Background Bevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients. Methods Patients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared. Results Among the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease ( p = 0.03) and a lower dose of Bev at the first time during the first cycle administration ( p < 0.01) than in group B. Progression-free survival (PFS) was better in group A than in group B ( p < 0.01). Multivariate analysis revealed that group A was a better prognostic factor for PFS (hazard ratio 0.53, p = 0.03). Stable duration was longer in group A than in group B ( p < 0.01). The incidences of adverse effects, including hematological toxicities such as neutropenia ( p = 0.01) and nonhematological toxicities such as hypertension ( p < 0.01), intestinal obstruction ( p < 0.01), and thromboembolic events ( p < 0.01), were lower in group A than in group B. Conclusions Weekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

Approximately 50%-80%of cancer patients have been reported to result in a devasting syndrome such as cancer cachexia (CC) and at least 20% patients reach the death [1]. Sarcopenia accompanying with muscle loss shows the most clinically relevant phenotypic feature of CC, such as asthenia, fatigue, impaired physiologic function, reduced tolerance to treatments, resulting in impaired quality of life and shorter survival. Such wasting syndromes as sarcopenia are shown in 20%-70% cases depending on the tumor type. Accordingly, reversion of CC and sarcopenia is of most importance and interest. In addition, high serum IL-6 has been reported to result in cancer metastases, invasion and resulting in CC [2,3]. Early detection of such sarcopenia syndromes is clinically most important. If sarcopenia can be precedently predicted, better treatment strategies will be possible. It is well-known that sarcopenia is accompanied by increased levels of inflammation factors TNF-alpha and IL-6 [4]. It has been reported that activation of the IL-6/STAT3 pathway also plays a causative role in the pathogenesis of cancer cachexia, one of the most distressing complications associated with the development of ovarian cancer [5]. Indeed, cachexia usually accompanies the development of ascites and chemoresistance in the most advanced stages of the disease [6]. The majority of advanced gynecologic cancer (GC) patients develop cachexia, which is a major contributor of morbidity and mortality in these patients. Cachexia is primarily responsible for body and muscle weight loss and correlates with tumor burden, increased proinflammatory cytokine levels, fatigue, and reduced response to chemotherapy and radio-therapy [7]. Patients presenting with advanced stage GC often show large tumor and ascites burden that, in turn, results into severe malnourishment because of decreased oral intake and compromised bowel functions. Despite its significant negative impact on quality of life, no effective treatment is currently available for GC-related cachexia. Indeed, muscle loss and low skeletal muscle attenuation are often detected in women undergoing primary debulking surgery for the treatment of GCs. Along the same line, recent evidence suggests that baseline sarcopenia represents one of the most accurate prognostic factors for survival in advanced GC and during chemotherapy treatment [8]. Clinically, we find out that elevation of serum IL-6 in patients with gynecologic cancers is varied by effect of the adjuvant chemotherapy.

e17059 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizmab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A combination therapy using weekly administration of B with eribulin and oxaliplatin (EriOX) in relapsed patients with platinum-resistant and refactory ovarian carcinomas (PR-ROC) was evaluated retrospectively, and the association with response and serum biomarkers was investigated. Methods: Medical charts of the patients who met the criteria shown below were identified: (a) histologically confirmed epithelial ovarian cancer (b) diagnosed as platinum-resistant ovarian cancer (c) treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2), and oxaliplatin (30mg/m2), three weeks on and one week off, q4weeks (d) written informed consent. Biomarker analyses including serum VEGF, BNP, p53, and IL-6 were also conducted. Results: A total of 34 patients were treated with weekly-B-EriOX. Median age of the patients was 58.5 years (range: 35-76), and median number of previous regimen was 4(range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade 2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. The patients with elevation of serum mutated p53 protein and IL-6 had poorer prognosis. Conclusions: Weekly B and EriOX administration showed a remarkable response for patients with PR-ROC. Elevation of serum mutated p53 protein and IL-6 could be biomarkers for this regimen. These results warrant further prospective studies with additional biomarker analyses.

e17124 Background: The immunotherapy drug, nivolumab, is now approved for several metastatic cancers, and has resulted in responses previously not seen with these cancers. Molecular targeting agents, such as mammalian target of rapamycin (mTOR) inhibitor, have also recently been shown to have modest activity for endometrial cancers, however, the efficacy was limited. The present retrospective analysis is to evaluate the efficacy of Nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers. Methods: A retrospective evaluation for medical charts of the patients were conducted: (a) the cases with histologically confirmed endometrial cancers, (b) those that had recurrent diseases, (c) diagnosed as refractory for the previous chemotherapy, (d) those that were treated with combination therapy using tri-weekly Nivolumab (100mg/body, every 3 weeks) alone, or combination with molecular targeting agents. The association with serum markers and response was also investigated. Results: A total of 16 patients were identified: 5 cases with endometrioid G1/2, 4 cases with endometrioid G3, and the 6 cases with serous, and one case with mucinous histology. Median age was 61 years old (range:43-76), and median number of the previous chemotherapy was 4 regimens (range:1-5). Combined drugs included everolimus (n = 9), temozolomide (n = 1), trametinib (n = 1), and nintedanib (n = 1). Among 12 cases with evaluable disease, a complete response over 20 months was observed in one case: a case with endometrial carcinoma G2 treated with Nivolumab and evelorimus (5mg/day, continuously). Stable disease more than three months was achieved in 8 cases (67%), and clinical benefit rate (CR+SD > 3months) was achieved in 75% of the cases. Median progression-free survival was 5 months (range: 3-20+). Non-hematological adverse events included general fatigue, mucositis, dysgeusia, skin rash, edema, and liver dysfunction, but the toxicity greater than grade2 was observed and in a case with liver dysfunction (G3). There was no significant relationship between response and serum levels of VEGF, p53, and IL-6, however, clinical benefit was observed in higher abundance of endometrioid histology compared with serous subtype (86% vs. 50%). Conclusions: Combination therapy using Nivolumab with evelolimus could be a candidate for recurrent and refractory endometrial cancers. Biomarker analyses for the responders are mandatory for further investigation for larger clinical studies.

11051 Background: Uterine sarcomas are associated with poor prognosis snce the complete remission is extreme rare. Therefore, treatment with chemotherapy including eribulin or trabectedin, hormone therapy or molecular-targeted therapy including pazopanib or olaratumab was expectd, but the effect is not satisfactory. Thus, we evaluated the effects of temozoromide (T), derivateives of dacarbazine, and bevacizumab (B) (TB) containing or not cabozantinib (C), a multikinase inhibitor of MET, AXL, RET and VEGFR2 (TBC) in heavily pretreated cases of uterine sarcomas. Methods: From 2009 to 2018, 29 patients (pts) with heavily pretreated uterine sarcomas were enrolled. Fifteen of 29 patients were treated with T (80mg/body/day) and B (2mg/kg; days1, 8 and 15, q 4 weeks) (TB). Since 2013, C (140mg/body/week) was added to TB (TBC, n = 14). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse events were assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seven pts (24 %) had carcinosarcoma, fifteen (52 %) had leiomyosarcoma, five (17 %) had undifferentiated uterine sarcoma, one (3 %) had adenosarcoma, and one (3 %) had uterine sarcoma-not other specified. Twenty-three of 29 pts were subjected to response evaluation. Five pts (22 %) had complete response (CR), three (13 %) had partial response, six (26 %) had stable disease (SD). The response rate (RR: CR+PR) and disease-control rate (DCR: CR+PR+SD) were 35 % and 70 %, respectively. The median progression-free survival was 6.5 (2-89) months. When adding C to T and B, DCR was improved from 64 % (TB) to 75% (TBC). Median administration of cycles is 7 (TB) and 5 (TBC). There were 2 dead cases from perforation, but toxicity was almost mild and manageable. Conclusions: We have experienced 5 cases of CR by TB or TBC. Moreover, addition of C to T and B resulted in better disease-control rate. Compared to other reported treatment, TB combined with C could be substantially effective in cases with heavily pretreated uterine sarcomas. These results warrant further prospective and randomized studies.

2592 Background: Cancer cachexia occurs in more than half of cancer patients and can be the primary cause of death for at least 20% of all patients. Cancer cachexia also lowers quality of life in cancer survivors due to a severe loss of skeletal muscle mass. Although a multitude of cytokines have been implicated in facilitating a cachectic state, the correlation of serum IL-6 and cancer-induced muscle wasting in gynecologic cancer patients has not been elucidated. Methods: The correlation between serum level of IL-6 and skeletal muscle volume in the patients with gynecologic cancers that received multiple lines of therapy was retrospectively evaluated. We used the psoas muscle index [PMI (cm2/m2)], the psoas major muscle area at the fifth lumber level divided by the height squared, measured using digital axial CT images, for the value of skeletal muscle volume. The level of IL-6 cut-off for elevation was defined as more than 12.0 pg/mL. The comparison of the survival distributions from the day of IL-6 measuaments was made using a log-rank test. Results: A total of 74 cases were assessed for the serum IL-6 and PMI: 32 cases with Mullerian cancers, 24 cases with endometrial cancers, 13 cases with cervical cancers, and 5 patients with others. The group with elevated IL-6 were associated with the lower PMI (t-test, p = 0.0154). The patients with IL-6 elevation had significantly worse survival compared with those with normal IL-6 (1y-OS; 31% vs. 80%, p < 0.0001). In 28 patients with more than two-point measurements of IL-6, the patients with the decrease to the level of IL-6 cut-off had favorable survival compared with those without the decrease (6m-OS; 100% vs. 52%, p = 0.0069). Conclusions: Serum level of IL-6 could be a sentinel biomarker for cancer-induced sarcopenia in the patients with gynecologic cancers. Additionally, IL-6 could be a biomarker to determine further continuation of aggressive chemotherapy for the patients that had received multiple lines of chemotherapy.

Background: Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. Methods: Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. Results: The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). Conclusions: As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.

a) Ovarian cancers: In ovarian cancer, even exploratory study of sentinel biomarkers is extremely infant, while detection of sentinel lymphnodes is also difficult and the anatomical regions have been poorly investigated, to predict sentinel nodes. The more accurate lymphatic drainage pathways of the ovaries must be examined. Because metastases of ovarian cancer are lymphatic spread, the sentinel lymphnode can be find out in the para-aortic and paracaval regions, obturator fossa and surrounding internal iliac arteries, and inguinal regions. Thus, the strategy of injecting tracers in both ovarian ligaments to identify sentinel nodes is supported [1]. For ultra-early diagnosis of ovarian cancers, analyses of metaboromes including proteomes and cancer exosomes in serum are of most importance. Especially gene expression within CTCs is investigated frequently. However, studies identifying the clinical utility of these biomarkers have not been reported. Thereby, the additional value for these biomarkers seems to be the investigated evidence levels.

e17544 Background: Cancer cachexia occurs in approximately 80% of cancer patients, and is the primary cause of death for 22–30% of all cancer patients. Cancer cachexia also diminishes quality of life in cancer survivors due to a severe loss of skeletal muscle mass. Although a multitude of cytokines have been implicated in facilitating a cachectic state, the correlation of serum IL-6 and cancer cachexia in gynecologic cancer patients has not been elucidated. Methods: The correlation between serum level of IL-6 and skeletal muscle volume in the patients with gynecologic cancers that received multiple lines of chemotherapy was retrospectively evaluated. We used the psoas index [PI (mm2/m2)], the psoas muscle major cross-sectional area divided by the height squared, measured using digital axial CT images, for the value of skeletal muscle volume. Serum level of IL-6 was dived into three categories: high ( > 12.0pg/mL), middle (4.0-12.0pg/mL), and low ( < 4.0pg/mL). PI value was also dived into three categories: high ( > 600mm2/m2), middle (500-600mm2/m2), and low ( < 500mm2/m2). Results: A total of 55 cases were assessed for the serum level of IL-6 and PI value: 26 cases with Mullerian cancers, 14 cases with endometrial cancers, 10 cases with cervical cancers, and 5 patients with others. In 22 cases with low IL-6, PI value was low in 9 cases (41%), middle in7 cases (32%), and high in 6 cases (27%). In 12 patients with middle IL-6, PI value was low in 3 cases (25%), middle in7 cases (58%), and high in 2 cases (17%). Among 21 cases with high IL-6, PI value was low in 14 cases (67%), middle in7 cases (33%), and high in no case (0%). High level of serum IL-6 was significantly associated with lower PI value in gynecologic cancer patients (p = 0.025). Conclusions: Serum level of IL-6 could be a sentinel biomarker for cancer cachexia in the patients with gynecologic cancers. Additionally, IL-6 could be a candidate for therapeutic target for the patients complicated with sarcopenia after multiple lines of chemotherapy.

e17562 Background: Although most of gynecologic cancers receive platinum-containing chemotherapy after the first surgical procedure, the most cases eventually relapse and develop to platinum-resistance. Therefore, strategies to platinum-resistance are urgently necessary. The present study was performed to elucidate the differential effects of nivolumab on the heavily pretreated and platinum-resistant gynecologic cancers by measuring serum IL-6 and mutant P53 protein (mP53). Methods: All of 37 cases with gynecologic cancers received treatment by more than 3 regimens containing platinum and thereafter treatment by nivolumab (100 mg/body/ 3 week, more than 3 times) was performed. Serum IL-6 and mP53 was determined by CLEIA and ELISA methods, respectively. Response and adverse effect (AE) were assessed by the response evaluation criteria in solid tumors (RECIST) v1.1 and common terminology criteria for adverse events (CTCAE) v4.0, respectively. Results: Response rate (RR) and clinical benefit rates (CBR) by nivolumab were observed in order of uterine endometrial cancer (26% and 53%), ovarian cancer (15% and 39%) and uterine cervical cancer (11% and 22%), respectively. Intriguingly, in 7 cases with elevation of mP53 response by nivolumab was not observed, while in all 5 cases with lowering effects of IL-6 by nivolumab the positive tumor response was observed and 1 case with uterine endometrial cancer had complete response after 6 courses of nivolumab. In 1 case with ovarian cancer fulminant type I diabetes occurred after 3 courses of nivolumab and treatment was stopped. Except for this case, AE with more than grade 3 was not observed and the toxicity was almost manageable. Conclusions: In this preliminary study, we confirmed that the effect of nivolumab was obtained in the order of uterine endometrial cancer, ovarian cancer and uterine cervical cancer. Interestingly, elevation of mP53 in serum can predict non-responsive to nivolumab, while IL-6 lowering effect by nivolumab suggests clinical improvement. These results warrant further prospective studies with more large cases.

11056 Background: Uterine leiomyosarcomas (ULMs) tend to recur regardless of their stage, and there is no satisfactory report for relapsed ULMs. Temozolomide (T) is derivatives of dacarbazin and these agents have been used for treatment of ULMs. ULMs has a plenty of vessels compared to uterine myoma so that bevacizumab (B) was used in ULMs. In the present study, we evaluated the effect of TB in heavily pretreated relapsed ULMs. Methods: From 2009 to 2016, total 19 patients (pts) with heavily pretreated ULMs were enrolled. Patients were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse effect (AE) was assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seventeen of 19 pts were subjected to response evaluation. Median age of pts was 56.3 years (range: 31-69). Three pts (18%) had complete response (CR), 2 (12%) had partial response, and 7 (41%) had stable disease (SD). The response rate (RR: CR+PR) and clinical benefit rate (CBR: CR+PR+SD) were 29% and 71%. The median progression-free survival was 14.2 months (range: 0-89). Median administration cycle was 9.5 (range: 2-48). AE with grade 3 and more over were observed in 6 pts. There was one dead case from perforation, but toxicity was almost manageable. Conclusions: We experienced 3 cases of CR, and two of them had CR for more than two years. Intriguingly, TB could be substantially effective even in relapsed patients with heavily pretreated ULMs. These results warrant further prospective and randomized studies.

Abstract Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD>3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB. Conclusions: Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies. nCRPRSDPDRR(%)CBR(%)TB/CTB1732842976TB921333367CTB811512587.5 Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.

5550 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed epithelial ovarian cancer (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2), three weeks on and on week off, q4weeks. The study was conducted using two-stage design of Simon (type I error = 0.05, power = 0.9, true response rate = 25%). Biomarker analyses including serum VEGF, BNP, p53, IL-6, and Her-2 were also conducted. Results: A total of 34 patients were enrolled in the present study: 13 cases in the first-stage, and additional 21 cases in the second-stage. There were 3 responders (≧2) in the first-stage, and the protocol was proceeded to the second-stage. Median age of the patient was 58.5 years (range: 35-76), and median number of previous regimen was 4 (range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. As there were 10 responders (≧6), the protocol was considered for additional investigation. The Patients with elevated serum mutated p53 / IL-6 showed lower response and worse prognoses. Conclusions: Weekly B and EriOX administration was considered for additional investigation for patients with PR-ROC. Serum mutated p53 protein and/or IL-6 could be biomarkers in PR-ROC patients treated with weekly B and EriOX.

Triple-negative breast cancer (TNBC) is aggressive, with high risk of visceral metastasis and death. A substantial proportion of patients with TNBC is associated with BRCA mutations, implying that these tumors are sensitive to DNA-damaging agents. We report successful treatment of a metastatic TNBC in a woman with a BRCA2 germline mutation using combined bevacizumab/paclitaxel/carboplatin (BPC) therapy. The patient was pregnant and had liver metastases, and a complete clinical response was sustained for approximately 5 years. Mastectomy was performed during the 29th week of pregnancy, and the baby was later delivered by caesarean section. Subsequently, multiple metastases in both liver lobes were detected using computed tomography and magnetic resonance imaging and the patient was treated with a BPC regimen, which led to complete disappearance of metastatic lesions in the liver. No additional treatment was provided, and after 5 years the patient consented to direct sequencing of BRCA2 and a 6781delG mutation was identified. At the most recent (5-year) follow-up, the patient was alive with good quality of life and no evidence of metastases.This finding suggests that BPC therapy might be considered a good therapeutic option for the treatment of metastatic TNBC in a woman with a BRCA2 germline mutation.

5583 Background: Recurrent clear cell carcinoma (RCCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. A phase II trial to evaluate the effect of combination therapy with temsirolimus and trabectedin for patients with RCCC was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed ovarian clear cell adenocarcinoma (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients with RCCC were treated with weekly regimen using two drugs: 15mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest). Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. There was no significant difference of serum level of VEGF according to the response evaluation. Biomarker analyses including serum VEGF and BNP were also conducted. Results: A total of 21 patients were analyzed in the present study. There were no cases that discontinued the therapy due to toxicities. Median age was 59 years (range: 30-69), and median number of previous chemotherapy was 3 (range: 1-6). All cases were assessable by RECIST and CTCAE. One patient (5%) had a complete response (CR), and two cases (10%) achieved a partial response (PR), and 6 patients (29%) had a stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD > 3month) of 43%. Median response duration in CBR case was 3.5 months (range: 3-40+). There were no cases that developed toxicities more than grade2. There was no significant difference of serum level of VEGF according to the response evaluation. Conclusions: Combination therapy with temsirolimus and trabectedin was a candidate for salvage therapy for patients with RCCC. These results warrant further study in such clinical settings with biomarker analyses.

5590 Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS (Ref.). In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2014, total 20 patients (pts) with heavily pretreated relapsed ULMS were enrolled. Fourteen of 20 pts were treated with T (80mg/body/day, 3 week one week rest) and B (2mg/kg; days 1, 8 and 15, q4 weeks) (TB, n = 14). Since 2013, C (140mg/body/week) was added to TB (TBC, n = 6). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse effects were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, four (20%) of 20 pts had complete response (CR), four (20%) had partial response (PR) and nine (45%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD>3mo) were 40% and 85%, respectively. The median progression-free survival was 10.5 (3 - 44) months. Intriguingly, when added C to TB, the effect was significantly reinforced, showing that two (33%) of 6 cases had CR, and the RR and CBR was 50% and 100%, respectively. Toxicity was mild and manageable. Conclusions: Addition of C to T and B resulted in synergistic effects with mild toxicity in heavily pretreated relapsed ULMS as shown in Table. These results warrant further prospective and randomized studies. Response to TB/TBC in heavily pretreated relapsed ULMS. n CR PR SD PD RR CBR TB/TBC 20 4 4 9 3 40% 85% TB 14 2 3 6 3 35% 78% TBC 6 2 1 3 0 50% 100% Reference:Sasaki N, Takano M, Kikuchi Y, et al. Effects of temozolomide and bevacizumab in patients with pretreated relapsed uterine leiomyosarcoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 5603)

Connective tissue growth factor (CTGF) has been reported to play critical roles in the tumorigenesis of several human malignancies. This study was performed to evaluate CTGF protein expression in head and neck squamous cell carcinoma (HNSCC). Surgical specimens from 76 primary HNSCC were obtained with written informed consents and the expression level of CTGF was immunohistochemically evaluated. The cytoplasmic immunoreactivity of CTGF in cancer cells was semiquantitatively classified into low and high expression. Among all 76 cases with or without neoadjuvant therapy, low CTGF showed significantly longer (P = 0.0282) overall survival (OS), but not disease-free survival (DFS) than high CTGF. Although low CTGF in patients with stage I, II and III did not result in any significant difference of the OS and DFS, stage IV HNSCC patients with low CTGF showed significantly longer OS (P = 0.032) and DFS (P = 0.0107) than those with high CTGF. These differences in stage IV cases were also confirmed using multivariate analyses. These results suggest that low CTGF in stage IV HNSCC is an independent prognostic factor, despite with or without neoadjuvant therapy.

5517 Background: Recurrent clear cell carcinoma (RCCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. A phase II trial to evaluate the effect of combination therapy with temsirolimus and trabectedin for patients with RCCC was performed. Methods: Simon's two-stage design was used. In the first stage, 9 patients were accrued. If there were no responder in these patients, the study would be stopped. Otherwise, eight additional patients will be accrued for a total of 17. If three or more responder were observed in 17patients, this design yields a type I error rate of 0.05 and power of 0.81 when the true response rate were 25%. Patients with RCCC were treated with weekly regimen using two drugs: 15mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest) with written informed consents. Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. Results: Among 9 patients in the first stage, two responses were observed, and a total of 17 patients were analyzed in this study. There were no cases that discontinued the therapy due to toxicities. Median age was 60 years (range: 30-69), and median number of previous chemotherapy was 3 (range: 1-6). All cases were assessable by RECIST and CTCAE. One patient (6%) had a complete response (CR), and two cases (12%) achieved a partial response (PR), and 5 patients (29%) had a stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD>3month) of 47%. Median response duration in CBR case was 3.5 months (range: 3-24+). There were no cases that developed toxicities more than grade2. Conclusions: Combination therapy with temsirolimus and trabectedin was a candidate for salvage therapy for patients with RCCC. These results warrant further study in such clinical settings.

5603 Background: Treatments for patients with uterine leiomyosarcoma (ULM) include anthracyclin-based chemotherapy and Docetaxel/Gemcitabine, but these regimens are not satisfactory. Temozolomide (T) has been reported to show a moderate response rate in advanced or recurrent ULM. In addition, ULM has a plenty of vascularity, unlike leiomyoma. Thus, we evaluated the effects of T combined with bevacizumab (B) in patients with pretreated/relapsed ULM. Methods: Simon's two-stage design was used. In the first stage, 7 patients were accrued. If there were no responder in these patients, the study would be stopped. Otherwise, seven additional patients will be accrued for a total of 14. If three or more responder were observed in 14 patients, this design yields a type I error rate of 0.03 and power of 0.81 when the true response rate were 30%. Enrolled patients with pretreated/relapsed ULM were treated with weekly B (2mg/kg; days 1, 8, and 15, q4w) and T (80mg/day, daily), and treatment continued until disease progression. Results: Among 7 patients in the first stage, two responses were observed, and a total of 14 patients were analyzed in this study. Among 14 cases, two (14%) had a complete response (CR) and three (21%) had a partial response (PR). Additionally, six patients (43%) had a stable disease (SD) for at least three months. The response rate (CR+PR) and clinical benefit rate (CR+PR+SD>3mo) were 35% and 78%, respectively. The median progression-free survival was 10.5 months (range from 3 to 44 months). There were no treatment-related deaths or CTCAE grade 4 toxicities, and no dose reduction due to toxicity was observed. Conclusions: T combined with B was effective in patients with relapsed ULM with tolerable toxicity profile. Remarkably, two cases achieved a complete remission more than 6 months. The regimen could be a candidate for the patients with ULM in further prospective studies.