NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma.

Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC.

CT and PET: early prognostic indicators of response to imatinib mesylate in patients with gastrointestinal stromal tumor.

OBJECTIVE: We report results from a pilot study aimed at optimizing the use of CT bidimensional measurements and 18F-FDG PET maximum standardized uptake values (SUVs-(max)) for determining response to prolonged imatinib mesylate treatment in patients with advanced gastrointestinal stromal tumors (GISTs). SUBJECTS AND METHODS: Sixty-three patients enrolled in a multicenter trial evaluating imatinib mesylate therapy for advanced GIST underwent FDG PET at baseline and 1 month after initiation of treatment. Of these 63 patients, 58 underwent concomitant CT. Time-to-treatment failure (TTF) was used as the outcome measure. Patients were followed up over a range of 23.7 to 37 months (median, 31.7 months). The predictive power of change in CT bidimensional measurements, change in PET SUVmax, and PET SUVmax at 1 month after initiation of treatment were determined, optimized, and compared. The effectiveness of combining metrics was also evaluated. RESULTS: Both a threshold PET SUVmax value of 2.5 at 1 month (p = 0.04) and the European Organization for Research and Treatment of Cancer (EORTC) criteria for partial response on FDG PET (25% reduction in PET SUVmax) at 1 month (p = 0.004) were predictive of prolonged treatment success. The Southwest Oncology Group (SWOG) criteria for partial response ((3) 50% reduction in CT bidimensional measurements) at 1 month were not predictive (p = 0.55) of TTF. Optimizing metrics improved results performance. An optimized PET SUVmax threshold of 3.4 (p = 0.00002), a reduction in the SUVmax of 40% (p = 0.002), and an optimized CT bidimensional measurement threshold--that is, no growth from baseline to 1 month (p = 0.00005)--outperformed the existing standards (i.e., EORTC and SWOG criteria). Combinations of metrics did not improve performance. CONCLUSION: The two best metrics were the optimized PET SUVmax threshold of 3.4 at 1 month (p = 0.00002) and the optimized CT bidimensional measurement threshold (no growth from baseline to 1 month, p = 0.00005) in this patient group.

Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012.

Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.

BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804).

PURPOSE: On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade. PATIENTS AND METHODS: A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point. RESULTS: Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms. CONCLUSION: The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.

A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer.

BACKGROUND: The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC. PATIENTS AND METHODS: Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m(2), 10 mg to 60 mg/m(2), and 10 mg to 70 mg/m(2). The primary end point was the safety and tolerability of combination therapy. RESULTS: Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction ≥ 50% during treatment with everolimus together with docetaxel. All 4 patients with a PMR according to PET imaging experienced a PSA reduction in response to everolimus with docetaxel, and 3 of 4 had PSA declines ≥ 50%. CONCLUSION: Everolimus 10 mg daily and docetaxel 60 mg/m(2) was safe in CRPC patients and these were the recommended doses in combination. FDG-PET response might serve as a biomarker for target inhibition by mTOR inhibitors.

Assessing a prostate cancer brachytherapy technique using early patient-reported symptoms: a potential early indicator for technology assessment?

Brachytherapy for early prostate cancer can cause long-term urinary, bowel, and sexual dysfunction. Modifying technique may mitigate complications, but definitive outcome assessment requires long-term follow-up. Although radiation dose plausibly mediates all treatment-related toxicity, short-term symptoms may indicate long-term outcomes. We sought an early indication of whether a modified brachytherapy technique successfully decreased toxicity in the anticipated direction by assessing changes in symptoms and symptom distress 3 months after treatment. In a prospective study of clinically localized prostate cancer using a validated, patient-reported questionnaire, we assessed 85 men, whose primary treatment was brachytherapy alone, prior to treatment and 3 months after the procedure. Twenty-two men received standard ultrasound-guided brachytherapy (SB), and 63 men received magnetic resonance imaging-guided brachytherapy (MB), a technique intended to decrease urinary toxicity by reducing urethral irradiation. Patient age and other sociodemographic variables were similar in the 2 groups. The MB group experienced a greater increase in urinary obstruction/irritation symptoms (P = 0.02) and sexual function distress, but not sexual dysfunction (P = 0.22), whereas the SB group reported a smaller increase in bowel symptoms (P = 0.04) and bowel distress (P = 0.02). We found reduced short-term urinary obstruction/irritation and increased bowel problems after MB consistent with the hypothesized effects of the modified technique, although no obvious mechanism explains the decreased sexual function distress in MB patients. Whether these short-term changes predict long-term outcome differences will require much longer follow-up. However, these results suggest that measuring early symptoms may indicate whether an altered brachytherapy treatment technique has intended favorable consequences, potentially accelerating technology assessment.

Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer.

Heat shock protein 70 (Hsp70) is a stress-inducible protein that is also known for its inhibitory effects on apoptosis. Increased Hsp70 expression is reported in a variety of tumor tissues. Heat shock protein 70 is detectable in plasma and could potentially be used as a biomarker for diagnosis or disease stratification. The relationship between plasma levels of Hsp70 and prostate cancer status has not been well studied. Our study was designed to test this relationship. One hundred twenty-five patients with localized/untreated or hormone-refractory prostate cancer were identified. Forty-five healthy male blood donors between 50 and 73 years of age served as controls. EDTA plasma was subjected to quantitative sandwich immunoassays for both Hsp70 and prostate-specific antigen (PSA). Wilcoxon rank-sum tests were used to examine differences by category. Maximally selected c2 statistics were used to identify cutoff points to best distinguish between categories. Plasma Hsp70 levels in the patients with localized untreated disease (n = 68; median, 0.8 ng/mL; interquartile range, 0.5-2.0) were significantly higher than those in the control group (n = 45; median, 0.5 ng/mL; interquartile range, 0.3-0.8; P = 0.0037). Although the primary cutoff point (1.15 ng/mL) significantly distinguished the localized untreated patients from the control group, plasma Hsp70 levels did not prove more effective than PSA as a predictor for diagnosis or stratification of patients with prostate cancer in the context of group comparisons. Nonetheless, several patients in the localized untreated group showed higher plasma levels of Hsp70 than the primary cutoff point even though their PSA levels were within normal range (< 4 ng/mL). Heat shock protein 70 is a marker of prostate cancer, although its clinical utility is uncertain. It is possible that when used in conjunction with PSA it might prove useful in identifying patients with early-stage prostate cancer who might otherwise be missed by PSA screening alone.

Vandetanib plus chemotherapy for induction followed by vandetanib or placebo as maintenance for patients with advanced non-small-cell lung cancer: a randomized phase 2 PrECOG study (PrE0501).

INTRODUCTION: After early reports of vandetanib's efficacy in the induction setting, we evaluated the effect of combination docetaxel, carboplatin, and vandetanib, followed by maintenance therapy with either vandetanib, or placebo on progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. METHODS: Patients with advanced non-small-cell lung cancer were randomized to induction docetaxel (75 mg/m) + carboplatin (area under the curve of 6) on day 1 of a 21-day cycle, and daily vandetanib (100 mg/day orally) for four cycles, followed by daily vandetanib (300 35 mg/day orally) or placebo until progression. Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0 of 1, and no prior cytotoxic or targeted agents for advanced disease. RESULTS: One hundred sixty-two patients were randomized; 158 began induction treatment. Fifty-eight patients began maintenance vandetanib or placebo (median, 3.5 cycles). Median PFS for patients randomized to maintenance vandetanib was 4.5 months (95% confidence interval, 3.3-5.8 months), and for patients randomized to maintenance placebo was 4.2 months (95% confidence interval, 2.8-4.9 months). An exploratory analysis showed prolonged PFS for patients randomized to vandetanib maintenance (stratified log-rank p= 0.07) as also in a multivariate model adjusting for sex and stage (p= 0.02). Differences in PFS were not observed among patients who began maintenance therapy. Toxicities were similar to other studies of these agents. CONCLUSION: Neither arm showed improvement over historical median PFS of 4.6 months, although patients who began maintenance and were randomized to vandetanib had somewhat better outcomes than those randomized to placebo. Given its acceptable toxicity profile, there may be a role for vandetanib in maintenance.

Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer.

PURPOSE: Pain is prevalent among patients with cancer, yet pain management patterns in outpatient oncology are poorly understood. PATIENTS AND METHODS: A total of 3,123 ambulatory patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled onto this prospective study regardless of phase of care or stage of disease. At initial assessment and 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy. RESULTS: Of the 3,023 patients we identified to be at risk for pain, 2,026 (67%) reported having pain or requiring analgesics at initial assessment; of these 2,026 patients, 670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables (odds ratio, 0.51; 95% CI, 0.37 to 0.70; P = .002). Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a minority treatment site, and having nonadvanced disease without concurrent treatment. CONCLUSION: Most outpatients with common solid tumors must confront issues related to pain and the use of analgesics. There is significant disparity in pain treatment adequacy, with the odds of undertreatment twice as high for minority patients. These findings persist over 1 month of follow-up, highlighting the complexity of these problems.

Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial.

PURPOSE: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. PATIENTS AND METHODS: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. RESULTS: From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. CONCLUSION: Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

The telomerase reverse transcriptase regulates chromatin state and DNA damage responses.

Constitutive expression of telomerase prevents senescence and crisis by maintaining telomere homeostasis. However, recent evidence suggests that telomerase is dynamically regulated in normal cells and also contributes to transformation independently of net telomere elongation. Here, we show that suppression of the telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] expression abrogates the cellular response to DNA double strand breaks. Loss of hTERT does not alter short-term telomere integrity but instead affects the overall configuration of chromatin. Cells lacking hTERT exhibit increased radiosensitivity, diminished capacity for DNA repair, and fragmented chromosomes, demonstrating that loss of hTERT impairs the DNA damage response.

Liposarcoma subtypes: identification with computed tomography and ultrasound-guided percutaneous needle biopsy.

The purpose of the study was to evaluate the feasibility of image-guided percutaneous needle biopsy to enable specific subtype classification of liposarcoma in patients with previously diagnosed disease and compare the yield of fine and large needle techniques for each subtype. We reviewed the medical records and pathology reports of 69 fine (20 g) needle and large (15, 16 g) needle biopsies performed in 44 patients enrolled in a clinical trial evaluating the effect of a novel therapy for advanced liposarcoma in the abdomen and pelvis. Cytopathologists and surgical pathologists identified features that enabled them to classify the tumor into one of four subtypes: well differentiated, myxoid/round cell, pleomorphic and dedifferentiated. The pre-study open surgical biopsy was used as the standard for comparison. The diagnostic yield (proportion of biopsies with correct subtype diagnosis) of percutaneous biopsy for identifying all subtypes of liposarcoma was 81% (64% for fine needles and 73% for large needles alone). There was a significant association between pathologic subtype and the probability of a correct diagnosis (P=0.05). Accurate diagnostic subset classification of liposarcoma by percutaneous biopsy is feasible, although both fine and large needles should be used. Although these data cannot be extrapolated to primary diagnosis of liposarcoma, they are important for screening and subtyping of possible recurrence.