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.

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, ß-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 ß-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.

Real-World Data on Olaparib in Relapsed BRCA-mutated Ovarian Cancer: A Multicenter GINECO RETROLA Cohort Study.

BACKGROUND/AIM: Olaparib was approved in 2014 by the European Medicines Agency (EMA) as maintenance treatment for patients with breast cancer gene (BRCA)-mutated platinum-sensitive relapsed high-grade epithelial ovarian cancer (EOC) following the results of the Study 19. We present the results of a national real-world study on the effectiveness of olaparib in relapsed BRCA-mutated EOC patients. PATIENTS AND METHODS: Patients with EOC, peritoneal, and/or fallopian-tube cancer treated with olaparib in a French Center between May 2014 and March 2017 were included. The primary end-point of the study was progression-free survival. RESULTS: Of the 128 patients analyzed, 89 were treated according to the EMA label. The median progression-free survival was 17.0 months. The most common treatment-related toxicity was fatigue. Treatment-related myelodysplastic syndrome (n=5) and a second cancer (n=1) were diagnosed. CONCLUSION: In this real-life setting, olaparib confirmed its efficacy and safety profile, as previously shown in clinical trials.

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.

Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.

Clinical impact of extensive molecular profiling in advanced cancer patients.

Previous precision medicine studies have investigated conventional molecular techniques and/or limited sets of gene alterations. The aim of this study was to describe the impact of the next-generation sequencing of the largest panel of genes used to date in tumour tissue and blood in the context of institutional molecular screening programmes. DNA analysis was performed by next-generation sequencing using a panel of 426 cancer-related genes and by comparative genomic hybridization from formalin-fixed and paraffin-embedded archived tumour samples when available or from fresh tumour samples. Five hundred sixty-eight patients were enrolled. The median number of prior lines of treatment was 2 (range 0-9). The most common primary tumour types were lung (16.9%), colorectal (14.4%), breast (10.6%), ovarian (10.2%) and sarcoma (10.2%). The median patient age was 63 years (range 19-88). A total of 292 patients (51.4%) presented with at least one actionable genetic alteration. The 20 genes most frequently altered were TP53, CDKN2A, KRAS, PTEN, PI3KCA, RB1, APC, ERBB2, MYC, EGFR, CDKN2B, ARID1A, SMAD4, FGFR1, MDM2, BRAF, ATM, CCNE1, FGFR3 and FRS2. One hundred fifty-nine patients (28%) were included in early phase trials. The treatment was matched with a tumour profile in 86 cases (15%). The two main reasons for non-inclusion were non-progressive disease (31.5%) and general status deterioration (25%). Twenty-eight percent of patients presented with a growth modulation index (time to progression under the early phase trial treatment/time to progression of the previous line of treatment) >1.3.Extensive molecular profiling using high-throughput techniques allows for the identification of actionable mutations in the majority of cases and is associated with substantial clinical benefit in up to one in four patients.

[Hereditary ovarian carcinomas: clinico-biological features and treatment]. / 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.

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.

"Metronomic" chemotherapy in advanced soft tissue sarcomas.

PURPOSE: Angiogenesis plays a crucial role in metastatic progression of soft tissue sarcomas (STS). Endothelial cells are the primary target of metronomic chemotherapy. We report the safety and the efficacy of metronomic chemotherapy in metastatic STS patients. METHODS: The medical charts of 26 metastatic STS patients treated at Institut Bergonie (Bordeaux, France) with metronomic etoposide (100 mg/day orally for 21 consecutive days, repeated every 4 weeks) were reviewed by two independent investigators. RESULTS: Median age was 49. All but three patients received prior treatment with doxorubicin and/or ifosfamide. One patient (4%) had partial response and 11 patients (42%) had stable disease for more than 24 weeks. The 6-month and the 1-year progression-free survival rates were 42% [95% CI: 23; 61] and 23% [95% CI: 7; 39], respectively. The 6-month and the 1-year overall survival rates were 69% [95% CI: 51; 87] and 31% [95% CI: 13; 49], respectively. Two patients experienced grade 4 febrile neutropenia and one of them died of sepsis. CONCLUSION: In this series, metronomic etoposide was associated with significant clinical activity in STS. Further prospective investigations are necessary to identify those patients who are more likely to benefit from this strategy.