral) and a short metastasis free interval ( < 24 months) were the most important prognostic factors in multivariate analysis. The description of treatment sequences (duration, prognostic value) will be presented. Conclusions: In this real-life setting database, mTNBC remain of poor prognosis despite a trend for a better OS than the historical data available (12-13 ms). This TNBC ESME cohort is one of the largest available and offers an updated assessment of the outcomes of this population.

Background: Neaodjuvant endocrine therapy (NET) has demonstrated efficacy in terms of clinical response and outcome in hormone-receptor positive (HR+) post-menopausal patients (pts) with breast cancer (BC) not eligible for primary breast conservative surgery (BCS). However, the monitoring of tumor response to NET is challenging and clinical response is the current gold standard. The aim of the present study was to investigate the contribution of the early metabolic response (eMR) at one month in FDG-PET/CT in a NET setting for post-menopausal pts with HR+, HER2- BC compared to morphological and pathological responses. We also aimed to evaluate the prognostic value of eMR. Methods: This was a prospective and ancillary study of CARMINA 02, UCBG0609 (Cancer in press), a phase II clinical trial evaluating the efficacy of 4 to 6 months neoadjuvant anastrozole or fulvestrant. FDG-PET/CT exams were performed at baseline (M0), after 1 month of treatment (M1: eMR) and pre-Op (late metabolic response: lMR) in 11 pts (74.2 years ± 3.6) from 2007 to 2010. Pts were classified “metabolic responders” (mR) if SUVmax values decrease was ≥ 40% at M1 and “non-metabolic responders” (mNR) if otherwise; lMR was also assessed in mR and mNR groups defined at M1. We compared eMR to morphological response (clinical, breast US and MRI) at M1 and pre-op, to the pathological response according to Sataloff classification and to Ki67 score variation during treatment. Early metabolic response was also correlated with the PEPI (Preoperative Endocrine Prognostic Index) score and survival (overall survival, OS and relapse free survival, RFS). Results: Main results are summarized in Table I. There was a significant difference between mR and mNR pts at M1 (eMR) and pre-op (lMR). One patient with a complete metabolic response at pre-op had the best pathological response (Sataloff TB). Also, mR pts had a better clinical response: 2 partial response (PR) in mR vs 1 in mNR group and 2 mNR patients were classified PD (progressive disease). There was a trend toward better survival for mR pts in OS and RFS (Kaplan-Meier p=0.18 and 0.06, respectively) and all the pejorative events occurred in the mNR group: 3 deaths and 3 metastatic progressions. Besides, no difference in eMR was observed regarding the histological subtype (ductal or lobular; p>0.05) nor the treatment group (p>0.05). Table I: Metabolic, morphological and pathological response at M1, Pre-Op and on the surgical specimen. MR : 5ptsmNR : 6ptsP valueM1SUVmax2.6±1.13.9±1.40.00017 Clinical size42.5mm±11.951.7mm±7.50.19 US size22.6mm±6.334.2mm±2.40.02 MRI size21.2mm±4.239.7mm±4.79.16 E-5 Ki 673.6%±1.98.2%±80.19Pre-OpSUVmax2±1.33.3±1.40.018 Clinical size31mm±12.448.3mm±10.80.035 US size18.5mm±7.331.3mm±9.50.07 MRI size17.9mm±7.134.8mm±7.70.003Surgical SpecimenSataloff (TA+TB vs TC+TD)20% vs 80%0 vs 100%1 PEPI score (I+II vs III)80% vs 20%33 vs 67%0.048 Ki 678.6%±9.812.3%±7.90.41 Conclusions: These preliminary results showed the value of the early metabolic response in FDG- PET/CT in a NET setting compared to the morphological or the pathological responses alone. Early metabolic responders patients had better OS, RFS and PEPI scores. Citation Format: Boughdad S, Champion L, Becette V, Cherel P, Fourme E, Edeline V, Lemonnier J, Lerebours F, Alberini JL. Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-03.

Febrile neutropenia (FN) is one of the most common and most critical adverse effects of chemotherapy. Despite many existing guidelines based on the use of granulocyte-colony stimulating factor (G-CSF), FN continues to impair the quality of life and interfere with the treatment of many patients. The purpose of this study was to assess the incidence and management of FN associated with chemotherapy for early breast cancer in routine clinical practice. All patients with early-stage breast cancer (ESBC) treated by chemotherapy at Institut Curie, Hopital Rene Huguenin, in 2014 were retrospectively included. The incidence and management of FN were reported. Risk factors associated with FN were studied by robust-error-variance Poisson regression. A total of 524 patients received either neoadjuvant (N = 130) or adjuvant chemotherapy (N = 394). Most patients (80%) were treated with a combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100; 3 cycles) followed by docetaxel 100 mg/m2 (D; 3 cycles). The overall incidence of FN was 17%. Eighteen percent of patients received primary prophylaxis (PP) for FN with G-CSF, using pegfilgrastim in 64% of cases and 74% of patients over the age of 70 received PP. Less than 5% of patients who received PP experienced FN. Recurrent FN after secondary prophylaxis was observed in 9% of patients. Forty-seven percent of cases of FN occurred after the first cycle and 30% occurred after the fourth cycle, corresponding to D ± trastuzumab (T). The FEC100 regimen was associated with a relative risk of FN of 1.98 (p = 0.09). Autoimmune (AI) and inflammatory diseases were associated with a higher risk of FN (RR 3.08; p

Gene amplification is one of the characteristics of cancer cells. In vitro studies suggested that alterations of the TP53 gene might be responsible for gene amplification. We have examined the presence of TP53 mutations and looked for cytogenetic evidence of gene amplification in a series of 79 primary colorectal carcinomas. Other parameters such as the pattern of cytogenetic alterations, microsatellite instability, tumor site, and histological staging were also considered. A multiparametric study supported by statistical analyses suggests the existence of two major pathways of colorectal carcinogenesis. No relationships could be established between the presence of TP53 alterations and gene amplification.

The aim of this study was to evaluate the efficacy and toxicity of two chemotherapy regimens based on platinum and cytarabine in association with etoposide and methylprednisolone (ESHAP) or with dexamethasone (DHAP) with or without Rituximab (± R) in patients with refractory or a relapsed Primary Central Nervous System Lymphoma (PCNSL). All consecutive patients from two French centers with refractory or relapsed PCNSL treated with ESHAP/DHAP ± R were included. We analyzed the overall response rate (ORR), toxicity and overall survival (OS) after salvage chemotherapy. Intensive chemotherapy and hematopoietic stem cell rescue (IC + HCR) was offered to patients less than 65 years of age and consisted of high-dose thiotepa, busulfan and cyclophosphamide. These results were compared with two previously reported series of PCNSL patients treated with the CYVE (high-dose cytarabine and etoposide) regimen at relapse. Twenty-two patients received a total of 60 DHAP/ESHAP cycles (median 3; range 1–5). The median age was 59 years. The ORR after salvage chemotherapy was 59%. Toxicity was mainly hematological, 18% of patients showing febrile neutropenia. There was no treatment-related death. ESHAP or DHAP regimens led to similar ORRs compared to the CYVE regimen in relapsed or refractory PCNSL, although they seemed less toxic. The therapeutic results of the ESHAP/DHAP regimens in relapsed or refractory PCNSL were also similar to those for relapsed systemic non-Hodgkin’s lymphomas (sNHL). Both chemotherapies, CYVE regimen and ESHAP/DHAP are treatment options to be considered in relapsed or refractory PCNSL, especially when IC + HCR is planned as a consolidation treatment. More efforts are still needed to improve the ORR at relapse.

Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy.In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete.Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred.This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment.

The utility of screening for occult malignancies in very elderly people is controversial. Indeed, the following factors must be taken into account: increasing life expectancy, better efficacy and tolerability of cancer therapies, the cost of screening, and medico-legal issues. The dilemma is between missing a curable cancer and over-diagnosing and over-treating a vulnerable patient. Proper patient information is clearly needed The informed patient's own preference is crucially important. This paper focuses on the most frequent malignancies that can be detected by screening, namely breast, colorectal and prostate cancer.

This prospective and bi-centric study was conducted in order to determine the impact of antidiabetic treatments (AD) on (18)F-FDG bowel uptake in type 2 diabetic patients.Fifty-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). (18)F-FDG uptake in small intestine and colon was visually graded and semi-quantitatively measured using the maximum standardized uptake value.(18)F-FDG bowel uptake was significantly increased in AD patients (group 1) as compared to controls (group 2) (p0.001). Bowel uptake was significantly higher in AD patients including metformin (group 1a) as compared to AD patients excluding metformin (group 1b) (p0.01), 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, p0.0001) and in the colon (OR=95.3, p0.0001), 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.This study emphasizes that metformin significantly increases (18)F-FDG uptake in colon and, to a lesser extent, in small intestine. It raises the question of stopping metformin treatment before an (18)F-FDG PET/CT scan is performed for intra-abdominal neoplasic lesion assessment.

National audience; Following the report in 1999 of a cluster of cancers in children attending a school built on an old factory site, epidemiologic and environmental studies initially ruled out a possible link between these cancers and the attendance of the school. In May 2001, the notification of new cases generated a state of crisis. A Scientific Committee (SC) gathering 16 national experts was brought together. The purpose of this article is to analyze its work, the difficulties encountered in particular in its relations with the parties involved and the lessons learnt. The SC's missions were to examine the questions raised by the population, to analyze the results of investigations that got under way and to propose and carry out the necessary studies. In 3 years, the SC carried out important work of expertise on many epidemiologic and environmental studies. The hiatus existing first of all between social expectations and the scientific approach, the communication gap with the stakeholders and the lack of resources constituted the principal difficulties encountered by the SC. However, as time went by, a positive interaction was established between the SC and the stakeholders, in particular with the population. The SC recommends, in such situations, to bring into play a joined up mechanism of expertise and decision, light and reactive, integrating all the stakeholders as soon as possible.; Suite au signalement en 1999 d'un regroupement de cancers chez des enfants fréquentant une école bâtie sur un ancien site industriel, les études épidémiologiques et environnementales écartent dans un premier temps un lien possible entre ces cancers et la fréquentation de l'école. En mai 2001, le signalement de nouveaux cas génère une situation de crise. Un Comité scientifique (CS) regroupant 16 experts est réuni. L'objectif de cet article est d'analyser son travail, les difficultés rencontrées notamment dans ses relations avec les parties prenantes et les enseignements tirés. Les missions du CS étaient d'examiner les questions de la population, d'analyser les résultats des investigations engagées et de proposer et suivre les études nécessaires. En trois ans, le CS a effectué un travail conséquent d'expertise de nombreuses études épidémiologiques et environnementales. Le hiatus existant initialement entre les attentes sociales et la démarche scientifique proposée, le déficit de communication avec les parties prenantes, le manque de moyens constituèrent les principales difficultés rencontrées par le CS. Cependant, au fil du temps, une interaction positive s'est établie entre le CS et les parties prenantes, la population notamment. Le CS recommande, dans de telles situations, de mettre en oeuvre des dispositifs articulés d'expertise et de décision, légers et réactifs, intégrant dès que possible toutes les parties prenantes.

Objectifs Etudier la valeur de la reponse metabolique precoce apres un mois (M1) d’hormonotherapie neoadjuvante chez des patientes (pts) menopausees presentant un cancer du sein localement avance exprimant des recepteurs hormonaux. Analyser la valeur pronostique de la reponse metabolique precoce sur les parametres de survie (survie globale OS et survie sans metastases a distance DFMS). Patients et methodes Il s’agissait d’une etude prospective ancillaire de l’essai clinique CARMINA 02 comparant l’efficacite de l’anastrozole et du fulvestrant en neoadjuvant pendant 4 a 6 mois. Les pts etaient considerees comme « repondeuses metaboliques » precoces (mR) en cas de diminution du SUVmax de la tumeur mammaire ≥ 40 % a M1 ou « non-repondeuses metaboliques » (mNR) sinon. La reponse metabolique preoperatoire a egalement ete evaluee. La reponse metabolique precoce a ete comparee aux reponses morphologiques (clinique et IRM), histologique selon le score de Sataloff, a l’evolution de l’expression du Ki 67, mais aussi a l’OS et a la DFMS. Resultats Cinq pts sur 11 (74,2 ans ± 3,6) etaient mR a M1 (−57,5 % ± 11,9 mR vs −16,7 % ± 10,2 mNR ; p = 0,00017), avec une reponse metabolique preoperatoire persistante (−63,6 % ± 25,6 mR vs −30 % ± 16,1 mNR ; p = 0,018). Il existait une diminution de la taille tumorale clinique (26,2 % ± 14,1 mR vs −8,3 % ± 26,4 mNR ; p = 0,21) et IRM (−33,6 % ± 22,36 mR vs −18 % ± 21,2 mNR ; p = 0,27) plus importante mais non significative en preoperatoire dans le groupe mR. La seule patiente en reponse metabolique complete preoperatoire a presente la meilleure reponse histologique (Sataloff TB). L’expression du Ki 67 etait plus faible a M1 chez les pts mR, bien que non significative (3,6 % ± 1,9 mR vs 8,2 % ± 8 mNR ; p = 0,25). Meme si aucune difference de survie n’a pu etre mise en evidence pour l’OS ( p = 0,32) et la DFMS ( p = 0,2) entre les deux groupes, un deces lie a la progression et 2 progressions metastatiques ont eu lieu dans le groupe mNR. Conclusion Ces resultats preliminaires montrent l’interet de la reponse metabolique precoce a l’hormonotherapie neoadjuvante par rapport a la reponse morphologique et peut-etre un meilleur pronostic des patientes mR.

The " Standards, Options and Recommendations " (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives : To update the Standards, Options and Recommendations clinical practice guidelines for the management of ductal carcinoma in situ of the breast (DCIS). Methods : The working group identified the questions requiring up-dating from the previous guideline. Medline(r) and Embase(r) were searched using specific search strategies from year 1996 to year 2003. In addition several Internet sites were searched in October 2002. Results : Clinical guidelines have been defined for the management of diagnosis, treatment, follow-up, and treatment of recurrence of DCIS. The issue of hormone replacement therapy has also been addressed in the context of DCIS.

This study investigated the multidrug resistance, proliferation and apoptosis expression in renal cell carcinomas compared to adjacent normal kidney (ANK) tissues. Multidrug resistance (MDR1), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Topoisomerase-II alpha (TOPO-IIalpha), thymidylate synthase (TS), thymidine kinase (TK), Ki67, BAX and BCL-2 genes were analysed in a series of 30 renal cell carcinomas (RCC) and 16 biopsies from adjacent normal kidney (ANK) tissue using reverse-transcription-PCR (rt-PCR). The mean MDR1 expression was significantly lower in RCC than that of ANK (0.4 +/- 0.2 sd versus 0.75 +/- 0.19, p = 0.0008). The expression of MRP, GST-pi and TOPO-IIalpha was not significantly different in RCC as compared with ANK. The mean TK expression in RCC was significantly higher than in ANK (0.31 +/- 0.15 versus 0.09 +/- 0.08, p = 0.002). The TS and Ki67 expression in RCC was significantly higher than in ANK (87.5%, IC95% 71-100% versus 0%, p = 0.001; 56% IC95% 32-81% versus 0%, p = 0.004, respectively). BAX and BCL-2 expression in RCC was significantly higher than that of ANK (0.51 +/- 0.08 versus 0.18 +/- 0.12, p = 0.0001; 0.73 +/- 0.16 versus 0.5 +/- 0.22, p = 0.01, respectively). No significant correlation was found between MDR1, MRP, GST-pi, TOPO-IIalpha, TS, TK and BAX expression with the grade and the clinical stage in RCC.

BACKGROUND Initial debulking surgery followed by chemotherapy is the current treatment for International Federation of Gynecology and Obstetrics Stage IIIC/IV ovarian carcinoma but has a limited efficacy when optimal cytoreduction is not achieved at the end of the surgical procedure. An alternative treatment for these patients could be neoadjuvant chemotherapy. The purpose of this retrospective study was to report the results of neoadjuvant chemotherapy in operable patients (no medical contraindication to surgery) presenting with primary unresectable tumors. METHODS Between January 1996 and March 1999, operable patients presenting with Stage IIIC or IV ovarian carcinoma underwent, in six French gynecologic oncology departments, surgical staging to evaluate tumor resectability. When the tumor was deemed unresectable by standard surgery, the patient received three to six cycles of platinum-based neoadjuvant chemotherapy according to the response and the center's usual protocol. Patients were surgically explored after completion of neoadjuvant chemotherapy when the tumor did not progress during treatment. Debulking was performed during this secondary surgery when a response to chemotherapy was observed. RESULTS Fifty-four patients were treated by neoadjuvant chemotherapy. The first surgical staging procedure was laparoscopy in 33 patients (61%) and laparotomy in 21 patients (39%). The median number of neoadjuvant chemotherapy cycles was 4 (range, 0–6). Forty-three patients (80%) responded to neoadjuvant chemotherapy and then tumors were debulked. Optimal cytoreduction was obtained in 39 patients (91% of the patients who underwent debulking) and with standard surgery in 32 patients (82%). For patients whose tumors were optimally debulked, blood transfusions were administered to 17 patients (43%), median intensive care unit stay was 0 days (range, 0–7 days), and median postoperative hospital stay was 10 days (range, 4–62 days). Median overall survival for the total series was 22 months. Survival was better for patients debulked after neoadjuvant chemotherapy compared with patients with nondebulked tumors (P < 0.001). CONCLUSIONS Neoadjuvant chemotherapy for primary unresectable ovarian carcinoma leads to the selection of a subset of patients sensitive to chemotherapy in whom optimal cytoreduction can be achieved after chemotherapy by standard surgery in a high proportion of cases. Conversely, aggressive surgery can be avoided in patients with initial chemoresistance, in whom the prognosis is known to be poor regardless of treatment. Cancer 2001;91:2329–34. © 2001 American Cancer Society.

TPS662 Background: Leptomeningeal metastases (LM) are commonly associated with breast cancer (BC), announcing short term prognosis that intrathecal (IT) chemotherapy poorly modifies. Incidence is particularly marked in HER2+ tumours. With the better control of extra-cerebral disease and prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main hypothesis is that intra-cerebral recurrences are not reached by this high molecular weight (148 kD) monoclonal antibody. Analyses performed in cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting that LM of HER2+ BC would remain potentially sensitive to anti-HER2 agents as long as they could by-pass the meningeal blood brain barrier. Intraventricular (via Ommaya port) or IT administration of T would allow keeping control on LM progression through high T therapeutic concentrations in CSF. This prospective trial is the first phase I-II study sponsored by Institut Curie to investigate the safety and efficacy of the IT administration of T for HER2+ LM BC. Methods: Eligible patients must be 18+, have a diagnosis of LM either on CSF with HER2+ cytology or on clinical/MRI pictures of meningitis, and normal end-organ functions. The phase I cohort investigates the maximum tolerated dose (MTD) and recommended dose of T given weekly IT (or via Ommaya port) + hemisuccinate hydrocortisone 25 mg, while aiming at yielding a T target-concentration in CSF close to the plasma one (30 µg/mL) obtained with standard IV schedule. The MTD is defined as the highest dose level (DL) tested with ≥2 dose-limiting toxicity (DLT, any grade ≥3 NCI CTCAE v4.0 attributed to T) observed in ≤6 patients (3+3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a maximum of 24 patients. The phase II cohort will investigate the efficacy of the recommended dose (DLMTD-1) defined in cohort I on neurological progression-free survival at 2 months, in ≤19 patients. Secondary endpoints include CSF and MRI response, quality of life, FCGR3A influence, and comparative CSF/plasma pharmacokinetics. Since study activation in May 2011, 5 patients have been included at DL1, 3 being evaluable for DLT. DL2 is now open for accrual.

Abstract #4101 Background Taxanes have been approved in the adjuvant setting for the treatment of node positive (pN+) breast cancer (BC) patients (pts), given either sequentially or in combination with anthracyclines. Controversies remain regarding their role in high-risk node negative (pN0) disease. Methods In 1999, we initiated a randomised phase III trial comparing 4 cycles of adjuvant doxorubicin + docetaxel (AT, 50/75/mg/m²) with 4 cycles of standard doxorubicin + cyclophosphamide (AC, 60/600/mg/m²) in a mixed population of high-risk pN0 and limited pN+ (≤3) early BC pts. Chemotherapy was delivered postoperatively q3w without prophylactic G-CSF, followed by radiation therapy according to standard guidelines and endocrine treatment for 5 years in pts with ER±PgR-positive tumours. This trial was closed prematurely for toxicity in 2003 and we have reported the safety data (JAMA 293:2367, 2005). We now report on time to recurrence (TTR, primary endpoint defined as locoregional relapse, controlateral BC or distant metastasis, which ever occurs first) as well as the effect of treatment by stratification factors [pN and Ki67 (90%). Multivariate analysis including all prognostic covariates will be performed and presented at the meeting. Given the high risk of life-threatening complications already reported, AT is not manageable without preventive strategies (e.g. G-CSF) and cannot be considered as a standard combination for intermediate risk early BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4101.

10513 Background: To determine overall survival and independent prognostic factors for patients with brain metastases from breast carcinoma treated with whole brain radiation therapy (WBRT). Methods: From January 1998 through December 2003, 132 patients with brain metastases (BM) from breast carcinoma were treated with WBRT (median dose: 3000 cGy/ 10 fractions). We analyzed a number of potential predictors of survival after WBRT: age, presence of other systemic metastases, performance status, RTOG recursive partition analysis (RPA) class (1–2 vs 3), total dose of WBRT, number of brain metastases, interval between primary tumor and brain metastases, SBR score, tumor receptor hormonal (RH) status, lymphocyte count (< 700 vs ≥ 700 G/L), serum lactate dehydrogenase and HER-2 overexpression. The survival time with BM was defined as the time from the date of BM to the date of death or date of last of follow-up. Multivariate analysis was used to determine the effect of prognostic factors on overall survival using the Cox proportional hazard model. Results: One hundred and seventeen patients received exclusive WBRT. Surgery was followed by WBRT in 14 patients and stereotactic radiosurgery was followed by WBRT in 1. The median survival with BM was 6 months (range: 0–52). The 1-year and 2-years survival rates were 31% (CI95%: 23.5–39.8) and 16% (CI95%: 9.8–24.9). In multivariate analysis, RTOG RPA class III, lymphopenia ( No significant financial relationships to disclose.

ContextAdjuvant chemotherapy with new cytotoxic agents for breast cancer must be properly assessed for toxicity.ObjectiveTo describe adverse events associated with adjuvant chemotherapy for breast cancer, which led to premature termination of a clinical trial.Design, Setting, and PatientsWe conducted a prospective randomized multicenter study (Reposant sur des Arguments Pronostiques et Predictifs [RAPP]-01) to compare the effectiveness of 2 chemotherapy regimens. Patients (women aged 18-70 years) had primary unilateral breast cancer and either a moderate number of positive axillary lymph nodes (≤3) or no positive axillary lymph nodes (N0), but were at a high risk of relapse. Patients were treated at 11 French cancer referral centers from June 1999 through January 2003. Primary prophylaxis for febrile neutropenia was not recommended in the study protocol.InterventionsDoxorubicin, 50 mg/m2, plus docetaxel, 75 mg/m2, or doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, given postoperatively for 4 courses.Main Outcome MeasuresThe main end point was the disease-free survival rate at 5 years, as estimated using the Kaplan-Meier product limit method. Secondary end points included safety, which is the focus of this article, and overall survival.ResultsA total of 627 women were enrolled. Median follow-up is currently too short (24 months) to analyze the primary end point. The trial was terminated prematurely when 2 deaths related to drug toxicity and 1 case of perforative peritonitis occurred among patients with febrile neutropenia, all in the doxorubicin-docetaxel group. The incidence of febrile neutropenia was significantly higher with the doxorubicin-docetaxel regimen (40.8%) than with the doxorubicin-cyclophosphamide regimen (7.1%) (P