Delphine Garbay

YWHAE rearrangement identified by FISH and RT-PCR in endometrial stromal sarcomas: genetic and pathological correlations

Endometrial stromal sarcomas represent the second most common mesenchymal uterine tumor. The 2003 WHO classification distinguishes low-grade and undifferentiated endometrial stromal sarcomas with different prognoses. Endometrial stromal sarcomas are a genetically heterogeneous group of sarcomas harboring different cytogenetic anomalies. Recently, a fusion between the YWHAE and FAM22A/B genes subsequent to a t(10;17) (q22;p13) has been described in endometrial sarcomas with high-grade histology. We examined YWHAE rearrangements by FISH break-apart and RT-PCR in a series of 27 undifferentiated uterine stromal sarcoma without JAZF1 rearrangements. Immunohistochemistry (IHC) was carried out with a panel of antibodies (estrogen (ER) and progesterone (PR) receptors, CD10, Cyclin D1, β-catenin, p53, and Ki-67). We identified a subgroup of endometrial sarcomas with high-grade histology and uniform morphology harboring YWHAE rearrangements. FISH break-apart was interpretable in 20 cases (74%). Twelve cases (60%) showed <10% of tumor cells with a YWHAE rearrangement, 4 cases (20%) showed between 10 and ≤20%, and 4 (20%) >20%. RT-PCR was tested on 24/27 cases (88%) and 19 cases were interpretable (79%). Five cases (26%) showed a specific fusion transcript YWHAE–FAM22A/B sequence. The best concordance rate between FISH and RT-PCR (94%) was obtained with the threshold of 20% of cells with a YWHAE rearrangement. The YWHAE-rearranged cases showed high-grade morphology with uniform appearance, spindle or round epithelioid cells, low ER and PR, CD10 expression, and a high and diffuse positivity for Cyclin D1, p53, and nuclear β-catenin negativity. Cyclin D1 was the most sensitive marker for high-grade endometrial sarcomas with YWHAE rearrangement. All undifferentiated uterine sarcomas with pleomorphic appearances did not harbor any YWHAE rearrangements, except for one case. Overall, for endometrial sarcoma cases with high-grade morphology we recommend to test for YWHAE rearrangements by FISH break-apart, a cost- and time-efficient method, and to complete the investigation by RT-PCR in borderline cases.

Uterine smooth muscle tumor analysis by comparative genomic hybridization: A useful diagnostic tool in challenging lesions

The diagnosis and management of uterine smooth muscle tumors with uncertain malignant potential (STUMP) is often challenging, and genomic data on these lesions as well as on uterine smooth muscle lesions are limited. We tested the hypothesis that genomic profile determination by array-CGH could split STUMP into a benign group with scarce chromosomal alterations akin to leiomyoma and a malignant group with high chromosomal instability akin to leiomyosarcoma. Array-CGH genomic profile analysis was conducted for a series of 29 cases of uterine STUMP. A group of ten uterine leiomyomas and ten uterine leiomyosarcomas served as controls. The mean age was 50 years (range, 24–85) and the follow-up ranged from 12 to 156 months (average 70 months). Since STUMP is a heterogenous group of tumors with genomic profiles that can harbor few to many chromosomal alterations, we compared genomic indices in leiomyomas and leiomyosarcomas and set a genomic index=10 threshold. Tumors with a genomic index <10 were classified as nonrecurring STUMPs and those with a genomic index >10 represented STUMPs with recurrences and unfavorable outcomes. Hence, the genomic index threshold splits the STUMP category into two groups of tumors with different outcomes: a group comparable to leiomyomas and another similar to leiomyosarcomas, but more indolent. In our STUMP series, genomic analysis by array-CGH is an innovative diagnostic tool for problematic smooth muscle uterine lesions, complementary to the morphological evaluation approach. We provide an improved classification method for distinguishing truly malignant tumors from benign lesions within the category of STUMP, especially those with equivocal morphological features.

Neoadjuvant endocrine treatment in breast cancer: analysis of daily practice in large cancer center to facilitate decision making

BACKGROUND To examine outcomes of neoadjuvant endocrine therapy in daily practice to inform decision making. METHODS We retrospectively selected 204 patients who received neoadjuvant endocrine therapy with T2 (≥30 mm) or T3 tumors, examining subsequent breast-sparing surgery and long-term outcomes. RESULTS Neoadjuvant endocrine therapy was administered for 7.3 months (median) and breast-sparing surgery was achievable in 53% of patients. Smaller initial tumor size and modified version of the Scarff-Bloom and Richardson grades 1 to 2 were associated with breast-sparing surgery. Disease progression during treatment was 6.9%; actuarial risk of local relapse was 3% at 5 years and 15% at 10 years. Five- and 10-year metastasis relapse-free survival was 78% and 63%, respectively. Grade 3, negative progesterone receptors, and absence or slow response to neoadjuvant therapy were associated prognostic factors. CONCLUSION These daily practice data provide important information about feasibility, efficacy, and long-term results of neoadjuvant endocrine therapy and can be used to inform patients for decision making between mastectomy and endocrine induction therapy.

Bone Marrow Metastases in a Patient with Primary Mediastinal Non-Seminomatous Germ Cell Tumor – an Unusual Pattern of Relapse

Background: Bone marrow is a very unusual site of metastasis for germ cell tumors. Case Report: We report the case of a 21-year-old male patient who was treated with chemotherapy and secondary surgery for a primary mediastinal non-seminomatous germ cell tumor (NSGCT). The patient achieved complete remission. However, 4 months after completion of therapy, he complained of rapidly worsening bone pain. No evidence for disease relapse was found in the computed tomography scan of thorax and abdomen, magnetic resonance imaging of the spine, or bone scan. A blood test revealed pancytopenia and elevated serum tumor markers. A bone marrow aspirate showed infiltration by tumor cells positive for AE1/AE3 and AFP confirming the diagnosis of isolated bone marrow metastatic relapse. Salvage chemotherapy was started and resulted in a rapid decrease of serum tumor markers. However, pancytopenia did not improve and the patient died of severe sepsis 3 weeks later. Conclusion: We report here the first case of isolated bone marrow metastatic relapse of an NSGCT. 2 other cases of bone marrow metastasis in patients with NSGCT have been reported. In these 2 cases, as in our patient, the primary site was not testicular but mediastinal suggesting a non-fortuitous association.

Les formes héréditaires du cancer de l’ovaire : particularités clinico-biologiques et thérapeutiques

Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.

Abstract C48: BIP (Bergonie Institute profiling) program: Fighting cancer by matching molecular alterations and drugs in early phase trials

Background: BIP is an institution-wide permanent screening program started in 2014 to identify patients (pts) referred to Institut Bergonie (Bordeaux, France) with somatic alterations that can be matched to targeted therapies in early phase clinical trials. Methods: Pts with advanced solid tumors and with ECOG performance status ≤ 2 were eligible. Tumor DNA was isolated from a FFPE archived sample when available or from a fresh tumor biopsy. DNA analysis was performed by next generation sequencing (NGS) using a panel of up to 287 genes and by comparative genomic hybridization (CGH). Results for each patient were discussed during a weekly multidsicplinary molecular tumor board in order to assess the eligibility of the patient to early phase clinical trials. Results: From Jan 1 2014 to June 30 2015, 542 pts were enrolled with median 2 prior treatments for advanced disease (range 0-9). The main tumor types were: lung (19.2%), colorectal (16.2%), breast (13.3%), ovarian (11%), and sarcomas (10%). Median age was 61 years (range 18-84). In 28 cases (5%) molecular analysis failed mainly because of insufficient tissue. The median time from first referral to reporting was 9 weeks (range 1-36). The 20 genes most frequently altered were TP53, CDKN2A,PTEN, CDKN2B, PIK3CA, MYC, ARID1A, KRAS, RB1, EGFR, ERBB2, FGFR1, APC,RICTOR,ZNF703,ATM,BRAF,NF1,FGFR3 and CCND1. Among the patients included between Jan 1 2014 and January 31 2015 (n = 286), 176 patients (68%) of patients had at least one genetic alteration that was considered actionable by the molecular tumor board. 85 patients (29.7%) were included in a clinical trial with a median delay of 17 weeks between first referral and date of treatment onset. The treatment was matched with the tumor profile in 49 cases (17%). The main reasons for non-inclusion in a clinical trial despite the identification of an actionable mutation were: non progressive disease on the current line of treatment (31.5%), general status deterioration (26%), death (13%), clinical trial not available (13%), screening failure (6.5%), lost of follow-up (5.5%), and patient refusal (4.5%). 79 patients were evaluable for response according to RECIST 1.1. The disease control rate (objective response + stable disease) was 47% for patients included in clinical trials matched with the tumor profile versus 53% (p = 0.9) for the group of patients included in other clinical trials The median progression-free survival was 3.6 months (95 CI 1.8-5.3) versus 3.6 months (95 CI 0.9-6.3) (p = 0.5). Conclusions: Extensive molecular profiling by using high-throughput techniques is feasible in routine practice, allow identification of actionable mutations in the majority of cases and can be used to enroll patients in early phase trials matched to their tumor genotype. Citation Format: MAUD TOULMONDE, THOMAS GRELLETY, CELINE AUZANNEAU, YEC9HAN LAIZET, KEVIN TRAN, ANNE FLOQUET, DELPHINE GARBAY, JACQUES ROBERT, ISABELLE HOSTEIN, ISABELLE SOUBEYRAN, ANTOINE ITALIANO. BIP (Bergonie Institute profiling) program: Fighting cancer by matching molecular alterations and drugs in early phase trials. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C48.

Conception, mise en place et fonctionnement d’une RCP dédiée aux essais précoces : l’exemple de l’Institut Bergonié

Nous rapportons l’experience de l’Institut Bergonie dans la mise en place en routine d’un programme de cartographie genomique tumorale au sein d’une reunion de concertation pluridisciplinaire (RCP) dediee. Nous discutons egalement les nombreux defis emergeant dans l’acces a la medecine de precision en oncologie.

Les formes héréditaires du cancer de l’ovaire : particularités clinico-biologiques et thérapeutiquesHereditary ovarian carcinomas: clinico-biological features and treatment

Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.