Gynecologic Carcinosarcomas Research Articles

Tissue-specific signatures of activating PIK3CA and RAS mutations in carcinosarcomas of gynecologic origin

ObjectivesGynecologic carcinosarcoma is an aggressive malignancy that requires more effective treatment approaches. However, therapeutic implications regarding the specific gynecologic site of origin and the admixture of carcinomatous and sarcomatous elements that define this tumor remain uncertain. Therefore, broad genotyping was performed to identify tissue-specific somatic mutational profiles that may help direct targeted therapies in this complex neoplasia. MethodsGenotyping was conducted on primary gynecologic carcinosarcomas arising from various disease sites (uterus, ovary, fallopian tube, vagina) and within isolated histological subcomponents. Nucleic acids extracted from diagnostic tissue were used in a genotyping platform that simultaneously queried >120 common mutations across 14 cancer genes. Mutational status was correlated with clinical variables using logistic regression and Kaplan–Meier survival estimates. ResultsCancer gene mutations were identified in 46% of the 52 patient cohort and include TP53 (23%), PIK3CA (19%), KRAS (15%), CTNNB1 (4%) and NRAS (2%). Mutation in a single gene was observed in 31% of patient samples, while synchronous mutations involving 2 and 3 genes were noted in 13% and 2% of samples, respectively. Comparative evaluation of the carcinomatous and sarcomatous elements within a tumor demonstrated a similar mutation signature. Mutations in PIK3CA, KRAS and NRAS were exclusive to tumors of uterine origin and age-adjusted Cox proportional hazards modeling associated advanced age, stage and TP53 mutations with decreased survival in the uterine subset. ConclusionWhile carcinosarcomas across gynecologic disease sites are histologically similar, therapeutically relevant mutations in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways predominated in carcinosarcomas arising in the uterus.

Carboplatin, ifosfamide, and mesna (CIM) for the treatment of gynecological carcinosarcoma

e16539 Background: A GOG trial comparing cisplatin/ifosfamide/mesna chemotherapy versus whole abdominal irradiation for FIGO stages I-IV carcinosarcoma (CS) showed an estimated median survival (MS) of 50 months for chemotherapy but high toxicity. This study investigates the efficacy and tolerability of a novel regimen using carboplatin AUC 5, ifosfamide 3 g/m2 and mesna 1 g/m2 (CIM) in both the adjuvant and metastatic setting. Methods: Retrospective analysis of women with CS treated from May 1997-May 2007 with CIM (group 1) versus other chemotherapy regimens (group 2). Toxicity was graded according to the Common Toxicity Criteria and MS estimated using the Kaplan-Meier method. Results: Of 51 eligible women (median age 71 years) 35 (69%) had stage 3 or 4 disease. 35/51 (69%) received chemotherapy; 2 with stage 1c disease received pelvic radiotherapy (pRT) alone whilst the remaining 14 were unfit for any treatment. Median follow-up for the treated patients is 45 months. 11/35 patients (31%) received CIM as first-line chemotherapy. Other regimens included: carboplatin (n = 14); carboplatin/paclitaxel (n = 3); carboplatin/epirubicin (n = 3); carboplatin/doxorubicin (n = 2); doxorubicin/ifosfamide (n = 1); cisplatin/ifosfamide (n = 1). 20/35 (57%) received adjuvant chemotherapy (AC) of which 8 received CIM; 11/20 patients also received adjuvant pRT. MS in the CIM AC group is 54.7 months compared to 37.4 months for other regimens. 3/8 patients (37.5%) in the CIM arm developed recurrent disease compared to 9/12 (75%) for other regimens. 4/16 patients received CIM as first- or second-line palliative chemotherapy. All patients responded of whom 2 achieved clinical and radiological complete response (CR). One woman subsequently relapsed and achieved a second CR with CIM. MS for all chemotherapy-treated patients is 54.7 months (group 1) versus 20.6 months (group 2) (p = 0.07). No patients in group 1 experienced any grade 3/4 toxicity and all patients completed the prescribed treatment. There were 2 unexpected treatment-related deaths in group 2, one of whom received carboplatin/paclitaxel and the other carboplatin/epirubicin. Conclusions: CIM appears to be efficacious and well tolerated in the treatment of CS and merits further investigation in clinical trials. No significant financial relationships to disclose.

Methylation of the tumor suppressor gene <i>p16</i> in gynecological carcinosarcoma

目的: 女性生殖器に発生する癌肉腫は稀ではあるが, 臨床的には悪性度の高い腫瘍であり, 組織学的には癌腫および肉腫の両成分を有する. これまでの研究で, 著者らは, 染色体9p21部位で癌肉腫に高頻度のヘテロ接合性消失 (LOH) を発見した. 9p21部位には重要な癌抑制遺伝子p16が存在しており, p16はヒト腫瘍において, 高頻度に異常の見出される遺伝子の1つである. p16は, そのCpG islandのメチル化で不活化される事が多く, mutationやhomozygous deletionは稀である. 今回, 癌肉腫におけるp16異常の関与につき検討した. 方法: 18症例の癌肉腫症例のパラフィン薄切切片よりマイクロディセクション法にてDNAを採取し, 解析に用いた. single-strand conformational polymorphism (SSCP) 法によりp16 mutationの検索をした. methylation specific PCR (MSP) およびmethylation-sensitive restriction enzyme digest PCR (MSREDP) 法によりp16 promoter, exon 1およびexon 2におけるメチル化の有無を検索した. また, combinebisulfite-restrictionanalysis (COBRA) 法によりマイクロディセクトした癌, 肉腫成分ごとにメチル化の程度を測定した. 結果: 癌肉腫においてp16遺伝子のmutationは見つからなかった. メチル化は18例中4例 (22.2%) がpromoter領域, 5例 (27.8%) がexon 1, 15例 (83.3%) がexon 2に検出された. さらに, COBRA法によって癌と肉腫のメチル化程度がほぼ同じ約30%であるのに対して, 軟骨肉腫成分は約20%であり, 10%ほど低い事も見出した. 結論: 癌肉腫において癌抑制遺伝子p16のメチル化が高頻度で存在し, その部位は, promoter領域やexon 1ではなく, exon 2が主である. これまでに, exon 2のメチル化はある種の進行癌や, 少数の腫瘍に見出されている. よって, 癌肉腫では, 9p21のLOHとp16 exon 2のメチル化が, 2-hitによるp16不活化の特徴的な機序と考えられる. さらに, メチル化の程度が, 癌肉腫の組織分化能に影響している可能性も示された.