Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature.

As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, we investigated after long-term follow-up whether mutation status influenced the rate of ipsilateral and contralateral breast cancers after breast-conserving treatment (BCT). BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had undergone BCT and radiotherapy. Patients were matched to 261 controls with sporadic breast cancer according to age at diagnosis and year of treatment. Controls were followed up for at least as long as the interval between diagnosis and genetic screening in familial cases. Rates of ipsilateral and contralateral cancer between groups were compared by the log-rank test. The BRCA1/2 mutations occurred in 20.6% of tested patients. Tumours in mutation carriers were more likely to be grade III (P < 10(-4)) and oestrogen receptor negative (P = 0.005) than in non-carriers and controls. Overall median follow-up was 161 months. There was no significant difference in ipsilateral tumours between mutation carriers, non-carriers and controls (P = 0.13). On multivariate analysis, age was the most significant predictor for ipsilateral recurrence (P < 10(-3)). The rate of contralateral cancer was significantly higher in familial cases: 40.7% (mutation carriers), 20% (non-carriers), and 11% (controls) (P < 10(-4)). After 13.4 years of follow-up, the rate of ipsilateral tumours was no higher in mutation carriers than in non-carriers or controls. As tumours in BRCA1/2 mutation carriers might be more sensitive to radiation, BCT is a possible treatment option.

[Implications of genetic risk factors in breast cancer: culprit genes and associated malignancies]. / Comment prendre en compte le risque génétique de cancer du sein? Gènes impliqués et risques tumoraux associés.

Our understanding of hereditary forms of breast cancer has made enormous advances over the past 15 years, based on epidemiological and molecular genetic studies, and the development of a vast number of informative genetic markers. These studies have involved women with both familial and sporadic forms of breast cancer. Genetic susceptibility to breast cancer can involve several modes of inheritance: Mendelian inheritance, mostly involving autosomal dominant mutations with high penetrance and a high risk of malignancy (the BRCA1, BRCA2, TP53, PTEN and STK11 genes); dominant mutations associated with a lower risk (ATM, BRIP1, PALB2, etc), and multigenic patterns involving common susceptibility variants, i.e., polymorphisms located within predisposing gene loci (FGFR2, TNRC9, MAP3K1, LSP1, etc.) or intergenic regions. Other predisposing factors remain to be discovered, as genetic factors associated with a high breast cancer risk (BRCA1, BRCA2, TP53, PTEN STK11, etc) are only found in about 20% of genetically screened breast cancer families. So far, only the first class of genes have found clinical applications, guiding the choice of medical or surgical treatment. More refined individual risk profiles will benefit from genome-wide polymorphic DNA variant studies anda better understanding of the impact of non genetic factors, such as the obstetrical and gynaecological history, and mutagen exposure.

[Hormonotherapy for breast cancer prevention: What about women with genetic predisposition to breast cancer?]. / Que penser de l'hormonoprévention du cancer du sein chez les femmes porteuses d'une mutation délétère BRCA1/BRCA2 ?

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.

[Hormonal replacement therapy and breast cancer]. / Traitement hormonal substitutif et risque de cancer du sein.

The recent publication of some randomised control trials results and of two important cohort studies makes possible a better understanding of the relation between hormonal replacement therapy (HRT) and breast cancer. It is now well established that estrogen-progestin replacement therapy is associated with an elevation of breast cancer risk. It is not possible to define duration of treatment without risk. Data for estrogens alone are discordant. Five years after stopping HRT, the risk will join the level of non-users. By now, HRT may be prescribed in women that suffer intense climacteric symptoms, and after careful information about benefits, risks, and mammary effects of HRT. The minimal dose of estrogens is required for the control of menopausal symptoms. Estrogens alone will be prescribed in hysterectomised women. Mammography has to be performed before the beginning of HRT, and then every two years, in the absence of important risks factors of breast cancer. The indication of HRT has to be discussed every year, and some therapeutic pauses must be planned. In case of increased breast density at mammography, ultra-sonography may be useful. Breast surveillance must go on after HRT termination.

[Genetic predisposition and ovarian cancer]. / Prédisposition génétique et cancer de l'ovaire.

The genetic predisposition to epithelial ovarian cancer can be distinguished in two different forms: familial breast and/or ovarian cancer; familial colon, endometrium, ovarian cancer or HNPCC syndrome (hereditary non polyposis colorectal cancer). The BRCA1 and BRCA2 genes are involved in familial breast and (or) ovarian cancer. Mutations of these two genes could explain 5.5% (2-7%) of ovarian cancers. The hMLH1, hMSH2, and hMSH6 genes are involved in the HNPCC syndrome. The mutations of these genes could explain 1% to 2% of ovarian cancers. The clinical management of women at ovarian cancer risk is variable and dependent on the predisposition going from regular examination until prophylactic oophorectomy in the presence of BRCA mutations.

Breast and ovarian cancer risk management in a French cohort of 158 women carrying a BRCA1 or BRCA2 germline mutation: patient choices and outcome.

Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women.

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.

A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk.

The increased risk of breast cancer recently observed with some specific estro-progestin associations has raised concerns about the harmful effects of menopausal hormone replacement therapy (HRT). It has been proposed that phytoestrogens (PEs), which have a similar chemical structure to estrogens, could be used as HRT. The main selling points of these preparations concern the management of hot flashes and their potential beneficial effects on breast tissue. In this review, we will address the effects of PE on hot flashes and breast cancer risk as well as the questions raised on a chemical point of view. We conclude that the efficacy of a PE rich diet or nutritional supplements is not clearly established. The use of PE as an alternative for HRT cannot be advocated for now, due to insufficient and conflicting data on efficacy and safety. Moreover, due to the hormone dependence of breast cancer, PE use must be contraindicated in breast cancer survivors.

Lack of sufficient information on the specificity and selectivity of commercial phytoestrogens preparations for therapeutic purposes.

Phytoestrogens (PEs) are polyphenols of plant origin among which flavones, flavanones, isoflavones, coumarins, chalcones, lignans and stilbenes are the best representatives. By interacting with specific residues of the estradiol-binding pocket of estrogen receptors (ERs), they induce estrogenic responses, supporting the concept that they could be of benefits against the menopausal disorders due to endogenous estradiol depletion. According to literature data, PEs target a panel of proteins, suggesting that their effects are not limited to ER-dependent transcription pathways. In this regard, commercial preparations usually contain a mixture of compounds of which nature and concentration are not specified. Such mixtures being freely accessible and escaping thereby medical survey, they could exert unwanted effects, depending on their qualitative and quantitative composition as well as the physiopathological status of the women. This work outlines the necessity to inform consumers of the exact nature of these PEs preparations. Moreover, women who want to take PEs should inform their practitioner to be under strict medical survey. In the case of hormone-dependent cancer antecedents or predispositions, use of PEs is extremely inadvisable.

Controversies concerning the use of phytoestrogens in menopause management: bioavailability and metabolism.

It has been proposed that the use of phytoestrogens (PE) in menopausal therapy could be beneficial to woman health, particularly with respect to hot flushes. Indeed, PE may compensate the lack of endogenous 17beta-estradiol occurring during menopause. However, therapeutic benefits remain questionable, as highlighted by recent publications. Indeed, data are often subjected to controversy since a number of exogenous and endogenous factors influencing the responsiveness of patients are not sufficiently taken into account. In the present paper, we will discuss the role of bioavailability and metabolism in the instability of individual response to PE.

Cancer and fecundity issues mandate a multidisciplinary approach.

OBJECTIVE: To review the existing options for preserving fecundity in young cancer patients, outlining the differences that exist in each individual cancer situation and how these affect our choice of fecundity-preserving measures. DESIGN: Review the pathophysiology data on ovarian function that serve for outlining the advantages and/or drawbacks of certain fecundity-preserving measures such as ovarian freezing and emergency IVF. Provide support arguments for outlining the need for setting locally rooted cancer and fecundity task forces that throw the bases for a multidisciplinary approach in this field. SETTING: Review of literature data. PATIENT(S): Women of reproductive age affected with different types of cancer. MAIN OUTCOME MEASURE(S): Outcome of selected emergency fertility preserving measures such as ovarian tissue freezing followed by grafting or emergency IVF. RESULT(S): When performed in the 30s-the typical age for breast cancer, the most frequently encountered cancer in women of reproductive age, ovarian freezing hampers ovarian recovery and the chances for spontaneous pregnancy. CONCLUSION(S): Based on a review of the different situations encountered, we recommend that fecundity-preserving measures offered to young cancer patients, including ovarian freezing and emergency IVF, emanate from multidisciplinary approaches.

[Breast cancer and fertility: critical review, considerations and perspectives]. / Cancer du sein et fertilité: revue critique, réflexions et perspectives.

In young breast cancer patients, adjuvant therapies may have some impact on fertility and ovarian function. Adjuvant chemotherapy can induce ovarian failure, which depends on age, type and dose of cytotoxic agents and must be discussed with patients. A variety of techniques of fertility preservation were recently proposed in cancer patients, namely embryo cryopreservation, oocyte cryopreservation, cryopreservation of ovarian tissue, and coprescription of LH-RH analogues during chemotherapy. These experimental techniques are reviewed, and their use in women with breast cancer is discussed, especially with regards of hormonal aspects. Infertility approach after breast cancer is complex and requires a careful analysis by both oncologists and fertility specialists. The age of woman, and a precise evaluation of her ovarian reserve are key factors to determine the options available. Alternatives to hormonal stimulation may sometimes be useful, and must be proposed. The problem of ovarian stimulation after breast cancer is discussed, as the use of Assisted Reproduction Techniques such as in vitro fertilisation, oocyte donation, and embryo donation.

[HRT in post menopausal women and breast cancer at the Institut Curie]. / Traitement hormonal substitutif de la ménopause et cancer du sein à l'Institut Curie entre 1988 et 1999.

Several recent papers have suggested the role of HRT in the development of breast cancers. From the data base of the Institut Curie we compared the clinical characteristics, histoprognosis factors and survival of a cohort of 6737 patients recorded between 1988 and 1999 in which 1482 declared having receive HRT for more than 6 months. Surgical procedure, locoregional recurrence, metastasis, disease free and global survival were compared bet the patient who received an HRT versus the patients who didn't receive this treatment Mammographic diagnosis was more frequent in the HRT group and the age at diagnosis was smaller (p < 10(-4)). Cancers diagnosed in the HRT group were smaller and had a more favourable biologic profile as well as there were more lobular carcinomas and the conservative treatment was more frequent (p < 10(-4)). Mean follow up was 97 months. Recurrence free survival was not different in the two groups but the metastasis free and global survival were better in the HRT group. HRT remained an independent prognostic factor in a multivariate analysis. In western countries the increasing incidence of breast cancer concerns pre as well as post menopausal women. HRT cannot be considered as the only responsible of this augmentation.

Prophylactic salpingo-oophorectomy in a series of 89 women carrying a BRCA1 or a BRCA2 mutation.

BACKGROUND: Prophylactic salpingo-oophorectomy (SO), which is recommended in BRCA1/2 mutation carriers, still needs to be reappraised. METHODS: In all, 89 BRCA1/BRCA2 mutation carriers underwent SO between 1994-2004. Past medical and familial history, SO, results and survival after SO were analyzed. RESULTS: The series consisted of 56 BRCA1 and 33 BRCA2 mutation carriers. All but 1 had a family history of breast (BC) and/or ovarian cancer; 42 BRCA1 and 31 BRCA2 had a personal history of BC. The median age at SO was 44 (BRCA1) and 49.5 (BRCA2) years for women without previous BC (not significant) and 48 (BRCA1) and 53 BRCA2) years (P=.03) for women with previous BC. Occult ovarian (n=2) and/or fallopian (n=3) carcinomas were found in 4 patients (4.5%): 1 experienced recurrence (4 years), 2 are disease-free (26 and 38 months of follow-up), and 1 died from BC (12 months). Among the other 69 patients with previous BC (median follow-up, 42 months), 14 developed ipsilateral or contralateral BC and 8 developed metastatic disease. Among the 16 patients without previous BC (median follow-up, 27 months), 3 developed BC. Of the 89 patients, 85 are still alive: 3 died from BC and 1 died from pancreatic cancer. No peritoneal malignancy was observed. CONCLUSIONS: This study shows that prophylactic SO remains an important option for BRCA1/2 mutation carriers as asymptomatic ovarian/fallopian cancers were found in 4.5% of patients. However, a longer follow-up and larger series are required to more precisely evaluate the benefits of this procedure in terms of BC incidence, peritoneal malignancy, or recurrence.

[Standards, Options and Recommendations for the management of ductal carcinoma in situ of the breast (DCIS): update 2004]. / Recommandations pour la pratique clinique: Standards, Options et Recommandations 2004 pour la prise en charge des carcinomes canalaires in situ du sein (rapport abrégé).

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.

[Are the hereditary forms of BRCA1 and BRCA2 breast cancer sensitive to estrogens?]. / Les formes héréditaires de cancer du sein liées à BRCA1 et BRCA2 sont-elles sensibles aux oestrogènes ?

There is emerging evidence from clinical and experimental data that familial breast cancers, including BRCA1 and BRCA2 related forms, could be in fact estrogen-sensitive. Interactions between BRCA1 gene expression and estrogens have been reported. On one hand, BRCA1 expression could be induced by estradiol in experimental models. On the other hand, recent studies indicate that BRCA 1 interacts with and regulates the activity of estrogen receptor ERalpha. Endogenous or exogenous estrogens, such as oral contraceptive, may also increase the risk of breast cancer in BRCA1 mutation carriers in clinical studies. Conversely, prophylactic oophorectomy and anti-estrogens may decrease the risk of familial breast cancer. Prospective studies are thus required to estimate the potential benefits of estrogen suppression therapies for prevention or adjuvant treatment of familial breast cancer. Oral contraception and hormonal replacement therapy after menopause should be used with caution in BRCA1 or BRCA2 mutation carriers.