Christina Messiou

Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval

PURPOSEnSelective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers.nnnPATIENTS AND METHODSnPatients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity.nnnRESULTSnFifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002).nnnCONCLUSIONnOlaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer

PURPOSEnIt has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.nnnPATIENTS AND METHODSnThis was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued.nnnRESULTSnA decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on abiraterone acetate and dexamethasone.nnnCONCLUSIONnCYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.

Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate

PURPOSEnThe principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).nnnPATIENTS AND METHODSnIn this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of > or = 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of > or = 30% and > or = 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration.nnnRESULTSnDocetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of > or = 30%, > or = 50% and > or = 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study > or = 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a > or = 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated.nnnCONCLUSIONnAbiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.

Metastatic Ovarian and Primary Peritoneal Cancer: Assessing Chemotherapy Response with Diffusion-weighted MR Imaging—Value of Histogram Analysis of Apparent Diffusion Coefficients

PURPOSEnTo prospectively evaluate apparent diffusion coefficient (ADC) histograms in the prediction of chemotherapy response in patients with metastatic ovarian or primary peritoneal cancer.nnnMATERIALS AND METHODSnResearch ethics committee approval and patient written informed consent were obtained. Diffusion-weighted (DW) magnetic resonance (MR) imaging was performed through the abdomen and pelvis before and after one and three cycles of chemotherapy in 42 women (mean age, 63.0 years ± 11.4 [standard deviation]) with newly diagnosed or recurrent disease. Reproducibility and intra- and interobserver agreement of ADC calculations were assessed. Per-patient weighted ADC histograms were generated at each time point from pixel ADCs from five or fewer target lesions. Mean ADC, percentiles (10th, 25th, 50th, 75th, 90th), skew, kurtosis, and their change were analyzed according to histologic grade, primary versus recurrent disease status, and response, determined with integrated biochemical and morphologic criteria, with a linear mixed model. Areas under receiver operating characteristic curve (AUCs) for combinations of parameters were calculated with linear discriminant analysis.nnnRESULTSnCoefficients of variation for repeat measurements and for within and between observers were 4.8%, 11.4%, and 13.7%, respectively. Grade and disease status did not significantly affect histogram parameters. Pretreatment ADCs were not predictive of response. In responders, all ADCs increased after the first and third cycle (P < .001), while skew and kurtosis decreased after the third (P < .001 and P = .006, respectively); however, in nonresponders, no parameter changed significantly. Percentage change of the 25th percentile performed best in identifying response (AUC = 0.82 and 0.83 after first and third cycle, respectively), whereas combination of parameters did not improve accuracy.nnnCONCLUSIONnAn early increase of ADCs and later decrease of skew and kurtosis characterize chemotherapy response. Quantitative DW MR imaging can aid in early monitoring of treatment efficacy in patients with advanced ovarian cancer.

Diffusion-weighted Imaging in Cervical Cancer with an Endovaginal Technique: Potential Value for Improving Tumor Detection in Stage Ia and Ib1 Disease

PURPOSEnTo establish apparent diffusion coefficients (ADCs) of invasive cervical carcinoma compared with nontumor cervical epithelium and determine sensitivity and specificity of diffusion-weighted (DW) magnetic resonance (MR) imaging used in conjunction with T2-weighted MR imaging to help detect invasive cervical carcinoma in patients with stage Ia and Ib1 disease.nnnMATERIALS AND METHODSnLocal research ethics committee approval was obtained with written consent from each subject. Group 1 comprised patients (mean age, 38.7 years +/- 13.2 [standard deviation]) with histologically confirmed cervical intraepithelial neoplasia (CIN) found on smear (n = 20) or stage Ib1 cervical tumors (n = 18). Patients were imaged with endovaginal T2-weighted fast spin-echo and single-shot DW echo-planar MR imaging of the cervix. ADCs from invasive cervical carcinoma and nontumor regions were compared within (t test) and between (U test) patients. A derived threshold ADC level indicative of invasive cervical carcinoma was used with T2-weighted imaging by two independent observers to identify possible invasive cervical carcinoma in group 2, patients with suspected disease (n = 21; mean age, 42.0 years +/- 16.4). Surgical specimens were the reference standard. Interobserver agreement was assessed.nnnRESULTSnIn group 1, ADCs from cervical carcinoma (757 x 10(-6) mm(2)/sec +/- 110) and adjacent epithelium (1331 x 10(-6) mm(2)/sec +/- 159) or CIN (1291 x 10(-6) mm(2)/sec +/- 156) were significantly different (P < .0001). In group 2, respective sensitivity and specificity to help detect invasive cervical carcinoma on T2-weighted images were 55.6% and 75% for observer 1 and 66.7% and 41.7% for observer 2, and 88.9% and 66.7% for observer 1 and 77.8% and 58.3% for observer 2 when ADC maps with a threshold level of 1100 x 10(-6) mm(2)/sec were added. Interobserver agreement was fair (kappa = 0.37) for T2-weighted images alone and good (kappa = 0.80) with ADC included.nnnCONCLUSIONnADCs from invasive cervical carcinoma are significantly lower than those from nontumor epithelium; good interobserver agreement by using T2-weighted and DW MR imaging makes this technique potentially useful to help detect early-stage disease.

A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors

PurposeThe CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic–pharmacodynamic profile, and antitumor activity.MethodsPatients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15xa0mg/kg by 90-min intravenous infusion on days 1, 28, and every 2xa0weeks thereafter (dose escalation) or 10 or 15xa0mg/kg every 2xa0weeks (dose-expansion). Pharmacodynamic assessments were also performed.ResultsForty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1–2 fatigue (9xa0%), nausea (7xa0%), headache (7xa0%), vomiting (5xa0%), and pruritus (5xa0%). The recommended phase II dose was 15xa0mg/kg every 2xa0weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6–9.6xa0days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50xa0% and RECIST SD for 10.5 and 5xa0months, respectively. Two other patients had RECIST SD for 7.2 and 15.7xa0months.ConclusionsCarlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.

Optimising diffusion weighted MRI for imaging metastatic and myeloma bone disease and assessing reproducibility

ObjectivesTo establish normal bone marrow values of apparent diffusion coefficient (ADC) over an age range, compare them with metastatic and myelomatous involvement, to establish reproducibility and to optimise b values.MethodsThe ADCs of bone marrow in 7 volunteers (mean age 29.7xa0years), 34 volunteers (mean age 63.3xa0years) and 43 patients with metastatic and myelomatous involvement (mean age 65.5xa0years) were measured. In 9 volunteers diffusion weighted MRI was repeated within 7xa0days. b values were derived to optimise contrast between normal and pathological marrow.ResultsThe mean ADC of bone marrow in younger volunteers was significantly higher than that of older volunteers. The coefficient of reproducibility was 14.8%. The ADC mean of metastatic and myeloma bone disease was

Monitoring the response of bone metastases to treatment with Magnetic Resonance Imaging and nuclear medicine techniques: A review and position statement by the European Organisation for Research and Treatment of Cancer imaging group

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