Diagnostic histologique et moléculaire des cancers de l'ovaire - recommandations pour la pratique clinique Saint-Paul 2021: Histological and molecular diagnosis of ovarian.

Oncogenetic testing is now part of standard management in high grade ovarian cancer, including at least mutational status of BRCA1/BRCA2 genes. If necessary, tumor genetic testing is followed by constitutional testing to either confirm the constitutional origin of variants identified in BRCA1/2 genes or detect variants in other predisposition genes. The whole process including prescription of tumoral testing, retrieval of analysis report and communication of results must be formalized, as well as information on possible consequences of the results for the patient and her family. Tumor material must meet criteria of size and cellularity to allow high-quality analysis. These samples are processed during the preanalytical phase with two major steps : time of cold ischemia and fixation. Only pathogenic (Class V) and likely pathogenic (Class IV) variants shown in tumor tissue are mentioned in the report. Currently, only BRCA1 and BRCA2 genes are routinely studied but, in the future, analysis will be extended to other genes involved in homologous recombination repair. In patients without BRCA mutation, other biomarkers reflecting sensitivity to PARP inhibitors, such as HRD scores (homologous recombination deficiency) that appeared recently, will have to be implemented in routine practice in order to better select patients for these treatments and choose optimal therapy.

Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic MSH2 somatic mutations.

The invalidation of the Mismatch Repair (MMR) system is responsible for a so-called "deficient MMR" phenotype (dMMR) characterized by microsatellite instability and abnormal pattern of expression of MMR proteins in tumor tissue. This phenotype occurs in at least 20% of sporadic endometrial adenocarcinomas by epigenetic silencing of MLH1 gene. It is also observed in virtually all tumors occurring in patients with Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR-pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR-pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome. We report the case of a woman with an early-onset endometrial adenocarcinoma who was suspected to be affected with Lynch syndrome based on tumor dMMR phenotype (MSI associated with loss of expression of MSH2 and MSH6 proteins). After complete germline and somatic evaluations, this phenotype was eventually explained by two MSH2 somatic mutations and the diagnosis of Lynch-like syndrome due to an unidentified MSH2 germline mutation was ruled out. Somatic mosaicism at low mutation rate was unlikely as no mutation was detected by DNA analysis from various tissue samples. Nevertheless, the three patient's children were tested for the two mutations and these tests were negative. Biallelic somatic mutations of one MMR gene is a mechanism of invalidation of the MMR system in sporadic cases. Clinicians have to be aware of this mechanism because of the great clinical implication for the patients and their relatives.

Cancers de l'ovaire BRCA muté : consultation d'oncogénétique et prescription des inhibiteurs de PARP.

BRCA MUTATED OVARIAN CARCINOMAS: GENETIC COUNSELING AND PARP INHIBITORS PRESCRIPTION: Upon the availability of the PARP inhibitors in relapsed ovarian carcinoma, the pathways of the oncogenetic counseling were modified. Any research for a constitutional alteration of the BRCA1 and BRCA2 genes must be accompanied by an oncogenetic counseling. BRCA testing is recommended from the diagnosis to every woman with an ovarian or fallopian tube or peritoneum of high grade adenocarcinoma, whatever the age at the diagnosis and her family history. In case of sensitive relapse or potential inclusion in a clinical trial and in the absence of preliminary constitutional research, the oncogenetic counseling is organized according to a fast track pathway and a somatic analysis can be realized in parallel. Today, olaparib is indicated for patients with a high grade serous ovarian or fallopian tube or peritoneum adenocarcinoma, with deleterious mutation of BRCA genes (constitutional or somatic), and in sensitive platinum relapse, and in maintenance therapy after a response to chemotherapy including platinum. The indication of a treatment with olaparib can be discussed in multidisciplinary staff for the other non-serous high grade ovarian carcinoma if all other criteria are gathered. Olaparib is prescribed in monotherapy, to start at the latest 8 weeks after the last chemotherapy cycle, under narrow surveillance, because of its gastrointestinal and hematologic toxicities.

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation.

Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan-Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31-1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.

Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family.

BACKGROUND: Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. OBJECTIVE: We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). METHODS: We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. RESULTS: The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. LIMITATIONS: The study was not population based. CONCLUSIONS: This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.