Degnim, Amy C.

Abstract Background: The Breast Cancer Surveillance Consortium (BCSC) model predicts invasive breast cancer risk in women with Benign Breast Disease (BBD), and recently incorporated BBD histology into the model. The BCSC has been validated in the Mayo Mammography Health Study, but has yet to be examined in Mayo Clinic’s BBD cohort. The Benign Breast Disease to Breast Cancer (BBD-BC) model predicts risk of both invasive and in situ breast cancer. Here we compare the performance of the BCSC and BBD-BC in Mayo Clinic’s BBD cohort. Methods: Eligible women underwent a breast biopsy with benign findings at the Mayo Clinic between years 1997-2001 and had a 4-view screening mammogram within six months of biopsy. Clinical BI-RADS density assessments using the 4th edition American College of Radiology were available on all mammograms, and were coded as almost entirely fat, scattered fibroglandular densities, heterogeneously dense, and extremely dense. Risk at 5 and 10 years of invasive cancer only (BCSC model) or both invasive and in situ cancer (BBD-BC model) were estimated. In situ cancers were censored at time of diagnosis for both models. Concordance statistics, i.e. model discrimination (higher is better), for each model were calculated using a Cox proportional hazards model with predicted risk as the sole predictor, and were compared using permutation tests. The ratio of total predicted (sum of predicted risk) to observed number of invasive breast cancers was used to assess model calibration. Calibration was not formally compared across models due to differences in how DCIS was treated in the development of each (BCSC censored; BBD-BC event). Results: 999 women met inclusion criteria. BI-RADS density was categorized as fatty in 46 (4.6%), scattered densities in 372 (37.2%), heterogeneously dense in 423 (42.3%), and extremely dense in 158 (15.8%). 62 invasive cancers occurred over a median 13.3yrs of follow-up, with 16 (25.8%) and 48 (77.4%) of the cancers occurring with-in 5 and 10 years. The concordance of the BCSC at 5 years was 0.550 (95% CI 0.409—0.691), compared to 0.719 (95% CI 0.578—0.860) for the BBD-BC (p-value=0.005). At 10 years the BCSC concordance was not significantly different from the BBD-BC, at 0.624 (95% CI 0.542—0.706) and 0.662 (95% CI 0.580—0.744), respectively (p-value=0.306). The BCSC over predicted the number invasive cancers in the BBD cohort at 5 years (predicted-to-observed=1.54; 95% CI 1.01—2.70), but was well calibrated at 10 years (1.06; 95% CI 0.83, 1.47). Conclusions: The BCSC model performed reasonably well in the BBD Cohort 10 years post-biopsy, but overestimated risk at 5 years. Additional study is needed to improve models for prediction of breast cancer risk among women with BBD. Citation Format: Ryan D. Frank, Celine M. Vachon, Stacey J. Winham, Robert A. Vierkant, Marlene H. Frost, Derek C. Radisky, Daniel W. Visscher, Amy C. Degnim. Validation of the BCSC model within the Mayo Benign Breast Disease Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5299. doi:10.1158/1538-7445.AM2017-5299

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. Methods: With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. Results: 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). Conclusions: ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text]

60 Background: Indications for nipple-sparing mastectomy (NSM) with immediate reconstruction have expanded. For cancer patients, NSM is thought best-suited for early stage patients, with nodal involvement initially viewed as a relative contraindication. We undertook this study to evaluate the use and early outcomes of NSM in node-positive (LN+) breast cancer. Methods: We identified 240 cancers in 226 patients (14 bilateral) scheduled for NSM and operated on at our institution 1/2009-6/2014. Data on intraoperative conversion from NSM, recurrence and follow-up was abstracted from the medical record. Chi-square and long-rank tests were used for statistical analysis. P-values < 0.05 were considered significant. Results: Of 240 cancers, 182 were LN- and 58 were LN+. More LN+ patients had T2/T3 tumors (27/58, 47%) than LN- patients (31/182, 17%), p < 0.0001, but ER and HER2 status was similar. Of 58 LN+ cases, 19 (33%) were cN1 confirmed by positive LN cytology and 39 (67%) were cN0 but LN+ at operation. 10 patients LN+ at diagnosis received neoadjuvant therapy (NT) followed by operation (at which 6 were pLN+ and 4 rendered ypN0); 39 cN0 (4 NT, 35 primary surgery) and 9 cN1 primary surgery patients were pLN+ at operation with a median of 1 LN+. NSM was successful in 13/14 LN+ NT patients (93%) and 39/44 LN+ primary surgery patients (89%), p = 0.64. Six LN+ patients (10%) were converted to skin-sparing mastectomy (SSM) at initial operation based on frozen section pathology (n = 5) or at a second operation (n = 1) vs 13/182 LN- patients (7%), p = 0.44. Among cancer patients treated with NSM, 7 locoregional recurrences (5 in LN+, 2 in LN- patients) occurred at 25 mos median follow-up. 3-year locoregional disease-free estimates were 87% (95% CI 75-100%) for LN+ vs 99% (95% CI 97-100%) for LN- patients, p = 0.007. One nipple-areolar recurrence occurred, in a LN- patient. 3-year breast cancer-specific survival was 97% (95% CI 92-100%) in LN+ vs 99% (95% CI 98-100%) in LN- patients, p = 0.40. Conclusions: Conversion from planned NSM to SSM did not differ significantly between LN+ and LN- patients. Short-term oncologic outcomes were satisfactory. These data suggest that NSM may be appropriate for carefully selected LN+ breast cancer patients.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

247 Background: There are no prospective and few large retrospective studies of male breast cancer (MBC). This study’s aim was to describe our institutional experience with MBC and evaluate the ability of the AJCC staging system to stratify survival. Methods: All MBC cases were identified from our institution’s cancer registry from 1984-2008. Data collected included tumor characteristics, lymph node status, treatment, age, and survival. Results: During the study period 166 MBC cases were identified. Median age at diagnosis was 62 years (range 27-87). Most common presentation was a palpable breast mass (77%). Stage at diagnosis was stage 0 (6%), stage 1 (27%), stage 2 (36%), stage 3 (17%), stage 4 (5%), and unknown (9%). Procedure performed was mastectomy in 148 patients (89%), lumpectomy in 10 patients (6%) and unknown in 8 patients (5%). Median tumor size was 2.0 cm (range 0.2-11.0 cm). Most common histology was invasive ductal carcinoma (91%). Estrogen and progesterone receptor status assessed at diagnosis was positive in 93% and 86% of cases tested respectively. HER2/neu status was positive in 6 of 47 cases tested (13%). Nodal staging was performed by axillary dissection (AD) (70%), sentinel node biopsy (SN) alone (11%), SN and AD (11%) and no axillary staging (8%); 43% were node positive, 47% node negative and 10% unknown. Adjuvant chemotherapy was given to 40 patients (24%), adjuvant hormonal therapy to 42 patients (25%) and adjuvant radiation therapy was used in 33 cases (20%). With a median follow-up of 5.5 years, 86 patients (52%) have died: 44 due to breast cancer, 23 due to causes unrelated to breast cancer, and in 19 the cause of death is unknown. Median overall survival was 9.3 years. Median cancer-specific survival was 16.0 years. For patients initially diagnosed at stage 2, 3, and 4 median cancer-specific survival was 12.9, 7.2, and 0.8 years respectively. Median cancer-specific survival was significantly different for stages 2 vs. 3 (p = 0.03) and 3 vs. 4 (p = 0.0006). Conclusions: MBC most commonly presents as a palpable mass, is hormone responsive, and is most commonly treated with mastectomy. The TNM system appropriately stratifies men with MBC by duration of survival.

240 Background: Contralateral prophylactic mastectomy (CPM) is increasingly chosen by patients with breast cancer. Satisfaction after CPM is high. However, decreased satisfaction has been associated with reoperation after reconstruction. This study’s aim was to examine the adverse aspects patients attribute to reconstruction and the subsequent effect on psychosocial consequences and satisfaction with CPM. Methods: 487 unilateral breast cancer patients with a family history of breast cancer who underwent CPM between 1960 and 1993 were mailed a questionnaire evaluating QOL and satisfaction with CPM. Results: Of 269 respondents, 210 (78%) underwent reconstruction and 59 (22%) did not. Mean age at CPM was 46 and 50 years respectively (p=0.01). Mean follow-up was 20.2 years. Reconstruction was immediate in 96%, 98% with implants and 2% with tissue flap. Reconstruction was associated with lower satisfaction with CPM (p=0.03), but still only 7% (vs 2% in those without reconstruction) said they were dissatisfied. Most (83%) of those with reconstruction said they would choose reconstruction again while 7% were unsure and 10% said they would not. In those who did not undergo reconstruction, 18% said they would choose reconstruction if able to make the choice again while 5% were unsure and 77% said they still would not. 95 patients (45%) of those that underwent reconstruction required one or more reoperations for complications. Those with reoperation reported poorer responses for satisfaction with CPM (p=0.04), choice to have CPM again (p=0.008), and choice to have reconstruction again (p=0.004) when compared to patients with reconstruction and no reoperation. Those with and without reconstruction did not differ significantly with respect to femininity, sexual relationships or emotional stability, but those without reconstruction reported significantly poorer effects related to self esteem (p=0.04) and body appearance (p=0.002). Conclusions: In patients who undergo CPM, many years after surgery satisfaction with CPM is higher in those choosing not to have reconstruction than those with reconstruction although it was high in both groups. Reoperation is common after reconstruction and is associated with lower satisfaction.

144 Background: Many patients require hospitalization after mastectomy, predominantly for pain management and treatment of postoperative nausea and vomiting (PONV). In order to improve a woman's perioperative experience after mastectomy and facilitate mastectomy on an outpatient basis, we initiated a clinical pathway for perioperative management of unilateral mastectomy patients at Mayo Clinic Rochester. Methods: The clinical pathway consists of preoperative oral medications (celecoxib and gabapentin), preoperative ultrasound guided paravertebral block using bupivacaine, intraoperative anesthesia management with total intravenous anesthetic, and minimal use of long-acting opioids and postoperative acetaminophen and oxycodone. All patients are evaluated by the surgical team on the afternoon after surgery and if patients are recovering well are discharged on the day of surgery. The following morning, the surgical team telephones the patient to follow up on management of pain, nausea or vomiting, and drain output. Results: Eighteen patients have been treated on this clinical pathway. Mean age of patients was 66 (range 51-81). Majority of patients (n=16, 89%) underwent unilateral mastectomy with sentinel lymph node biopsy, with 1 patient undergoing bilateral mastectomy and 1 patient undergoing mastectomy and axillary dissection. All patients are evaluated by the surgical team on the afternoon of surgery. Fourteen patients (78%) were without evidence of hematoma or PONV, pain was well-controlled on oral medications and they were discharged on the day of surgery. On morning after telephone calls, pain scale ratings ranged from 1 to 3 and no patients verbalized complaints of nausea. Four patients (22%) treated on this clinical pathway required overnight observation in the hospital, one for urinary retention, two for pain control, and one for high sanguineous drain output. Conclusions: The clinical pathway presented provides preemptive analgesia and regional anesthesia for patients undergoing mastectomy, enabling the majority of patients to be discharged on the day of surgery. The clinical pathway is a safe and effective way to improve the perioperative experience of breast surgery patients and decrease hospital admission.