Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS: Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS: Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION: Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-term Update of NRG/RTOG 9202.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with coronary heart disease and myocardial infarction (MI) in prostate cancer patients, but controversy persists regarding its effects on cardiovascular mortality (CVM). OBJECTIVE: We assessed the long-term relationship between ADT and CVM in a prostate cancer randomized trial (NRG Oncology/Radiation Therapy Oncology Group 9202). DESIGN, SETTING, AND PARTICIPANTS: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c-T4, prostate-specific antigen <150 ng/ml) received radiotherapy with 4 mo (short-term [STADT]) versus 28 mo (longer-term [LTADT]) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the Fine-Gray and Cox regression models, the relationship between ADT and mortality was evaluated. RESULTS AND LIMITATIONS: With a median follow-up of 19.6 yr, LTADT was associated with improved overall survival (OS) versus STADT (adjusted hazard ratio [HR] 0.88; p = 0.03) and prostate cancer survival (subdistribution HR [sHR] 0.70, p = 0.003). Comparing LTADT with STADT, prostate cancer mortality improved by 6.0% (15.6% [95% confidence interval 13.0-18.3%] vs 21.6% [18.6-24.7%]) at 15 yr, while CVM increased by 2.2% (14.9% [12.4-17.6%] vs 12.7% [10.4-15.3%]). In multivariable analyses, LTADT was not associated with increased CVM versus STADT (sHR 1.22 [0.93-1.59]; p = 0.15). An association between LTADT and MI death was detected (sHR 1.58 [1.00-2.50]; p = 0.05), particularly in patients with prevalent cardiovascular disease (CVD; sHR 2.54 [1.16-5.58]; p = 0.02). CONCLUSIONS: With 19.6 yr of follow-up, LTADT was not significantly associated with increased CVM in men with locally advanced prostate cancer. Patients may have increased MI mortality with LTADT, particularly those with baseline CVD. Overall, there remained a prostate cancer mortality benefit and no OS detriment with LTADT. PATIENT SUMMARY: In a long-term analysis of a large randomized prostate cancer trial, radiation with 28 mo of hormone therapy did not increase the risk of cardiovascular death significantly versus 4 mo of hormone therapy. Future studies are needed for patients with pre-existing heart disease, who may have an increased risk of myocardial infarction death with longer hormone use.

Mismatch in Supply and Demand for Neuro-Ophthalmic Care.

BACKGROUND: Previous research suggests the number of neuro-ophthalmologists in the United States may be below a level that provides sufficient access to neuro-ophthalmic care in much of the United States. However, national estimates of the amount of clinical time spent on neuro-ophthalmology are lacking. METHODS: The North American Neuro-Ophthalmology Society administered a survey on professional time allocation to its active members. Survey response was 95%. The survey characterized the hours each week each respondent allocated to overall work, clinical work, clinical work in ophthalmology/neurology, and clinical work in neuro-ophthalmology specifically. The survey additionally collected information regarding demographics, current wait times to be seen for new patients, and the difference in clinical time spent in neuro-ophthalmology spent between the current day compared with that shortly after completing clinical training. Linear regression was used to identify potential relationships between the above and average wait time. RESULTS: On average, responding physicians spent 70% of their clinical time on neuro-ophthalmology. In 6 states, there were no reported practicing neuro-ophthalmologists, and in only 8 states was the clinical full-time equivalent to population ratio below the suggested threshold of 1 for every 1.2 million. The median wait time for a new patient was 6 weeks. This wait time was associated with the fraction of clinical time spent in neuro-ophthalmology (0.2 weeks longer wait for a 10 percentage point increase in the fraction of time spent in neuro-ophthalmology; P = 0.02), and suggestively associated with training (training in ophthalmology was associated with 1.0 week shorter wait time; P = 0.06). CONCLUSION: The survey suggests that neuro-ophthalmologists are unable to see patients in a timely manner and a decreasing number of clinicians are entering the field. Future interventions should be considered to incentivize neuro-ophthalmology training in ophthalmology and neurology residents such that the United States population is able to appropriately access neuro-ophthalmic care.

Mendelian randomization analysis of arsenic metabolism and pulmonary function within the Hispanic Community Health Study/Study of Latinos.

Arsenic exposure has been linked to poor pulmonary function, and inefficient arsenic metabolizers may be at increased risk. Dietary rice has recently been identified as a possible substantial route of exposure to arsenic, and it remains unknown whether it can provide a sufficient level of exposure to affect pulmonary function in inefficient metabolizers. Within 12,609 participants of HCHS/SOL, asthma diagnoses and spirometry-based measures of pulmonary function were assessed, and rice consumption was inferred from grain intake via a food frequency questionnaire. After stratifying by smoking history, the relationship between arsenic metabolism efficiency [percentages of inorganic arsenic (%iAs), monomethylarsenate (%MMA), and dimethylarsinate (%DMA) species in urine] and the measures of pulmonary function were estimated in a two-sample Mendelian randomization approach (genotype information from an Illumina HumanOmni2.5-8v1-1 array), focusing on participants with high inferred rice consumption. Among never-smoking high inferred consumers of rice (n = 1395), inefficient metabolism was associated with past asthma diagnosis and forced vital capacity below the lower limit of normal (LLN) (OR 1.40, p = 0.0212 and OR 1.42, p = 0.0072, respectively, for each percentage-point increase in %iAs; OR 1.26, p = 0.0240 and OR 1.24, p = 0.0193 for %MMA; OR 0.87, p = 0.0209 and OR 0.87, p = 0.0123 for the marker of efficient metabolism, %DMA). Among ever-smoking high inferred consumers of rice (n = 1127), inefficient metabolism was associated with peak expiratory flow below LLN (OR 1.54, p = 0.0108/percentage-point increase in %iAs, OR 1.37, p = 0.0097 for %MMA, and OR 0.83, p = 0.0093 for %DMA). Less efficient arsenic metabolism was associated with indicators of pulmonary dysfunction among those with high inferred rice consumption, suggesting that reductions in dietary arsenic could improve respiratory health.

Mendelian randomization of inorganic arsenic metabolism as a risk factor for hypertension- and diabetes-related traits among adults in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort.

BACKGROUND: Hypertension and diabetes have been associated with inefficient arsenic metabolism, primarily through studies undertaken in populations exposed through drinking water. Recently, rice has been recognized as a source of arsenic exposure, but it remains unclear whether populations with high rice consumption but no known water exposure are at risk for the health problems associated with inefficient arsenic metabolism. METHODS: The relationships between arsenic metabolism efficiency (% inorganic arsenic, % monomethylarsenate and % dimethylarsinate in urine) and three hypertension- and seven diabetes-related traits were estimated among 12 609 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). A two-sample Mendelian randomization approach incorporated genotype-arsenic metabolism relationships from literature, and genotype-trait relationships from HCHS/SOL, with a mixed-effect linear model. Analyses were stratified by rice consumption and smoking. RESULTS: Among never smokers with high rice consumption, each percentage point increase in was associated with increases of 1.96 mmHg systolic blood pressure (P = 0.034) and 1.85 mmHg inorganic arsenic diastolic blood pressure (P = 0.003). Monomethylarsenate was associated with increased systolic (1.64 mmHg/percentage point increase; P = 0.021) and diastolic (1.33 mmHg/percentage point increase; P = 0.005) blood pressure. Dimethylarsinate, a marker of efficient metabolism, was associated with lower systolic (-0.92 mmHg/percentage point increase; P = 0.025) and diastolic (-0.79 mmHg/percentage point increase; P = 0.004) blood pressure. Among low rice consumers and ever smokers, the results were consistent with no association. Evidence for a relationship with diabetes was equivocal. CONCLUSIONS: Less efficient arsenic metabolism was associated with increased blood pressure among never smokers with high rice consumption, suggesting that arsenic exposure through rice may contribute to high blood pressure in the Hispanic/Latino community.

Changes in blood pressure associated with lead, manganese, and selenium in a Bangladeshi cohort.

BACKGROUND: Heavy metal contamination is widespread in Bangladesh. Previous studies have observed lead increases blood pressure over time. However, the role of other metal contaminants and essential micronutrients, which could also adversely affect blood pressure or act as protective factors, is understudied. OBJECTIVES: We therefore evaluated the associations of lead, manganese, and selenium with blood and pulse pressure trajectories. METHODS: We prospectively followed placebo-assigned participants nested within a randomized trial for the prevention of arsenic-related skin cancer (n = 255). Blood lead, manganese, and selenium were measured at baseline; blood pressure was measured at baseline and at 3 biennial follow-up examinations. Mixed-effect linear regression models were used to estimate associations with average annual changes in systolic, diastolic, and pulse pressure. RESULTS: In models simultaneously adjusted for baseline blood lead, manganese, and selenium concentrations in addition to other potential confounders, lead was linearly associated with increases in systolic blood pressure, but not with diastolic blood pressure or pulse pressure. A non-linear association was observed for manganese, such that mid-range concentrations were associated with decreases in systolic, diastolic, and pulse pressure. Baseline selenium concentrations in the highest quartile were also associated with longitudinal decreases in both systolic and diastolic blood pressure, while null associations were observed with pulse pressure. In exploratory analyses, the combination of mid-range manganese and high selenium concentrations completely offset lead-associated increases in blood and pulse pressure. CONCLUSIONS: The results indicate a direct, linear association of lead exposure with systolic blood pressure, and manganese and selenium exposures within certain ranges may have a blood pressure-lowering effect in this population.

Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer.

Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established.Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset.Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10-5; replication P < 1.00 × 10-6), NEK10 (P = 3.57 × 10-4; replication P < 1.00 × 10-6), and SIVA1 (P = 5.49 × 10-4; replication P < 1.00 × 10-6). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684).Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus.Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057-64. ©2018 AACR.

Investigating the Effect of Reirradiation or Systemic Therapy in Patients With Glioblastoma After Tumor Progression: A Secondary Analysis of NRG Oncology/Radiation Therapy Oncology Group Trial 0525.

PURPOSE: To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. METHODS AND MATERIALS: This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. RESULTS: The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). CONCLUSIONS: Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction.

PURPOSE: Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor. METHODS: We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods. RESULTS: No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association. CONCLUSION: Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.