[PARP inhibitors in breast cancer: Current clinical development and perspectives]. / Inhibiteurs de PARP dans les cancers du sein : développement clinique actuel et perspectives.

The association of a germline mutation in the BRCA1/2 genes in breast cancer leads to a higher genomic instability and, thus, a potential higher sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this review, we will summarize the different DNA-repair pathways including PARP-dependent mechanisms that support the use of PARP inhibitors. We will present clinical trials evaluating PARP inhibitors alone or in combination in early or advanced stage breast cancer. We will then discuss the different mechanisms involved in the resistance to PARP inhibitors. We will also introduce the concept of BRCAness by which the use of PARP inhibitors could be extended to BRCA1/2-wild type patients. Finally, we will describe the new channels implemented for the theranostic genetic screening.

[What attitude to women at high risk of breast cancer?] / Les femmes à haut risque de cancer du sein : quelle attitude ?

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).

[The French Genetic and Cancer Consortium guidelines for multigene panel analysis in hereditary breast and ovarian cancer predisposition]. / Recommandations françaises du Groupe Génétique et Cancer pour l'analyse en panel de gènes dans les prédispositions héréditaires au cancer du sein ou de l'ovaire.

INTRODUCTION: Next generation sequencing allows the simultaneous analysis of large panel of genes for families or individuals with a strong suspicion of hereditary breast and/or ovarian cancer (HBOC). Because of lack of guidelines, several panels of genes potentially involved in HBOC were designed, with large disparities not only in their composition but also in medical care offered to mutation carriers. Then, homogenization in practices is needed. METHODS: The French Genetic and Cancer Group (GGC) - Unicancer conducted an exhaustive bibliographic work on 18 genes of interest. Only publications with unbiased risk estimates were retained. RESULTS: The expertise of each 18 genes was based on clinical utility criteria, i.e. a relative risk of cancer of 4 and more, available medical tools for screening and prevention of mutation carriers, and pre-symptomatic genetic tests for relatives. Finally, 13 genes were selected to be included in a HBOC diagnosis gene panel: BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, EPCAM. The reasons for excluding NBN, RAD51B, CHEK2, STK11, ATM, BARD1, BRIP1 from the HBOC diagnosis panel are presented. Screening, prevention and genetic counselling guidelines were detailed for each of the 18 genes. DISCUSSION: Due to the rapid increase in knowledge, the GGC has planned a yearly update of the bibliography to take into account new findings. Furthermore, genetic-epidemiological studies are being initiated to better estimate the cancer risk associated with genes which are not yet included in the HBOC diagnosis panel.

Ovarian cancer patients at high risk of BRCA mutation: the constitutional genetic characterization does not change prognosis.

Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients. Out of 617 ovarian cancer patients, we identified 104 patients who were considered at high risk of mutation. The 33 mutated patients were more likely to present a personal (33 vs. 10 %, p = 0.003) or a family (42 vs. 24 %, p = 0.06) history of breast/ovarian cancers. BRCA1/2 mutation carriers and wild type patients displayed similar prognosis: median progression-free survival (PFS) of 20.9 versus 37.7 months (p = 0.21); median overall survival (OS) of 151.2 versus 122.5 months (p = 0.52). Personal history of breast cancer increased both PFS [HR = 0.45 (95CI 0.25-0.81)] and OS [HR = 0.35 (95CI 0.16-0.75)]. In multivariate analysis, this parameter was an independent prognostic feature, whereas the identification of a BRCA1/2 mutation was not. In our cohort, all patients at high risk of BRCA mutation share a similar prognosis, whatever is their germline mutation status. Prognosis seems to be more influenced by clinical history than by germline mutations identification. If it is confirmed in larger and independent series, this result suggests that the hypothesis of other BRCA pathway alterations (BRCAness phenotype) deserves to be deeply explored.

[Having a child and PND/PGD access in women with a BRCA1/2 mutation? Different approach whether ill or healthy]. / Avoir un enfant et accéder au DPN/DPI pour des femmes porteuses d'une mutation BRCA ? Malades et indemnes appréhendent la question différemment.

Genetic tests in families with a mutation related to breast and ovarian cancers (BRCA1/2) are now offered to the persons before completion of their reproductive project. The aim of this qualitative study was to descriptively explore how the issues of reproduction are faced in women belonging to these families, and how the possible use of prenatal diagnostic (PND) and preimplantation genetic diagnosis (PGD) would be faced in a theoretical context. We conducted in-depth interviews, face to face, according to the so-called Grounded Theory approach. Twenty women with a BRCA genetic mutation participated in the study (age range: 31-57 years); 12 have had a breast and/or ovarian cancer. The knowledge of having the mutation did not modify the parental project; however prophylactic anexectomy was likely to alter it in some women. If the majority of women were in favor of PGD (n = 14), medical termination of pregnancy was a constraint towards the position in relation to PND. Besides ethical and moral arguments, the women's attitudes were constructed differently according to their own personal or familial experience of the disease. The women's perceptions of the cancer severity, risk and cure were organized according to this experience.

[Personalized medicine and breast cancer: anticipatory medicine, prognostic evaluation and therapeutic targeting]. / Médecine personnalisée et cancer du sein : médecine anticipatoire, évaluation pronostique et ciblage thérapeutique.

Breast cancer is now considered as a large collection of distinct biological entities, the management of which is increasingly personalized. Personalized medicine - defined as a medicine, which uses molecular profiles, notably genetic profiles, from patients and/or tumors to tailor therapeutic decisions - is now introduced in the management of breast cancer at any stages: screening and prevention of hereditary forms, prognostic and predictive evaluation of early breast cancer, and, more recently, novel clinical trials in advanced breast cancer, where genetic characterization of tumor tissue based on genomics, including next-generation sequencing tools, is used to drive specific therapeutic targeting.

Is the controversy on breast cancer as part of the Lynch-related tumor spectrum still open?

Several studies report an increased risk of breast/pancreatic cancer in MMR (DNA mismatch repair) mutation carriers that has significant consequences on standard cancer screening in such population. The French national network involved in Lynch syndrome molecular characterization registered 15 families with an identified MMR germline mutation and the occurrence of breast/pancreatic adenocarcinoma in mutations carriers. Corresponding tumors were investigated and the MMR function was shown to be intact. This observation tends to exclude breast/pancreatic cancers from Lynch tumor spectrum defined by a complete loss of the MMR function in tumor cells and to support the hypothesis of another causal factor.