A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

[Follow-up of patients treated for localized invasive breast carcinoma]. / Surveillance après traitement des cancers du sein localisés invasifs.

The follow-up of patients treated for invasive breast carcinoma remains a major challenge because of breast cancer prevalence and the frequent patient's preferences for a regular follow-up. Concerning this last point, there is a lack of studies about the consequences of a systematic follow-up. Few decades ago, regular and systematic follow-up was considered as a dogma. In 1994, it was seriously questioned by two randomised Italian trials: they did not find any benefit in terms of survival and quality of life in patients who had a regular search of asymptomatic metastasis. Follow-up strategy after early breast cancer is still an unexplored field, despite higher performance of investigation tests and development of new treatments strategies that allowed a significant decrease of recurrences and increase of cancer care. Currently, the international guidelines deeply recommend a regular physical examination and mammography. But a systematic search for non-symptomatic metastases is unnecessary. We now need a coordination between practitioners to avoid useless tests, and to respond to patients' will.

[Role of MRI in the presurgical work-up of breast cancer: appropriate utilization of MRI as a complement to mammography and ultrasound]. / Place de l'IRM dans le bilan préchirurgical du cancer du sein: pour une utilisation raisonnée de cet examen complémentaire du bilan mammo-échographique.

The role of MRI for presurgical local staging of breast cancers amenable to conservative treatment has been the subject of multiple publications and tends to become a "validated" indication in routine practice. The purpose of the paper is to review the advantages and limitations of this imaging modality that is part of a comprehensive management that must be validated by clinical data especially with regards to local recurrence and survival. Knowledge of these elements combined with more precise indications should result in improved patient management while avoiding overtreatment or unnecessary anxiety-producing examinations.

Evaluation of the pharmacological benefit and determination of the influencing factors of intraarterial cis-diamminedichloroplatinum administration in patients with uterine cervical cancer.

cis-Diamminedichloroplatinum (100 mg/m2) was administered to the same patients (n = 9) with advanced uterine cervical tumors, via i.v. and intraarterial (i.a.) (bilateral hypogastric arteries) routes. Measurement of plasma pharmacokinetic parameters enabled us to show up areas under the curve (AUC) of free cis-diamminedichloroplatinum versus time significantly (P less than 0.01) lower after i.a. injection (mean value, 3.9 mg.h/liter) than after i.v. injection (mean value, 5 mg.h/liter). However, the increase in intratumoral concentrations after i.a. administration was only at the limit of statistical significance (P = 0.05). Consequently, the benefit of local i.a. administration, evaluated according to the method of Collins, was small (1.2-2.3). An explanation of the phenomena observed can be given using the generalized compartmental model of Collins. We have demonstrated that the parameters of this model can be entirely calculated by taking into account both the i.v. and i.a. pharmacokinetic measurements. Calculations from experimental data of the model parameters, clearances of the body (ClB), and exchange rate between the site of administration and the rest of the body (Q) were in accordance with the physiological values. On the basis of the parameter values, it was confirmed that the low benefit of i.a. administration was due to the fast blood exchange between the injection site and the rest of the body and the probable cis-diamminedichloroplatinum binding on healthy tissues irrigated by the hypogastric artery.

Tamoxifen adjuvant treatment duration in early breast cancer: initial results of a randomized study comparing short-term treatment with long-term treatment. Fédération Nationale des Centres de Lutte Contre le Cancer Breast Group.

PURPOSE: In 1986, The Fédération Nationale desCentres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with life long adjuvant tamoxifen treatment. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group. RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P: =.001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor-positive patients (P: =.03) as well as in estrogen receptor-negative patients (P: =.05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers. CONCLUSION: Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.

Results of a European Organization for Research and Treatment of Cancer/Early Clinical Studies Group phase II trial of first-line irinotecan in patients with advanced or recurrent squamous cell carcinoma of the cervix.

PURPOSE: To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma. PATIENTS AND METHODS: Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m(2) every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A (>/= one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field). RESULTS: Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events. CONCLUSION: Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer.

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

Absence of germline mutations of exons 5 to 8 of the P53 gene in 26 breast cancer families from the north of France.

We looked for germline mutations of exons 5 to 8 of the P53 gene in 27 female patients from 26 families originating from the north of France who had breast cancer and at least one first degree relative also affected with breast cancer. Detection of the mutations was made by single strand conformation polymorphism analysis. No mutation was found in any patient, confirming that germline mutations of the P53 gene are very rare in familial breast cancer (apart from Li Fraumeni families).

Plasma insulin-like growth factor-1 (IGF-1) concentrations in human breast cancer.

Insulin-like growth factor-1 (IGF-1) is capable of stimulating breast cancer cell growth in vitro and the presence of IGF-1 receptors has been demonstrated in primary breast cancers. We determined plasma IGF-1 in a primary breast cancer population and in a control population. Radioimmunoassays were performed either directly on plasma, IGF-1 (NE), or after an acid-ethanol extraction of the plasma, IGF-1 (E). We demonstrated an inverse correlation between age and IGF-1: for this reason, only results obtained in females of the same age range (> 35 years) were compared. Median concentrations of IGF-1 were significantly higher in primary breast cancers [IGF-1 (E) = 152 ng/ml, IGF-1 (NE) = 26 ng/ml, n = 44] than in controls [IGF-1 (E) = 115 ng/ml, IGF-1 (NE) = 20 ng/ml, n = 92]. To our knowledge such a growth factor increase has never been described in breast cancer. We conclude that IGF-1 could be an important factor involved in the development of breast cancer and that treatment reducing IGF-1 levels could be beneficial for patients.

Cancer genetic clinics: why do women who already have cancer attend?

Cancer patients attend oncogenetic clinics so that the existence of a genetic risk can be checked and the relatives informed. The aim of this study was to describe the expectations of cancer patients about genetic counselling and their beliefs about the aetiology of their disease. A survey based on self-administered questionnaires before and after the consultation was carried out on 115 women with breast/ovarian cancer who attended one of the six French participating clinics. In 59 cases (51%), the consultees' expectations focused on the preventive options available and in 86 cases (75%) on their offspring; 87 (76%) found the consultation informative. On average, the women rated heredity and diet as lower risk factors (P < 0.05) after the consultation than before. Heredity, stress and the environment were thought to be more decisive than diet, smoking and alcohol. 34 patients who seemed unlikely to have a genetic risk in the consultant's opinion thought heredity to be less relevant (P < 0.05) after the consultation than before. At the time of the survey, cancer patients accounted for at least half of the consultees attending oncogenetic clinics in France. They need to have the clinical specificities of their disease and its medical management explained. They attend mainly for their offspring's sake, whereas healthy clients attend for their own sake.

Cancer genetics clinics: target population and consultees' expectations.

The aim of this study was to determine in healthy consultees attending cancer genetics clinics their risk status, their pathways leading to the clinics, their expectations and perception of cancer risk. In 1994, the consultees at six French centres completed a questionnaire before their first oncogenetic consultation. The oncogeneticists subsequently filled in a standardised form giving their risk assessment. Among the 206 healthy consultees, 91.3% were women, 92.2% had at least one cancer-affected first-degree relative and 73% had a "cancer family risk" as assessed by the oncogeneticist. Sixty-nine per cent of the consultees were referred to the clinics by a physician, 10.4% by their family and 18.8% on their own initiative: 83.5% of the sample perceived their family risk of cancer as being high and this belief was confirmed in 74.3% of the cases studied by the oncogeneticist. The families of self-referred consultees were less often at risk than those of consultees referred by a physician or by their family (P = 0.012). The majority (78%) expected to be informed about cancer prevention and screening, and this expectation depended on the consultee's level of education (P = 0.001). This study shows that medical pathways are more effective than the media as a means of reaching the members of the general population who are genuinely at risk, and shows that fuller information about prevention needs to be provided at cancer genetic consultations.

Further characterization of the light breast cyst fluid protein, GCDFP-15.

A light protein of breast cyst fluid from women with gross cystic disease, termed GCDFP-15 in the literature, has been investigated. This light protein was purified by preparative electrophoresis on sodium dodecyl sulfate polyacrylamide gel. Its isoelectric point has been determined as 3.75 and its molecular weight has been estimated at 17 400. The light protein was a glycoprotein containing about 163 amino acid residues; the glucidic fraction corresponded to 11% of the molecular weight. The N-terminal amino acid was blocked and the C-terminal amino acid was determined as valine. Antisera raised against this light protein have proved to be specific. In the literature, there is evidence suggesting that apocrine secretion is of prime importance in conditioning the biochemical composition of breast cyst fluid. Further information is needed to substantiate the hypothesis that in gross cystic disease the apocrine epithelium itself or some of its functional aspects are associated with the risk of neoplasia. The physicochemical characterization of the breast cyst fluid protein can contribute to the study of its biosynthesis and provide a better understanding of the physiopathology of gross cystic disease and its relationship to breast carcinoma.

Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.

UNLABELLED: Twenty-eight patients (12 men with prostate cancer, 16 women with breast cancer) were included in a phase II trial to evaluate the efficacy of 186Re-hydroxyethylidene diphosphonate (HEDP) on pain from bone metastasis and the toxicity of this agent. METHODS: After intravenous administration of 1295 MBq 186Re-HEDP, the efficacy was evaluated by means of a daily log. RESULTS: We observed an objective response in 67% of prostate cancer patients and in 36% of breast cancer patients. The mean duration of response was 45 d for prostate cancer patients and 24 d for breast cancer patients. No major adverse effects were observed. Marrow toxicity did not exceed grade 2 for white blood cells and grade 3 for platelets using National Cancer Institute criteria. CONCLUSION: 186Re-HEDP provides safe symptomatic relief of pain in prostate cancer patients. The benefit of this treatment is less clear in breast cancer patients. Further studies should be conducted to evaluate treatment by 186Re-HEDP at an earlier stage of the disease.

Disclosure to the family of breast/ovarian cancer genetic test results: patient's willingness and associated factors.

Informed probands are key actors for disclosing genetic information to their relatives when a mutation has been identified in the family. The objectives were to study women's attitudes towards the family disclosure of positive breast cancer genetic testing results and to determine the predictive factors of the diffusion patterns observed. A national multi-center cross-sectional survey was carried out at five French cancer genetic clinics during a 1-year period. Self-administered questionnaires were completed after the consultation by 84.5% (398/471) of women attending breast cancer genetic clinics for the first time. Among the 383 respondents who had at least one living first-degree relative to inform, 8.6% would inform none, 33.2% would inform at least one of them, and 58.2% would inform all of them. The sibship would be the most frequently informed blood relatives, sisters in 86.9% and brothers in 79% compared with mother in 71.4%, children in 70.4%, and father in 64.9%. Women of the family would be more frequently informed than men (P < 0.05). After multivariate adjustment, age, the fact to be affected by cancer, the number of daughters, and the emotional disturbance due to cancer in a close relationship were the main determinants (P < 0.05) of the diffusion patterns observed. The first step of the relatives' attendance to genetic counseling and the proband's willingness to disclose breast cancer genetic tests results was high in this study and was clearly dependent on the women's personal and emotional characteristics.

Comparison of physicians' and cancer prone women's attitudes about breast/ovarian prophylactic surgery. Results from two national surveys.

Prophylactic surgery is a major issue for breast/ovarian cancer prone women. Bio-clinical data to help in the decision-making are not sufficient. In this context of uncertainty, physicians' and women's attitudes to prophylactic surgery is information of great value. The physicians' attitudes were assessed by a randomised national sample of practitioners involved in breast and ovarian cancer management. The patients' attitudes were appraised with a pre-consultation self- administered questionnaire presented during a one-year period to all women in five cancer genetic clinics chosen, for their representative geographical locations and their activity level. Consent to prophylactic surgery is higher among physicians than among patients (p < 0.0001). Acceptability of mastectomy is lower than that of oophorectomy in both patients and physicians (p < 0.0001 in both groups). In addition, age at which the intervention is proposed to be performed is a key determinant for both mastectomy and oophorectomy acceptability, in both physicians and patients (p < 0.001 for each comparison). Particularly, the age of 40 years seems to be a critical threshold for the acceptability of prophylactic oophorectomy. In contrast, respondents' age at the time of the survey has no significant effect on the acceptability rate. The higher acceptability rate of prophylactic oophorectomy compared to that of mastectomy observed in the physicians' survey is paradoxical because a more substantial medical impact on life expectancy was expected from the latter. Our results indicate that assumed reduced mortality is not the main criterion steering acceptability. It was anticipated that prophylactic mastectomy should be rarely performed in France.

Insulin-like growth factor 1 receptors (IGF1-R) and IGF1 in human breast tumors.

To appreciate the IGF1 sensitivity of breast tumors we detected IGF1-R with a biochemical assay (RRA). We then localized and quantified IGF1-R on frozen tissue sections by histo-autoradiographic analysis (HAA). In some cases, the IGF1 and IGF1-R mRNA expression were studied by Northern blot analysis. We also studied the IGF1 plasma concentration in primary breast cancers compared to controls. IGF1-R (RRA) were found in 87% (n = 297) of the breast cancers. The mean geometric value was 3.87% (specific binding as percentage of total radioactivity); we found a highly significant correlation between IGF1-R and ER on the one hand (P = 0.0001) and PgR on the other (P = 0.0001) (Spearman test). The presence of IGF1-R was associated with a better prognosis, either on relapse-free survival (actuarial analysis: P = 0.004; Cox analysis: P = 0.005) or overall survival (respectively P = 0.003; P = 0.005). The median duration of follow-up was 30 months. By Cox analysis IGF1-R was a better prognostic factor than ER and PgR. In a series of 77 cases of benign breast disease only 47% (36/77) were positive; the mean geometric level was 1.8%. The HAA IGF1-R quantification in 20 breast carcinomas and 12 cases of benign breast disease confirmed the RRA results and demonstrated that the labeling was localized on the epithelial component. In four breast cancers, we did not detect IGF1 mRNA; IGF1-R probe demonstrated two major mRNAs of 11 and 7 kB. Finally we found that IGF1 plasma level was higher in breast cancer patients than in healthy controls of the same age. These results show that IGF1 is implicated in breast cancer growth and suggest that anti-IGF1 treatment might be useful in human breast cancer: for this reason, we and others carried out a phase II clinical trial with somatostatin.

Correlation between free platinum AUC and total platinum measurement 24 h after i.v. bolus injection of cisplatin in humans.

The plasma kinetics of platinum after i.v. bolus administration of cisplatin was determined for 17 patients with advanced cancer. Statistical analysis of individual values revealed a high correlation between the area under the plasma concentration-time curve (AUC) of free platinum (unbound to proteins) and the concentration of platinum bound to plasma proteins 24 h after drug administration (Cp24). A similar correlation was found between the peak plasma values of ultrafiltrable platinum (Cp0) and Cp24. When studied in the same patient, increases in free platinum AUC and Cp0 were also found to result in increased Cp24. It is suggested that a single measurement of plasma platinum concentration 24 h after i.v. infusion of cisplatin could be a simple method either of detecting patients with extreme values of AUC and Cp0 or of studying the evolution of these parameters during multiple courses of treatment, although it cannot be used to give precise values for AUC and Cp0.

Platinum concentration in human tumors of head and neck, uterine cervix, and breast following treatment with cisplatin.

Intratumoral platinum concentrations were measured in three tumor sites (head and neck, uterine cervix, and breast) 48 h after cisplatin administration according to the same protocol. The platinum levels were in the same order of magnitude in all tumors, but the concentration in breast tumors was found to be higher than that in tumors of the head and neck and of the uterine cervix.

Germline BRCA1 mutations in patients from 84 families with breast and/or ovarian cancers in northern France.

The BRCA1 gene modification is responsible for an autosomal dominant syndrome of inherited early onset breast and/or ovarian cancer. This gene is estimated to account for almost half of inherited breast cancers and three quarters of inherited breast/ovarian cancers. This suggests that about 1 in every 500 women may carry the BRCA1 mutation. The BRCA1 was isolated by positional cloning in 1994. More than 100 different mutations have been found in the germline of affected individuals. Using systematic sequencing, we looked at BRCA1 germline mutations in 84 patients treated at the Centre Oscar Lambret for breast and/or ovarian cancer who belonged to high-risk families. We found 39 mutations: 22 true mutations inducing modifications of the BRCA1 protein (BRCA1+), six mutations with unknown consequences on the BRCA1 protein, and eleven mutations corresponding to polymorphisms that had been described previously. All the BRCA1+ cases had a HPG3 tumour. The median age of discovery and the receptor positivity percentage are lower in hereditary breast cancer than in the standard population of the breast cancers treated in our centre. Conversely, most of the BRCA1+ patients are without node involvement. This shows that BRCA1 mutations are not always related to parameters thought to indicate a bad prognosis.

Time elapsing from cancer diagnosis and anxiety in women attending cancer genetic clinics.

The aim of this study was to investigate the effects of cancer genetic consultations on feelings of anxiety in women with breast/ovarian cancer. Among the 138 women attending six French clinics during a one-year period, 115 (83.3%) answered pre- and post-consultation questionnaires. The state anxiety score (Spielberger's STAI) was lower (paired t-test, p<0.001) after the consultation (34.7 9.4) than before (38.8 10.5). The time elapsing since cancer diagnosis (r=-0.28, p=0.007) was the main predictor of the decrease in anxiety. The patients consulting earlier after their cancer was diagnosed were more anxious before the consultation than those consulting later: whereas their anxiety states after the consultation were similar. The consultation effectively decreased the anxiety observed and the anxiety felt by cancer patients before the consultation may constitute an anticipatory stress response that should be investigated.