Mutation screening of MIR146A/B and BRCA1/2 3'-UTRs in the GENESIS study.

Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3'- untranslated regions (3'-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3'-UTR and one in BRCA2 3'-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3'-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3'-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.

Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.

Comparison of the screening practices of unaffected noncarriers under 40 and between 40 and 49 in BRCA1/2 families.

This study aimed to 1) compare the cancer screening practices of unaffected noncarrier women under 40 and those aged 40 to 49, following the age-based medical screening guidelines, and 2) consider the way the patients justified their practices of screening or over-screening. For this study, 131 unaffected noncarriers-77 women under age 40 and 54 between 40 and 49, all belonging to a BRCA1/2 family-responded to a questionnaire on breast or ovarian cancer screenings they had undergone since receiving their negative genetic test results, their motives for seeking these screenings, and their intentions to pursue these screenings in the future. Unaffected noncarriers under age 40 admitted practices that could be qualified as over-screening. Apart from mammogram and breast ultrasounds, which the women under 40 reported seeking less often, these women's screening practices were comparable to those of women between 40 and 49. Cancer prevention and a family history of cancer were the two most frequently cited justifications for pursuing these screenings. We suggest that health care professionals discuss with women under 50 the ineffectiveness of breast and ovarian cancer screenings so that they will adapt their practices to conform to medical guidelines and limit their exposure to the potentially negative impacts of early cancer screening.

Predictive value of neoadjuvant chemotherapy failure in breast cancer using FDG-PET after the first course.

The aim of this study was to prospectively evaluate the predictive value of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to detect the absence of pathological response to preoperative chemotherapy in patients (pts) with breast cancer. 63 consecutive pts with non-metastatic, non-inflammatory breast cancer, eligible for neoadjuvant chemotherapy (3 FEC 100 followed by 3 Docetaxel) were enrolled. FDG-PET was performed just before the first as well as before the second course. Metabolic activity (tumour FDG uptake) was measured by standardised uptake value (SUV(max)). Pts were classified as non-responders (NR) when the decrease of SUV(max) in the primary tumour was less than 15% at the time of the second PET (EORTC 1999 criteria). The metabolic response in FDG-PET was correlated with WHO criteria (clinical evaluation and ultrasound and/or mammography) evaluated after three cycles, pathological complete response (pCR) after surgery (according to Sataloff classification) and 4-year relapse-free survival (RFS). The mean SUV(max) decrease according to histological response was -52 ± 21% in case of pCR (Sataloff A) and 25 ± 34% in other cases (Sataloff B + C + D). Out of the 16 pts with no PET response (SUV decrease less than 15%), only one had a clinical response after the third cycle, and no pCR was observed. The 4-year RFS rate was significantly longer for metabolic responders than for NR (respectively, 85 vs. 44%; P = 0.01). This prospective study shows that a decrease in the SUV of less than 15% after the first chemotherapy course is a very potent predictor for failure of neoadjuvant chemotherapy, especially of pCR. It is interesting to note that this was shown despite the fact that the chemotherapy regimen was changed after the third course.

Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial.

Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations are considered as an extreme risk population for developing breast cancer. Prophylactic mastectomy provides a valid option to reduce such risk, impacting however, the quality of life. Medical prevention by aromatase inhibitor that has also recently shown to have preventive effect may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial to evaluate the efficacy of 5-year letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (NCT00673335). We present data on the uptake of this trial. We compared characteristics of women in the LIBER trial (n = 113) to those of women enrolled in the prospective ongoing national GENEPSO cohort (n = 1,505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 to the 20 (85%) centres. According to the characteristics of the women enrolled in the GENEPSO cohort and the survey, approximately one-third of BRCA1/2 mutation carriers were eligible for the trial. Five hundred and thirty-four women eligible from chart review have been informed by mail about the prevention trial and were invited to an oral information by participating centres. Forty-four percentage of them came to the dedicated medical visit. Uptake of drug prevention trial was 32% among women informed orally and 15% of all the eligible women. The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. Additionally, we noticed that prior prophylactic oophorectomy and previous unilateral breast cancer were more frequent in women enrolled in the LIBER trial than in the French cohort (93% vs. 60% and 50% vs. 39%, respectively). Based on an overall 15% uptake among all eligible subjects, greater and wider information of the trial should be offered to women with BRCA1/2 mutation to improve recruitment. Women with previous unilateral breast cancer or prior prophylactic oophorectomy are more likely to enter a medical prevention trial.

[Personality disorders in oncology: characteristic and management]. / Les troubles de la personnalité en oncologie : caractéristiques et prise en charge.

Confronted with a patient with a personality disorder, the oncologist must recognize it and adapt his treatment accordingly. Some pathological character types require interpersonal adjustments to ensure a good understanding of the cancer disease and also to obtain the best compliance with supportive care. Given the fact that specific pharmacological treatment does not exist, collaboration between oncologists and the psycho-oncology team is paramount. The interaction between the somatic disease and the psychiatric disorder demand collaboration among caregivers sharing explanations and recommendations. Clinical examples will illustrate each personality disorder and will focus on the several problems raised by the psychiatric disorder. Treatment principles will be addressed in a second section.

Radical fimbriectomy: a reasonable temporary risk-reducing surgery for selected women with a germ line mutation of BRCA 1 or 2 genes? Rationale and preliminary development.

OBJECTIVE: Bilateral salpingo-oophorectomy (BSO) is the gold standard prophylactic surgery for BRCA1 or 2 mutation carriers. However, due to the resulting early menopause and fertility desires, young women are reluctant to undergo this procedure. In view of the recent literature on ovarian carcinogenesis, we wish to report a novel conceptual surgical procedure we called "radical fimbriectomy." This procedure is aimed to protect this subset of high-risk women from high-grade serous pelvic carcinoma, while preserving their ovarian function. METHODS: Women with BRCA mutation, who were scheduled for BSO, were informed of the procedure approved by our local review board. Radical fimbriectomy consists of removing all the tube and the fimbrio-ovarian junction, step immediately followed in this developmental phase by completion oophorectomy. Four methods of partial ovarian transsection were prospectively compared: sharp division, stapler, bipolar division and harmonic scalpel. Surgical safety and pathological alterations were assessed. All specimens underwent extensive pathological evaluation using both SEE-FIM protocol and serial sections. RESULTS: Fourteen women were enrolled in the study. Sharp and EndoGIA® appeared to be the safest methods of ovarian resection providing the best specimen quality for pathological examination. CONCLUSION: We believe this technique could be suggested to young mutation carriers reluctant to undergo BSO. This approach is preferable to no prophylactic surgery at all. However, until the safety and validity of this procedure is confirmed by a multi-institutional study, women who undergo radical fimbriectomy should continue to receive regular multimodal evaluation and be advised of the risks involved until they finally accept secondary castration.

[Screening pelvic tumours for hereditary risk of ovarian neoplasms, a cancer center experience]. / Inefficacité du dépistage des cancers tubo-ovariens dans les situations de risque héréditaire de cancer de l'ovaire ; l'expérience du Centre Oscar-Lambret.

As part of a study in the North of France for screening pelvic tumours with plasma proteomic analysis, we included 82 women with hereditary risk of ovarian cancer. We report here the consequences of organized screening with usual tests. CA 125 sampling and a transvaginal pelvic ultrasound by a radiologist were systematically conducted every 6 months. Seventy-two patients were eventually evaluable. Two incident cases of peritoneal carcinomatosis (FIGO IIIB, malignant epithelial serous high-grade tumors) were discovered in two asymptomatic women with a deleterous BRCA1 mutation (2.7%). We did not observe any other primary cancer cases but an ovarian metastasis of a breast cancer. Forty women went off the study: 32 had a prophylactic bilateral salpingo-oophorectomy. Consistent with the literature, biannual screening tests combining CA125 and pelvis ultrasound is ineffective for early detection of a pelvic tumor of tubal or ovarian origin. Testing for BRCA1 or BRCA2 deleterious mutations is then crucial for suspected family syndromes of breast and ovarian cancer. For women carrying a deleterous mutation on BRCA1/2 a salpingo-oophorectomy is the only way, only the time of this surgery is debatable.

Time to prophylactic surgery in BRCA1/2 carriers depends on psychological and other characteristics.

PURPOSE: To investigate the medical and psychosocial factors determining the time to prophylactic surgery of unaffected women carriers of a deleterious BRCA1/2 mutation. METHODS: Prospective study on a French national cohort of unaffected BRCA1/2 carriers (N = 244); multivariate Cox proportional hazard modeling. RESULTS: Median follow-up time was 2.33 years (range, 0.04-6.84 years). Time to surgery was shorter when the psychological impact of BRCA1/2 result disclosure was stated to be higher (P ≤ 0.01). Those who intended to opt for prophylactic surgery before being tested did so faster and more frequently after test disclosure than those who were undecided/opposed. The older the women were, the faster their uptake of risk-reducing salpingo-oophorectomy (adjusted hazard ratio >2.95; P < 0.001) was; the uptake of those with at least two children was also faster (adjusted hazard ratio = 2.51; [1.38-4.55]). Those who opted most quickly for risk-reducing mastectomy more frequently had a younger child at the time of testing (adjusted hazard ratio = 4.63 [1.56-13.74]). Time to surgery was shorter when there was a first-degree relative with ovarian/breast cancer (P ≤ 0.01). CONCLUSION: Time to prophylactic surgery depends on the stated psychological impact of disclosure and on women's cognitive anticipation of surgery after adjusting on sociodemographic characteristics.

Social sharing of genetic information in the family: a study on hereditary breast and ovarian cancers.

The present study assessed how preventive medical information about hereditary breast and ovarian cancer is spread within the family before actual genetic test results. Forty-two women (19 had a breast or ovarian tumor and 23 did not) were asked to fill out a questionnaire about: (1) the spread within the family of the medical information received during the consultation; and (2) the reasons for sharing this information. Results indicate that all of the women socially shared medical information with an immediate family member for preventive purposes, and generally not for seeking emotional or informative social support.

No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study.

BACKGROUND: The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. METHODS: To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. RESULTS: We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. CONCLUSIONS: These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.

[Cancer diagnosis announcement: an act to seal the pact of trust between doctors and patients]. / L'annonce du diagnostic de cancer: l'acte qui doit sceller le pacte de confiance médecin-malade.

The announcement of the cancer diagnosis, an important moment in the set up of the doctor/patient relationship, must come together, if possible, with a quality of communication. This announcement is never insignificant, often traumatic both for the one who receives it and sometimes for the person who provides it. It must observe some rules of temporality, in its enunciation and take into account the psychological defences of patient's mechanisms. More accessible, but also more complex medical information is supposed to be more transparent, taking into account the wishes of patients considered as full actors of their health. As such, the announcement of bad news is in a relationship of care, trust represents the start of a full therapeutic act. One of the challenges of the diagnosis announcement remains the education of patients and physicians to encourage better adaptation to the disease and its treatments. This education can only take place in a pluridisciplinarity in order to optimize care. The diagnosis announcement must continuously oscillate between fair distance and proximity while respecting the autonomy, dignity and freedom of patient's choice. The respect of ethical principles will prevent incomprehension phenomena and seal the pact of trust between doctors and patients.

[Information spreading about hereditary carriage of a BRCA1/2 mutation and ovarian cancer and rate of consultation of the concerned relatives]. / Transmission de l'information dans les familles à risque héréditaire de cancer du sein et de l'ovaire mutées BRCA1/2 et taux de consultation des apparentés.

Five to 10% of breast and ovarian cancer are linked to a BRCA1 or BRCA2 mutation. In our country, the information given to the relatives is inevitably mediated by the persons who have consulted. The report of a gap between the number of presumed persons concerned by the genetic information according to our genealogies and the actual number of consultants brought us to question about the transmission of the information in the family, about the possible motives for the lack of transmission, about the rate of consultation of the concerned relatives and on the presumed motives of non-consultation. This sample includes 31 target consultants (index cases) of mutated families which received the result of the genetic test during the period from January, 2003 till June, 2005. According to the information gathered, most of the relatives (73.1%) are informed about the presence of a deleterious mutation in the family, especially women (80.7%). The motives for non-information are the social and emotional distance, as well as the stressful character of the information. Apparently the information is disclosed through the family by the women who are alive and carry the mutation. On the other hand, a minority of the women (39.7%) who are supposed to be informed and living in the region attended the oncogenetic consultation, which represents 32 % of all concerned women who come of age. The motives for short-term absence of consultation can just be presumed. The characteristics which we studied do not allow us to point out some particularities among women who consulted except the nearness with one mutated relative.

[Informed consent or choice? An ethical dilemma in oncology practice]. / Consentement éclairé ou choix informé? Un dilemme éthique en pratique quotidienne.

How articulate information, mutidisciplinary practice, choice and decision of the treatment in a good patient-doctor relationship, an ethical relationship ? Doctor is an expert who gets the information (patients have more and more others sources of information). Choice of the treatment depends of the facts (the evidence) and personal values (the preferences). The selection between the different options (most often they are several options) may be done by the physician or by physicians in a multidisciplinary clinics, in the presence of the patient or not. The final decision to do or not the treatment belongs to the patient (who is not always aware of that). Initial sharing of the information between patient and doctor may permit the patient to choose himself the best option. More complete is sharing of the information, more the patient is able to do a free choice (without the influence of the doctor). It is often possible (genetics, prevention, screening, adjuvant treatments) to share in full the available information (knowing its relativity and limits). In oncology, the full sharing of the information is not always realistic, neither asked by the patient. Nevertheless, it is possible to go progressively with the patient to a preferred choice through a deliberative process, a co-construction of the decision. But often, the doctor refer to a pre-established protocol, build by physicians, representing the choice of the majority (doctors and/or patients) in the "same" situation. Only one option is offered to the patient from whom consent is asked, the information been then delivered to explain the choice already done. This paternalistic attitude is very effective, comfortable and don't alter the satisfaction of the majority of the patients, however, it limits the patient's autonomy. The patient is not allowed to choose between all the possibilities but accept or refuse the doctor's choice. With the extreme variability of the situations, it would be illusive to defend a unique attitude. Doctor has yet to try to adapt himself to every single case.

Patients' characteristics and rate of Internet use to obtain cancer information.

The aim of this study was to present baseline data on the access to Internet by French breast cancer patients attending genetic clinics and to examine factors affecting Internet health-related use. Twenty-four percent of participants used Internet to obtain information about the disease. This rate was higher among patients with health occupations [adjusted odds ratio (adjOR) 2.6; 95% confidence interval (CI) 1.3-5.1], the most highly educated (adjOR 2.1; 95% CI 1.1-4.0) and those under 41 years of age (adjOR 7.3; 95% CI 2.1-26.2). Almost one of every three women was dissatisfied of this source of information.

Impact of an information booklet on satisfaction and decision-making about BRCA genetic testing.

The aim of this study was to assess the impact of a standardized patient information booklet on decisions women make about genetic testing. This French national multi-centre survey included all women with cancer to whom genetic testing for BRCA1/2 mutation had been proposed. The control group was surveyed before the booklet became available (n = 263), and the experimental group, after being given it personally (n = 297). After multivariate adjustment, the booklet had a positive impact on satisfaction with the information provided (Odds ratio (OR) = 2.9; 99% confidence interval (CI) = 1.7-5.0; P = 0.001), decreased the decisional conflicts due to lack of information (OR = 1.9; 99% CI = 1.1-3.3; P = 0.002), and had a marginal impact on knowledge (R2-gain = 3%; P = 0.001). The women in the experimental group decided more frequently to undergo testing (99% vs. 95%; P = 0.009). In addition to a consultation providing more tailored information, a standardized written document improved the decision-making process involved in giving informed consent to genetic testing.

Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after the consultation.

The aim of this study was to assess the effects of cancer genetic consultations on women's perception of their family risk of breast/ovarian cancer, and to determine which factors were associated with an inaccurate perception after the consultation. A multicenter prospective survey was carried out on women (n = 397) attending cancer genetic clinics in France for the first time, in which the perceived family risk was measured both before and after the consultation, using self-administered questionnaires. The effects of the consultation on risk perception were significant among low (P <.001) and moderate risk women (P <.05). However, after the consultation, 76.3% of the "low"-risk women did not perceive their family as "low"-risk families, and 21.9% of the moderate-risk women were still definitely sure there was a genetic risk running in their family. The consultation did not affect the family risk perception of the high risk women (n = 171): the risk was thought to be very high both before (87.7%) and after (89.5%) the consultation (NS); however 10.5% of this group still perceived their family as being unlikely to be at risk after the consultation. In the low- and moderate-risk groups after multivariate adjustment, the inaccurate perceptions varied, depending on the clinics and on the psychosocial context of the consultation: they increased when the consultee was personally affected by cancer, and decreased when the consultee had a health occupation. Cancer genetic consultations had only marginal effects on the perception of family risk on the whole, although they were significant in the case of low- and moderate-risk women. The question arises as to whether a more comprehensive approach should be implemented and how to go about providing efficient cancer risk information in the context of health care systems.