Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

High chemokine receptor CXCR4 level in triple negative breast cancer specimens predicts poor clinical outcome.

INTRODUCTION: Basal-like tumors or triple negative breast cancers are those that lack hormone-receptor and HER-2 expressions. They are considered to be aggressive tumors, and molecular mechanism to account for this is poorly understood. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that high CXCR4 overexpression level in cancer specimens predicts a poor outcome in patients with triple negative breast cancers. METHODS: One hundred fifty-one patients with triple negative breast cancers were prospectively accrued and analyzed. All had undergone standardized treatment and surveillance protocols. From each specimen, CXCR4 levels were detected using Western blots. Results were quantified against 1 microg of HeLa cells (positive controls). CXCR4 expression was defined as high (>or=6-fold) or low (<6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. RESULTS: At a median follow-up of 37 mo, patients whose tumors had high CXCR4 overexpression (>or=6-fold) had a significantly higher incidence of cancer recurrence (P=0.014) and cancer-related death (P=0.026) than those in the low CXCR4 group (<6-fold). After adjusting for tumor size and nodal status, the relative risk for cancer recurrence and death in the high CXCR4 group was 2.1-fold (P=0.007; 95% CI: 1.22 to 3.8) and 2-fold (P=0.047; 95% CI: 1.01 to 4.06) higher than those in the low CXCR4 group, respectively. CONCLUSION: High CXCR4 overexpression in cancer specimens predicts a worse outcome in patients who have triple negative breast cancer.

Predictive value of eIF4E reduction after neoadjuvant therapy in breast cancer.

INTRODUCTION: Initiation factor 4E (eIF4E) overexpression has prognostic significance in breast cancer. Up-regulation of downstream gene products associated with high eIF4E overexpression has been linked to chemoresistance. We hypothesize patients whose tumors had eIF4E reduction after neoadjuvant chemotherapy will have lower cancer recurrence compared with those who did not. METHODS: Seventeen locally advanced breast cancer patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. eIF4E was quantified by Western blots. Primary end-point was cancer recurrence. RESULTS: Low eIF4E was defined as < or =7.5-fold elevation and high eIF4E was >7.5-fold elevation. Of 17 patients, six tumors remained low after neoadjuvant therapy, six dropped from high to low eIF4E, and five remained high. With a median follow-up of 29 mo, four of five patients with tumors that remained high have recurred while only three of 12 patients in the low eIF4E post-therapy group have recurred (P=0.05, chi(2)). Survival analysis using the Kaplan-Meier method showed a higher rate of cancer recurrence in patients with post-treatment high eIF4E overexpression (P=0.026, log rank test). CONCLUSIONS: Breast cancer patients whose tumors had low eIF4E overexpression after neoadjuvant chemotherapy had lower cancer recurrence compared with those who did not.

Eukaryotic initiation factor 4E overexpression in triple-negative breast cancer predicts a worse outcome.

BACKGROUND: Triple-negative (estrogen receptor [ER], progesterone receptor [PR], and HER2/neu receptor negative) breast neoplasms are typically high grade and portend a higher risk for relapse. Not being amendable to ER, PR, or HER2-targeted therapy, adjuvant cytotoxic chemotherapy remains the only option. High eukaryotic Initiation Factor 4E (eIF4E) overexpression in tumor specimens is an independent predictor for relapse in breast cancer, perhaps secondary to tousled-like kinase 1B upregulation and subsequent doxorubicin resistance. In this prospective study, eIF4E elevation in triple-negative breast cancer (TNBC) specimens was studied to determine its effect on cancer outcome. METHODS: A prospective study of 103 TNBC patients was initiated. Tumor specimens were quantified for eIF4E expression using Western blots. Clinical outcomes data were collected after standardized adjuvant treatment and surveillance protocols. Primary end points were cancer recurrence and cancer-related death. The eIF4E levels in cancer specimens were quantified as x-fold over benign samples from noncancer patients. Statistical procedures performed include survival analysis by Kaplan-Meier method, log-rank test, Cox proportional hazards regression model, and the chi-square test. RESULTS: Levels of eIF4E were categorized into 3 tertiles. Among 103 patients, 36 were in the low group (< or =7.5-fold), 40 were in the intermediate group (7.5- to 15-fold), and 27 were in the high group (> or =15-fold). Patients with triple-negative neoplasms that were in the high eIF4E group had greater rates of cancer recurrence (P = .04) and cancer-related death (P = .02) than the low eIF4E group. Among patients with node-negative disease, high eIF4E overexpression in tumor specimens continues to portend a greater rate of cancer recurrence (P = .02), and a higher rate of cancer death (P = .03) than those in the low eIF4E group. CONCLUSION: TNBC patients with high eIF4E overexpression are more likely to recur and die from cancer recurrence. High eIF4E seems to be a significant prognostic marker, even in TNBC patients.

Race/Ethnicity has no effect on outcome for breast cancer patients treated at an academic center with a public hospital.

BACKGROUND: African American women have a higher breast cancer mortality rate than Caucasian women. To understand this difference, socioeconomic status (SES) needs to be controlled, which can be achieved by evaluating outcome within a population that is underinsured or low SES. We elected to examine the effect of race/ethnicity on outcome of patients with operable breast cancer by evaluating outcome in a population with low SES and similar access to care. METHODS: From a prospective breast cancer database created in 1998, we examined outcome for 786 patients with stage 0 to III breast cancer treated up to September 2008. Patients were treated at Louisiana State University Health Sciences Center in Shreveport and E.A. Conway Hospital and the majority received standard definitive surgery as well as appropriate adjuvant treatment. Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, Cox proportional hazards model, independent-samples t test, and chi(2) test. P