Erratum: Author Correction: Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study.

[This corrects the article DOI: 10.1038/npjbcancer.2016.17.].

Molecular Characterization and Mortality From Breast Cancer in Men.

Purpose Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men, and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer. Materials and Methods We studied men and women with hormone receptor-positive breast cancer and the 21-gene Breast Recurrence Score (RS) results. Differences in clinical characteristics and gene expression were determined, and distribution of RS results was correlated with 5-year breast cancer-specific survival (BCSS) and overall survival. Results There were 3,806 men and 571,115 women. Men were older than women (mean age, 64.2 v 59.1 years; P < .001). RS < 18 predominated in both genders, but RS ≥ 31 was more frequent in men (12.4% v 7.4%; P < .001), as were very low scores (RS < 11; 33.8% v 22.1%; P < .001). Mean gene expression was higher in men for the estrogen receptor (ER), proliferation, and invasion groups. ER was lowest and progesterone receptor was highest in women younger than 50 years of age, with a progressive increase in ER with age. Men younger than 50 years of age had slightly lower ER and progesterone receptor compared with older men. Survival data were available from SEER for 322 men and 55,842 women. Five-year BCSS was 99.0% (95% CI, 99.3% to 99.9%) and 95.9% (95% CI, 87.6% to 98.7%) for men with RS < 18 and RS 18-30, respectively, and for women, it was 99.5% (95% CI, 99.4% to 99.6%) and 98.6% (95% CI, 98.4% to 98.8%), respectively. RS ≥ 31 was associated with an 81.0% 5-year BCSS in men (95% CI, 53.3% to 93.2%) and 94.9% 5-year BCSS (95% CI, 93.9% to 95.7%) in women. Five-year BCSS and overall survival were lower in men than in women. Conclusion This study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for RS testing in both men and women.

Adjusting for covariates in evaluating markers for selecting treatment, with application to guiding chemotherapy for treating estrogen-receptor-positive, node-positive breast cancer.

In many clinical contexts, biomarkers that predict treatment efficacy are highly sought after. Such treatment selection or predictive biomarkers have the potential to identify subgroups most likely to benefit from the treatment, and may therefore be used to improve clinical outcomes and reduce medical costs. A methodological challenge in evaluating these biomarkers is determining how to take into account other variables that predict clinical outcomes, or that influence the biomarker distribution, generically termed covariates. We distinguish between two questions that arise when evaluating markers in the context of covariates. First, what is the biomarker's added value for selecting treatment, over and above the covariates? Second, what is the marker's performance within covariate strata-does performance vary? We lay out statistical methodology for addressing each of these questions. We argue that the common approach of testing for the marker's statistical interaction with treatment, in the context of a multivariate model that includes the covariates as predictors, does not directly address either question. We illustrate the methodology in new analyses of the Oncotype DX Recurrence Score, a marker used to select adjuvant chemotherapy for the treatment of estrogen-receptor-positive breast cancer.

Effect of age on breast cancer screening using tomosynthesis in combination with digital mammography.

PURPOSE: To determine the effect of tomosynthesis imaging as a function of age for breast cancer screening. METHODS: Screening performance metrics from 13 institutions were examined for 12 months prior to introduction of tomosynthesis (period 1) and compared to those after introduction of tomosynthesis (period 2, range 3-22 months). Screening metrics for women ages 40-49, 50-59, 60-69, and 70+ , included rates per 1000 screens for recalls, biopsies, cancers, and invasive cancers detected. RESULTS: Performance parameters were compared for women screened with digital mammography alone (n = 278,908) and digital mammography + tomosynthesis (n = 173,414). Addition of tomosynthesis to digital mammography produced significant reductions in recall rates for all age groups and significant increases in cancer detection rates for women 40-69. Largest recall rate reduction with tomosynthesis was for women 40-49, decreasing from 137 (95% CI 117-156) to 115 (95% CI 95-135); difference, -22 (95% CI -26 to -18; P < .001). Simultaneous increase in invasive cancer detection rate for women 40-49 from 1.6 (95% CI 1.2-1.9) to 2.7 (95% CI 2.2-3.1) with tomosynthesis (difference, 1.1; 95% CI 0.6-1.6; P < .001) was observed. CONCLUSIONS: Addition of tomosynthesis to digital mammography increased invasive cancer detection rates for women 40-69 and decreased recall rates for all age groups with largest performance gains seen in women 40-49. The similar performance seen with tomosynthesis screening for women in their 40s compared to digital mammography for women in their 50s argues strongly for commencement of mammography screening at age 40 using tomosynthesis.

Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database.

PURPOSE: The Oncotype DX® Breast Recurrence Score™ (RS) assay is validated to predict breast cancer (BC) recurrence and adjuvant chemotherapy benefit in select patients with lymph node-positive (LN+), hormone receptor-positive (HR+), HER2-negative BC. We assessed 5-year BC-specific survival (BCSS) in LN+ patients with RS results in SEER databases. METHODS: In this population-based study, BC cases in SEER registries (diagnosed 2004-2013) were linked to RS results from assays performed by Genomic Health (2004-2014). The primary analysis included only patients (diagnosed 2004-2012) with LN+ (including micrometastases), HR+ (per SEER), and HER2-negative (per RT-PCR) primary invasive BC (N = 6768). BCSS, assessed by RS category and number of positive lymph nodes, was calculated using the actuarial method. RESULTS: The proportion of patients with RS results and LN+ disease (N = 8782) increased over time between 2004 and 2013, and decreased with increasing lymph node involvement from micrometastases to ≥4 lymph nodes. Five-year BCSS outcomes for those with RS < 18 ranged from 98.9% (95% CI 97.4-99.6) for those with micrometastases to 92.8% (95% CI 73.4-98.2) for those with ≥4 lymph nodes. Similar patterns were found for patients with RS 18-30 and RS ≥ 31. RS group was strongly predictive of BCSS among patients with micrometastases or up to three positive lymph nodes (p < 0.001). CONCLUSIONS: Overall, 5-year BCSS is excellent for patients with RS < 18 and micrometastases, one or two positive lymph nodes, and worsens with additionally involved lymph nodes. Further analyses should account for treatment variables, and longitudinal updates will be important to better characterize utilization of Oncotype DX testing and long-term survival outcomes.

Multigene Expression Assay and Benefit of Radiotherapy After Breast Conservation in Ductal Carcinoma in Situ.

Background: Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods: Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994-2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score-adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results: The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions: The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study.

The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40-84 years of age, and had node-negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results (N=38,568). Unadjusted 5-year BCSM were 0.4% (n=21,023; 95% confidence interval (CI), 0.3-0.6%), 1.4% (n=14,494; 95% CI, 1.1-1.7%), and 4.4% (n=3,051; 95% CI, 3.4-5.6%) for Recurrence Score <18, 18-30, and ⩾31 groups, respectively (P<0.001). In multivariable analysis adjusted for age, tumor size, grade, and race, the Recurrence Score result predicted BCSM (P<0.001). Among patients with node-positive disease (micrometastases and up to three positive nodes; N=4,691), 5-year BCSM (unadjusted) was 1.0% (n=2,694; 95% CI, 0.5-2.0%), 2.3% (n=1,669; 95% CI, 1.3-4.1%), and 14.3% (n=328; 95% CI, 8.4-23.8%) for Recurrence Score <18, 18-30, ⩾31 groups, respectively (P<0.001). Five-year BCSM by Recurrence Score group are reported for important patient subgroups, including age, race, tumor size, grade, and socioeconomic status. This SEER study represents the largest report of prospective BCSM outcomes based on Recurrence Score results for patients with HR+, HER2-negative, node-negative, or node-positive breast cancer, including subgroups often under-represented in clinical trials.

Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).

BACKGROUND: Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. METHODS AND RESULTS: Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. CONCLUSIONS: No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone.

Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 Cp units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.

Five-Year outcomes of patients enrolled in the REVEAL Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH. METHODS: The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years. RESULTS: Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively. CONCLUSIONS: Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Validation of two predictive models for survival in pulmonary arterial hypertension.

The French Pulmonary Hypertension Network (FPHN) registry and the Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) have developed predictive models for survival in pulmonary arterial hypertension (PAH). In this collaboration, we assess the external validity (or generalisability) of the FPHN ItinérAIR-HTAP predictive equation and the REVEAL risk score calculator. Validation cohorts approximated the eligibility criteria defined for each model. The REVEAL cohort comprised 292 treatment-naïve, adult patients diagnosed <1 year prior to enrolment with idiopathic, familial or anorexigen-induced PAH. The FPHN cohort comprised 1737 patients with group 1 PAH. Application of FPHN parameters to REVEAL and REVEAL risk scores to FPHN demonstrated estimated hazard ratios that were consistent between studies and had high probabilities of concordance (hazard ratios of 0.72, 95% CI 0.64-0.80, and 0.73, 95% CI 0.70-0.77, respectively). The REVEAL risk score calculator and FPHN ItinérAIR-HTAP predictive equation showed good discrimination and calibration for prediction of survival in the FPHN and REVEAL cohorts, respectively, suggesting prognostic generalisability in geographically different PAH populations. Once prospectively validated, these may become valuable tools in clinical practice.

Relationship between serum low-density lipoprotein cholesterol and in-hospital mortality following acute myocardial infarction (the lipid paradox).

Lipoprotein levels are currently recognized as independent risk factors for long-term cardiovascular events after acute myocardial infarction (AMI). During the acute-phase reaction after AMI, previous studies have reported trends of decreased low-density lipoprotein cholesterol (LDL-C), increased triglycerides, and variable high-density lipoprotein cholesterol (HDL-C) levels. However, the association between LDL-C and HDL-C levels and in-hospital mortality has not been well established following AMI. The relationship between lipid levels and in-hospital all-cause mortality in 115,492 patients hospitalized for AMI (July 2002 to December 2006), registered in the National Registry of Myocardial Infarction (NRMI) 4b-5, was evaluated using multivariable-adjusted logistic regression models. Mean LDL-C was 104 ± 38, HDL-C was 41 ± 14, and triglycerides 143 ± 83 mg/dl. Compared with the lowest quartile of LDL-C (<77 mg/dl), the risk of in-hospital mortality in the second to fourth quartiles was decreased (adjusted odds ratio 0.79, 0.80, and 0.85, respectively). For HDL-C, only those in the lowest quartile (<31 mg/dl) had higher risk of in-hospital mortality (odds ratio 1.20) compared with the highest quartile (≥47 mg/dl). Results from NRMI 4b-5 suggest a lipid paradox, with lower LDL-C levels associated with increased risk of in-hospital mortality, contrary to findings outside the acute setting. Consistent with previous analyses, lowest HDL-C levels were associated with increased in-hospital mortality. In conclusion, further explorations of the relationship between very low levels of LDL-C, myocardial necrosis, and subsequent adverse cardiovascular events are warranted.

Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) analysis.

BACKGROUND: Data from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) were used previously to develop a risk score calculator to predict 1-year survival. We evaluated prognostic implications of changes in the risk score and individual risk-score parameters over 12 months. METHODS: Patients were grouped by decreased, unchanged, or increased risk score from enrollment to 12 months. Kaplan-Meier estimates of subsequent 1-year survival were made based on change in the risk score during the initial 12 months of follow-up. Cox regression was used for multivariable analysis. RESULTS: Of 2,529 patients in the analysis cohort, the risk score was decreased in 800, unchanged in 959, and increased in 770 at 12 months post-enrollment. Six parameters (functional class, systolic blood pressure, heart rate, 6-minute walk distance, brain natriuretic peptide levels, and pericardial effusion) each changed sufficiently over time to improve or worsen risk scores in ≥5% of patients. One-year survival estimates in the subsequent year were 93.7%, 90.3%, and 84.6% in patients with a decreased, unchanged, and increased risk score at 12 months, respectively. Change in risk score significantly predicted future survival, adjusting for risk at enrollment. Considering follow-up risk concurrently with risk at enrollment, follow-up risk was a much stronger predictor, although risk at enrollment maintained a significant effect on future survival. CONCLUSIONS: Changes in REVEAL risk scores occur in most patients with pulmonary arterial hypertension over a 12-month period and are predictive of survival. Thus, serial risk score assessments can identify changes in disease trajectory that may warrant treatment modifications.

Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance.

BACKGROUND: Clinical studies of pulmonary arterial hypertension have used the change in the 6-minute walk distance (6MWD) as a clinical end point; however, its association with survival outcomes has not been well established. In this analysis, we examined the prognostic value of the baseline 6MWD, absolute thresholds of the 6MWD, and change in the 6MWD. METHODS: Patients in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) with 6MWD at enrollment, with or without a follow-up assessment within the first year of observation, were included. Kaplan-Meier survival estimates were computed for sub-sets with baseline 6MWD results that were above or below all possible thresholds and for sub-sets with a change in the 6MWD that was 10 percentage points above or below all possible thresholds, including improvement thresholds and worsening thresholds. Multivariable Cox regression models assessed the effect of improvement and worsening in the 6MWD on 1-year survival, adjusted for baseline factors. RESULTS: One-year survival estimates were higher for patients with a baseline 6MWD above vs below a threshold, although no specific threshold was more prognostic than another. In a model adjusted for the baseline 6MWD and risk score, worsening of the 6MWD over time significantly predicted decreased survival, but improvement in the 6MWD did not affect survival. CONCLUSIONS: No 6MWD improvement threshold carries particular prognostic value. Improvement in the 6MWD was not associated with survival, but worsening of the 6MWD was strongly and significantly associated with poor prognosis.

Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight Study.

PURPOSE: To determine improvement in breast cancer detection by using supplemental three-dimensional (3D) automated breast (AB) ultrasonography (US) with screening mammography versus screening mammography alone in asymptomatic women with dense breasts. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant study. The SomoInsight Study was an observational, multicenter study conducted between 2009 and 2011. A total of 15 318 women (mean age, 53.3 years ± 10 [standard deviation]; range, 25-94 years) presenting for screening mammography alone with heterogeneously (50%-75%) or extremely (>75%) dense breasts were included, regardless of further risk characterization, and were followed up for 1 year. Participants underwent screening mammography alone followed by an AB US examination; results were interpreted sequentially. McNemar test was used to assess differences in cancer detection. RESULTS: Breast cancer was diagnosed at screening in 112 women: 82 with screening mammography and an additional 30 with AB US. Addition of AB US to screening mammography yielded an additional 1.9 detected cancers per 1000 women screened (95% confidence interval [CI]: 1.2, 2.7; P < .001). Of cancers detected with screening mammography, 62.2% (51 of 82) were invasive versus 93.3% (28 of 30) of additional cancers detected with AB US (P = .001). Of the 82 cancers detected with either screening mammography alone or the combined read, 17 were detected with screening mammography alone. Of these, 64.7% (11 of 17) were ductal carcinoma in situ versus 6.7% (two of 30) of cancers detected with AB US alone. Sensitivity for the combined read increased by 26.7% (95% CI: 18.3%, 35.1%); the increase in the recall rate per 1000 women screened was 284.9 (95% CI: 278.0, 292.2; P < .001). CONCLUSION: Addition of AB US to screening mammography in a generalizable cohort of women with dense breasts increased the cancer detection yield of clinically important cancers, but it also increased the number of false-positive results.

Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study.

BACKGROUND: Few studies have prospectively reported outcomes in patients with pulmonary arterial hypertension (PAH) treated with epoprostenol in the modern-day era of oral therapy and combination treatments. The Registry to Prospectively Describe Use of Epoprostenol for Injection (Veletri, prolonged room temperature stable-epoprostenol [RTS-Epo]) in Patients with Pulmonary Arterial Hypertension (PROSPECT) was established to prospectively describe the course of PAH in patients prescribed RTS-Epo. METHODS: PROSPECT is a multicenter, US-based drug registry of primarily group 1 patients with PAH treated with RTS-Epo who were parenteral-naive or parenteral-transitioned at enrollment. Patients were followed until discontinuation of RTS-Epo, withdrawal, loss to follow-up, death, or end of study (maximum 1 year). One-year freedom from hospitalization (FH) and survival estimates were summarized by prostacyclin history (parenteral-naive or parenteral-transitioned), sex, and chronic renal insufficiency (CRI). RESULTS: A total of 336 patients were included. The overall 1-year FH estimate was 51.0% ± 2.8% and was lower in parenteral-naive patients than parenteral-transitioned patients (42.8% ± 4.3% vs 57.1% ± 3.7%, respectively; P = .002). FH estimates were lower in male patients than female patients (38.3% ± 5.9% vs 54.6% ± 3.2%, respectively; P < .015) and in patients with CRI than patients without CRI (17.0% ± 8.4% vs 53.7% ± 2.9%, respectively; P < .001). The overall 1-year survival estimate was 84.0% ± 2.1%. Survival was poorer in parenteral-naive patients, male patients, and patients with CRI. CONCLUSIONS: Risk of hospitalization and mortality remain high in patients with PAH. In particular, patients who are parenteral-naive at initiation of RTS-Epo therapy, male patients, and patients with CRI require close monitoring and aggressive clinical management.