21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

Screening Beyond the Evidence: Patterns of Age and Comorbidity for Breast, Cervical, and Colorectal Cancer Screening.

BACKGROUND: Little evidence exists to guide continuation of screening beyond the recommended ages of national guidelines for breast, cervical, and colorectal cancers, although increasing age and comorbidity burden is likely to reduce the screening benefit of lower mortality. OBJECTIVE: Characterize screening after recommended stopping ages, by age and comorbidities in a large, diverse sample. DESIGN: Serial cross-sectional. PARTICIPANTS: All individuals in the PROSPR-I consortium cohorts from 75 to 89 years of age for breast cancer screening, 66-89 years of age for cervical cancer screening, and 76-89 years of age for colorectal cancer screening from 2011 to 2013. The lower age thresholds were based on the guidelines for each respective cancer type. MAIN MEASURES: Proportion of annual screening by cancer type in relation to age and Charlson comorbidity score and median years of screening past guideline age. We estimated the likelihood of screening past the guideline-based age as a function of age and comorbidity using logistic regression. KEY RESULTS: The study cohorts included individuals screening for breast (n = 33,475); cervical (n = 459,318); and colorectal (n = 556,356) cancers. In the year following aging out, approximately 30% of the population was screened for breast cancer, 2% of the population was screened for cervical, and almost 5% for colorectal cancer. The median number of years screened past the guideline-based recommendation was 5, 3, and 4 for breast, cervical, and colorectal cancer, respectively. Of those screening > 10 years past the guideline-based age,15%, 46%, and 25% had ≥ 3 comorbidities respectively. Colorectal cancer screening had the smallest decline in the likelihood of screening beyond the age-based recommendation. CONCLUSIONS: The odds of screening past guideline-based age decreased with comorbidity burden for breast and cervical cancer screening but not for colorectal. These findings suggest the need to evaluate shared decision tools to help patients understand whether screening is appropriate and to generate more evidence in older populations.

Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like. METHODS: S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1-14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905. FINDINGS: Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6-20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3-9·2) in the cisplatin plus veliparib group and 6·4 months (4·3-8·2) in the cisplatin plus placebo group (HR 0·79 [95% CI 0·38-1·67]; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3-7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3-5·0) in the cisplatin plus placebo group (HR 0·57 [95% CI 0·37-0·88]; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5-4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2-4·4) in the cisplatin plus placebo group (HR 0·89 [95% CI 0·60-1·33]; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 [46%] of 155 patients in the cisplatin plus veliparib group vs 29 [20%] of 147 in the cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]), anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four [3%]). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure). INTERPRETATION: The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer. FUNDING: National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.

Vitamin D Insufficiency as a Risk Factor for Paclitaxel-Induced Peripheral Neuropathy in SWOG S0221.

BACKGROUND: Prior work suggests that patients with vitamin D insufficiency may have a higher risk of chemotherapy-induced peripheral neuropathy (CIPN) from paclitaxel. The objective of this study was to validate vitamin D insufficiency as a CIPN risk factor. METHODS: We used data and samples from the prospective phase III SWOG S0221 (ClinicalTrials.gov identifier: NCT00070564) trial that compared paclitaxel-containing chemotherapy regimens for early-stage breast cancer. We quantified pretreatment 25-hydroxy-vitamin D in banked serum samples using a liquid chromatography-tandem mass spectrometry targeted assay. We tested the association between vitamin D insufficiency (≤20 ng/mL) and grade ≥3 sensory CIPN via multiple logistic regression and then adjusted for self-reported race, age, body mass index, and paclitaxel schedule (randomization to weekly or every-2-week dosing). We also tested the direct effect of vitamin D deficiency on mechanical hypersensitivity in mice randomized to a regular or vitamin D-deficient diet. RESULTS: Of the 1,191 female patients in the analysis, 397 (33.3%) had pretreatment vitamin D insufficiency, and 195 (16.4%) developed grade ≥3 CIPN. Patients with vitamin D insufficiency had a higher incidence of grade ≥3 CIPN than those who had sufficient vitamin D (20.7% vs 14.2%; odds ratio [OR], 1.57; 95% CI, 1.14-2.15; P=.005). The association retained significance after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; 95% CI, 1.18-2.30; P=.003) but not race (adjusted OR, 1.39; 95% CI, 0.98-1.97; P=.066). In the mouse experiments, the vitamin D-deficient diet caused mechanical hypersensitivity and sensitized mice to paclitaxel (both P<.05). CONCLUSIONS: Pretreatment vitamin D insufficiency is the first validated potentially modifiable predictive biomarker of CIPN from paclitaxel. Prospective trials are needed to determine whether vitamin D supplementation prevents CIPN and improves treatment outcomes in patients with breast and other cancer types.

Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226).

BACKGROUND: Some patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum®TKa highlighting differences vs. a Research Use Only version is reported. METHODS: 1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum® unit of Activity) is adopted. RESULTS: A DiviTum®TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals. CONCLUSIONS: DiviTum®TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET.Trial registration: NCT00075764.

Impact of treatment experience on patient knowledge of colony-stimulating factors among patients receiving cancer chemotherapy: evidence from S1415CD-a large pragmatic trial.

PURPOSE: Primary prophylactic granulocyte colony-stimulating factors (PP-CSFs) are prescribed alongside chemotherapy regimens that carry a significant risk of febrile neutropenia (FN). As part of S1415CD, a prospective, pragmatic trial evaluating the impact of automated orders to improve PP-CSF prescribing, we evaluated patients' baseline knowledge of PP-CSF and whether that knowledge improved following the first cycle of chemotherapy. METHODS: Adult patients with breast, colorectal, or non-small-cell lung cancer initiating chemotherapy were enrolled in S1415CD between January 2016 and April 2020. Eight questions assessing knowledge of CSF indications, risks, benefits, and out-of-pocket costs were included in a baseline survey and in a follow-up survey at the end of the first cycle of chemotherapy. Responses were stratified by the trial arm and whether chemotherapy was low, intermediate, or high FN risk. RESULTS: Of the 3605 eligible patients, 3580 (99.3%) completed the baseline survey, and 3420 (95.5%) completed the follow-up survey. At baseline, 803 (22.4%) patients responded "Don't know" to all 8 questions, and all patients averaged 2.75 correct questions. At follow-up, knowledge increased by 0.34 in the high-FN-risk group (p < 0.001) but declined for the other FN-risk groups. In multivariate analysis, receiving a high-FN-risk regimen and younger age were significantly associated with knowledge improvement. CONCLUSION: Chemotherapy patients had poor knowledge of PP-CSF that improved only modestly among recipients of high-FN-risk chemotherapy. Further efforts to inform patients about the risks, benefits, and costs of PP-CSF may be warranted, particularly for those in whom prophylaxis is indicated. TRIAL REGISTRATION: NCT02728596, April 6, 2016.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer.

BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).

Successes and challenges of implementing a cancer care delivery intervention in community oncology practices: lessons learned from SWOG S1415CD.

BACKGROUND: Cancer Care Delivery (CCD) research studies often require practice-level interventions that pose challenges in the clinical trial setting. The SWOG Cancer Research Network (SWOG) conducted S1415CD, one of the first pragmatic cluster-randomized CCD trials to be implemented through the National Cancer Institute (NCI) Community Oncology Program (NCORP), to compare outcomes of primary prophylactic colony stimulating factor (PP-CSF) use for an intervention of automated PP-CSF standing orders to usual care. The introduction of new methods for study implementation created challenges and opportunities for learning that can inform the design and approach of future CCD interventions. METHODS: The order entry system intervention was administered at the site level; sites were affiliated NCORP practices that shared the same chemotherapy order system. 32 sites without existing guideline-based PP-CSF standing orders were randomized to the intervention (n = 24) or to usual care (n = 8). Sites assigned to the intervention participated in tailored training, phone calls and onboarding activities administered by research team staff and were provided with additional funding and external IT support to help them make protocol required changes to their order entry systems. RESULTS: The average length of time for intervention sites to complete reconfiguration of their order sets following randomization was 7.2 months. 14 of 24 of intervention sites met their individual patient recruitment target of 99 patients enrolled per site. CONCLUSIONS: In this paper we share seven recommendations based on lessons learned from implementation of the S1415CD intervention at NCORP community oncology practices representing diverse geographies and patient populations across the U. S. It is our hope these recommendations can be used to guide future implementation of CCD interventions in both research and community settings. TRIAL REGISTRATION: NCT02728596 , registered April 5, 2016.

Out of reach? Correlates of cervical cancer underscreening in women with varying levels of healthcare interactions in a United States integrated delivery system.

One in five U.S. women with health insurance are underscreened for cervical cancer. We sought to identify whether underscreening correlates differed among women with different levels of health care interaction. Among women age 30-64 years who were members of an integrated U.S. health system, we used 2014-2015 electronic health record data to identify underscreened cases (≥3.4 years since last Papanicolaou (Pap) test, n=3352) and screening-adherent controls (<3.4 years since last Pap test, n=45,359) and extracted data on potential underscreening correlates (demographics, health history, and healthcare utilization). We calculated the odds of underscreening in the total population and by subgroups defined by healthcare visits and online health portal usage in the prior 12 months. Underscreening was associated with older age (50-64 vs. 30-39; odds ratio (OR)=1.6; 95%CI=1.4-1.8), current tobacco use (vs. never use; OR=2.1; 95%CI=1.8-2.2), higher BMI (≥35 kg/m2 vs <25 kg/m2, OR=2.0; 95%CI=1.8-2.3), screening non-adherence for colorectal cancer (OR=5.1; 95%CI=4.6-5.7) and breast cancer (OR=8.1, 95%CI=7.2-9.0), and having no recent visit with their primary care provider (PCP) nor recent health portal use (vs. recent PCP visit and portal use; OR=8.4, 95%CI=7.6-9.4). Underscreening correlates were similar between the total study population and within all healthcare interaction groups. Interaction with the healthcare system is associated with lower odds of underscreening, but sociodemographic and health status correlates are similar regardless of primary care visits or online portal use. These data support the need for additional interventions to reach insured women who remain underscreened for cervical cancer.

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307).

PURPOSE: Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis. METHODS: SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided. RESULTS: Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ. CONCLUSION: ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this. CLINICAL TRIAL NUMBER: NCT00127205 REGISTRATION DATE: July 2005.

Molecular Identification of Mutations Conferring Resistance to Azoxystrobin in Cercospora nicotianae.

Cercospora nicotianae, the causal agent of frogeye leaf spot (FLS) of tobacco, has been exposed to quinone outside inhibitor (QoI) fungicides for more than a decade through azoxystrobin applications targeting other major foliar diseases. From 2016 to 2018, a total of 124 isolates were collected from tobacco fields throughout Kentucky. Sensitivity of these isolates to azoxystrobin was previously characterized by determining the effective concentration to inhibit 50% conidial germination (EC50). Based on azoxystrobin EC50, isolates were categorized into three discrete groups: high sensitivity (<0.08 µg/ml), moderate sensitivity (0.14 to 0.64 µg/ml), and low sensitivity (>1.18 µg/ml). Variability in sensitivity in a limited number of C. nicotianae isolates was previously shown to be a result of resistance mutations in the fungicide target gene. To improve understanding of C. nicotianae cytochrome b (cytb) structure, the gene was cloned from three isolates representing each EC50 group, and sequences were compared. Our analysis showed that cytb gene in C. nicotianae consists of 1,161 nucleotides encoding 386 amino acids. The cytb sequence among the cloned isolates was identical with the exception of the F129L and G143A point mutations. To more rapidly determine the resistance status of C. nicotianae isolates to azoxystrobin, a polymerase chain reaction (PCR) assay was developed to screen for mutations. According to this assay, 80% (n = 99) of tested C. nicotianae isolates carried an F129L mutation and were moderately resistant to azoxystrobin, and 7% (n = 9) carried the G143A mutation and were highly resistant. A receiver operating characteristic curve analysis suggested the PCR assay was a robust diagnostic tool to identify C. nicotianae isolates with different sensitivity to azoxystrobin in Kentucky tobacco production. The prevalence of both the F129L and G143A mutations in C. nicotianae from Kentucky differs from that of other pathosystems where resistance to QoI fungicides has been identified, in which the majority of sampled isolates of the pathogen species have a broadly occurring cytb mutation.

Healthcare utilization and cost of care in elderly breast cancer patients enrolled in SWOG clinical trials.

IMPORTANCE: Patients with cancer are at risk for unplanned hospitalizations during treatment which can increase the cost of care. OBJECTIVES: To determine demographic and clinical factors associated with healthcare utilization and costs among clinical trial participants. DESIGN, SETTING, AND PATIENTS: We conducted a retrospective analysis among breast cancer patients over the age of 65 treated on SWOG clinical trials from 1999 to 2011 with trial data linked to Medicare claims. MAIN OUTCOMES AND MEASURES: The outcomes were healthcare utilization (emergency room visits (ER), hospitalizations) and costs from Medicare Claims. Demographic, clinical, and prognostic factors were captured from clinical trial records. We identified cardiovascular comorbidities/risk factors (CVD-RFs) of diabetes, hypertension, hypercholesterolemia, and coronary artery disease (CAD) from Medicare claims. Multivariable logistic and linear regression were used to assess the association between CVD-RFs and outcomes. RESULTS: Among the 708 patients included in the analysis, 160 (22.6%) experienced 234 separate hospitalizations, and 193 (27.3%) experienced 311 separate ER visits. Black race was associated with an increase in hospitalizations (OR [95% CI], 2.52 [1.10-5.79], p = 0.03), but not emergency room visits compared to white race. Diabetes, hypertension, hypercholesterolemia, and CAD were all independently associated with increased risk of both hospitalizations and ER visit. Hypertension had the strongest association, with more than a threefold risk of hospitalization for those with hypertension compared to those without (OR [95% CI], 3.16 [1.85-5.40], p < 0.001). For those with ≥ 3 RFs, the risk of hospitalization was nearly 3 times greater compared to 0 or 1 CVD-RFs (OR [95% CI], 2.74 [1.71-4.38], p < 0.001). Similar results were seen for ER visits. In the first 12 months after trial registration, patients with diabetes ($38,324 vs $30,923, 23.9% increase, p = 0.05), hypercholesterolemia ($34,168 vs $30,661, 11.4% increase, p = 0.02), and CAD ($37,781 vs $31,698, 19.2% increase, p = 0.04) had statistically significantly higher total healthcare costs. Additionally, those with ≥ 2 significant CVD-RFs ($35,353 vs. $28,899, 22.3% increase, p = 0.005) had statistically significantly higher total healthcare costs. CONCLUSIONS: Among participants treated on clinical trials, black race and presence of multiple cardiovascular comorbidities was associated with a substantial increase in ER visits, hospitalizations and healthcare costs. Efforts to reduce unplanned hospitalizations should focus on this high-risk group.

Cytochrome b Mutations F129L and G143A Confer Resistance to Azoxystrobin in Cercospora nicotianae, the Frogeye Leaf Spot Pathogen of Tobacco.

Azoxystrobin is the only synthetic, systemic fungicide labeled in the United States for management of frogeye leaf spot (FLS) of tobacco (Nicotiana tabacum L.), caused by Cercospora nicotianae. Though traditionally considered a minor disease in the United States, FLS has recently become yield and quality limiting. In 2016 and 2017, 100 C. nicotianae isolates were collected from symptomatic tobacco from eight counties in Kentucky, United States. Prior to azoxystrobin sensitivity testing, some C. nicotianae isolates were found to utilize the alternative oxidase pathway and, after assay comparisons, conidial germination was utilized to evaluate sensitivity in C. nicotianae as opposed to mycelial growth. Azoxystrobin sensitivity was determined by establishing the effective concentration to inhibit 50% conidial germination (EC50) for 47 (in 2016) and 53 (in 2017) C. nicotianae isolates. Distributions of C. nicotianae EC50 values indicated three qualitative levels of sensitivity to azoxystrobin. Partial cytochrome b sequence, encompassing the F129L and G143A mutation sites, indicated single-nucleotide polymorphisms (SNPs) conferring the F129L mutation in C. nicotianae of moderate resistance (azoxystrobin at 0.177 ≤ EC50 ≤ 0.535 µg/ml) and the G143A mutation in isolates with an azoxystrobin-resistant phenotype (azoxystrobin EC50 > 1.15 µg/ml). Higher frequencies of resistant isolates were identified from greenhouse transplant (4 of 17) and conventionally produced (58 of 62) tobacco samples, as compared with field-grown tobacco (<4 weeks prior to harvest; 4 of 62) or organically produced samples (1 of 7), respectively. Together, these results suggest that resistance to azoxystrobin in C. nicotianae occurs broadly in Kentucky, and generate new hypotheses about selection pressure affecting resistance mutation frequencies.

Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.

OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy.

BACKGROUND: Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. METHODS: We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival. RESULTS: At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05). CONCLUSIONS: Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).

Evidence for Detection Bias by Medication Use in a Cohort Study of Breast Cancer Survivors.

In previous studies, we found modestly decreased and increased risks of second breast cancer events with the use of statins and antibiotics, respectively, after adjustment for surveillance mammography. We evaluated detection bias by comparing receipt of surveillance mammography among users of these 2 disparate classes of medication. Adult women diagnosed with early-stage breast cancer during 1990-2008 (n = 3,965) while enrolled in an integrated health-care plan (Group Health Cooperative; Washington State) were followed for up to 10 years in the Commonly Used Medications and Breast Cancer Outcomes (COMBO) Study. Categories of antibiotic use included infrequent (1-3 dispensings/12 months) and frequent (≥4 dispensings/12 months) use, and categories of statin use included less adherent (1 dispensing/6 months) and adherent (≥2 dispensings/6 months). We examined associations between medication use and surveillance mammography using multivariable generalized estimating equations and evaluated the impact of adjusting for surveillance within Cox proportional hazard models. Frequent antibiotic users were less likely to receive surveillance mammography (odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.82, 0.99) than were nonusers; no association was found among infrequent users (OR = 0.96, 95% CI: 0.90, 1.03). Adherent statin use was associated with more surveillance compared with nonuse (OR = 1.11, 95% CI: 1.01, 1.25), but less adherent statin use was not (OR = 1.03, 95% CI: 0.81, 1.31). No difference in associations between medications of interest and second breast cancer events was observed when surveillance was removed from otherwise adjusted models. The influence of detection bias by medication use warrants further exploration.

Primary Care Providers' Beliefs and Recommendations and Use of Screening Mammography by their Patients.

BACKGROUND: Revised breast cancer screening guidelines have fueled debate about the effectiveness and frequency of screening mammography, encouraging discussion between women and their providers. OBJECTIVE: To examine whether primary care providers' (PCPs') beliefs about the effectiveness and frequency of screening mammography are associated with utilization by their patients. DESIGN: Cross-sectional survey data from PCPs (2014) from three primary care networks affiliated with the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium, linked with data about their patients' mammography use (2011-2014). PARTICIPANTS: PCPs (n = 209) and their female patients age 40-89 years without breast cancer (n = 30,233). MAIN MEASURES: Outcomes included whether (1) women received a screening mammogram during a 2-year period; and (2) screened women had >1 mammogram during that period, reflecting annual screening. Principal independent variables were PCP beliefs about the effectiveness of mammography and their recommendations for screening frequency. KEY RESULTS: Overall 65.2% of women received >1 screening mammogram. For women 40-48 years, mammography use was modestly lower for those cared for by PCPs who believed that screening was ineffective compared with those who believed it was somewhat or very effective (59.1%, 62.3%, and 64.7%; p = 0.019 after controlling for patient characteristics). Of women with PCPs who reported they did not recommend screening before age 50, 48.1% were nonetheless screened. For women age 49-74 years, the vast majority were cared for by providers who believed that screening was effective. Provider recommendations were not associated with screening frequency. For women ≥75 years, those cared for by providers who were uncertain about effectiveness had higher screening use (50.7%) than those cared for by providers who believed it was somewhat effective (42.8%). Patients of providers who did not recommend screening were less likely to be screened than were those whose providers recommended annual screening, yet 37.1% of patients whose providers recommended against screening still received screening. CONCLUSIONS: PCP beliefs about mammography effectiveness and screening recommendations are only modestly associated with use, suggesting other likely influences on patient participation in mammography.

Variation in Mammographic Breast Density Assessments Among Radiologists in Clinical Practice: A Multicenter Observational Study.

Background: About half of the United States has legislation requiring radiology facilities to disclose mammographic breast density information to women, often with language recommending discussion of supplemental screening options for women with dense breasts. Objective: To examine variation in breast density assessment across radiologists in clinical practice. Design: Cross-sectional and longitudinal analyses of prospectively collected observational data. Setting: 30 radiology facilities within the 3 breast cancer screening research centers of the Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Participants: Radiologists who interpreted at least 500 screening mammograms during 2011 to 2013 (n = 83). Data on 216 783 screening mammograms from 145 123 women aged 40 to 89 years were included. Measurements: Mammographic breast density, as clinically recorded using the 4 Breast Imaging Reporting and Data System categories (heterogeneously dense and extremely dense categories were considered "dense" for analyses), and patient age, race, and body mass index (BMI). Results: Overall, 36.9% of mammograms were rated as showing dense breasts. Across radiologists, this percentage ranged from 6.3% to 84.5% (median, 38.7% [interquartile range, 28.9% to 50.9%]), with multivariable adjustment for patient characteristics having little effect (interquartile range, 29.9% to 50.8%). Examination of patient subgroups revealed that variation in density assessment across radiologists was pervasive in all but the most extreme patient age and BMI combinations. Among women with consecutive mammograms interpreted by different radiologists, 17.2% (5909 of 34 271) had discordant assessments of dense versus nondense status. Limitation: Quantitative measures of mammographic breast density were not available for comparison. Conclusion: There is wide variation in density assessment across radiologists that should be carefully considered by providers and policymakers when considering supplemental screening strategies. The likelihood of a woman being told she has dense breasts varies substantially according to which radiologist interprets her mammogram. Primary Funding Source: National Institutes of Health.

Breast cancer screening using tomosynthesis in combination with digital mammography compared to digital mammography alone: a cohort study within the PROSPR consortium.

Digital breast tomosynthesis (DBT) is emerging as the new standard of care for breast cancer screening based on improved cancer detection coupled with reductions in recall compared to screening with digital mammography (DM) alone. However, many prior studies lack follow-up data to assess false negatives examinations. The purpose of this study is to assess if DBT is associated with improved screening outcomes based on follow-up data from tumor registries or pathology. Retrospective analysis of prospective cohort data from three research centers performing DBT screening in the PROSPR consortium from 2011 to 2014 was performed. Recall and biopsy rates were assessed from 198,881 women age 40-74 years undergoing screening (142,883 DM and 55,998 DBT examinations). Cancer, cancer detection, and false negative rates and positive predictive values were assessed on examinations with one year of follow-up. Logistic regression was used to compare DBT to DM adjusting for research center, age, prior breast imaging, and breast density. There was a reduction in recall with DBT compared to DM (8.7 vs. 10.4 %, p < 0.0001), with adjusted OR = 0.68 (95 % CI = 0.65-0.71). DBT demonstrated a statistically significant increase in cancer detection over DM (5.9 vs. 4.4/1000 screened, adjusted OR = 1.45, 95 % CI = 1.12-1.88), an improvement in PPV1 (6.4 % for DBT vs. 4.1 % for DM, adjusted OR = 2.02, 95 % CI = 1.54-2.65), and no significant difference in false negative rates for DBT compared to DM (0.46 vs. 0.60/1000 screened, p = 0.347). Our data support implementation of DBT screening based on increased cancer detection, reduced recall, and no difference in false negative screening examinations.

Breast cancer screening initiation after turning 40 years of age within the PROSPR consortium.

PURPOSE: Although United States clinical guidelines differ, the earliest recommended age for average risk breast cancer screening is 40 years. Little is known about factors influencing screening initiation. METHODS: We conducted a cohort study within the National Cancer Institute-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. We identified 3413 women on their 40th birthday in primary care networks at Geisel School of Medicine at Dartmouth (DH) and Brigham and Women's Hospital (BWH) during 2011-2013 with no prior breast imaging or breast cancer. Cumulative incidence curves and Cox modeling were used to determine time from the 40th birthday to first breast cancer screening, cohort exit, or 42nd birthday. We calculated hazards ratios and 95 % confidence intervals from multivariable Cox proportional hazards models. RESULTS: Breast cancer screening cumulative incidence by the 42nd birthday was 62.9 % (BWH) and 39.8 % (DH). Factors associated with screening initiation were: a primary care visit within a year (HR 4.99, 95 % CI 4.23-5.89), an increasing number of primary care visits within a year (p for trend <0.0001), ZIP code of residence annual median household income ≤$52,000 (HR 0.79, 95 % CI 0.68-0.92), and health insurance type (Medicaid HR 0.72, 95 % CI 0.58-0.88; Medicare HR 0.55, 95 % CI 0.39-0.77; uninsured HR 0.37, 95 % CI 0.25-0.57). CONCLUSIONS: Breast cancer screening uptake after the 40th birthday varies by health system, primary care visits, median household income, and health insurance type, suggesting the need for further exploration. Future research should evaluate screening performance metrics after initiation and consider cumulative benefits and risks associated with breast cancer screening over time.