Citations

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

Abstract Background Metaplastic breast cancer (MBC), characterized by a mixture of epithelial, squamous or mesenchymal elements and a usually triple-negative (TN) phenotype, accounts for <1% of breast cancer diagnoses. MBC has a poor prognosis with frequent distant spread, but, paradoxically, a lower than expected rate of nodal positivity (6 to 40%). Due to its rarity there is little data on how best to evaluate and manage the axilla in women with these tumors. Thus we undertook this study to evaluate axillary management and oncologic outcomes. Methods With IRB approval, we identified adult patients diagnosed with MBC at our institution from 2001 to 2011 from our prospective surgical pathology database. Patient, pathology, imaging, treatment and outcome data were obtained from electronic medical record, tumor registry, pathology slide and imaging review. Median follow-up for surviving patients was 66 months. Statistical analyses were performed using JMP 10.0 software. Results We identified 41 MBC patients, median age 60 years (range 33-89 years), with a median tumor size of 2.7 cm; 33 (80%) were TN. 23 patients (56%) had a preoperative axillary ultrasound (AUS): 9 (39%) showed at least one suspicious axillary lymph node (LN) of whom 6 had a preoperative fine needle LN biopsy (FNA) of which 3 were positive for metastasis. 6 patients, including the 3 LN+ on FNA, had neoadjuvant chemotherapy (NAC). Operation included axillary dissection (ALND) in 14, sentinel LN biopsy (SLNB) in 23, and SLNB followed by ALND in 1, while 3 patients had no axillary surgery. 10 patients were LN+ at operation. Among 22 patients who had both an AUS and axillary surgery, AUS had a sensitivity of 100% and specificity of 78%. Patient and tumor variables in association with pathologic LN status are summarized in the table. LN positivity correlated with increasing tumor size, T stage, grade and angiolymphatic invasion. 16 patients recurred, most with distant disease (10/16, 63%), although there was a solitary axillary recurrence 8 months after a negative SLNB in one patient who did not have a preoperative AUS. Thus the accuracy of SLNB was 96% (23/24) overall, but among those without preoperative AUS, 1/7 (14%) SLNBs were falsely negative. 5-year disease-free and breast cancer-specific survival estimates were 49% and 63%. LN- N=28 (74%)LN+ N=10 (26%)p-valueSize, median (IQR), cm2.7 (1.6-4.6)6.6 (2.5-16.5)0.001T stage 0.03T19 (100%)0 (0%) T214 (78%)4 (22%) T33 (60%)2 (40%) T42 (33%)4 (67%) Grade 0.04Low6 (16%)0 (0%) Intermediate/High22 (58%)10 (26%) Estrogen Receptor 0.61Positive (>1%)5 (71%)2 (29%) Negative (<1%)23 (74%)8 (26%) Angiolymphatic Invasion 0.002No26 (87%)4 (13%) Yes2 (25%)6 (75%) Dominant Histology 0.65Adenosquamous2 (100%)0 (0%) Matrix producing4 (80%)1 (20%) Spindle cell14 (74%)5 (26%) Squamous*8 (67%)4 (33%) *any squamous component Conclusion Our study is the first to specifically address AUS and SLNB for patients with metaplastic breast cancer. AUS had 100% sensitivity and 78% specificity, while one patient without a preoperative AUS had a falsely negative SLNB. Further, AUS with FNA of suspicious LNs was useful for staging at the time of diagnosis and informing treatment. We recommend this approach for patients with MBC. Citation Format: Murphy BL, Fazzio RT, Hoskin TL, Glazebrook KN, Keeney MG, Habermann EB, Hieken TJ. Management of the axilla in metaplastic breast carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-01.

Abstract In breast adipose tissue, macrophages that encircle damaged adipocytes form “crown-like structures of breast” (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups (n = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B–positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, P = 0.01) and BBD cases (21/86 = 24%, P = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B positive, BMI 25–29: 13%, and BMI ≥ 30: 29% (P = 0.0005). Among BBD biopsies, a high CLS-B count [>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), P = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4–32.4), P = 0.02, after adjusting for adipose tissue area (cm2), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. Cancer Prev Res; 11(2); 113–9. ©2017 AACR.

Background and ObjectivesAdenoid cystic carcinoma (ACC) is a rare, typically triple‐negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment.MethodsWe identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed.ResultsWe identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2‐4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node‐negative, while the remaining five had no axillary surgery. With 3.6 years median follow‐up (range 0.2‐38.6 years), three patients experienced an in‐breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes.ConclusionsWe observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

Abstract Introduction: The 21-gene Recurrence Score (RS) assay has been shown in retrospective studies to predict benefit of adjuvant chemotherapy (AC) in node positive (N+) breast cancer (BC) patients (pts). This study evaluates the trends and patterns of use of RS assay in N+, ER+/HER2-breast cancer and the impact of RS on decision to use AC in a real-world multi-institutional database. Methods: Pts with T1-T4c, N1mi-N3, ER+/HER2- BC diagnosed between 2010 and 2013, included in the National Cancer Data Base were analyzed. Pts who received neo-AC were excluded. Analyses included Cochrane-Armitage tests for trends and multivariable logistic regression assessing factors influencing RS testing and AC recommendations based on RS. Results: Among 73,049 pts, RS was obtained in 20.6%, increasing from 14.9% in 2010 to 24.4% in 2013 (p<0.001). RS testing was most common in N1mi (43.6%) and N1 (22.0%) and rare in N2/N3 (3.3%) BC. Of the 12,540 BC with quantitative RS results, 61.1% were low RS, 32.3% intermediate RS and 6.6% high RS. AC recommendation was less frequent in pts with RS testing compared to pts not tested (50.4% recommended AC vs 80.9%, p<0.001). In pts with N1mi/N1 BC, recommendation rates for AC were higher with higher RS (see table), however in N2/N3 BC, AC was recommended in the majority (71-88%) regardless of RS. Most pts (>85%) with RS 26-30 or high risk RS were recommended AC regardless of N stage. For pts with low risk RS, recommendation for AC increased significantly with increasing N stage (see table). On multivariable analysis, in pts with low risk RS, AC was more likely to be recommended in those with N1/N2+ stage (OR 2.3 and 9.1 vs N1mi), T2 and T3/T4 tumors (OR 1.3 and 2.2 vs T1 tumors), poorly differentiated tumors (OR 1.6) and younger age (OR 3.4 and 1.7, respectively, for <40 and 40-49 vs 50-59) (all p<0.001). Among pts with RS 18-25, AC was more likely to be recommended in those with higher tumor grade, younger age but the effect of N stage was less pronounced. Histology (IDC vs ILC) did not influence AC recommendation in any RS subset. Path N StageRS Risk GroupLow RiskIntermediate RiskHigh RiskRS<18RS 18-25RS 26-30RS>30N1mi AC No1,854 (75.9%)389 (36.9%)36 (14.6%)16 (7.0%)N1mi AC Yes590 (24.1%)666 (63.1%)210 (85.4%)212 (93.0%)N1 AC No3,000 (60.6%)699 (33.0%)75 (14.8%)33 (6.0%)N1 AC Yes1,954 (39.4%)1,422 (67.0%)431 (85.2%)518 (94.0%)N2/N3 AC No76 (29.0%)17 (16.7%)3 (12.5%)7 (14.9%)N2/N3 AC Yes186 (71.0%)85 (83.3%)21 (87.5%)40 (85.1%)p-value<0.001<0.0010.880.16 Conclusions: RS was obtained in about one fifth of pts with N+ ER+/HER2- BC, predominantly for N1mi and N1 disease. Overall, RS testing decreased frequency of recommendation of AC in N+ BC pts. The RS influenced use of AC particularly in N1mi and N1 pts, likely avoiding overtreatment of those with low risk RS and RS 18-25. Prospective data regarding RS to direct AC in N+ BC are awaited. Citation Format: Peethambaram PP, Hoskin TL, Heins CN, Habermann EB, Boughey JC. How 21-gene recurrence score assay is being used to individualize adjuvant chemotherapy recommendations in ER+/HER2 -node positive breast cancer -A national cancer data base study [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 PD7-05.

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.

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]