Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling

OBJECTIVES: The molecular pathogenesis of ovarian serous tumors of low malignant potential (S-LMP) is not well understood, although the collective data suggest that they arise through molecular mechanisms distinct from those leading to conventional serous carcinomas (S-Ca). To further examine the molecular differences between these two diseases, we studied the gene expression pattern of ovarian S-LMP and S-Ca using high-density spotted cDNA and tissue microarrays. METHODS: Total RNA from 23 ovarian S-LMP and S-Ca was analyzed on 43,200 spot cDNA microarrays and the differential expression of proteins encoded by differentially expressed genes was validated using tissue microarrays. RESULTS: Unsupervised hierarchical clustering analysis of filtered data showed a complete separation between S-LMP and S-Ca, based predominantly on a small set of genes expressed at higher levels in S-LMP than in S-Ca. Many genes previously identified as up-regulated in ovarian carcinoma relative to normal ovarian tissue were expressed at even higher levels in S-LMP. These genes included mucin-1, mesothelin, HE4, PAX 8, and apolipoprotein J/clusterin. Immunohistochemical staining of tissue microarrays confirmed higher expression of selected proteins encoded by these genes in the S-LMP. Few genes were expressed at a higher level in S-Ca; these included E2F1, topoisomerase IIalpha, and cyclin E, with higher levels of cyclin E protein confirmed by immunohistochemistry. CONCLUSIONS: S-LMP and S-Ca are distinguished at the molecular level by a relatively small gene set, suggesting the pathogenesis of S-LMP as well as S-Ca may involve molecular pathways that escape detection by global gene expression profiling. In order to obtain biologically and clinically relevant information about the mechanisms involved in ovarian carcinogenesis, future studies based on molecular profiles of ovarian cancer should include analyses of low malignant potential tumors. Inclusion of such tumors is also critical to the evaluation of the efficacy of potential new diagnostic and/or therapeutic biomarkers.     

Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma

The objective of this study was to evaluate the pattern of chemoresistance in invasive micropapillary/low-grade serous ovarian carcinoma (invasive MPSC/LGSC) and high-grade serous ovarian carcinoma (HGSC) according to extreme drug resistance (EDR) assay testing. Surgical specimens of 44 recurrent ovarian cancer patients harvested at the time of cytoreductive surgery between August 1999 and February 2004 were identified retrospectively from the tumor registry database. Thirteen patients (29.5%) had recurrent invasive MPSC/LGSC and 31 (70.5%) patients had recurrent HGSC. Eight drugs were evaluated; EDR assay results were compared between LGSC and HGSC groups using Fisher exact tests and exact logistic regression models. Compared to HGSC, invasive MPSC/LGSC were more likely to manifest EDR to the drugs paclitaxel (69% vs 14%, P < 0.001), carboplatin (50% vs 17%, P= 0.05), cyclophosphamide (40% vs 23%, P= 0.41), gemcitabine (36% vs 19%, P= 0.40), and cisplatin (33% vs 28%, P= 0.72) and less likely to be resistant to etoposide (0% vs 44%, P= 0.007), doxorubicin (8% vs 45%, P= 0.03), and topotecan (8% vs 21%, P= 0.65). Exact logistic regression estimates revealed that invasive MPSC/LGSC patients had significantly increased probabilities of paclitaxel resistance odds ratio (OR) = 12.5 (95% CI: 2.3-100.0), P= 0.001 and carboplatin resistance OR = 4.8 (95% CI: 0.9-25.0), P= 0.07, while the HGSC cases were more likely to be resistant to etoposide OR = 12.1 (95% CI: 1.7-infinity), P=0.009 and doxorubicin OR = 8.6 (95% CI: 1.0-413.7), P= 0.05. In this retrospective analysis, patients with recurrent invasive MPSC/LGSC were more likely to manifest EDR to standard chemotherapy agents (platinum and paclitaxel). These observations may help to guide chemotherapeutic decision making in these patients if confirmed in a large-scale study.     

Surgical staging for epithelial ovarian tumors of low malignant potential

From January 1975 to December 1991, 34 patients with a diagnosis of epithelial ovarian tumors of low malignant potential (LMP) were admitted to the Istituto Nazionale Tumori of Milan. Eighteen of them (group 1) underwent complete staging laparotomy and retroperitoneal para-aortic and pelvic lymphadenectomy, as for ovarian cancer. In the remaining 16 cases (group 2), the surgical treatment ranged from unilateral oophorectomy to incomplete staging procedure. In group 1, nine patients (50%) were found to have retroperitoneal nodal involvement. In group 2, all patients had stage I disease. Patients were followed up for 20–222 months (mean 108, median 86). There were two recurrences in group 2 (after 5 years) and none in group 1 (NS). Currently all patients are alive and disease free. Nine of 18 group 1 patients were upstaged to stage III on the basis of lymph node involvement only. However, at least in this retrospective series, lymph node metastases did not affect prognosis or survival.     

Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum

Objective

To determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum.

Methods

We searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as “patient-regimens.” Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed.

Results

We identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2 months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6 months. Patient-regimens involving ER +/PR + disease produced a longer median TTP (8.9 months) than patient-regimens involving ER +/PR − disease did (6.2 months; p = 0.053). This difference approached but did not reach statistical significance.

Conclusions

Hormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.     

Frequency of serous tubal intraepithelial carcinoma (STIC) in patients with high grade serous ovarian cancer

ObjectiveSerous tubal intraepithelial carcinoma (STIC) is a known precursor of high-grade serous ovarian cancer (HGSOC). This study aimed to evaluate the proportion of STIC in patients with HGSOC and analyze the STIC-related prognosis in patients with HGSOC.Materials and methodsAll pathology reports at our institution that included bilateral salpingectomies of patients with HGSOC from January 2013 to December 2018 were reviewed by two experienced pathologists. The specimens from the ovaries and the salpinx including fimbria were examined. We analyzed the correlation between STIC and HGSOC and compared the clinical characteristics and STIC-related prognostic outcomes in patients with HGSOC.ResultsEleven of the 76 cases were STIC. BRCA mutations were found in 16.9% of patients with HGSOC. STIC was observed in 30.0% of patients with BRCA mutations and in 14.3% of patients without BRCA mutations. The incidence of STIC in patients with BRCA mutations was approximately twice that in patients without BRCA mutations; however, the difference was not statistically significant (P = 0.231). Further, the 5-year survival rate of patients without STIC appeared to be high; nevertheless, the difference was not statistically significant (59.7% vs. 47.4%, P = 0.633). Moreover, there was no significant difference in disease-free survival rate according to STIC (36.4% vs. 33.1%, P = 0.956).ConclusionSTIC was identified in patients with HGSOC, and STIC incidence was prominent in HGSOC related to BRCA mutation. Although low frequency, STIC was detected in patients without BRCA mutation. Therefore, prophylactic salpingectomy may be useful for prevention of HGSOC.     

Carcinosarcoma of the ovary compared to papillary serous ovarian carcinoma: A SEER analysis

Objective

The aims of this study are to determine if outcomes of patients with ovarian carcinosarcoma (OCS) differ from women with high grade papillary serous ovarian carcinoma when compared by stage as well as to identify any associated clinico-pathologic factors.

Methods

The Surveillance, Epidemiology, and End Results (SEER) Program data for all 18 registries from 1998 to 2009 was reviewed to identify women with OCS and high grade papillary serous carcinoma of the ovary. Demographic and clinical data were compared, and the impact of tumor histology on survival was analyzed using the Kaplan–Meier method. Factors predictive of outcome were compared using the Cox proportional hazard model.

Results

The final study group consisted of 14,753 women. 1334 (9.04%) had OCS and 13,419 (90.96%) had high grade papillary serous carcinoma of the ovary. Overall, women with OCS had a worse five-year, disease specific survival rate, 28.2% vs. 38.4% (P < 0.001). This difference persisted for each FIGO disease stages I–IV, with five year survival consistently worse for women with OCS compared with papillary serous carcinoma. Over the entire study period, after adjusting for histology, age, period of diagnosis, SEER registry, marital status, stage, surgery, radiotherapy, lymph node dissection, and history of secondary malignancy after the diagnosis of ovarian cancer, carcinosarcoma histology was associated with decreased cancer-specific survival.

Conclusions

OCS is associated with a poor prognosis compared to high grade papillary serous carcinoma of the ovary. This difference was noted across all FIGO stages.     

Ovarian tumors of low malignant potential: a retrospective study of 234 patients

Two-hundred and thirty-four consecutive patients with a histologic diagnosis of low malignant potential (LMP) ovarian tumors between 1972 and 1994 form the basis of this study. Six patients had a synchronous intra-abdominal or pelvic malignancy and six were considered to have areas of early stromal invasion, these patients being considered separately. The patients ages ranged from 16–93 years. The histologic type was mucinous in 53%, serous in 37%, mixed in 7%, and other in 3%. Ovarian tumors were bilateral in 15% with mucinous and 39% with serous disease. Fourteen patients had pseudomyxoma peritonei. Extra ovarian disease was found in 28 (34%) patients with serous and 15 (13%) with mucinous tumors. Five (6%) patients with serous tumors had invasive implants and four had lymph node implants. Clinically 175 patients had stage I disease, 19 had stage II and 28 stage III disease but only 88 patients were formally staged. Follow-up details were available for 173 (74%) patients, ranging from 2 months to 20 years, mean 54 months. Thirteen patients (6%) died of disease, of whom six had pseudomyxoma peritonei. Twelve patients (6%) had developed invasive malignancy of whom seven died. None of the patients with formally staged Ia or Ib disease had a recurrence. With the exception of patients with synchronous malignancy or pseudomyxoma peritonei the prognosis is good. Surgical staging offers limited prognostic information but sacrifice of fertility is not justified. Adjuvant therapy is not indicated in early stage disease and its role for patients with extra ovarian disease remains controversial.     

Prognostic value of elevated preoperative serum CA125 in ovarian tumors of low malignant potential: a multinational collaborative study (ANZGOG0801)

Objective

Previous studies on prognostic factors in ovarian tumors of low malignant potential (LMP) were too small for robust conclusions. We examined the prognostic impact of preoperative serum CA125 ≥ 50 U/ml levels in patients diagnosed with ovarian LMP tumors in a large multinational cohort.

Methods

This retrospective study included 940 patients with ovarian LMP tumors diagnosed between 1985 and 2008 at six gynecologic cancer centers. Patients either had radical treatment (bilateral salpingo-oophorectomy with or without hysterectomy) or conservative, fertility-sparing treatment. Multivariate Cox proportional hazard models were used to determine independent prognostic factors for disease-free (DFS) and overall survival (OS). Based on receiver operating characteristic curve (ROC), a preoperative serum CA125 level ≥ 50 U/ml was considered “elevated”.

Results

CA125 was more often elevated in serous than in mucinous tumors and in advanced FIGO stages (2 to 4) compared to stage1. DFS at 5 years was 89% and 95% in patients with elevated and normal CA125 levels (p < 0.05). Similarly, the 5-year OS was 90% among patients with elevated CA125 compared to 95% among patients with normal levels (p < 0.05). For both DFS and OS elevated CA125 levels and advanced stages of the disease were independent prognostic factors. Analysis of subgroups revealed that CA125 was only prognostic in serous LMP tumors.

Conclusions

In the context of serous ovarian LMP tumors, elevated preoperative serum CA125 represents a biomarker independently associated with impaired disease-free and overall survival. CA125 is available in most centers and could inform surgeons about the risk of treatment failure.     

Comparison of clinical outcomes of patients with clear cell and endometrioid ovarian cancer associated with endometriosis to papillary serous carcinoma of the ovary

Objective

The aim of this investigation was to compare outcomes of patients with clear cell carcinoma (CCC) and endometrioid carcinoma (EC) of the ovary associated with endometriosis to patients with ovarian papillary serous carcinoma (PSC).

Methods

Patients with CCC and EC of the ovary associated with endometriosis were identified and matched by age and stage to PSC controls. Student's t test and chi square test were used to analyze continuous and categorical data. The Kaplan–Meier method was used for survival analysis.

Results

67 cases associated with endometriosis were identified, of which 45 were arising in endometriosis. Cases were matched to 134 PSC controls. 27 patients with tumors associated with endometriosis presented at stage I (40.3%), 27 at stage II (40.3%), ten at stage III (14.9%) and three at stage IV (4.5%). There was no difference in rate of optimal cytoreduction or response to chemotherapy in cases vs. PSC controls. There was a significant increase in synchronous endometrial cancer in tumors associated with endometriosis compared to PSC (25.4% vs. 3.7%; P < 0.001). 18 cases (26.9%) had recurrent disease vs. 55 (41%) controls (P = 0.03). The 5-year disease-free survival (DFS) and overall survival (OS) of patients with tumors associated with endometriosis compared to PSC controls were 75% vs. 55% (P = 0.03) and 85% vs. 77% (P = 0.2), respectively.

Conclusions

Patients with tumors associated with endometriosis had a higher rate of synchronous endometrial cancer. Cases also demonstrated a lower rate of recurrence and improved 5 year DFS; however, this did not translate into a difference in OS.     

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

Objective

Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma.

Methods

Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I–IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes.

Results

LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r = 0.31, p = 0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93–20.4, p = 0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p = 0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54–5.88, p = 0.001) and overall survival (HR 2.69, 95%CI 1.18–6.23, p = 0.021) while ER-expression did not remain as a significant variable in multivariate analysis.

Conclusion

Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma.     

Laparoscopy in the treatment of ovarian tumours of low malignant potential

Laparoscopy is increasingly used by gynaecologists for the investigation of adnexal masses. Uncertainty exists whether ovarian tumours of low malignant potential can effectively be treated by laparoscopy, whether staging bears a benefit for all patients, whether port-site metastases are a problem and how long patients need to be followed up after surgery. This review summarises the evidence to address these important questions.     

BRAF polymorphisms and the risk of ovarian cancer of low malignant potential

OBJECTIVE: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. METHODS: We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. RESULTS: Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). CONCLUSION: We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.     

Utility of F-FDG PET/CT in follow-up of patients with low-grade serous carcinoma of the ovary

Objective

Ovarian low-grade serous carcinoma (LGSC) is a rare and indolent tumor. The utility of ¹⁸F-FDG PET/CT in monitoring patients with LGSC has not been established. We assessed the accuracy and clinical impact of ¹⁸F-FDG PET/CT in patients with ovarian LGSC after initial treatment.

Methods

A retrospective analysis was performed on patients with ovarian LGSC who had undergone ¹⁸F-FDG PET/CT scans during follow-up after primary treatment. The impact of ¹⁸F-FDG PET/CT on the management plan was assessed. The sensitivity, specificity, and accuracy of ¹⁸F-FDG PET/CT findings in the detection of recurrence were calculated. Total lesion glycolysis (TLG) was determined to assess metabolic activity of tumors. Potential prognostic factors for disease-free and overall survival after recurrence were assessed.

Results

Forty-eight patients were included in the analysis, 39 with recurrent disease and 9 without recurrence. A total of 91 ¹⁸F-FDG PET/CT scans were performed, and 30% of these (27/91) had an impact on the management plan. Sensitivity, specificity, and accuracy in the detection of LGSC recurrence were 94%, 100%, and 97%, respectively, for ¹⁸F-FDG PET/CT; 89%, 95%, and 93%,respectively, for CT; and 68%, 89%, and 73%, respectively, for serum CA-125. There was no significant difference in sensitivity between PET/CT and CT. Survival after recurrence was poorer in patients with a TLG value greater than 67.7 g.

Conclusions

¹⁸F-FDG PET/CT may provide useful information during the follow-up of patients with LGSC after initial treatment. TLG may be a predictor of survival after recurrence.     

Role of hysterectomy and lymphadenectomy in the management of early-stage borderline ovarian tumors

Objective

To examine survival of women with stage T1 borderline ovarian tumors (BOTs) stratified by hysterectomy and lymphadenectomy status at surgery.

卵巢上皮性包涵体的起源与低级别卵巢浆液性癌的发病机制

目的 探讨卵巢上皮性包涵体的起源与低级别卵巢浆液性癌的发病机制.方法 收集山东大学齐鲁医院和美国亚利桑那大学附属医院病理科自2000年5月至2010年4月间收治的卵巢浆液性肿瘤患者及行预防性附件切除术患者的手术标本共198份.其中,卵巢肿瘤标本138份,包括卵巢浆液性囊腺瘤53份、卵巢交界性浆液性肿瘤44份、低级别卵巢浆液性癌41份;无明显病理学变化的同侧卵巢及输卵管标本116份(卵巢及输卵管分别为60、56份),取自60例行预防性附件切除术患者的一侧附件.HE染色后镜下观察所有标本的病理学形态特点;并采用免疫组化单染色法检测其免疫表型配对盒基因8抗原( PAX8)、钙结合蛋白(calretinin)、微管蛋白(tubulin)、核增殖相关抗原(Ki-67)的表达,免疫组化双染色法检测其免疫表型PAX8/calretinin的表达.结果 免疫组化PAX8、calretinin单染色法检测显示,90％( 54/60)的卵巢表面生发上皮细胞的免疫表型为PAX8阴性(-)、calretinin阳性(+),HE染色后镜下观察符合间皮组织的形态特点,为间皮型上皮;但有10％(6/60)的卵巢表面生发上皮细胞的免疫表型为PAX8(+)、calretinin(-),HE染色后镜下观察其与输卵管上皮组织的形态相似,为输卵管型上皮.60份正常卵巢中共有921个卵巢上皮性包涵体,表现出两种免疫表型,79％( 728/921)为PAX8(+)、calretinin(-),HE染色后镜下观察其与输卵管上皮组织的形态相似,为输卵管型包涵体;21％(193/921)为PAX8(-)、calretinin(+),HE染色后镜下观察其与间皮组织的形态相似,为间皮型包涵体.免疫组化PAX8/calretinin双染色法进一步验证了卵巢上皮性包涵体的这两种免疫表型.免疫组化PAX8、calretinin、tubulin单染色法检测显示,免疫表型为PAX8(+)、calretinin(-)、tubulin(+)的卵巢表面生发上皮和卵巢上皮性包涵体均包含纤毛型细胞和分泌型细胞2种柱状细胞,形态上接近输卵管黏膜上皮;而免疫表型为PAX8(-)、calretinin(+)、tubulin(+)的卵巢表面生发上皮和卵巢上皮性包涵体则为单层扁平或立方形细胞,与间皮组织的细胞形态类似.免疫组化tubulin、Ki-67单染色法检测显示,分泌型细胞与纤毛型细胞数的比值和细胞增殖指数在卵巢上皮性包涵体及卵巢浆液性囊腺瘤、卵巢交界性浆液性肿瘤、低级别卵巢浆液性癌中呈明显递增趋势(P＜0.05).结论 免疫表型为PAX8(+)、calretinin(-)的卵巢上皮性包涵体可能起源于输卵管,低级别卵巢浆液性癌的发生可能与分泌型细胞的克隆扩增有关.     

Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer

OBJECTIVE: Evaluation whether Jewish founder mutations in BRCA predispose to borderline tumors as they do to early invasive ovarian cancers. METHODS: All Jewish women with borderline or invasive ovarian tumors, diagnosed over a 5-year period (1994-1999), were identified in the frame of a nationwide epidemiological study on ovarian cancer in Israel. Out of a total of 1489 patients, 1269 were interviewed; of them 256 (20.2%) patients were identified with stage I and II invasive epithelial ovarian tumors, and 233 (18.3%) patients were identified with borderline tumors. All patients underwent interviews, and blood or tissue samples from 117 borderline tumors and 161 early stage invasive tumors were analyzed for the presence of the 185delAG and 5382insC BRCA1, and the 6174delT BRCA2 Jewish founder mutations. RESULTS: Patients with borderline tumors were younger at diagnosis, and more frequently of the serous type (P < 0.001) as compared to patients with early stage ovarian cancer. Prevalence of Jewish founder mutations in BRCA1 and BRCA2 was only 4.3% of patients with borderline tumors as compared to 24.2% of patients with early stage ovarian cancer (P = 0.001). CONCLUSIONS: This nationwide study comparing patients with early stage borderline and invasive epithelial tumors of the ovary confirms our previous pilot study that showed a lower incidence of BRCA mutations in patients with borderline tumors. Our results suggest that the genetic predisposition and the molecular mechanisms underlying tumor initiation differ between invasive and borderline tumors of the ovary.     

Phase II trial of imatinib mesylate in patients with recurrent platinum- and taxane-resistant low-grade serous carcinoma of the ovary, peritoneum, or fallopian tube

Objective

To evaluate the efficacy and tolerability of imatinib mesylate in patients with recurrent low-grade serous carcinoma (LGSC) of the ovary, peritoneum, or fallopian tube.

Methods

This open-label, single-institution phase II trial enrolled patients with platinum-resistant LGSC who had measurable disease, had received up to 4 platinum- and/or taxane-containing chemotherapy regimens, and had been previously screened for at least one imatinib targeted biomarker (c-kit, platelet-derived growth factor receptor [PDGFR]-β, or bcr-abl). Imatinib (600 mg) was administered daily for one 6-week course and continued in the absence of toxicity and disease progression.

Results

Thirteen patients were enrolled; 12 were evaluable for toxicity, and 11 were evaluable for response. A total of 17 courses were administered (median, 1 course; range, 1-5 courses). Complete or partial responses were not observed. One patient had stable disease for 7.3 months. c-Kit, bcr-abl, or PDGFR-β were present in 48%, 77%, and 100% of patients, respectively. No correlation between best response (stable disease) and the presence of imatinib-targeted biomarkers was observed. Adverse events included grade 3 skin rash in one patient leading to discontinuation of the drug, and grade 3 febrile neutropenia and grade 2 weight gain in two patients leading to dose reductions. The most common grade 1 or 2 toxicities were fatigue (66%), nausea/vomiting (66%), and diarrhea (41%); grade 3 toxicities included skin rash and granulocytopenia events. No grade 4 or 5 toxicities were observed. The median progression-free survival time was 1.3 months (95% CI, 1.27, 1.40 months), and the median overall survival time was 14.9 months (95% CI, 11.0, 18.9 months).

Conclusion

Imatinib is well-tolerated but has no activity in patients with platinum- and taxane-resistant LGSC or the ovary, peritoneum, or fallopian tube.