Research Spotlight

Posted May 15th 2018

Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.

Gregory P. Swanson M.D.

Gregory P. Swanson M.D.

Hussain, M., C. M. Tangen, I. M. Thompson, Jr., G. P. Swanson, D. P. Wood, W. Sakr, N. A. Dawson, N. B. Haas, T. W. Flaig, T. B. Dorff, D. W. Lin, E. D. Crawford, D. I. Quinn, N. J. Vogelzang and L. M. Glode (2018). “Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.” J Clin Oncol: May 20;36(15):1498-1504. Epub 2018 Apr 6.

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Purpose: Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods: Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] >/= 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA greater than 10 ng/mL plus biopsy GS > 6. Patients with PSA less than or equal to 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided alpha = .05. Results: Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion: MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.


Posted May 15th 2018

Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.

Jacqueline O'Leary M.D.E

Jacqueline O’Leary M.D.

Hezode, C., N. Reau, E. S. Svarovskaia, B. P. Doehle, R. Shanmugam, H. Dvory-Sobol, C. Hedskog, J. McNally, A. Osinusi, D. M. Brainard, M. D. Miller, H. Mo, S. K. Roberts, J. G. O’Leary, S. D. Shafran and S. Zeuzem (2018). “Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.” J Hepatol 68(5): 895-903.

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BACKGROUND & AIMS: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1-6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. METHODS: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12weeks (n=1,778) in the ASTRAL-1-3, ASTRAL-5 and POLARIS-2-3 studies. RESULTS: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4-6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778=1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. CONCLUSIONS: Sofosbuvir/velpatasvir taken for 12weeks once daily resulted in high SVR rates in patients infected with GT1-6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. LAY SUMMARY: Sofosbuvir/velpatasvir taken once daily for 12weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.


Posted May 15th 2018

Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Haruma, T., T. Nagasaka, K. Nakamura, J. Haraga, A. Nyuya, T. Nishida, A. Goel, H. Masuyama and Y. Hiramatsu (2018). “Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability.” PLoS One 13(4): e0195655. April 16. eCollection 2018.

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BACKGROUND: The molecular characterization of endometrial cancer (EC) can facilitate identification of various tumor subtypes. Although EC patients with POLE mutations reproducibly demonstrate better prognosis, the outcome of patients with microsatellite instability (MSI) remains controversial. This study attempted to interrogate whether genetic stratification of EC can identify distinct subsets with prognostic significance. MATERIALS AND METHODS: A cohort of 138 EC patients who underwent surgical resection with curative intent was enrolled. Sanger sequencing was used to evaluate mutations in the POLE and KRAS genes. MSI analysis was performed using four mononucleotide repeat markers and methylation status of the MLH1 promoter was measured by a fluorescent bisulfite polymerase chain reaction (PCR). Protein expression for mismatch repair (MMR) proteins was evaluated by immunohistochemistry (IHC). RESULTS: Extensive hypermethylation of the MLH1 promoter was observed in 69.6% ECs with MLH1 deficiency and 3.5% with MMR proficiency, but in none of the ECs with loss of other MMR genes (P < .0001). MSI-positive and POLE mutations were found in 29.0% and 8.7% EC patients, respectively. Our MSI analysis showed a sensitivity of 92.7% for EC patients with MMR deficiency, and a specificity of 97.9% for EC patients with MMR proficiency. In univariate and multivariate analyses, POLE mutations and MSI status was significantly associated with progression-free survival (P = 0.0129 and 0.0064, respectively) but not with endometrial cancer-specific survival. CONCLUSIONS: This study provides significant evidence that analyses of proofreading POLE mutations and MSI status based on mononucleotide repeat markers are potentially useful biomarkers to identify EC patients with better prognosis.E


Posted May 15th 2018

Human Leukocyte Antigens Antibodies after Lung Transplantation: Primary Results of the HALT Study.E

Medhat Z. Askar M.D.

Medhat Z. Askar M.D.

Hachem, R. R., M. Kamoun, M. M. Budev, M. Askar, V. N. Ahya, J. C. Lee, D. J. Levine, M. S. Pollack, G. S. Dhillon, D. Weill, K. B. Schechtman, L. E. Leard, J. A. Golden, L. Baxter-Lowe, T. Mohanakumar, D. B. Tyan and R. D. Yusen (2018). “Human Leukocyte Antigens Antibodies after Lung Transplantation: Primary Results of the HALT Study.” Am J Transplant. Apr 24. [Epub ahead of print].

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Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.


Posted May 15th 2018

Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.

Peter McCullough M.D.

Peter McCullough M.D.

Haase, V. H., G. M. Chertow, G. A. Block, P. E. Pergola, E. M. deGoma, Z. Khawaja, A. Sharma, B. J. Maroni and P. A. McCullough (2018). “Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.” Nephrol Dial Transplant. Apr 16. [Epub ahead of print].

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Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.