Elizabeth C. Riley

Increasing use of elective mastectomy and contralateral prophylactic surgery among breast conservation candidates: a 14-year report from a comprehensive cancer center.

Background: First-line surgical options for early-stage breast cancer include breast-conserving surgery (BCS) or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. Methods: We analyzed the rates of mastectomy and BCS for 1634 women who underwent upfront surgical treatment for AJCC stage 0, I, or II breast cancer between 1995 and 2008 using data from the University of Louisville James Graham Brown Cancer Center Tumor Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Results: Overall, 65.9% of women received BCS, and 34.1% received mastectomy over a 14-year period (annual BCS rate range, 38.6% to 77.7%). The mastectomy rate substantially decreased from 43.5% in 1995 to 22.5% in 2004 (P=0.0007) but then increased to 51.7% in 2008 (P<0.0001). During the years between 2004 and 2008 (vs. 1995 to 2003), there was a significant increase in the rates of mastectomy performed in conjunction with immediate reconstruction (IR: 35.7% vs. 8.4%; P<0.0001) and/or contralateral prophylactic mastectomy (CPM: 22.9% vs. 3.3%; P<0.0001). On the basis of the multivariate analysis, the rate of receiving mastectomy was drastically higher for patients treated since 2004 (vs. before 2004), uninsured and government-insured (vs. privately insured) patients, patients with pT2 disease (vs. pTis or pT1), patients with pN1 disease (vs. pNX or pN0). Conclusions: In this longitudinal registry study, major independent determinants of mastectomy for early-stage breast cancer include year of diagnosis, insurance status, and stage. Mastectomy rates declined until 2004, but have since increased in conjunction with immediate reconstruction and contralateral prophylactic mastectomy. Additional study is needed to identify the underlying reasons for and unintended consequences of the reemergence of radical surgery for early-stage breast cancer in the era of multidisciplinary care.

A Phase 2 Trial of Once-Weekly Hypofractionated Breast Irradiation: First Report of Acute Toxicity, Feasibility, and Patient Satisfaction

PURPOSE To report on early results of a single-institution phase 2 trial of a 5-fraction, once-weekly radiation therapy regimen for patients undergoing breast-conserving surgery (BCS). METHODS AND MATERIALS Patients who underwent BCS for American Joint Committee on Cancer stage 0, I, or II breast cancer with negative surgical margins were eligible to receive whole breast radiation therapy to a dose of 30 Gy in 5 weekly fractions of 6 Gy with or without an additional boost. Elective nodal irradiation was not permitted. There were no restrictions on breast size or the use of cytotoxic chemotherapy for otherwise eligible patients. Patients were assessed at baseline, treatment completion, and at first posttreatment follow-up to assess acute toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and quality of life (European Organization for Research and Treatment of Cancer QLQ-BR23). RESULTS Between January and September 2011, 42 eligible patients underwent weekly hypofractionated breast irradiation immediately following BCS (69.0%) or at the conclusion of cytotoxic chemotherapy (31.0%). The rates of grade ≥2 radiation-induced dermatitis, pain, fatigue, and breast edema were 19.0%, 11.9%, 9.5%, and 2.4%, respectively. Only 1 grade 3 toxicity-pain requiring a course of narcotic analgesics-was observed. One patient developed a superficial cellulitis (grade 2), which resolved with the use of oral antibiotics. Patient-reported moderate-to-major breast symptoms (pain, swelling, and skin problems), all decreased from baseline through 1 month, whereas breast sensitivity remained stable over the study period. CONCLUSIONS The tolerance of weekly hypofractionated breast irradiation compares well with recent reports of daily hypofractionated whole-breast irradiation schedules. The regimen appears feasible and cost-effective. Additional follow-up with continued accrual is needed to assess late toxicity, cosmesis, and disease-specific outcomes.

Delay of adjuvant chemotherapy after elective mastectomy and immediate reconstruction in breast-conservation candidates: a matched-pair analysis.

Objectives:To analyze factors that influence the timing of adjuvant chemotherapy in patients who are candidates for breast-conservation therapy (BCT) but elect mastectomy with immediate reconstruction (M-IR). Methods:We identified 35 consecutively treated patients with stage I or II breast cancer between 2004 and 2009 who underwent M-IR and adjuvant chemotherapy from the University of Louisville Cancer Registry. We matched these patients for age and AJCC stage to 35 controls who underwent BCT and adjuvant chemotherapy. We examined the timing and delay of initiation of chemotherapy using univariate logistic regression and McNemar test for matched pairs. Results:For the 70 patients evaluated, the median age was 46 years (range, 30 to 65 y), and the distribution for stage I, IIA, and IIB was 22.9%, 65.7%, and 11.4%, respectively. The 2 groups were well balanced in terms of race, rural/urban status, smoking, diabetes, insurance coverage, and histology. For BCT and M-IR, the median time to chemotherapy initiation was 38 days (range, 25 to 103 d) and 55 days (range, 30 to 165 d), respectively. Patients undergoing M-IR were more likely to experience any delay (>45 d; 54.3% vs. 22.9%; P<0.001) and/or significant delay (>90 d; 20.0% vs. 2.9%; P<0.001). On univariate logistic regression analysis, surgery type had a major impact on delay of chemotherapy (odds ratio=8.35; 95% confidence interval, 2.86-24.4; P<0.001). Conclusions:The use of M-IR in breast-conservation candidates independently predicts for delay in initiation of adjuvant chemotherapy. Further study is needed to qualify the causes and clinical significance of these delays.

Mobile Mammography, Race, and Insurance: Use Trends Over a Decade at a Comprehensive Urban Cancer Center

PURPOSE To assess the use of a mobile mammography unit (MMU) as it relates to race and insurance status in the largest county in Kentucky. METHODS We retrospectively reviewed 48,324 screening mammograms of 21,857 patients conducted over a 10-year period. Descriptive statistics for patient age, race, and insurance status were computed by entire cohort and within subsets of cohorts. This analysis was limited to trends in use by race and insurance status. To study the patterns of frequency distributions, indiscrete variables were performed using the Pearson χ(2) test. For continuous variable range, a 95% CI of mean was estimated. Comparisons with a P value less than .05 were considered statistically significant. RESULTS Self-reported blacks constituted significant use of the MMU (29% v census data demographic reports of 19%). Race significantly correlated with likelihood to screen ≥ three times, with blacks (30.5%) more likely, and whites (27.8%) and Hispanics (20.2%) less likely (P < .001). Insurance status also affected frequency of use (P < .001). CONCLUSION In this data set, blacks were more likely to repeat use of the MMU. Although preliminary, these data suggest outreach efforts of mobile mammography are appropriately reaching certain targeted populations.

When the picture is fragmented: Vitamin B12deficiency masquerading as thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has high mortality and necessitates prompt recognition of microangiopathic hemolytic anemia (MAHA) and initiation of plasmapheresis. We present a challenging diagnostic workup and management of a 42-year-old man who presented with anemia, thrombocytopenia, and schistocytes on peripheral smear, all pointing to MAHA. Plasmapheresis and steroid therapy were promptly initiated, but hemolysis continued. Further workup showed megaloblastic anemia, severe Vitamin B12deficiency, high iron saturation, and absent reticulocytosis, none of which could be explained by TTP. Severe Vitamin B12deficiency can lead to hemolytic anemia from the destruction of red cells in the marrow that have failed the process of maturation. However, this should not cause thrombotic microangiopathy. Previous reports of B12deficiency presenting with MAHA and a TTP-like manifestation have identified acute hyperhomocysteinemia as a missing link between B12deficiency and MAHA, so this possibility was further explored. Our patient similarly had significantly elevated serum homocysteine levels, confirming this suspicion of Vitamin B12deficiency. Vitamin B12replacement led to normalization of the elevated levels of homocysteine, the disappearance of schistocytes on the peripheral smear, and resolution of the microangiopathic hemolysis, thereby confirming the diagnosis. It is pertinent that intensivists not only know the importance of early recognition and treatment of TTP but are also familiar with rare conditions that can present in a similar fashion.

A phase II trial of once-weekly hypofractionated breast irradiation (WHBI): Interim analysis of cosmetic outcome and quality of life.

67 Background: A planned interim analysis of an institutional Phase II trial of once-weekly radiotherapy for patients undergoing breast-conserving surgery (BCS). METHODS Patients who underwent BCS for AJCC Stage 0, I or II breast cancer with negative surgical margins were eligible to receive whole-breast radiotherapy to a dose of 30Gy in 5 weekly fractions of 6 Gy with or without an additional boost. There were no restrictions on age, breast size or the use of cytotoxic chemotherapy for otherwise eligible patients. Patients were evaluated at baseline, 6 and 12 months with digital photography, physician assessment of cosmesis (Harvard Scale) and self-assessment (BCTOS). RESULTS Between January 2011 and January 2013, 82 eligible patients underwent WHBI immediately following BCS (82.7%) or at the conclusion of adjuvant cytotoxic chemotherapy (17.3%). The median age was 60 years (range: 30-80y) and the median followup was 33.1 months and all patients had at least 1 year followup. The rate of Excellent/Good vs. Fair/Poor cosmesis at 12 months was 77.3% vs. 22.7%. The rate of significant cosmetic change from baseline was 14.7%. The only factor predictive of significant cosmetic change was smoking status (OR: 6.94; p = 0.016). The median BCTOS score increased only slightly from baseline (31) to one year (32), with patient-reported breast size differences worsening but complaints of pain improving over the study period. CONCLUSIONS Cosmetic outcome after WHBI compares well with reports of daily hypofractionated whole-breast irradiation. Further follow-up with continued accrual is needed to assess cosmetic stability and disease-specific outcomes. CLINICAL TRIAL INFORMATION NCT01278212.

Abstract P2-08-04: Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC)

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon9s 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi9s unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

Abstract P1-11-07: Multivariable analysis of repeat utilization of mobile mammography units: 10 year analysis of a comprehensive cancer center

Introduction: Mobile Mammography Units (MMU) are a model of outreach. This study analyzes the association of race, insurance and location to MMU utilization. Our group previously reported these variable as independent predictors of MMU repeat use. This study explores if race, age, insurance and location jointly can predict the utilization of MMU. Methods: From Jan 2001- Dec 2010, 48,324 screening mammograms were performed with 21,587 unique subjects. Demographic data was retrospectively reviewed to identify race/ethnicity, insurance and location for each encounter. Locations were grouped as Corporate (C), Partnership Clinic (PCl,) Partnership Community (PCo.) Insurance type was classified as Private Insurance (PI,) Medicaid (MCaid), Medicare (MCare) and Uninsured (UI.) Insurance type was classified based on the primary insurer. Utilization was defined as 1x or more than 2x in 10 yrs. Descriptive statistics related to different predictors were produced and statistical comparisons were conducted. P-values were calculated using Chi-square test for comparison between the two groups. Odds ratio and its 95% confidence interval were provided. Logistics regression analysis is used to jointly model the effect of independent factors on repeat unitization of MMU. Reference range for race, insurance and location were chosen based on prior work. Results were declared significant at significance level of 5%. Results: Univariable analysis of race, insurance status, location and age were predictive of repeat utilization of the MMU over a 10 yrs. (p= value Conclusions: To our knowledge this is the reported largest database of MMU. Race, insurance status and location remained independent predictors of repeat utilization. Interestingly an insured subset (MCare) was more likely to repeat utilize the van regardless of race and location. This may reflect the average age of screening mammography however a better understanding of the uninsured subset may be important given the intended outreach of the MMU. Citation Format: Tezo Karedan, Elizabeth Riley, Lane Roland, Laura Barkley, Jianmin Pan, Shesh Rai, Sarah Mizuguchi. Multivariable analysis of repeat utilization of mobile mammography units: 10 year analysis of a comprehensive cancer center [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-11-07.

Uninsured utilization of the mobile mammography: 10-year analysis.

12 Background: Mobile Mammography Units (MMU) historically increase access breast cancer screening to uninsured patients. Our group previously reported insurance status predicts MMU repeat utilization (insured cohort most likely to repeat.) The purpose of this study is to examine the uninsured subset in multivariable analysis to understand the low repeat utilization by this group. METHODS From Jan 2001 to Dec 2010, 48,324 screening mammograms were performed in the largest county in KY. Of 21,587 unique subjects, 9,422 were uninsured (44%.) Demographic data was retrospectively reviewed to identify age, race/ethnicity, insurance status and location for each encounter. Utilization was defined as once or more than two times in a 10-year period. P-values were calculated using Chi-square test for comparison between the two groups. Odds ratio and its 95% confidence interval were provided. Logistics regression analysis is used to jointly model the effect of independent factors on repeat unitization of MMU. Results were declared significant at significance level of 5%. RESULTS Race, location, and age remain independent variables in likelihood of repeat utilization within a 10-year period (p value < .001.) The estimated OR are depicted in the table. We previously reported in the entire dataset (all insurance cohorts) and estimated OR of Whites (W) vs Blacks (B) of 0.897 (CI 0.843-0.955) and Hispanics (H) vs B 0.701 (CI 0.604-0.813.) Conclusions: Within the uninsured cohort, race and location remain independent predictors of repeat utilization of the MMU. However, the significance is weaker between W and B (p < .004 versus < .001) in the uninsured group than in the entire dataset which may suggest that insurance type becomes a stronger predictor of repeat utilization than race although further analysis will be necessary to confirm this trend.[Table: see text].

Abstract P1-09-19: Demographic trends in clinical trial withdrawal rate within the bubble study

Introduction: There are well described barriers to clinical trial enrollment and participation among varied racial, ethnic and demographic groups. Little is known about clinical trial drop-out rate among these groups. The purpose of this study is to analyze the demographic and clinical characteristics of patients who originally signed consent and enrolled in the Bubble Study but then withdrew at a later date. The Bubble Study is a non- blinded, prospective observational cohort study designed to assess the adherence rate of adjuvant endocrine therapy among women with early stage breast cancer. Materials and Methods: From August 2012 to May of 2013, 75 women were enrolled into the Bubble Study. Demographic data (age, race and insurance status) and treatment factors (stage, surgery type, and therapy duration) were collected. Descriptive statistics (such as mean, median, standard deviation, minimum and maximum for continuous measures and frequency and percentage for discrete measures) were produced for the entire cohort and the subjects of cohort. Frequencies were compared using a Chi-square test (Fisher9s exact test when expected cell frequencies are small). Continuous measures were compared using a two-sample t test or Wilcoxon rank sum test for normally or non-normally outcome measures, respectively (Matthews and Farewell, 2007). In addition, linear and logistic regression analyses were used to explore association with different factors. Results were declared significant at significance level of 5% and all analyses are performed using SAS (2003, 2005). Results: At the time of analysis, 75 patients enrolled into the Bubble Study. Table 1 summarizes the demographic, social economic, therapeutic factors such as race, age, stage, surgery type, insurance and therapy durations and their relevant frequency and percentage are presented. The p-values are shown based on the chi square test. Blacks represented 28% of the total enrollment. Private insurance represented the majority (61.3%) of those enrolled and Medicare, Medicaid and Uninsured followed in that order (24.3%, 13% and 1.3% respectively.) In regards to race and insurance status, there was no significant difference between the enrolled group and the withdrawal group although there was a trend toward Blacks and Medicare with higher rate of withdrawal. Stage, surgery type or age did not predict for withdrawal. The most common reasons reported for withdrawal were financial and/or insurance reasons (22%), inconvenience of pharmacy pick up (13%) and preference for the prior system (9%). Conclusions: Demographic characteristics that traditionally predict for underrepresentation in clinical trial enrollment did not predict for withdrawal from the Bubble Study. Although small, this data set suggests disparities in clinical trial participation are largely due to enrollment rather than withdrawal. Larger analysis is needed to confirm these findings. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-09-19.