Marker Of Tumor Response Research Articles

911P - Improved Enumeration of Circulating Tumor Cells and Correlation with Clinical Endpoints in Castration-Resistant Prostate Cancer Patients

ABSTRACT Background Circulating tumor cells (CTCs) are accepted as surrogate markers for tumor response and linked to shorter survival in castration-resistant prostate cancer (CRPC) patients. Thus, detection of CTCs has become an important addition to the clinical care toolbox. The only approved method, the CellSearch® prognostic kit, captures only epithelial cell adhesion molecule (EpCAM)-positive CTCs and suffers from low yield of CTCs and limited ability to perform molecular analysis. The CellSearch® profile kit also relies on EpCAM to enrich CTCs but integrates laser scanning cytometry (LSC) to perform molecular and genetic analysis of CTCs. This study compared CTC recovery by the CellSearch® prognostic kit and the CellSearch® profile kit in CRPC patients. We assessed the use of CTCs as a prognostic factor for clinical monitoring of CRPC patients in real time and evaluated the association between CTC number, laboratory and clinical characteristics, and overall survival (OS). Table: 911P CellSearch Prognostic * CellSearch Profile + LSC CTCs Enumerated 5-99 CTCs >100 CTCs 5-99 CTCs >100 CTCs Patients Enumerated 19 3 1 7 8 9 Median (range) 0 (0-4) 42 (40-70) - 0 (0-0) 37 (8-79) 209 (119-1314) Patients Alive 14 0 0 2 6 7 Patients Dead 5 3 1 5 2 2 Median OS Range 13.05(12.82-21.2) 4.44 (0.89-6.25) - 12.42 (0.89-13.05) - (4.67-21.2) - (2.63-9.87) * - 1 N/A Methods CTCs were enumerated using the CellSearch® prognostic kit and the CellSearch® profile kit in 24 CRPC patients. A side by side comparison was performed on two 7.5 mL blood samples collected from each patient. Clinical variables included metastatic site(s) and number, Gleason score, PSA, CEA, chromogranin A, NSE, alkaline phosphatase, LDH, sedimentation rate, and C-reactive protein. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results Overall, higher CTC counts were obtained by the CellSearch® profile kit and LSC method compared to the CellSearch® prognostic kit. Conclusions CTC enumeration by the integrated CellSearch® profile kit and LSC yielded improved CTC recovery compared to the standard method. CTC counts correlated with disease severity and support the use of CTCs as predictors of OS. We will present a comparison of CTC enumeration with a correlation to clinical variables. Disclosure V. Melnikova: I am an employee of ApoCell. Y. Zhang: I am an employee of ApoCell. W. Liu: I am an employee of ApoCell. K. Anderes: I am an employee of ApoCell. D.W. Davis: I am an employee of ApoCell. All other authors have declared no conflicts of interest.

HPEBP4 as a predictive marker for the pathological response of rectal cancer to preoperative radiotherapy

The ability to predict tumor sensitivity toward radiotherapy is important in the personalized application of preoperative radiotherapy for patients with rectal cancer. The aim of the present study was to test the human phosphatidylethanolamine-binding protein 4 (hPEBP4) as a predictive marker of tumor response to preoperative radiotherapy in patients with rectal cancer. A retrospective analysis was conducted, consisting of 86 patients with locally advanced rectal cancer who underwent short-course preoperative radiotherapy (20 Gy in five fractions for 1 week) followed by a radical resection. Both pretreatment biopsy specimens and resected primary tumor tissue were collected. Immunohistochemistry and tumor regression grading system were used to evaluate the expression of hPEBP4 in the pretreatment biopsy specimens and the response of rectal cancer to radiotherapy, respectively. Expression of hPEBP4 was correlated with tumor regression in the resected specimen and the clinical outcome of the patients as well. We found that high expression of hPEBP4 was associated with radioresistance in both univariate and multivariate analyses, and patients with a high hPEBP4 expression had a poorer progression-free survival than those with low hPEBP4 expression. Our study revealed the independent predictive values of hPEBP4 in response of rectal cancer to preoperative radiotherapy, which suggests that upregulating hPEBP4 might be a potential mechanism by which rectal cancer cells avoid the destructive effects of radiotherapy.

Plasma viral DNA as a marker of tumor response in EBV(+) Hodgkin lymphoma in a phase III study (E2496).

8003 Background: Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. Studies have suggested a correlation in HL between plasma EBV DNA and EBER ISH. We previously studied the DNase sensitivity of plasma EBV DNA and found plasma EBV of patients with EBV(+) HL was not protected from DNase digestion, consistent with tumor-derived DNA, while plasma EBV of patients with HIV without EBV(+) tumors was protected from DNase digestion, consistent with virion DNA. We sought to determine whether plasma EBV could serve as a surrogate for EBER ISH and whether reappearance of plasma EBV predicts treatment failure. Methods: Specimens from a Cancer Cooperative Intergroup Trial (E2496/Stanford V versus ABVD for HL) were used to compare pretreatment plasma EBV DNA copy number, assessed by real-time quantitative PCR, with EBV status by EBER ISH. An ROC analysis was performed using patients with both pretreatment plasma EBV and EBER results (n=121), identifying a cutoff of 60 viral copies/100 µL plasma (95% concordance, 92% sensitivity, 96% specificity for EBV status by EBER). Using this cutoff, pretreatment plasma specimens (n=274) were designated EBV(+) (n=54) or EBV(-) (n=220), as were serial follow-up specimens. Cox proportional hazard models were constructed to evaluate plasma EBV as a prognostic factor for failure-free survival (FFS). FFS was estimated by the Kaplan-Meier method. Results: Pretreatment EBV(+) plasma was associated with treatment failure with a hazard ratio of 2.1 (95% CI 1.2-3.6, p=0.01) after adjusting for International Prognostic Score, treatment arm, and histology. Of the EBV(+) patients with follow-up specimens (n=45), patients with EBV(+) plasma beyond 1 month of therapy (n=9) had inferior FFS compared to those who cleared their plasma of EBV (n=36), (3-year FFS 44% versus 69%, respectively; log rank p=0.03). Conclusions: HL patients with EBV(+) plasma at baseline have inferior FFS compared to others. Among patients with EBV(+) plasma at baseline, those in whom plasma EBV persists or reappears after initiation of therapy have inferior FFS. Such patients may benefit from experimental or intensified therapies.

Integration of neuropathy-sparing multimetronomic bevacizumab and multibiochemical modulation followed by regional consolidation and maintenance therapy for refractory ovarian cancer.

e15576 Background: In vitro disease models predicted advantages for use of 1/2-1/4 standard cytotoxic doses and selection of drugs each of which simultaneously interact with multiple drugs. Methods: Treatment (rx) combined 10mg/kg bevacizumab (B) q 2 weeks, cyclophosphamide (Cy) 400mg/m2 modified AC (Garcia Gyn Onc 05) with low dose GFLIP (carboplatin=P) P -/+ docetaxel (D) (Bruckner, ASCO 08). Regional therapy followed: +/- intraperitoneal, target directed or D+cisplatin, +/- or empirical HIPEC. To prevent further neuropathy, present in 8 of 10 pts, D was reserved for late addition (as needed) to create less than 0.5cm or otherwise “eligible for reduction surgery” tumors. Results: Overall S is 8/10 and 4/6 @ 6 and 12 mos. Two lead pts S at 18+ mos. 10/10 tumor marker responses (R); 9/10 objective R all with benefit. Patients (pts) had failed a median of 3 prior regimens and all had large rapidly worsening tumors during prior rx; 6/10 were considered “entirely untreatable.” There were no grade 4 complicated AEs, other than anemia. Epistaxis and HTN were minor, easily controlled AEs. Three deaths due to disease: One pt, PS3, refused surgery for a preexisting bowel obstruction and one, PS3, required weekly paracentesis and had sb obstruction. She relapsed after four mos OR. The third, PS4, pt was paracentesis and thorocentesis dependent and had a 6 mos OR. Median PFS is not yet reached. The lead pt, a 33yo third line, twice operated achieved a pCR in 4 mos, now stoma reversed, unmaintained for 14+ mos, following vaccine rx. Seven had OR without D; brief addition of D; brief addition of D produced 3/3 OR, a pCR, CR and PR. IRB provided prospective oversight of consent. Conclusions: This is an active multi-drug, in theory, anti BRCA rx, for very high risk and some otherwise “untreatable” pts. Simultaneous modulation of multiple drugs, both metronomically, six ways, (Cy-GFIC-D) and biochemically, up to five ways "each," 15 ways (5+4+3+2+1), is safe. Algorithms can offer cost savings (for B) by selecting a finite, short, “best” period for rx and then definitive, B free, consolidation rx. B driven response can create new windows of opportunity for test worthy multidisciplinary rxs.

Correlation of circulating tumor cells (CTCs) and clinical biomarker endpoints in metastatic prostate cancer patients.

e15124 Background: Circulating tumor cells (CTCs) are found in human blood when cancers undergo metastatic dissemination, and CTCs have been reported as a surrogate marker for tumor response and linked to shorter survival in metastatic prostate cancer patients. This study assessed the use of CTCs as a continuous factor for clinical monitoring of prostate cancers patient in real time and evaluated the association between baseline CTC number, various clinical characteristics, and survival. Methods: CTCs were enumerated using the CellSearch FDA cleared CTC kit in 206 patients with metastatic prostate cancer. Variables including metastatic site, PSA, Gleason score, level of testosterone and androgen treatment were tested for association with CTC number. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results: Baseline CTC numbers were strongly associated with survival (p<0.0001), with overall survival being significantly poorer in patients with ≥5 CTCs. Significantly higher CTC numbers were observed in patients with bone metastasis (mean=41.1 CTCs) compared to those with lymph node metastasis (mean=2.5 CTC, p=0.026). Analysis of the association between CTC counts and PSA level revealed a weak positive correlation between CTC number and PSA (Correlation coefficient r=0.269, Significance level p<0.001). CTC number further correlated with the Gleason score (p=0.009) and lower testosterone levels (p<0.0001). Patients with no androgen depletion had significantly lower numbers of CTCs (median=3.94) compared to those with androgen depletion (median=406, p<0.001). Conclusions: Baseline CTCs are predictive of patient survival and are significantly correlated with clinical characteristics in prostate cancer patients.Our study confirms previous findings that support the use of CTC levels as a prognostic biomarker for prostate cancer patients.

Expression of ERCC1 protein (excision repair cross complementing group 1) in patients with invasive carcinoma of the uterine cervix (CC) undergoing definitive chemoradiation (CR).

e15562 Background: CC is the leading cause of cancer death among women in developing countries. ERCC1 protein participates in DNA repair through the nucleotide excision repair pathway, involved in resistance to platinum-based chemotherapy. Its value as a predictive marker of tumor response to treatment, progression or death is still unknown. We evaluated ERCC1 protein expression and clinical variables as a predictive marker of progression-free survival (PFS) and overall survival (OS) in patients (pts) with CC submitted to CR. Methods: Retrospective data analysis of pts with histological diagnosis of CC, treated with CR between 2004-2009. Platinum-based chemotherapy was administered weekly (x6) concurrent to external beam radiotherapy (EBRT) to the pelvis (39.6 – 45.0 Gy), parametrial boost (14.0 – 20.0 Gy) when indicated and high-dose rate brachytherapy (HDR) (28.0 – 30.0 Gy). ERCC1 expression was assessed by immunohistochemistry (IHC). Results: We analyzed 75 pts, median age was 55 years (range 24-76), the performance status (PS) was 0 or 1 at baseline in 50 pts (66%) and 63 had squamous histology (84%). Thirty-two were stage IIB (43%) and 19 were IIIB (25%). Sixty-five patients received cisplatin 40mg/m2/w (87%) and 9, carboplatin AUC2/w (12%), median of 6 cycles (range 2-9). Median RT and HDR doses were 59.4 Gy (range 40.4 to 60.3) and 28.0 Gy (range 14.0 – 37.5), respectively. Thirty-two pts were available by ERCC1 IHC and all expressed the marker. Median PFS and OS were 35.5 (95% CI – 13.8 - 57.6) and 81 (95% CI- 21.2 - 140.8) months, respectively. In multivariate analysis, receiving < 6 chemotherapy cycles and baseline Hb <10.0 were correlated with disease progression and death, HR 0.302; p 0.011 (95% CI- 0.012-0.762) and HR 0.6; p 0.00 (95% CI- 0.474 – 0.760), respectively. PS at baseline did not correlate with PFS or OS, HR 0.985; p 0.614 (95% CI 0.930 – 1.044). Conclusions: In this population, since all pts expressed the protein, ERCC1 expression couldn't discriminate patients who most benefit from CR. Interestingly, a minimum of 6 chemotherapy cycles and a baseline Hb ≥ 10.0 seem to have a prognostic value.

Pilot study on antitumor efficacy of intravenously applied synergistic combinations of salicylic acids in patients with advanced solid tumors.

e13508 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Using this differentiation a new therapy method has been developed for targeted chemotherapy. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of diflunisal, paraaminosalicylic acid (PAS) and aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance. Methods: A total of 30 patients (n=30) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of diflunisal and aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response. Results: Out of 30 patients treated 4 patients suffered from colorectal cancer, 11 from breast cancer, 2 from ovarian cancer, 2 from lung cancer, 2 from gastric cancer, 2 from glioblastoma, 1 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 1 from pancreatic cancer, 1 from choledochus cancer, 1 from prostate cancer, respectively. Side effects related to the therapy have been fatigue (6,7%), nausea (13,3%), tinnitus (10%), hypertension (6,7%), dyspnea (3,3%) and burning sensation in tumor areas (3,3%). Out of 30 patients treated, until today 14 were evaluable for metric response, 12 for metabolic and 13 for tumor marker response assessment. For tumor marker follow up 2 patientis (6,7 %) had a CR, 6 (20 %) a PR, 4 (13,3 %) a SD of > 3 month and 1 (3,3 %) a PD. For metric follow up 0 patients (0 %) had a CR, 6 (20 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. For metabolic follow up 1 patients (3,3 %) had a CR, 3 (10 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. Conclusions: This pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous salicylic acids in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study will be performed.

Su1897 Prognostic Vaule of Early Postoperative Tumor Marker Response in Gastric Cancer

G A A b st ra ct s without PAC. Methods: Thirty-nine (n=39) consecutive patients proven to have PAC by positive FNA were recruited at the time of diagnosis by endoscopic ultrasound. Two controls, matched on age (±5 years), BMI (±3 kg/m2), and gender, were recruited for each case from patients presenting for elective colonoscopy (n=78). Patients with a previous history of diabetes mellitus were excluded. Serum CA 19-9 and FSG were obtained for all cases and controls. Conditional logistic regression analysis was performed to determine significant predictors of PAC. Descriptive statistics were used to determine the sensitivity and specificity in discriminating cases from controls using CA 19-9 alone, FSG alone, and both in combination. For analysis of CA 19-9 and FSG in combination, elevation in either test above a given cut-off threshold was considered positive. Results: Of the 39 cases, 21 were male (54%) and 18 were female (46%), mean age of cases was 65 ± 9.4 years and mean BMI was 25 ± 4.1 kg/m2. As continuous variables, both CA 19-9 and FSG were significant predictors of PAC. The sensitivity and specificity of CA 19-9 and FSG alone and in combination were determined for specific cutpoints and are tabled below along with the area under the receiver operator curve (ROC). Conclusion: For these cutpoints, the largest ROC value was .936, which corresponded to the combination of CA 19-9 > 37 and FSG > 99. The combination of CA 19-9 and FSG performed better than either test alone for discriminating patients with PAC from controls and may be beneficial as an initial test for screening high-risk groups for PAC.

Su1873 Early Tumor Marker Response as a Predictor for Clinical Outcome in Patients With Advanced Gastric Cancer Undergoing Palliative Chemotherapy

Su1873 Early Tumor Marker Response as a Predictor for Clinical Outcome in Patients With Advanced Gastric Cancer Undergoing Palliative Chemotherapy

Abstract 2489: A phase II trial of poly-ICLC in the management of recurrent or progressive pediatric low grade gliomas

Abstract Low-grade astrocytomas and gliomas are the most common type of childhood brain tumor. Although children with low-grade gliomas often survive many years after conventional treatment with surgery and radiotherapy, there can be tremendous morbidity depending on the location of tumor and the effects of therapy. Newer forms of treatment with reduced side effects are much needed. We have designed a phase II trial to examine efficacy and safety of the biological response modifier poly-ICLC in children with low-grade gliomas, and to identify surrogate biomarkers for response to this agent. Poly-ICLC, a synthetic complex of polyinosinic and polycytidylic acid, stabilized with polylysine and carboxymethyl cellulose is a double stranded RNA (dsRNA) that is a ligand for the Toll-like Receptor 3 (TLR3), an important component of innate immunity. It has been shown to have direct antiviral and antineoplastic effects mediated by at least two interferon inducible nuclear enzyme systems of OAS and PKR. A previous Phase I/II trial of poly-ICLC conducted in pediatric patients with brain tumors (all histopathologic subtypes) suggested the low-grade glioma cohort had the best response to this therapy (50% PR rate). Additional clinical trials in adult patients have confirmed that the most responsive subgroup to poly-ICLC is low-grade glioma patients. We are currently conducting a multi-institutional phase II study of poly-ICLC administered at 20mcg/kg/dose intramuscularly twice weekly to children with recurrent or progressive low-grade gliomas. Simon's two-stage design will be used for statistical analysis. The primary goal of this study is determine the radiographic response rate. We will also characterize toxicity and determine if surrogate markers of tumor response and progression can be identified in patient serum, peripheral blood mononuclear cells (PBMC), and/or cerebrospinal fluid (CSF). To date, 4 pediatric subjects (ages 2-15) with recurrent low-grade gliomas have enrolled in the study. Poly-ICLC therapy has been well tolerated and none of the subjects have shown radiologic or clinical progressive disease. These results suggest that poly-ICLC may have a beneficial role in children with low-grade gliomas while minimizing treatment side effects. We have begun analyzing blood and CSF samples to attempt biomarker identification and correlation with subject responses, in hopes to yield a basis towards stratification and personalized therapy with recurrent disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2489. doi:1538-7445.AM2012-2489

Abstract 1912: Jab1/Csn5 as a novel driver for therapeutic resistance in HER2-positive breast cancer

Abstract Her2-positive (Her2+) breast cancer has the second worst prognosis of the five subtypes of breast cancer. The most successful targeted therapy for Her2+ breast cancer to date is trastuzumab (Herceptin)-based. However, the median duration of response to trastuzumab is shorter than 1 year, and about 75% of patients who initially responsed, has experienced resistance to the therapy after a year. Thus, better treatment strategies for Her2+ subtype are urgently needed. We and other researchers previously demonstrated that c-Jun activation domain-binding protein 1 (Jab1) negatively regulates p27, mediates p27 nuclear-to-cytoplasmic export and degradation and contributes to the loss of p27 that is seen in >50% of breast tumors and that correlates with poor clinical outcome in breast cancer cells. Thus, implicates the potential role of Jab1 in interfering with trastuzumab. We identified Jab1/Csn5 as a novel oncogene. Jab1 is amplified and overexpressed in elevated in 50% of primary and 90% of metastatic breast tumors, but is low or absent in normal adult breast tissue. In addition, high Jab1 expression is associated with short progression-free survival durations in breast cancer patients. Our preliminary data showed that inactivation of Jab1/Csn5 in trastuzumab-resistant breast cancer cells sensitized the cells to trastuzumab in a dose- and time-dependent manners. However, the ways in which Jab1 expression is up-regulated in Her2+ breast cancer cells and how this up-regulation drives trastuzumab resistance remain largely unclear. In this study, we will seek to analyze the cross-talk between Src/Stat3 or Akt signaling and Jab1 activation in breast carcinoma. We have found that Stat3 is a novel positive regulator of Jab1 expression in breast cancer cells and that Jab1 overexpression driven by the Src/Stat3 pathway compensates for trastuzumab's inhibition of Her2 signaling in Her2+ breast cancer cells. This suggests that activated Stat3, by up-regulating Jab1 expression, inhibits trastuzumab-induced cell-cycle arrest. In general, our proposed study elucidates Jab1 as a novel contributor to trastuzumab resistance and determine its potential as a prognostic and predictive marker as well as an important therapeutic target. The successful completion of our study would benefit breast cancer patients in three ways. 1) Because Jab1 is rarely expressed in mammary epithelial cells, targeting Jab1 would be less toxic to normal epithelial cells, compared to other agents. 2) Combining Jab1 with trastuzumab would interfere with both Src/Stat3 and Akt pathway. This would significantly benefit patients with Her2+ breast cancer refractory to this therapy due to PTEN loss or activating mutant Stat3. 3) Because Jab1 expression is higher in trastuzumab-resistant cells than in trastuzumab-sensitive cells, Jab1 could be used as a marker of tumor response to trastuzumab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1912. doi:1538-7445.AM2012-1912

Telomere-Specific Reverse Transcriptase (hTERT) and Cell-free RNA in Plasma as Predictors of Pathologic Tumor Response in Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy

To investigate whether the plasma levels of cell-free RNA (cfRNA) and telomere-specific reverse transcriptase mRNA (hTERT) are associated with tumor response in rectal cancer patients who received preoperative chemoradiotherapy (pCRT). Patients who underwent pCRT for rectal cancer and for whom baseline and paired post-pCRT blood samples were available were studied. On the basis of tumor regression score, patients were classified as having response or having no response. Clinical variables and plasma levels of cfRNA and hTERT before and after the pCRT were evaluated. The association between each predictor and tumor response was assessed by univariate and multivariate analyses. Of 98 eligible patients, 45 were determined to respond to therapy, and 53 did not respond to therapy. In univariate analysis, gender (P = 0.040), baseline levels of cfRNA (P = 0.026), post-pCRT levels of both hTERT and cfRNA (P < 0.0001 and P = 0.001, respectively), and the difference between the post- and pre-pCRT levels of both hTERT and cfRNA (P = 0.009 and P = 0.001, respectively) were found to be significant predictors of tumor response. In multivariate analysis, using variables that were available before pCRT, cfRNA levels and gender independently predicted the tumor response, while in multivariate analysis, which used all of the variables available before the surgical procedure, the post-pCRT levels of cfRNA and the difference between the post- and pre-pCRT levels of cfRNA independently predicted tumor response. Plasma levels of cfRNA and hTERT are promising markers of tumor response to pCRT for rectal cancer.

Imaging Radiotherapy-Induced Apoptosis

Prediction of response to therapy has been identified as an important tool to obtain a more customized treatment. It allows the selection of those patients who will benefit most from a particular therapy and prevents the exposure of patients to toxic, noneffective regimens. Recent technical advances and the introduction of novel markers in anatomical and functional imaging have created exciting opportunities for in vivo visualization and quantification of cell death. This review will focus on in vivo apoptosis imaging as a predictive marker for tumor response after radiation.

Evaluation of diffusion-weighted imaging as a predictive marker for tumor response in patients undergoing chemoradiation for postoperative recurrences of cervical cancer

To investigate diffusion-weighted imaging (DWI) as a response biomarker in patients undergoing chemoradiation for postoperative recurrences of cervical cancer. From October 2008 to March 2011, 20 patients were included. All underwent T2-weighted (T2W) and DWI before and after chemoradiation. Gross tumor volume (GTV), lateral extent, apparent diffusion coefficient (ADC), and presence of regions of focally restricted diffusion were determined at baseline. Response to chemoradiation was categorized as either partial or complete. Receiver operator characteristics (ROC) curve identified thresholds of GTV and ADC that best predict for partial response. Univariate and multivariate analysis were performed on SPSS version 15. The median GTV was 24.5 cc (4.1-110 cc). Central and lateral disease was present in 8 and 12 patients, respectively. The median ADC was 1 × 10 -3 mm² /s (0.8-1.3 × 10⁻³ mm² /s) and 12/20 (60%) patients had focal restricted diffusion. Overall 10/20 patients had partial response. ROC analysis identified volume of 25 cc or higher [sensitivity = 80%, specificity = 80%, area under curve (AUC) = 0.76, P = 0.04] and ADC more than 1 × 10⁻³ mm² /s (sensitivity = 70%, specificity = 50%, AUC = 0.62; P = 0.34) to best predict for partial response. On univariate analysis bulky disease (77.7% vs. 27%; P = 0.03), lateral disease (66.6% vs. 25%; P = 0.08), and focal regions of restricted diffusion (66.6% vs. 25%; P = 0.06) predicted for partial response to chemoradiation. All factors continued to be significant on multivariate analysis. On restricting analysis to bulky tumors ADC greater than 0.95 × 10⁻³ mm² /s predicted partial response with high sensitivity (85.7%) and specificity (100%) (AUC 0.96; P = 0.05). On univariate analysis lateral disease (P = 0.04), high baseline ADC (P = 0.07) predicted for partial response. Baseline ADC and focal regions of ADC restriction predict for partial response with moderate sensitivity and specificity in patients with postoperative recurrences of cervical cancer and need to be validated in larger cohort.

P3-14-06: Combined Use of 18F-FDG PET/CT and MRI To Monitor Breast Cancer Response during Neoadjuvant Chemotherapy.

Abstract Background and aim: Contrast-enhanced breast magnetic resonance imaging (MRI) is commonly used for the evaluation of the therapeutic effect of neoadjuvant chemotherapy (NAC). A recent study demonstrated the relevance of breast cancer subtype with regard to the accuracy of MRI to predict response during NAC. The role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (FDG PET/CT) is under investigation, and varying results have been reported. MRI and 18F-FDG PET/CT, visualize different functional characteristics of the tumor (perfusion and glucose metabolism), but it is unclear if they complement one another to monitor response to NAC, and whether breast cancer subtype plays an independent role. Method and material: The study group consisted of 65 women with stage II or III breast cancer and measurable FDG tumor uptake, who were treated with NAC and participated in an ongoing MRI/FDG PET/CT study. MRI and FDG PET/CT scans were acquired prior to and during treatment, using prone patient positioning. Written informed consent was obtained. Prior to the start of NAC a biopsy was taken and tumors were divided into three subtypes, using immunohistochemistry: human epidermal growth factor receptor 2 (HER2) amplified (HER2+) (N=18), estrogen receptor positive/HER2 non-amplified (ER+/HER2−) (N=29), and triple negative (TN) tumors (N=18). MRI interpretation included lesion morphology at baseline, changes in morphology, tumor size, and contrast uptake kinetics (initial and late enhancement). At FDG PET/CT the maximum standardized uptake value (SUVmax) at baseline and during treatment was obtained. Tumor response at pathology was stratified to “incomplete response” (substantial presence of vital invasive tumor cells) and “favourable response” (complete absence of invasive residual tumor or only a small number of scattered tumor cells). Appropriate statistical analyses including T-tests, multivariate logistic regression and receiver operating characteristic (ROC) curves were employed to indentify factors associated with incomplete response at pathology. The following imaging and clinical features were candidates for forward feature selection in the multivariate analysis: lesion morphology, largest tumor diameter, pattern of reduction, absolute and relative change in largest tumor diameter at initial and at late enhancement during NAC, SUVmax at baseline; absolute and relative change in SUVmax during NAC; breast cancer subtype; chemotherapy regimen, and age. Results: At pathology after NAC, 32 tumors (49 %) showed favourable response and 33 (51 %) had residual disease. At multivariate analysis, breast cancer subtype, relative change in the diameter of late enhancement on MRI and relative change in SUVmax on FDG PET/CT were independent markers of tumor response at final pathology. The area under the ROC curve increased from 0.86 for MRI alone to 0.94 (p&amp;lt;0.01) in combination with FDG PET/CT and breast cancer subtype, yielding 84% sensitivity at 95 % specificity. Conclusion: MRI and FDG PET/CT show complementary potential to predict response during NAC, in addition to breast cancer subtype. Ackowledgement: This study was supported by the Center for Translational Molecular Medicine, project Breast CARE (grant ***03O-104). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-06.

Treating and Downstaging Hepatocellular Carcinoma in the Caudate Lobe with Yttrium-90 Radioembolization

This study was designed to determine the technical feasibility, safety, efficacy, and potential to downstage patients to within transplantation criteria when treating patients with hepatocellular carcinoma (HCC) of the caudate lobe using Y90 radioembolization. During a 4-year period, 8 of 291 patients treated with radioembolization for unresectable HCC had disease involving the caudate lobe. All patients were followed for treatment-related clinical/biochemical toxicities, serum tumor marker response, and treatment response. Imaging response was assessed with the World Health Organization (WHO) and European Association for the Study of the Liver (EASL) classification schemes. Pathologic response was reported as percent necrosis at explantation. Caudate lobe radioembolization was successfully performed in all eight patients. All patients presented with both cirrhosis and portal hypertension. Half were United Network for Organ Sharing (UNOS) stage T3 (n = 4, 50%). Fatigue was reported in half of the patients (n = 4, 50%). One (13%) grade 3/4 bilirubin toxicity was reported. One patient (13%) showed complete tumor response by WHO criteria, and three patients (38%) showed complete response using EASL guidelines. Serum AFP decreased by more than 50% in most patients (n = 6, 75%). Four patients (50%) were UNOS downstaged from T3 to T2, three of who underwent transplantation. One specimen showed histopathologic evidence of 100% complete necrosis, and two specimens demonstrated greater than 50% necrosis. Radioembolization with yttrium-90 appears to be a feasible, safe, and effective treatment option for patients with unresectable caudate lobe HCC. It has the potential to downstage patients to transplantation.

Pretreatment CD133 and Cyclooxygenase-2 Expression as the Predictive Markers of the Pathological Effect of Chemoradiotherapy in Rectal Cancer Patients

CD133 confers chemoradioresistance properties to cells and has recently been used to identify cancer-initiating cells. We investigated whether the overexpression of CD133 and cyclooxygenase-2 can be used as predictive markers of tumor response to preoperative chemoradiotherapy in patients with rectal cancer. The study was conducted at the National Defense Medical College Hospital in Japan. We recruited 96 patients who underwent a single regimen of preoperative short-term chemoradiotherapy (20 Gy in 5 fractions with 400 mg/day Tegafur/Uracil for 1 week) and radical resection. This was a retrospective study. We obtained pretreatment biopsy specimens of these patients and immunostained these specimens with antibodies for CD133, cyclooxygenase-2, p53, p27, p21, and epidermal growth factor receptor. The resected primary tumor was evaluated according to 2 different tumor regression grading systems that were based on the degrees of fibrosis and cytological alterations. Positivity for CD133 or cyclooxygenase-2 expression was associated with chemoradioresistance, which was determined by the degree of fibrosis, in both univariate (P = .02 and P = .0003) and multivariate (P = .03 and P = .001) analyses. Univariate and multivariate analyses of the degree of cytological alterations also revealed a significant association between chemoradioresistance and the expression of CD133 (P = .005 and P = .003) and cyclooxygenase-2 (P = .005 and P = .03), whereas other markers failed to associate. The information on patients' outcome was not available. Our study revealed the independent predictive values of CD133 and cyclooxygenase-2 expressions in histological tumor regression after preoperative chemoradiotherapy.

Antitumor activity of SS1P with pemetrexed and cisplatin for front-line treatment of pleural mesothelioma and utility of serum mesothelin as a marker of tumor response.

7026 Background: SS1P is an immunotoxin targeting mesothelin, a tumor antigen highly expressed in malignant mesothelioma (MM). Preclinical studies showed marked synergy between SS1P and chemotherapy, leading to this frontline trial in pleural MM. Methods: Patients with no prior treatment, advanced disease, ECOG 0-2, and good organ function received pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 every 3 weeks for 6 cycles. SS1P dose escalation was: 25 µg/kg; 35 µg/kg; 45 µg/kg and 55 µg/kg on days 1, 3 and 5 of cycles 1 and 2. CT scans were performed every 2 cycles. Results: Nineteen patients (16 males, 3 females) have been treated, with median age of 68 y (51 to 78 y). One patient at 55 µg/kg had Grade 3 fatigue, considered dose-limiting. The maximum tolerated dose (MTD) of SS1P with chemotherapy was 45 µg/kg. Adverse events possibly or probably related to SS1P included Grade 3 hypoalbuminemia (n=6), pain (n=3), and hypotension (n=2); and Grade 2 hypoalbuminemia (n=11), fatigue (n=9), edema (n=6), hypotension (n=5), and pain (n=5). One patient died from neutropenic sepsis during cycle 1. Of the 14 evaluable patients treated at all dose levels, 7 had partial response (PR), 3 stable disease (SD) and 4 progressive disease (PD). Of 7 patients treated at MTD, 5 had PR, 1 SD and 1 PD. Of the 10 patients whose serum mesothelin levels were evaluated before and at completion of treatment all 5 patients with PR had significant decrease in serum mesothelin (63-83%). Two of 3 patients with PD had increased mesothelin levels (16%-34%), while 1 pt had a slight decrease (7%). Two patients with SD had discordant responses (17% increase and 60% decrease). Conclusions: SS1P with pemetrexed and cisplatin is well tolerated and results in significant anti-tumor activity with 5 PRs, and 1 SD among the 7 patients treated at MTD. Serum mesothelin responses correlate with the radiological response with all patients who obtained a PR having significant decrease in serum mesothelin levels.

Population-Based Study of Treatment Guided by Tumor Marker Decline in Patients With Metastatic Nonseminomatous Germ Cell Tumor: A Report From the Swedish-Norwegian Testicular Cancer Group

From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response. Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for α-fetoprotein (AFP) of ≤ 7 days and/or for β-human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2. Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients. With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.

Paclitaxel as second-line chemotherapy in patients with gemcitabine-refractory pancreatic cancer: a retrospective study

We evaluated the efficacy and feasibility of paclitaxel in patients with gemcitabine-refractory pancreatic cancer. We also evaluated the correlation between tumor marker decline and response rate. Thirty patients histologically diagnosed with pancreatic cancer who had undergone paclitaxel treatment as salvage chemotherapy were retrospectively analyzed. Paclitaxel treatment was performed with 80mg/(m(2)week) for 3weeks followed by 1week rest, and this was continued until failure. Tumor marker response was evaluated by measuring levels of carbohydrate antigen 19-9, carcinoembryonic antigen, and DUPAN-2 monthly. In total, 272weekly paclitaxel treatments were performed. The median number of treatments per patient was 8 (range 1-22). The median overall survival from the start of paclitaxel treatment was 6.7months (range 1.2-18.8). The response rate was 10% (3/30 patients) and the disease control rate was 46.7% (14/30 patients). Although grade 3 and 4 hematological and non-hematological toxicities were seen in 7 and 6 patients, respectively, adverse events were managed by conservative treatment. We found a significant correlation between the disease control rate and tumor marker decline within 2months of paclitaxel treatment (P=0.01). Patients with tumor marker decline tended to survive longer. Weekly administration of paclitaxel in patients with gemcitabine-refractory pancreatic cancer seems to be well tolerated and can be effective. Paclitaxel treatment should be considered as salvage chemotherapy after gemcitabine failure in patients with good performance status.