Holly J. Pederson

A Clinical Scoring System for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 Probands

Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score-the Cleveland Clinic (CC) score-resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

Breast cancer risk associated with atypical hyperplasia and lobular carcinoma in situ initially diagnosed on core-needle biopsy

Breast cancer risk estimates for atypical lesions are based primarily on case‐control studies of patients with open biopsies. The authors report the cumulative breast cancer incidence after a core biopsy diagnosis of atypical hyperplasia (ductal or lobular) or lobular carcinoma in situ.

Time-Related Changes in Yield and Harms of Screening Breast Magnetic Resonance Imaging

PURPOSE Breast magnetic resonance imaging (MRI) is accepted as a useful adjunct to screening mammography for women at high risk for breast cancer. Nevertheless, concerns about false-positive findings remain, and data about MRI harms and yields are limited. The aim of this study was to quantify harms and yields of breast MRI over time in a large series of patients. METHODS A retrospective review was performed of patients at increased risk for breast cancer who underwent annual screening digital mammography and MRI from 2007 to 2013. Harms were defined as events not producing a breast cancer diagnosis (ultrasonography [US], imaging-guided core or surgical biopsy procedure, recommendation for short-term follow-up, or a combination). RESULTS Of 350 high-risk patients offered MRI screening, 320 underwent 757 screening MRI procedures over time. The median age at the first MRI was 48 years. All patients met American Cancer Society criteria for annual screening breast MRI. Total harms were highest with the first MRI procedure and decreased with subsequent MRI screening. Of 75 biopsy procedures performed, including 58 US- or MRI-guided core biopsy procedures and 17 surgical biopsy procedures, 6 specimens were found to be malignant, including 2 resulting from biopsy procedures performed based on findings from the first MRI scan, 0 from the second MRI scan, 3 from the third MRI scan, and 1 from the fourth MRI scan. CONCLUSION Among women followed with screening MRI, the number of harms was shown to decrease over time. Breast cancer continued to be detected in MRI studies performed over time. This study demonstrates the utility of MRI screening performed over time in high-risk women.

Abstract P3-09-09: Assessing utility of breast cancer risk assessment tool in comparison to Tyrer-Cuzick model for determination of breast cancer risk and implications for chemoprevention

Background Despite findings that the Tyrer-Cuzick (IBIS Breast Cancer Risk Evaluation Tool or TC) model is more predictive of breast cancer risk than the Gail model (NCI maintained Breast Cancer Risk Assessment Tool or BCRAT), BCRAT is commonly clinically used as per the United States Preventive Services Task Force (USPSTF), with a 5-year risk for breast cancer (BC) of greater than 3% on BCRAT, the benefits of preventive medication likely outweigh the risks. We aimed to compare the models, 1: to see if a 10 year risk estimate per the TC model reliably correlated with the 3% 5 year risk per BCRAT, and 2: to analyze the subset of patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) who are known both to be at high risk for breast cancer and to benefit from chemoprevention. Our hypothesis is that BCRAT has limited utility in risk estimation, and the most comprehensive model for risk estimation and clinical decision making is TC. Methods 200 women ages 35-64 women followed in benign breast clinic were included. Risk estimations were run using BCRAT, TC version 7 (v7) and TC version 8 (v8). A Pearson9s Correlation test was conducted to investigate the relationship between the TC models and the BCRAT model. A p-value Results Analysis showed a positive moderate-strength relationship between the TC v7 10-year risk and the 5-year BCRAT risk for this population (R = 0.468, P A total of 36 patients were diagnosed with AH, 2 patients were diagnosed with LCIS and 7 patients were diagnosed with both AH and LCIS. 11 patients who had AH had an estimated 5-year risk per the BCRAT model of Of the 30 patients who had a BCRAT 5-year estimated risk of BC of >3% but no AH or LCIS, 12 had two first degree relatives with breast cancer and 16 had a first-degree relative with BC and at least two benign breast biopsies. Conclusion BCRAT is limited and caution is warranted with its use in assessing risk and for counseling around chemoprevention benefit. There is not reliable correlation between the 5 year BCRAT risk estimate and the 10 year TC risk estimate. Chemoprevention should be discussed for patients with AH, LCIS or 2+ first degree relatives with breast cancer. Further, BCRAT may underestimate risk in minority populations and others with AH. For a limited group of patients with moderate risk, dual modeling may be clinically useful in making chemopreventive recommendations. Citation Format: Pederson HJ, Yanda C, Kline M, Stephens M, Goraya ST, Grobmyer SR, Kattan MW. Assessing utility of breast cancer risk assessment tool in comparison to Tyrer-Cuzick model for determination of breast cancer risk and implications for chemoprevention [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 P3-09-09.

Prophylactic Risk-Reducing Surgery for Breast Cancer

Advances in the understanding of the genetics and biology of breast cancer are defining patients at increased risk for the development of breast cancer. Prophylactic risk-reducing mastectomy and bilateral salpingo-oophorectomy are very good options for reducing breast cancer risk in selected patients with elevated breast cancer risk. Technical approaches to prophylactic surgery are evolving and are leading to improved patient cosmetic outcomes and lower morbidity. Decisions regarding utilization of these procedures for patients should take into account a specific patient’s risk for developing breast cancer based on genetic, family, and personal medical history; patient age; and comorbid conditions. Limitations of prophylactic surgical approaches, alternatives, and side effects of prophylactic operations should also be considered carefully with patients who are considering these surgical interventions for breast cancer risk reduction.

Locoregional Therapy Following Neoadjuvant Therapy for HER-2+ Breast Cancer: Opportunities and Challenges

Advances in the management of patients with HER-2+ breast cancer with combinatorial targeted therapies are leading to unprecedented rates of pathologic complete response. The high rates of complete pathologic response in the breast and the axillary lymph nodes following neoadjuvant therapy are raising new questions about the role of local therapies (surgery and radiation therapy) in treating these patients. The safe elimination of surgery and radiation therapy for selected breast cancer patients would ultimately reduce the short- and long-term morbidity associated with traditional breast cancer treatments and would represent a major step forward. However, numerous technical and clinical challenges remain which will be discussed in this chapter. Collaborative efforts to address these challenges are essential to improving current therapeutic approaches for patients with HER-2+ breast cancer.