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Purpose:We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor–positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503).Experimental Design:Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models.Results:Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12–1.97] and OS (HR, 2.08; 95% CI, 1.49–2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58–3.07) and death (HR, 3.4; 95% CI, 2.36–4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54–3.47) and OS (HR, 2.6; 95% CI, 1.59–4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients.Conclusions:CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

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Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1 +/− mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.One Sentence SummaryElevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers

Purpose: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor–positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). Experimental Design: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. Results: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12–1.97] and OS (HR, 2.08; 95% CI, 1.49–2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58–3.07) and death (HR, 3.4; 95% CI, 2.36–4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54–3.47) and OS (HR, 2.6; 95% CI, 1.59–4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. Conclusions: CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered. Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.

Category: Ankle Arthritis Introduction/Purpose: Peripheral vascular disease (PVD) is often cited as a contraindication for total ankle replacement (TAR); however, there are no studies looking at its impact on postoperative complications. The primary purpose of our study was to identify whether preoperative PVD increased the rate of infection, postoperative irrigation and debridement, or failure of the implant in patients undergoing total ankle arthroplasty using a large dataset. Methods: The PearlDiver Database was used to identify Medicare patients who underwent a TAR from 2005 to 2014 using ICD- 9 and CPT codes. The cohort was queried for postoperative infections within 90 days, subsequent irrigation and debridement, and failure of TAR. Failure of TAR was defined was a revision, conversion to tibiotalar arthrodesis, lower extremity amputation, or implant removal. A diagnosis of preoperative PVD only included those patients who had PVD as an ICD-9 diagnosis code and underwent a preoperative lower extremity angiogram prior to TAR. Preoperative co-morbidities including prior corticosteroid injections, diabetes mellitus, smoking, rheumatoid arthritis, congestive heart failure, hypertension, obesity, and end-stage renal disease requiring dialysis were taken into consideration. Three multivariable logistic regression models were then developed in order to identify risk factors associated with postoperative infections and failure after TAR. Results: 10,698 Medicare patients who underwent a primary TAR were identified. 334 patients had a postoperative infection within 90 days of their TAR and 95 of those patients required an irrigation and debridement. Patients with a preoperative diagnosis of PVD had the highest acute infection rate at 10.5% as well as the highest incidence of failure at 12.3%. Multivariable logistic regression modeling demonstrated that patients with PVD had the greatest risk of developing a postoperative infection within 90 days (OR 2.85, 95% CI 1.45-5.13, PConclusion: Our study suggests that a preoperative diagnosis of PVD has significant negative effects on outcomes following TAR. Preoperative PVD is an independent risk factor for an acute postoperative infection, postoperative irrigation and debridement, and failure of the implant.

Background: Despite limited evidence, peripheral vascular disease is often cited as a contraindication for total ankle arthroplasty. The purpose of our study was to identify whether peripheral vascular disease in patients undergoing total ankle arthroplasty increased the rate of infection, postoperative irrigation and debridement, or failure of the implant. Methods: The PearlDiver Database was used to identify Medicare patients who underwent a total ankle arthroplasty from 2005 to 2014. These data were then analyzed for postoperative infections within 90 days, subsequent irrigation and debridements, and failure of total ankle arthroplasties. A diagnosis of preoperative peripheral vascular disease only included those patients who had peripheral vascular disease as an ICD-9 diagnosis code and underwent a preoperative lower extremity angiogram prior to total ankle arthroplasty. Medical comorbidities were identified using ICD-9 diagnosis codes. Three multivariable logistic regression models were then developed in order to identify risk factors associated with postoperative infections and failure after total ankle arthroplasty. Results: A total of 10 698 Medicare patients who underwent a primary total ankle arthroplasty were identified. There were 334 patients who had a postoperative infection within 90 days of their total ankle arthroplasty, and 95 of those patients required an irrigation and debridement. Regression analysis demonstrated that patients with peripheral vascular disease had the greatest risk of developing a postoperative infection within 90 days (OR 2.85, P < .01), requiring an irrigation and debridement postoperatively (OR 4.87, P < .001), and having a total ankle arthroplasty failure at any time point postoperatively (OR 2.51, P < .001). Conclusions: Our study suggests that preoperative peripheral vascular disease is a significant risk factor for an acute postoperative infection, postoperative irrigation and debridement, and failure of the implant in Medicare patients undergoing a total ankle arthroplasty. Level of Evidence: Level III, therapeutic.

Background Point-of-care ultrasound is an emerging technology in critical care medicine. Despite requirements for critical care medicine fellowship programs to demonstrate knowledge and competency in point-of-care ultrasound, tools to guide competency-based training are lacking. Objective We describe the development and validity arguments of a competency assessment tool for critical care ultrasound. Methods A modified Delphi method was used to develop behaviorally anchored checklists for 2 ultrasound applications: “Perform deep venous thrombosis study (DVT)” and “Qualify left ventricular function using parasternal long axis and parasternal short axis views (Echo).” One live rater and 1 video rater evaluated performance of 28 fellows. A second video rater evaluated a subset of 10 fellows. Validity evidence for content, response process, and internal consistency was assessed. Results An expert panel finalized checklists after 2 rounds of a modified Delphi method. The DVT checklist consisted of 13 items, including 1.00 global rating step (GRS). The Echo checklist consisted of 14 items, and included 1.00 GRS for each of 2 views. Interrater reliability evaluated with a Cohen kappa between the live and video rater was 1.00 for the DVT GRS, 0.44 for the PSLA GRS, and 0.58 for the PSSA GRS. Cronbach α was 0.85 for DVT and 0.92 for Echo. Conclusions The findings offer preliminary evidence for the validity of competency assessment tools for 2 applications of critical care ultrasound and data on live versus video raters.

Background: Reconstruction of the stage II adult-acquired flatfoot deformity (AAFD) often requires the use of multiple osteotomies and soft tissue procedures that may not heal well in older patients. The purpose of our study was to determine whether patients older than 65 years with stage II AAFD had inferior clinical outcomes or an increased number of subsequent surgical procedures after flatfoot reconstruction when compared with younger patients. Methods: One-hundred forty consecutive feet (70 right, 70 left) with stage II AAFD in 137 patients were divided into 3 groups based on age: younger than 45 years (young; n = 21), 45 to 65 years (middle-aged; n = 87), and 65 years and older (older; n = 32). Preoperative and postoperative Foot and Ankle Outcome Scores (FAOSs) at a minimum of 2 years were compared. Hospital records were reviewed to determine if patients underwent a subsequent procedure postoperatively. Results: Patients in the older group did not demonstrate any differences in changes in FAOS subscales compared with patients in the young and middle-aged groups (all P > .15). The older group had significant preoperative to postoperative improvements in all the FAOS subgroups ( P < .01). In addition, patients in the older group were not more likely to undergo a subsequent surgery than were the younger patients (all P > .10). Conclusions: Our study found that patients older than 65 years with stage II AAFD have improvements in patient-reported outcomes and rates of revision surgery after surgical reconstruction that were not significantly different than those of younger patients. Level of Evidence: Therapeutic Level III, comparative series.

BackgroundSomatic mutations observed in clonal hematopoiesis are associated with increased age and risk of hematological malignancies. However, the limited number of acute myeloid leukemia (AML) patients in studies of clonal hematopoiesis thus far has precluded determination of the spectrum of mutations leading to AML and their impact on risk and time to diagnosis.MethodsThe relationship between baseline mutations and subsequent AML was determined in a case-control study design. 212 women eventually diagnosed with AML (median time: 9.8 years) were identified from the Women’s Health Initiative cohort alongside 212 matched AML-free controls. Deep sequencing of 67 genes was performed on DNA isolated from peripheral blood to detect subclonal mutations.ResultsThe presence of any mutation was associated with increased odds of eventual AML (odds ratio [OR] 4.0; 95% confidence interval [CI], 2.5-6.3). These odds were further elevated with mutations in IDH1/2 (OR 8.4; 95% CI, 1.4-51.9), TP53 (OR 54.2; 95% CI, 2.9-1017.7), or spliceosome genes (OR 5.6; 95% CI, 1.5-20.6). Eventual AML diagnosis occurred in all or most participants with mutations in TP53 (N=23/23) or IDH1/2 (N=15/16). Mutations indicated sooner AML diagnosis (median 8.0 vs. 11.9 years; P < 0.001) with TP53 mutations demonstrating increased odds of AML within 5 years (OR 3.6; 95% CI, 1.4-9.1).ConclusionsMutations are present in peripheral blood of AML patients a decade prior to AML diagnosis with mutations in TP53 producing especially rapid presentation. Strategies for monitoring of high-risk populations are needed and clinical trials of potential early interventions can be considered.

1049 Background: CALGB 40503 randomized HR+ MBC postmenopausal pts to Let alone or Let+Bev as first-line therapy. Adding Bev to Let prolonged progression-free survival (PFS) but not overall survival (OS) (Dickler JCO 2016). We performed a correlative study to assess prognostic and predictive value of CTCs in this population. Methods: Blood was collected prior to initiation of treatment. CTCs were enumerated using US FDA-cleared CellSearch assay; samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC-positive (CTC+). Correlation of CTCs with PFS and OS was assessed using Cox regression analysis. Median follow-up was 39 months (mo). Results: Of 343 pts treated, 294 had CTC data and were included in this analysis. Original study results that showed improved PFS (HR = 0.75; 95% CI: 0.59-0.96) but not OS (HR = 0.87; 95% CI: 0.65-1.18) in pts receiving Let+Bev compared to Let were recapitulated in this subset. In multivariable analysis, CTC+ pts (31%) had significantly reduced PFS (HR = 1.49; 95% CI: 1.12-1.97) and OS (HR = 2.08; 95% CI: 1.49-2.93) compared to CTC- pts. Moreover, CTC+ pts who did not receive Bev had worse PFS (HR = 2.31; 95% CI: 1.54-3.47) and OS (HR = 2.64; 95% CI: 1.59-4.40) (Table). CTC+ pts who received Bev had numerically longer median PFS (18.0 vs. 7.0 mo) and OS (33.6 vs. 27.1 mo) compared to CTC+ pts with no Bev; however, tests for interaction between CTC status and Bev (yes vs. no) were not statistically significant for PFS (p=0.70) or OS (p=0.84). Conclusions: CTCs were highly prognostic in this study involving addition of Bev to first-line Let in postmenopausal HR+ MBC. Further research to determine the potential predictive value of CTCs in the setting of both metastatic disease and early breast cancer is warranted. Support: U10CA180821, U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00601900. Survival in HR+ MBC pts receiving Let or Let+Bev stratified by CTC status. Clinical trial information: NCT00601900. [Table: see text]