Factor For Progression-free Survival Research Articles

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) pts receiving a new agent (NA)- based third line treatment: Final results from a multicenter Italian study.

e16521 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.

Re-challenge with BRAF-directed treatment: A multi-institutional retrospective study.

9512 Background: Most patients treated with BRAF inhibitors (BRAFi) +/- MEK inhibitors (MEKi) eventually progress on treatment. Along with genetic acquired resistance, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse outcomes for patients (pts) retreated with BRAF-directed therapy. Methods: 116 pts who received BRAFi based therapy and, after a break, were re-challenged with BRAFi +/- MEKi treated at 14 centres in Europe, US, and Australia were analysed for progression free survival (PFS) and response rate (RR), as well as factors predicting overall survival (OS) (demographics, disease stage, treatment, LDH level, duration of first BRAFi treatment, reason for first BRAFi discontinuation and interval between BRAFi stop and re-challenge). Multivariate Cox regression, regression trees and Kaplan Meier method were used. Results: Median duration of 1st BRAFi +/- MEKi treatment was 9.4 months (mts) and 7.7 mts for the subsequent treatment after discontinuation (immunotherapy 72%, other 17 %, drug holiday 11%). Brain metastases were present in 51 pts (44%). RR to re-challenge with BRAFi +/- MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease 24% and progressive disease (PD) 30%, 4% missing. Of 80 pts who previously discontinued BRAFi for PD, 31 (39%) responded (30 PR and 1 CR). Median OS from retreatment was 9.8 mts. Independent prognostic factors for survival at re-challenge included number of metastatic sites (HR = 1.32 for each additional organ with metastases, p < .001), LDH (HR = 1.37 for each multiple of the upper normal limit, p < .001), while combination of BRAFi+MEKi conferred a better prognosis vs BRAFi alone (HR = 0.5, p = .006). Pts with < 3 metastatic sites treated with BRAFi and MEKi had a better survival (median OS not reached) and pts with ≥ 3 metastatic sites and raised LDH treated with BRAFi alone had the worse outcome (median OS 4 mts). Number of metastatic sites (HR = 1.44, p < .001) and combination of BRAFi and MEKi (HR = 0.45, p < .001) were independent prognostic factors for PFS (median 5.0 mts). Conclusions: Re-challenge with BRAFi +/- MEKi induces a clinically significant response and should be considered for selected cases.

Therapeutic efficacy of epidermal growth factor receptor monoclonal antibody combined with concurrent chemoradiotherapy in treatment of locally advanced cervical cancer.

e17012 Background: There are few studies about epidermal growth factor receptor monoclonal antibody nimotuzumab for the treatment of locally advanced cervical cancer. We aimed to assess the therapeutic efficacy and analyse prognostic factors of chemoradiotherapy combined with nimotuzumab in cervical cancer (stage IIB-IVA) . Methods: We retrospectively analyzed 23 patients with locally advanced cervical cancer(stage IIB-IVA) ,who received concurrent chemoradiotherapy combined with nimotuzumab from 2012 to 2014 (the study group) ,and 30 patients with the similar baseline characteristics who received concurrent chemoradiotherapy alone (the control group). The overall response rates, 5-year overall survival rates, progression-free survival and acute adverse events of the two groups were compared .Multivariate prognostic analysis was performed by a Cox proportional hazards model. Results: The median follow-up time were 46 months (IQR 16-60) in the study group and 42 months (2-60) in the control group.The overall response rates were 87% and 73.3% (P = 0.384) . The 5-year overall survival rates were 63.6% and 36.1% (hazard ratio 2.208,95% CI 0.878-5.557,P = 0.092) .The median progression-free survival in the study group was not achieved (95%CI 9-55) versus 27 months (1-60) in the control group (hazard ratio 2.635, 95% CI 1.030-6.737, P= 0.043).Multivariate prognostic analysis indicated that stage and whether to be combined with nimotuzumab were the influential factors for progression-free survival time.Adverse events were similar between groups.The most common grade 3 or 4 adverse events during treatment in the study group versus the control group were leucopenia(9 [39%] vs 11 [36%]),thrombocytopenia (3 [13%] vs 6 [20%]),anaemia (4 [17%] vs 4 [13%]). Conclusions: Concurrent chemoradiotherapy combined with nimotuzumab in the treatment can improve the progression-free survival time of advanced cervical cancer, while not increasing the incidence of adverse reactions.However, because of the small size of sample in this research, these findings suggest that it is necessary to perform a prospective study with expanded sample size.

Microwave ablation in combination with chemotherapy versus chemotherapy in advanced non small cell lung cancer: A prospective, randomized, phase III clinical trial.

9048 Background: Previous studies showed that advanced non small cell lung cancer (NSCLC) benefited from microwave ablation in combination with platium-based doublet chemotherapy. This prospective, randomized, phase III clinical trial aimed to determining the survival benefit and safety of MWA combined with chemotherapy compared with chemotherapy alone, which was registered in Clinical Trials. gov (NCT02455843). Methods: Patients with untreated, stage IIIB or IV NSCLC and at least one additional measurable site other than the primary tumor site were recruited. They were divided into MWA/chemotherapy group and chemotherapy group, the former received MWA in the primary tumor sites, followed by chemotherapy and the latter treated with chemotherapy only. The primary endpoint was progression-free survival (PFS), the second endpoint included objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: From Mar 1st, 2015 to Oct 31th, 2016, Two hundreds and eighty-six patients were enrolled, including 141 in MWA/chemotherapy group and 145 in chemotherapy group. Complete ablation was observed in 95.0 % patients. ORR were 38.3 % and 34.1 % in the MWA/chemotherapy group and chemotherapy group, respectively(p = 0.677). MWA prolonged PFS [MWA/chemotherapy group 7.3 (95 % CI,5.3–13.6) ms vs. chemotherapy group 5.2 (95 % CI, 4.0–12.4) ms, p = 0.003]. Multivariate analyses showed that MWA was an independent prognostic factor of PFS. OS was immature. AEs of MWA were observed in 67.4 % patients, mainly was pheumothorax, and only 15% needing chest tube insertion. No ablation associated death was observed. Chemotherapy-associated AEs were observed in 49.1 and 53.6 % of patients in the MWA/chemotherapy and chemotherapy group, respectively. Conclusions: MWA plus chemotherapy combination improved the PFS of advanced NSCLC compared to chemotherapy alone. Adverse events of MWA was tolerable. Clinical trial information: NCT02455843.

Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.

9564 Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS (hazard ratio [HR] 1.487, 95% CI 0.34-6.45). A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS (hazard ratio [HR] 0.230, 95% CI 0.04-1.20) with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS (hazard ratio [HR] 2.02, 95% CI 0.39-10.53). Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. Clinical trial information: DRKS00009507.

Tumor associated macrophages to predict the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer.

e15103 Background: The tumor-associated macrophage (TAM) is one of the major components of tumor microenvironment. Neuroendocrine differentiation (NED) of the tumor has been linked to poor prognosis. We aimed to investigate the role of TAM infiltration and NED in tumor tissue on the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer. Methods: A total of 123 consecutive patients with advanced colorectal cancer treated with bevacizumab plus either irinotecan or oxaliplatin-based combination chemotherapy were included in the study. Along with clinicopathological parameters including age, tumor location (right versus left colon), pretreatment CEA level, KRAS mutation status, tumor grade, histologic subtype (mucinous vs non-mucinous), the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis. The patients with at least 2% or more staining with either synaptophysin or chromogranin A were regarded as NED positive. The +2 or less staining with anti-CD68 was regarded as low for TAM infiltration and +3 or +4 staining as high. The overall (OS) and progression-free survival (PFS) times were calculated from the start of bevacizumab. Results: Thirty-five percent of the patients were given bevacizumab in the first line setting, the others mainly at the second line. The chemo backbone was FOLFIRI in 75% of the patients. The median OS was 15,1 and PFS 7,1 months. The ratio of NED negative and TAM infiltration low patients were 73,9% and 13,8 %, respectively. The univariate analysis yielded only the NED and higher TAM infiltration as the significant factors for PFS. However, only NED was significant for PFS in the multivariate analysis (HR:0.542). The left-sided tumors and the low levels of TAM infiltration were the favorable factors for OS in the univariate analysis. However, the TAM level was the only independent factor predicting the OS (26,7±8,8 vs 14,1±1,7 months, respectively; HR: 0,301). Conclusions: Our results suggest that the TAM infiltration in the tumor tissue could be used as a predictive marker of efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer.

The impact of stereotactic radiotherapy to metastatic site on systemic treatment decision in oligometastatic breast cancer patients.

e12564 Background: Patients with oligometastatic disease achieve long-term survival with multimodality treatment strategies. However, little attention has been paid to the effect of adjusting systemic therapy after local therapy in clinical studies. The aim of this study was to investigate the effects of changing or continuing the same treatment regimen following local therapy on survival parameters. Methods: Out of 350 metastatic breast cancer patients, treated between 2012 and 2016, 43 patients (12%) with oligometastatic disease were included in our study. Oligometastasis was defined as < 5 metastatic sites in the same or different organs. Results: At a median follow-up of 32 months (7–53 months), 29 (67.4 %) patients had died. The one- and two-year overall survival (OS) rates were 95% and 78%, respectively, and the one- and two-year progression-free survival (PFS) rates were 77% and 51%, respectively. Following stereotactic body radiotherapy (SBRT) to oligometastatic sites, systemic treatment protocols were changed in 28 (65.1%) patients, while systemic treatment was continued unchanged in 15 (34.9%) patients. Changes to systemic treatment were significantly higher in patients with two organ metastases compared to patients with one organ metastasis ( p= 0.04). In the univariate analysis, estrogen receptor (ER) status and triple negative disease were significantly predictive of OS. The ER status and the number of metastatic organs were identified as significant predictors of PFS. In the multivariate analysis, only age emerged as a significant independent predictor of OS, while the number of initial organs involved and triple negative disease were significant factors for PFS. Conclusions: A hybrid treatment strategy is associated with higher survival rates in oligometastatic breast cancer patients. Post-SBRT systemic treatment change had no significant impact on OS and PFS in this study.

The impact of type 2 diabetes mellitus on prognosis of non-small cell lung cancer with brain metastases

Objective To investigate the impact of type 2 diabetes mellitus (DM) on prognosis of non-small cell lung cancer with brain metastases. Methods We retrospectively reviewed the clinical data of 406 patients, who were diagnosed as non-small cell lung cancer with brain metastases and admitted to the departments of brain tumor, radiation therapy, pulmonary medicine and pulmonary surgery at Tianjin University Cancer Institute & Hospital from October 2010 to May 2015. Log-rank analysis and Cox regression model were used to identify prognostic factors of non-small cell lung cancer with brain metastases and the impact of type 2 DM on the overall survival (OS) and progression-free survival (PFS). Results Univariate analysis of OS revealed that age, lymph node staging, DM, chemotherapy, Karnofsky performance score had statistical significance (all P<0.05). Univariate analysis of PFS revealed that lymph node staging, DM, chemotherapy had statistical significance (all P<0.05). Multivariate analysis showed that presence of DM (OR, 0.203, 95% CI 0.067-0.618, P=0.005), lymph node staging (OR, 0.573, 95% CI 0.420-0.781, P<0.001) and age (OR, 0.609, 95% CI 0.409-0.907, P=0.015) were considered independent prognostic factors for OS (P<0.05). In addition, DM (OR, 0.317, 95% CI 0.112-0.900, P=0.031), lymph node staging (OR, 0.723, 95% CI 0.556-0.941, P=0.016) and chemotherapy (OR, 0.450, 95% CI 0.253-0.798, P=0.006) were identified as independent prognostic factors for PFS (P<0.05). Conclusion It is suggested that a history of type 2 DM might be correlated with increased OS and PFS in patients with NSCLC with brain metastases. Key words: Carcinoma, non-small-cell lung; Diabetes mellitus, type 2; Prognosis; Brain metastasis

Prognostic value of CD8+ tumor-infiltrating lymphocyte density and PD-L1 expression in tumor cells in thymic epithelial tumors.

21 Background: The prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in thymic epithelial tumors (TETs; thymoma [TM] and thymic carcinoma [TC]) is unknown. We examined whether the density of CD8+ TILs and the PD-L1 expression level in TETs were correlated with patient outcome. Methods: Immunohistochemistry and a semi-automated software quantification analysis were used to examine formalin-fixed paraffin-embedded specimens from patients with TET who had been treated with chemotherapy. The density of CD8+ TILs was evaluated at two representative sites: within the tumor nest (intratumoral CD8), and at the invasive margin (stromal CD8, if evaluable). The average density of CD8+ TILs was used as the cut-off value, while an H-score of 5% was used as the cut-off for PD-L1 expression. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate prognostic factors. Results: Twenty-six patients (TM/TC 9/17) were evaluated. A high intratumoral CD8 density was correlated with a superior outcome in terms of both PFS (median, 7.6 vs 27.7 months; P = 0.002) and OS (median, 54.3 months vs not reached; P = 0.022) among the patients with TM, and a similar tendency was seen among the patients with TC, although the correlations were not statistically significant. PD-L1 expression was not significantly correlated with patient outcome in the TM and TC groups. Univariate and multivariate analyses demonstrated that a high intratumoral CD8 density was a significant predictive factor for PFS (Hazard ratio, 0.25 [95%CI 0.08–0.75]; P = 0.014) and OS (Hazard ratio, 0.06 [95%CI 0.007–0.44]; P= 0.006), whereas PD-L1 expression was not. The tendency for a change in the intratumoral CD8 density in pre/post-chemotherapy TM specimens was not consistent. The proportion of stromal CD8 density to intratumoral CD8 density in the TC specimens was not correlated with survival. Conclusions: A high intratumoral CD8 density had a positive prognostic impact for patients with TETs, especially those with TMs. The impact of this immune-related factor should be validated in a larger cohort.

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in pts with metastatic castration-resistant prostate cancer (mCRPC) receiving a new agent (NA)- based third-line treatment: Final results from a multicenter Italian study.

230 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p &lt; 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS . In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR &gt; 3.1 (log-rank; P &lt; 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P &lt; 0.0001) in pts with NLR ≤ 3.66 and &gt; 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.

Patients with metastatic castration-resistant prostate cancer (mCRPC) who are long-term responders (LTR) to the new agent (NA)-based second line: Clinical outcomes and prognostic factors of subsequent treatment with another NA.

254 Background: Three NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] are able to significantly prolong their overall survival (OS) after docetaxel failure. A quote of pts can obtain a prolonged disease control over 12 months with a second line NA and it is unclear if a clinical benefit may result from a subsequent treatment with another NA. The present study is aimed to assess the clinical outcomes and prognostic factors of subsequent NA treatment in those pts LTR to a second line NA. Methods: We collected data of pts who received sequentially two NAs after DOC. For each pt we recorded the clinical outcome of treatments received after DOC. We consider as LTR pts without progression over 12 months from the start of the NA second line. We assessed the independent prognostic value of a series of third-line baseline covariates, in terms of progression free survival (PFS) and OS by Cox regression analysis. Results: A consecutive series of 476 mCRPC pts received a NA-based second line: AA (261 pts), CABA (151), and ENZ (64): we identified 116 LTR pts (AA 71 – CABA 28 – ENZ 17). All pts received a subsequent NA-based third line: 27 received AA, 59 CABA, and 30 ENZ. Comparing the third-line outcomes of LTR and no-LTR pts , no statistically significant differences were observed in terms of both biochemical and objective response rate, and PFS, while LTR showed a statistically significant longer OS (median 18 vs 11.4 mos; p&lt; 0.0001). The third line OS was statistically significant different (p = 0.01) according to the sequence adopted (Table). At the multivariate analysis , performance status (PS) and the presence of visceral metastases were independent prognostic factors for PFS in third line, while PSA, PS and lactate dehydrogenase were independent prognostic factors for OS. Conclusions: In our experience, NA-based third line is active also in mCRPC LTR population with highest benefit in sequences with CABA and some factors may help in selecting patients with higher probability of achieving a disease control. [Table: see text]

Patients with metastatic castration-resistant prostate cancer (mCRPC) are primary resistant (PR) to the new agent (NA)-based second line: Clinical outcomes and prognostic factors of subsequent treatment with another NA.

e585 Background: Several NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] changed the prognosis of mCRPC pts being able to significantly prolong their overall survival (OS) after docetaxel failure. Unfortunately, a quote of pts experiences an early progression (within 3 mos) during the second line treatment and it is unclear if a clinical benefit may result from a subsequent treatment with another NA. The present study is aimed to assess the clinical outcomes and prognostic factors of subsequent NA treatment in those pts PR to the second line NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. For the purpose of the present analysis we consider as PR pts who progressed within 3 months from the start of the NA second line. Cox regression analysis was used to assess the independent prognostic value of a series of third-line baseline covariates, in terms of progression free survival (PFS) and OS. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. The NA-based second line consisted of AA (261 pts), CABA (151), and ENZ (64): we identified 55 PR pts (AA 24 – CABA 24 – ENZ 7). All pts received a subsequent NA-based third line: 22 received AA, 25 CABA, and 8 ENZ. Compared to no-PR pts, PR pts showed a lower biochemical response rate (12.2% vs 31.6%; p = 0.005), but no significant differences in terms of objective response rate (17.1% vs 15.2%), PFS (median 3.5 vs 4.7 mos), and OS (median 9.4 vs 12.9 mos). Considering the PR population, at the multivariate analysis , lactate dehydrogenase and PSA were independent prognostic factors for PFS in third line, while hemoglobin, PSA, administration of one NA in fourth line and lactate dehydrogenase were independent prognostic factors for OS. Conclusions: In our experience, NA-based third line is active also in mCRPC PR population and some factors may help in selecting patients with higher probability of achieving a disease control.

Clinical significance of circulating tumor cells in patients with small-cell lung cancer.

This study investigated the correlation of the presence of circulating tumor cells (CTCs) with clinical characteristics, and the predictive value of CTCs for progression-free survival (PFS) in patients with small-cell lung cancer (SCLC). Samples were obtained from 42 patients with SCLC before and after the first cycle of chemotherapy. CTCs were quantitated by negative immunomagnetic enrichment and immunocytochemistry using anti-CD45 and anti-pancytokeratin antibodies. CTCs were positive (≥2) in 76.19% of patients with SCLC and negative in the control group. The presence of CTCs was positively correlated with 6 clinical characteristics. PFS was 6.055 and 10.670 months for patients with ≥2 and <2 CTCs/7.5 mL of blood before chemotherapy; after chemotherapy PFS was 4.862 and 10.535 months, respectively. This study showed that both baseline CTC numbers and the change in CTC numbers after 1 cycle of chemotherapy are significant prognostic factors of PFS for SCLC.

Abstract P1-01-02: Circulating tumor cells (CTC) and endothelial cells (CEC) prognostic value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: First results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study

Abstract Background: increased levels of circulating tumor cells (CTC) are associated with worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC). It has been hypothesized that bevacizumab could modify CTC prognostic value. CEC variations to predict benefit of anti-angiogenic treatment is still controversial. Predictive markers for response to bevacizumab combined to chemotherapy in MBC remains a clinical unmet need. Patients &amp; methods: The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, CEC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat assessed by initial CTscan, serum estradiol level, and quality of life). We present here the first planned analysis on 203 pts evaluated for CTC and CEC using the FDA cleared CellSearch method. Results: For CTC substudy, 211 patients were included from 09/2012 to 5/2014. Median follow-up is 24 months. Median PFS was 10 months (CI95 9-12) and response rate was 57%. Median OS was not reached. 203 patients were evaluable for both CTC and CEC at baseline and first day of second cycle of CT (D1C2). At baseline, 97/203 (48%) pts had ≥ 5 CTC (median 4 (range 0-30,000). Median number CEC was 21 (0-2231) at baseline and 22 (1-881) at D1C2. LDH, CEA, CA15.3 and CYFRA 21 were above normal at baseline in 44%, 46%, 73% and 71% of the cases respectively. CTC level was not correlated with any patients' characteristics except a number of metastatic site &amp;gt;3. After one cycle of chemotherapy (D1C2) 37 pts (22%) had still ≥ 5 CTC: 36 pts with initial high level and only one patient with low CTC at baseline had increased CTC above 5. Prognostic factors for PFS at univariate analysis were visceral disease, number of metastatic sites (&amp;gt; 3), triple negative status, LDH, CTC level at baseline and CTC level after one cycle of chemotherapy (D1C2). None of serum marker nor CEC level at baseline or any variations had prognostic value. In multivariate analysis for PFS, CTC level after one cyle of chemotherapy predicts poor outcome Table 1 Multivariate analysis for PFSPts' characteristicsnRRCI 95%p-valueNumber of metastatic sites &amp;lt;3 sites971 &amp;gt;=3 sites1001.65[1.13 ; 2.41]0.010CTC D1C2 &amp;lt; 51321 &amp;gt;= 5372.17[1.43 ; 3.29]&amp;lt;0.001Hormonal status Luminal (HR+)1531 Triple negative372.86[1.85 ; 4.54]&amp;lt;0.001 Conclusion: We confirm in a large prospective series the lack of clinical validity of CEC to predict response to an antiangiogenic based treatment in MBC. A persistent elevated level of CTC after just one cycle of chemotherapy is a very strong and independent marker of poor outcome in a homogeneously bevacizumab-treated cohort of MBC patients. This marker could be used to stopped earlier an inefficient and costly treatment. Citation Format: Pierga J-Y, Tredant O, Chevrier M, Dubot C, Lorgis V, Romieu G, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Berger F, Lemonnier J, Proudhon C, Bidard F-C. Circulating tumor cells (CTC) and endothelial cells (CEC) prognostic value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: First results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-02.

Analysis of predictive factors of ramucirumab plus paclitaxel for advanced gastric cancer.

185 Background: Ramucirumab (RAM) is a novel anti-VEGF antibody approved in 2015 in Japan. Predictive factors for RAM in combination with paclitaxel (PTX) remain largely unknown. Methods: We reviewed 77 consecutive advanced gastric cancer patients who were treated with RAM plus PTX between June 2015 and June 2016 in our institution. We evaluated treatment outcome and analyzed potential predictive factors by univariate and multivariate analyses. Results: Median age was 67 years (range 35-83) and 51 % of the patients were male. The ECOG performance status (PS) was ≥ 2 in 8 patients. 89% (69/77) patients were treated as second line chemotherapy. Objective response rate (ORR) in patients who have measurable disease was 52 % (17/33). Median progression free survival (PFS) and overall survival (OS) and was 6.0 months (95% confidence interval [CI] = 4.3-7.1) and 10.4 months (95% CI 6.8-13.6), respectively. The most frequent adverse events were peripheral neuropathy (44%), G3 ≥ neutropenia (34%), hypertension (32%) and bleeding (27%). At multivariate analysis, hypertension was independent factor for OS (Hazard ratio [HR] = 0.35, 95% CI = 0.14-0.90, P = 0.03). Also, bleeding (HR = 0.23, 95% CI = 0.09-0.55, P = 0.001) was independent factor for PFS and hypertension (HR = 0.47, 95% CI = 0.22-1.02, P = 0.06) had trend toward to show better PFS. Conclusions: RAM plus PTX showed promising efficacy for advanced gastric cancer. RAM related toxicities such as hypertension and bleeding/hemorrhage were independent factors for better outcome. Further investigation is warranted to verify our analysis.

Reinduction of oxaliplatin-based chemotherapy after exposure to oxaliplatin in adjuvant setting for colorectal cancer.

755 Background: Oxaliplatin-based chemotherapy is commonly used chemotherapy in the adjuvant setting for colorectal cancer patients. In clinical practice, those patients may be retreated with oxaliplatin after relapse. The efficacy and predictive factor of oxaliplatin re-treatment are little known. Methods: We carried out a retrospective study of 53 consecutive patients who underwent surgery and adjuvant FOLFOX chemotherapy and who were re-treated oxaliplatin-based chemotherapy after relapse at Yonsei Cancer Center from April 2009 through October 2015. The main end-point was progression-free survival (PFS). Results: Among enrolled patients, 33 (62.2%) received curative resection in initially non-metastatic setting and the other 20 (37.7%) did R0 resection including metastasectomy in stage 4 at the time of previous oxaliplatin treatment. Median time from last cycle of adjuvant FOLFOX to the first cycle of palliative oxaliplatin based chemotherapy was 31.5 months. Palliative oxaliplatin was given as second and third or later in 37 (69.8%) and 16 (30.2%) patients respectively. Median PFS and overall survival (OS) were 5.1 and 17.5 months. Response rate and disease control rate to palliative oxaliplatin based treatment were 17.0 % and 66.0%. Patients with both shorter interval from first oxaliplatin exposure to recurrence (&lt;12 months) and shorter interval from recurrence to oxaliplatin re-exposure (&lt;18 months) experienced shorter PFS significantly compared to those who did not (2.8 vs. 7.3m, p = 0.004). It was an independent predictive factor for PFS in addition to use of targeted agent in multivaviate analysis. Conclusions: In this study, re-treatment with oxaliplatin based chemotherapy after recurrence demonstrated modest clinical efficacy. Non-use of targeted agent and both shorter interval from first oxaliplatin exposure to recurrence and shorter interval from recurrence to oxaliplatin re-exposure are poor predictive factors for PFS.

Predictive value of metabolic tumor volume and total lesion glycolysis in 18F-FDG PET-CT imaging for postoperative recurrence and prognosis in patients with pancreatic cancer

Objective To investigate the predictive value of metabolic tumor volume(MTV) and total lesion glycolysis (TLG) calculated from 18F-FDG PET-CT results for postoperative recurrence and prognosis in patients with resectable pancreatic cancer. Methods From may 2009 to December 2015, 30 patients with pancreatic cancer who underwent curative resection after PET-CT examination were enrolled, and the clinic pathological data and 18F-FDG PET-CT data were retrospectively analyzed. The prognostic value of SUVmax, SUVmean, MTV, TLG and other prognosis factors were analyzed. Results In 30 patients with pancreatic cancer, preoperative 18F-FDG PET-CT detected all primary lesion (10 0%). 29 patients were recurrence or metastasis, and 26 patients were died with median of 17.8 months (2.6-39.6 months) follow-up. The median progression-free survival (PFS) time was 6.5 months and the median overall survival(OS) time was 11.6 months. The multivariate analysis revealed the histological differentiation and MTV were the independent influencing factors for PFS (both P<0.05). The lymph node metastasis, MTV and TLG were the independent influencing factors for OS (all P<0.05). Conclusion The MTV and TLG of PET-CT may be predicting the recurrence and survival of patients with pancreatic cancer after curative resection, suggesting that it can be used to guide the individual treatment. Key words: Pancreatic neoplasms; Prognosis; Metabolic tumor volume; Deoxyglucose

Improved clinical outcomes of patients with ovarian carcinoma arising in endometriosis.

BackgroundDespite enormous efforts to dissect the role of endometriosis in ovarian cancer development, the difference in prognosis between ovarian cancer patients with or without endometriosis remains elusive. The purpose of this study is to assess the association between endometriosis and the prognosis in patients with ovarian cancer.ResultsOvarian cancer arising in endometriosis tended to be presented as clear cell histology, early stage, less intraperitoneal metastasis and ascites, and lower CA125 level compared with those without endometriosis. Multivariate Cox regression analysis identified endometriosis as an independent prognostic factor for progression free survival (P = 0.002) and overall survival (P = 0.009) in all patients and especially for early stage. A nomogram integrating endometriosis, FIGO stage and CA125 was established to predict progression free survival and overall survival.Materials and methodsThis study retrospectively enrolled 196 ovarian cancers arising or not in endometriosis judged by adjunctive use of CD10 immunohistochemistry in conjunction with H&E staining specimens. Clinicopathologic variables, progression-free survival (PFS) and overall survival (OS) were recorded. Kaplan-Meier analysis was performed to compare survival curves. Cox regression models were used to analyze the effect of endometriosis on PFS and OS. A prognostic nomogram was constructed based on the independent prognostic factors identified by multivariate analysis.ConclusionsEndometriosis is an independent predictor of prognosis in ovarian cancer patients.

Application of Next Generation Sequencing for Prognostic Stratification in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by a deregulation of blood cell formation with cytopenia in varying degrees and frequently develop into acute myeloid leukemia (AML). Next generation sequencing (NGS) has significantly contributed to diagnosis and prognostication in patients with MDS. To explore the role of acquired mutations in MDS biology and clinical features, we performed mutational profiling of 111 genes in 125 patients with MDS based on target-sequencing. The results showed that 89% of patients had one or more carcinogenic mutations. Mutation frequencies of several genes, including ASXL1 (16.8%), RUNX1 (14.4%) and TET2 (12%), were above 10% in MDS patients. According to univariate analysis in 108 patients with survival data, mutations of GATA1/2, TP53 and DNMT3A were identified as adverse prognostic factors for overall survival (OS), while RUNX1, KRAS/NRAS, SRSF2 and TET2 mutations were determined as unfavorable factors for progression free survival (PFS). By multivariate COX regression analysis, mutations of KRAS/NRAS, GATA1/2 and DNMT3A were independent risk factors for OS, whereas IDH1/2 gene mutations were favorable factors for PFS. By evaluation of the clinical benefit of hypomethylating agents (HMAs), it showed that for patients harboring mutations associated DNA methylation or not and receiving HMAs treatment or not, the order of the outcome from good to bad was geneWT with non-HMAs, geneWT with HMAs, genemut with HMAs and genemut with non-HMAs. Therefore, target-sequencing of mutational spectrum is a feasible and highly promising prediction method for prognostic evaluation in patients with MDS, which would contribute to personalized therapeutic decisions. DisclosuresNo relevant conflicts of interest to declare.

The impact of staging laparoscopy on treatment strategy in advanced ovarian cancer

Introduction: Complete primary cytoreductive surgery (PCS) is the most important prognostic factor for progression free survival (PFS) and overall survival (OS) in patients with advanced (FIGO stage III) ovarian cancer (AOC). In patients with poor general conditions or with heavy disease burden, complete PCS is difficult to achieve. Various patterns of abdominal disease spread represent biological aggressiveness affect prognosis and demands visual evaluation before planning treatment strategy. Beside imaging methods, laparoscopic pretreatment evaluation of resectability was proposed to more accurately identify those patients that can not be completely resected. In such cases neoadjuvant chemotherapy (NACT), followed with interval debulking surgery (IDS) is proposed. We present the preliminary results of treatment with NACT and IDS in patients selected according to laparoscopic evaluation of resectability. Methods: 2 years retrospective analysis (2011–2013) of 41 patients with clinical signs of AOC, where according to gyn-oncology consultative team, laparoscopy was proposed as a diagnostic and staging procedure. After evaluation of respectability, PCS by laparotomy was performed. Metastatic process of intestinal mesenterium and/or serosa was considered unresectable and NACT was started followed by IDS. Evaluation of laparoscopic procedures and impact on treatment strategy is presented through PFS analysis between the subgroup that had PCS and those started with NACT, followed with IDS. Results: Ascites together with elevated tumor markers, with or without pelvic mass were the most common clinical sign in population studied. 32 patients presented in Stage IIIC and 9 in stage IV. Laparoscopic staging included evaluation of omental infiltration, peritoneal and diaphragmatic carcinosis, intestinal mesenteric or serosal involvement, bowel infiltration, and liver superficial metastasis as well as amount of pelvic disease. In all stage IV patients only laparoscopy was performed. According to laparoscopic staging in stage III patients, conversion to laparotomy for PCS and adjuvant chemotherapy was performed in 21 patients; while in 12 neodjuvant chemotherapy was started. Laparoscopic procedures were: unilateral or bilateral adnexectomy (N = 18); omental biopsy (N = 21), peritoneal biopsy (N = 21); and cytology specimen (N = 15). Average start of chemotherapy was 10 days (7–14) after surgery No major intraoperative complications were registered. In 2 patients laparotomy was performed because of obstructive ileum on day 3 and 5 after laparoscopy. During the mean follow up of 21 (8–33) months 3/21 patients died in PCS subgroup and 5/12 in NACT subgroup; all in the first 8 months after surgery. PFS were 27.80 (19.41–36.19) months for complete PCS; 13.62 (8.54–18.7) months for suboptimal PCS and 15.80 (8.6–22.99) months for NACT with IDS. Estimated OS were 35.6 (30.09–41.26) months for complete PCS, 31.85 (26.35–37.35) months for suboptimal PCS and 31.33 (25.48–37.18) months for NACT with IDS. Conclusions: According to our results, laparoscopy as a staging procedure have a certain impact on treatment strategy in AOC by selecting patients where tumor biology disables complete PCS and making them candidates for NACT. Our preliminary analysis of PFS and estimated OS in this selected group demonstrates that this strategy is not inferior towards suboptimal PCS and adjuvant chemotherapy, but more cases should be analyzed for more definitive conclusions.