Citations

Abstract In recent years, there has been a deeper understanding of the mechanisms of immune evasion by cancer cells. This has led to the development of a number of immune checkpoint inhibitors for cancer therapy. The first inhibitor to be approved was ipilumumab, a monoclonal antibody that works to activate the immune system by targeting CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), a protein receptor that downregulates the immune system. Ipilimumab inhibits CTLA4, which is important for dampening T cell responses at the priming phase in lymph nodes, and is approved for the therapy of malignant melanoma. The role of checkpoint inhibitors in cancer therapy has blossomed over the last couple of years with the advent of PD1/PDL1 inhibitors. These agents are currently approved for the therapy of NSCLC, melanoma, renal cell carcinoma, bladder cancer hodgkins lymphoma and head and neck cancer. The approved agents are nivolumab, pembrolizumab and atezolizumab. A number of other checkpoint inhibitors are in development. Lung cancer mortality is disproportionately high in minority populations. Pembrolizumab and nivolumab are approved for the second line therapy of non-small cell lung cancer and combinations of PD-1/PD-L1 inhibitors and CTLA4 inhibitors such as nivolumab/ipilimumab are being evaluated for small cell and non-small cell lung cancer. As always, a number of clinical trials have been done with these agents, but these have included very few minority patients. The clinical effects and unique toxicities of these agents will be discussed, as will their cost. Implications of these new treatment modalities for minority and underserved populations with lung cancer will also be discussed. Citation Format: Alex A. Adjei. Lung cancer, immunotherapy and health disparities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA16.

Abstract Background: In Minnesota, the 2012 Cancer Report by the Department of Health reported both the incidence of liver cancer and mortality rates due to liver cancer among Blacks were significantly higher than Caucasians. African immigration to Minnesota is the third highest by percentage of state population in the US. Given that viral hepatitis disproportionately affects sub-Saharan Africans and that these individuals are emigrating from countries where childhood HBV vaccination has only recently been implemented on a national scale, we speculate that this unique immigrant community may be a major contributor to the increased burden of viral hepatitis and liver cancer complications in the state. Limited research exists on the burden of viral hepatitis and hepatocellular carcinoma among African immigrants. Thus, we conducted a prospective community-wide screening to assess the rates of chronic HBV and HCV infections among Somali, Liberian and Kenyan immigrants in Minnesota. Methods: Several African community health centers and organizations in Minnesota were selected for the study. Individuals of Somali, Liberian or Kenyan descent were enrolled in a prospective screening study for chronic HBV and HCV infection. Blood samples were collected and tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb), and anti-hepatitis C virus antibody (anti-HCV). Follow-up testing, health education, counseling, and referral were provided to participants. Results: 853 participants provided blood specimens. 13.5% of participants had chronic HBV infection while 32.4% had prior HBV exposure with spontaneous viral clearance. 7% of participants had chronic HCV infection. Follow up and linkage to care were provided to participants with chronic hepatitis while preventive advice was provided to those who were negative for both infections. In particular, participants susceptible to HBV were informed about the availability of HBV vaccine in order to protect against future HBV infection. Conclusions: Chronic HBV and HCV are major health problems among recent African immigrants in Minnesota. Community-based screening is an effective way to identify and provide health education and linkage to care for individuals with or at risk for viral hepatitis. Citation Format: Essa A. Mohamed, Nasra H. Giama, Hassan M. Shaleh, Abdul M. Oseini, Hager Ahmed Mohammed, Jessica Cvinar, Ibrahim A. Waaeys, Hamdi A. Ali, Loretta K. Allotey, Lewis R. Roberts. Community-wide outreach and screening to reduce hepatitis B, hepatitis C and liver cancer disparities among African immigrants in Minnesota. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C76.

Abstract Purpose: To identify within demographic features and theoretical models of health behavior, the variables demonstrating differences in the behaviors, beliefs, attitudes, associations, and capacities of sporadic (non-adherent) and persistent (adherent) mammographic screeners for the purpose of guiding future interventions to improve mammographic screening adherence. Procedures: A survey was designed and mailed to all screening-age women of one Bemidji Area tribe. The survey incorporated demographic questions, and questions designed to inform about salient features of respondents' health literacy, social networks, social support, social norms, planned behavior, and health beliefs. Prior to mailing, each survey was assigned a unique identifier and sealed in an envelope. Surveys were mailed to 1,554 women in manner that ensured anonymity of the women's responses and no potential for investigators to discern women's identity via their mailing addresses or other information. Self-report data from returned surveys was used to determine women's mammographic screening status as adherent with local screening guidelines (annual mammogram beginning at age 40 for women at average risk) or non-adherent. Responses for all demographic and theoretical models of health behavior were appropriately categorized and analyzed utilizing global tests of hypotheses. Inherent multicollinearity issues required a two-step process of factor analysis followed by a multivariate analysis of variance. Where themes (e.g., demographics, health literacy, etc.) and factors within themes were significant, a univariate analysis was conducted to ascertain specific questions and responses that significantly differentiated the non-adherent from adherent screeners. Summary of data: We found no significant differences in non-adherent and adherent screeners' responses to questions related to social networks or social norms. We did find that responses from these two groups did differ on demographic features as well as on aspects of health literacy, social support, planned behavior and health beliefs. o Demographic differences involved biopsy histories and employment status. o Differentiating health literacy variables involved recognition of certain terms (e.g., annual) and understanding concepts such as ultrasound and biopsy. o Social support variables that distinguished non-adherent from adherent screeners involved sources of information support, characteristics of providers of emotional support, and sources of emotional support (e.g., solitary or communal). o Planned behavior variables illuminating differences between the screening groups involved (in additions to self-reported screening behaviors): attitudes toward the behavior of obtaining mammograms, intentions to engage in screening, and control beliefs. o Health Beliefs variables distinguishing the two sets of screeners comprised responses to questions about perceived barriers, self-efficacy, and cues to action. Conclusions: Study findings point to opportunities for tribal health and Indian Health Service (IHS) providers and staff to intervene in two broad areas. 1. Some findings associated with social support, planned behavior, and health beliefs can be used to design patient intake forms to alert tribal health and IHS providers to current and potentially non-adherent. 2. Using this information, providers can design interventions to move non-adherent and potentially non-adherent women toward persistent mammographic screening participation. An intervention study will be funded by the Minnesota Department of Health through its Eliminating Health Disparities Initiative. Citation Format: Wesley O. Petersen, Ann M. Nicometo, Robert A. Vierkant, Corinna Sabaque. Elements of theoretical models of health behavior: Planning for breast cancer screening interventions in an American Indian tribe. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B83.

Abstract Background: It is documented that inequities in research participation by minority and underrepresented populations limits the progression of personalized medicine for cancer treatment for these groups. A lack of understanding essential information during the consent process and poor physician-patient communication have been noted as two overarching barriers to patients participating in translational, clinical and biospecimen research. To address these major patient barriers, we developed a plain language research literacy support (RLS) tool to improve the consent process and facilitate dialogue between physicians/research staff and patients. We describe the tool's iterative development process and testing of the developed culturally appropriate RLS tool. Methods: We tested the tool among: 1) patient participants ≥18 years of age, who were able to read and speak English from communities associated with five academic centers in the Midwest and Northeast United States; and 2) eligible recruiters who were employed at an academic center and actively recruiting patients into research. The development process for the RLS tool consisted of two phases: cognitive and beta testing. During cognitive testing, we solicited feedback from patient and recruiter participants about the content and format of the tool including low literacy language, pictures and recommendations for additional content. The tool consisted of concept cards to provide information to assist patients in making an informed decision about participating in research. During beta testing, a condensed version of the tool was tested to assess acceptability and change in knowledge about research participation. Results: Participants included 155 patients (52: cognitive testing phase; 103: beta testing phase) and 20 recruiter participants. Patient participants were mostly females (71%). Self-identified race of patients included: Whites (43%), African Americans (32%), Native Americans (20%), and other (6%). In addition, 23% of patient participants self-identified as Hispanic. During the cognitive testing phase, patient participants reported that the information was clearly laid out and the tool explained the different steps in the recruitment and enrollment process. Patient participants indicated they had learned new information related to randomization, standard of care, coded-information, and biobanking. Although some patient participants acknowledged the cards contained a great deal of information, most reported that the information was essential. Several participants suggested cards be tailored for the Native American population. Recruiters indicated that the cards provided useful information and would assist patients and research staff. During beta testing phase, 98% of participants agreed the information on the cards helped them understand clinical research. After reviewing the cards, 49% of patient participants reported that they would be very likely to participate in research and 32% reported being somewhat likely to participate in research. The majority (61%) of participants indicated that if invited to participate in a research study, they would prefer that the cards would be mailed to them in advance while 34% wanted to review the cards at their medical appointment. Half of the participants preferred accessing the cards on a computer if administered in a video format. Conclusion: The RLS tool was well received among patient and recruiter participants, making it a potentially valuable resource for enrollment of minority and underrepresented patients into health research. The next step will be to test the RLS tool for effectiveness in a randomized controlled trial. Citation Format: Erika E. de la Riva, Rodney Haring, Elisa M. Rodriguez, Evelyn Gonzalez, Mira Katz, Nikia Clark, Whitney Ann E. Henry, Rosa O. Ortiz, Barret J. Zimmermann, Marla L. Clayman, Deborah O. Erwin, Judith S. Kaur, Melissa A. Simon. Development and beta testing of a culturally appropriate research literacy support tool to increase research participation among minority and underrepresented populations. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr A11.

Abstract Background:Anti-HER2 agents are associated with an increased risk of cardiotoxicity, occurring mostly during treatment and being generally reversible. To date, no cardiac biomarkers have been validated as predictive markers of cardiotoxicity in patients (pts) receiving anti-HER2 therapies. We evaluated high sensitivity (HS) troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pts treated with neoadjuvant anti-HER2 therapies to evaluate if early elevation of cardiac biomarkers predicts early or late cardiac events. Material and Methods: 455 pts were randomized to receive either lapatinib (154 pts), trastuzumab weekly (149 pts), or lapatinib with trastuzumab for a total of 6 weeks (152 pts). After this biological window, pts continued on the same targeted therapy plus 12-weekly paclitaxel until definitive surgery. After surgery, patients received adjuvant FEC (3x) followed by the same HER2 therapy as in the neoadjuvant phase for further 34 weeks (to complete 52 weeks in total). Eligible pts had an LVEF ≥50%. Cardiac biomarkers were centrally tested in plasma samples collected at baseline, week 2 (W2) and at surgery. Elevated biomarker was defined as either TNT >0.015 μg/L or NT-proBNP >125 pg/mL. The small number of pts and rarity of marker elevations allowed only descriptive analyses. Results: At a median follow-up of 3.8 years, 280 pts had cardiac biomarkers tested at baseline (61.5%) and NT-proBNP was elevated in 39 pts (13.9%) while TNT was elevated in only 1 pt (0.35%). From those 39 pts with NT-proBNP elevated at baseline, only 1 pt experienced a cardiac event. Also, hypertension was presented in 14 pts (24.5%) with elevated NT-proBNP. Serial measurements were available in 173 pts (61.7%) and NT-proBNP was elevated in 25, 10 and 21 pts at baseline, W2 and at surgery, respectively, while among 171 pts (61%) TNT was elevated in 1, 1 and 5 pts, respectively. There were 13 cardiac events in 11 pts in the entire trial. Five of these pts had a measurement of cardiac biomarkers at baseline (non-elevated NT-prBNP and TNT were observed in 4 and 5 pts), 9 of them had a measurement at week 2 (non-elevated NT-prBNP and TNT were observed in 8 and 9 pts) and 3 of them at surgery (non-elevated NT-prBNP and TNT were observed in 3 and 3 pts), respectively. The following table show the low specificity of the cardiac biomarkers. Patients without cardiac event (N)Patients with cardiac event (N)Patients with elevated markerElevated NT-proBNP Baseline38139Week 229130Surgery40040Elevated TNT Baseline101Week 2101Surgery606 During adjuvant phase, 13 pts experienced LVEF drop to <50% and none had either NT-proBNP elevated or TNT at surgery. Conclusions: Despite the small sample size, we demonstrated that cardiac biomarkers are rarely elevated in pts receiving anti-HER2 therapies, which is probably due to the absence of myocyte necrosis with respect to TNT, and the lack of chamber dilation in the case of NT-proBNP after exposure to these drugs. In addition, few cardiac events were present in this population not previously exposed to anthracycline-based chemotherapy; therefore the use of cardiac biomarkers in this population may be unnecessary. Citation Format: de Azambuja E, Bradbury I, Ewer M, Campbell C, Zardavas D, Ameels H, Baselga J, Huober J, Izquierdo M, Bozovic-Spasojevic I, Maetens M, Harbeck N, Pusztai L, Piccart M, Rodeheffer R, Sutter T. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06) [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 P4-21-09.

Abstract Introduction: Smoking is a risk factor for poor outcomes following breast reconstructive surgery, including wound dehiscence and infection. Women who would choose to have reconstructive surgery after mastectomy for breast cancer are unable to do so if they have not quit smoking. The specific aims of this project are to 1) design and implement an intervention to assist these patients in quitting and 2) evaluate its efficacy. Methods: Baseline data regarding current practices was collected via a chart review of 75 smoking breast cancer surgery patients from 1/1/2012-12/31/13. Charts were analyzed for documentation of smoking status, quit advice, resources provided and used, and smoking status at follow-up. Formative research informed the design of an Ask-Advise-Refer intervention for all new breast cancer patients seen at Mayo Clinic. Intervention Design: Smoking patients were identified prior to their initial Breast Cancer evaluation at Mayo Clinic, Rochester, during a standard intake call. Smoking status was documented by the rooming assistant to alert the physicians of smoking status, and physicians asked these patients about their smoking behavior, discussed the risks of smoking both for surgical procedures and breast cancer, and offered a Nicotine Dependence Consultation with a tobacco treatment specialist in an “opt-out” strategy that emphasized the importance of smoking cessation as part of the breast cancer treatment process. The advice and referral was documented in the medical record. Evaluation of the intervention was performed via a chart review of patients seen after one year of implementation. Intervention Evaluation Results: Breast clinic physicians documented smoking status in all patients seen after implementation. Referral to the Nicotine Dependence Center for cessation counseling increased from 29% (22/75) to 74% (20/27). Among those referred, attendance at the consultation increased from 41% (9/22) to 75% (15/20), suggesting stronger provider encouragement of cessation services. 30-day abstinence rates for those who attended a consult prior to 5/1/16 were 46% (6/13), which is consistent with baseline data. Conclusions: An Ask-Advise-Refer intervention for new breast cancer patients seen at Mayo Clinic, Rochester, who report current smoking, has been associated with higher rates of provider counseling on tobacco dependence, referral to available services, and patient attendance at referrals. Attending a referral greatly increases a patient's chances of quitting smoking for at least 30 days compared to average spontaneous quit rates in this population. This model is low-cost, time-efficient for providers, and applicable to most practice settings. Finding ways to make this intervention self-sustaining and applicable to multiple other practices could greatly improve our patient's health outcomes. Citation Format: Nolan M, Ghosh K, Warner DO. Design, implementation and evaluation of a smoking cessation intervention for patients undergoing breast cancer surgery [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 P4-17-02.

Abstract Background: Despite the well-established survival benefit associated with adjuvant hormonal treatment, younger women with hormone receptor positive (HR+) breast cancer (BC) are less adherent to endocrine therapy (ET) as prescribed, compared to their older counterparts, and may have unique issues that contribute to ET non-adherence. In an effort to identify factors that can be targeted to improve ET uptake and adherence, we sought to evaluate ET initiation in young women with BC. Methods: As part of a multi-center, prospective cohort enrolling women with newly diagnosed BC at age ≤40 years between 2006-2016, we identified 657 women with HR+, Stage 0-III BC. Participants complete serial surveys that included questions about socio-demographics, fertility concerns, and treatment. Women who did not report taking tamoxifen or an aromatase inhibitor (AI) at least once in the 18 months after diagnosis (dx) were classified as non-initiators. Variables significant at p<0.20 in univariable models were entered into a multivariable logistic regression model to identify independent (p<0.05) predictors of non-initiation. Results: By 18 months post-dx, 15% (99/657) had not initiated ET; among women with Stage 0 BC, 77% (51/66) had not initiated vs 8% (48/591) with invasive BC (p<0.0001). Among initiators (N=558), 93% were on tamoxifen, with 7% reporting AI alone or in addition to tamoxifen; 97% started ET within 12 months of dx. Among women with invasive BC (Table), non-initiation was associated with having less than a college degree (OR: 2.49 95% CI: 1.25-4.94), non-Caucasian race (OR: 2.58 95% CI: 1.18-5.64) and non-receipt of radiation (OR: 0.40 95% CI: 0.21-0.75).Age at dx, marital status, having children, employment, perceived financial comfort, fertility concern, stage, surgery, and chemotherapy were not significantly associated with non-initiation. Conclusion: Most young women with HR+ DCIS do not take adjuvant ET despite the potential benefits (substantially reduced risk of local recurrence and contralateral BC) and very low risk of serious toxicity. Among young women with invasive HR+ BC, a significant minority fails to start ET within 18 months of dx. Adjuvant ET non-initiation may contribute in part to the racial and SES outcomes disparities that have been observed. Further study is needed to elucidate barriers to initiation with the goal of developing targeted interventions that will enhance ET initiation and adherence in general. Table. Predictors of ET non-initiation in women with invasive BC (N=577*) Univariable Multivariable Median (range)OR (95% CI)pOR (95% CI)ppAge at dx (years)36 (17-40)1.08 (0.99-1.18)0.07 N (%) Financial comfort300 (51)0.88 (0.49-1.60)0.68 Non-white59 (10)2.68 (1.25-5.71)0.012.58 (1.18-5.64)0.02Full employment282 (48)0.76 (0.42-1.39)0.38 Less than college graduate95 (16)2.61 (1.36-5.02)0.0042.49 (1.25-4.94)0.009Married/living as married452 (77)0.79 (0.41-1.55)0.50 Children pre-diagnosis369 (62)1.11 (0.60-2.05)0.75 Fertility concern234 (40)0.92 (0.50-1.70)0.80 Stage (ref=3) 1244 (41)1.22 (0.47-3.15)0.68 2259 (44)1.27 (0.50-3.24)0.62 Mastectomy vs lumpectomy335 (57)1.16 (0.64-2.12)0.63 Radiation therapy331 (56)0.40 (0.21-0.73)0.0030.40 (0.21-0.75)0.004Chemotherapy411 (70)0.66 (0.36-1.22)0.18 *multivariable analytic cohort Citation Format: Rosenberg SM, Gelber S, Ruddy KJ, Tamimi RM, Schapira L, Borges VF, Come S, Meyer ME, Partridge AH. Drugs don't work if people don't take them: Non-initiation of endocrine therapy in young women [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 P2-09-07.

Abstract Background: Triple negative breast cancer (TNBC) is a heterogeneous disease. Amplification of chromosome 9p24.1 encoding JAK2 and PD-L1 has been reported in up to 25% of TNBC and is associated with poor clinical outcome. In lymphoma, JAK2 is a transcriptional activator of both PD-1 ligands, and chromosome 9p copy number gain has been associated with therapeutic activity of nivolumab. We evaluated the interaction of JAK2 and PD-L1 expression in TNBC. Methods: 9p24.1 amplification in 4 TNBC cell lines (MDA-MB-231, MDA-MB-436, HCC1937, and HCC70) was measured using array comparative genomic hybridization (aCGH). Amplification was defined as aCGH log2ratio>2.0. Cell surface expression of PD-L1 was detected by flow cytometry and compared with the median fluorescence intensity (MFI) of isotype control Ig. To selectively inhibit JAK2, lentiviral vectors encoding two different shRNA were generated. JAK2, pSTAT1 and pSTAT3 expression were measured by immunoblot. The effects of the anti-JAK1/2 inhibitor ruxolitinib and interferon-gamma (IFN-γ) induction of PD-L1 was measured. Results: 9p24.1 copy number loss was measured in MDA-MB-231 (log2ratio =-1), neutral in HCC1937 ((log2ratio =0), gained in MDA-MB-436 ((log2ratio =+1) and amplified in HCC70 ((log2ratio =+2). No correlation was observed between PD-L1 expression and the 9p24.1 amplification, with the MFI ratio range from 5 to 16.5, mean 8.3 by flow cytometry. TNBC cell lines had higher baseline expression of PD-L1 compared to the ER+ cell lines T47D and MCF-7 (ratio, 0 p=0.1). Low dose IFN-γ (1.0-10.0 ng/ml) rapidly induced expression of PD-L1 in MDA-MB-231 (1.5 fold increase) and HCC70 (3.3 fold increase) with significant activation of the JAK2/STAT1 pathway. The induction of pSTAT1 and PD-L1 expression by IFN-γ was blocked with low dose (1mM) JAK1/2 inhibitor ruxolitinib. Knockdown of JAK2 with shRNA (>80%) did not impact PD-L1 baseline expression in MDA-MB-231 and HCC70 but abrogated IFN-γ –mediated induction of PD-L1 and the phosphorylation of STAT1. Conclusion: These data suggest that TNBC cell lines have baseline PD-L1 expression, but the cells with 9p24.1 amplification are highly sensitive to PD-L1 induction with IFN-γ which can be abrogated with inhibition with a JAK1/2 inhibitor or shRNA. Synergistic inhibition of PD1/PD-L1 and JAK2 may have therapeutic efficacy in the subset of TNBC with 9p24.1 amplification, and the dynamic effects of tumor PD-L1 expression in response to local inflammation should be considered in the evaluation of PD-1/PD-L1 checkpoint blockade. Citation Format: Chen M, Pockaj B, Andreozzi M, Barrett MT, Ocal IT, McCullough AE, Krishna S, Anderson KS. JAK2 and PD-L1 amplification enhance the dynamic expression of PD-L1 in triple negative breast cancer [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 P2-04-18.

Abstract Approximately 15% of genetic screens for mutations in BRCA1 and BRCA2 identify Variants of Uncertain Significance (VUS). Primarily missense mutations, VUS are often difficult to interpret, leading to either uncertainty in how to properly counsel a patient or an unnecessary prophylactic surgery. Given the paucity of data for which missenses are classified as truly pathogenic, computational deleterious missense prediction (DMP) algorithms are used to predict whether a mutation is likely deleterious or neutral. Accuracy of DMPs can vary considerably and have only been calibrated on a relatively small number of missense mutations of demonstrable effect on protein function. In this study, the performance of 41 different DMPs was compared to functional data from 455 functionally characterized missense variants in BRCA1 and BRCA2. New optimized thresholds for classifying missense mutations as deleterious are presented for several existing models as well as a newly derived naïve voting method (NVM). The areas under the curve estimates for the NVM approach are between 0.889-0.922, much higher than previous methods. We estimate that the overall pathogenic potential of missense variants to be 6.8% for BRCA1 and 3.2% of BRCA2, but can be as high as 50% depending on protein location. Overall these results provide key insights into how to predict deleterious missense mutations in BRCA1 and BRCA2. Citation Format: Hart SN, Hoskin T, Shimelis H, Feng B, Lindor NM, Monteiro A, Iversen E, Goldgar DE, Suman V, Couch FJ. Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes [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 P2-02-03.

Abstract Background: Negative margins are important in decreasing risk of local recurrence after breast conservation surgery. Further, positive margins on final pathology require a second operation, burdening patients and increasing costs. We identified factors predicting positive margins at lumpectomy prompting intraoperative re-excision in a large referral center. Methods With IRB approval we reviewed all breast cancer lumpectomy cases from January 2012 to December 2013. Associations between rates of positive margin (defined as tumor at ink) and patient and tumor factors were assessed using chi square tests and univariate and adjusted multivariable logistic regression, overall and stratified by DCIS or invasive cancer. Results 385 patients (105 DCIS and 280 invasive disease) were identified. Overall positive margin rate at lumpectomy requiring intraoperative re-excision was 62.3% and was higher in DCIS than in invasive disease (78.1% vs 56.4%, OR=2.78, p=0.001). Positive margin rates did not vary by surgeon, patient age, ER, PR or HER2 status of the tumor. On univariate analysis higher tumor grade was associated with a higher margin positive rate (grade 3 vs grade 1, OR=1.71, p=0.049). Within the 105 DCIS cases, no factors had statistically significantly different odds of positive margins on univariate or multivariable analysis. Within the 280 cases of invasive breast cancer, factors independently associated with lower odds of margin positivity were neoadjuvant chemotherapy (OR 0.30, p=0.037, relative to no neoadjuvant therapy) and seed localized excision (OR 0.24, p=0.03, relative to no localization). Multivariable Logistic Regression* Modeling DCISInvasive DiseaseVariableOdds RatioP-valueOdds RatioP-valueAge 50+ vs Age <502.860.111.590.23Grade 2 vs Grade 10.940.921.500.21Grade 3 vs Grade 13.250.121.580.37Estrogen Receptor Positive vs Negative3.950.221.640.42Progesterone Receptor Positive vs Negative0.840.871.110.84Her2 Positive vs Negative 1.270.68Stage T2 vs T1 2.540.45Stage T3 vs T1 2.180.69Ki67 <15% vs 15%+ 0.570.09Neoadjuvant Chemotherapy vs None 0.300.04Seed Localization vs No Localization 0.240.03Wire Localization vs No Localization 0.330.13Intraoperative Ultrasound vs No Localization 0.670.53*adjusted for individual surgeons (all p >0.05) Conclusion DCIS was associated with higher rate of positive margins at lumpectomy than invasive breast cancer. Within invasive disease, neoadjuvant chemotherapy and seed localization were associated with lower rates of margin positivity. Strategies to decrease positive margins would be best employed in cases of lumpectomy for DCIS and for invasive disease treated without neoadjuvant chemotherapy. Seed localization may be one strategy to lower positive margin rates. Citation Format: Boughey JC, Keeney MG, Glasgow AE, Keeney GL, Habermann EB. Tumor and procedural factors associated with positive margins at lumpectomy in women undergoing breast conservation surgery [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 P1-11-08.