Claudia B. Perez

Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) demonstrates lack of expression of hormone receptors and human epidermal growth factor receptor. However, there is no targeted therapy for TNBC. The authors analyzed 29 TNBC cases for Notch-1 and Notch-4 biomarker expression and subcellular location, Ki67 proliferation rate, and relevant clinical/survival data. Results demonstrated an unfavorable Ki67 rate in 90% of cases, Notch-1 expression in tumor and endothelial cells in 100% of cases, and Notch-4 expression in tumor cells in 73% of cases and endothelial cells in 100% of cases. Additionally, subcellular localization of Notch-1 and Notch-4 was predominantly nuclear and cytoplasmic. In conclusion, (a) the majority of TNBCs are high-grade infiltrating ductal carcinomas with high Ki67 proliferation rate and (b) both Notch-1 and Notch-4 receptors are overexpressed in tumor and vascular endothelial cells with subcellular localization different from that of hormone-positive breast cancer. Targeting Notch signaling with gamma secretase inhibitors should to be explored to further improve the survival rate of TNBC patients.

Does practice make perfect? Resident experience with breast surgery influences excision adequacy

BACKGROUND The adequacy of breast-conserving surgery (BCS) for invasive or in situ disease is largely determined by the final surgical margins. Although margin status is associated with various clinicopathologic features, the influence of resident involvement remains controversial. METHODS Patients who underwent BCS for malignancy from 2009 to 2012 were identified. The effects of various clinicopathologic characteristics and resident involvement were evaluated. RESULTS Of the 502 cases performed, a resident assisted with most surgeries (95%). The overall rate of positive margins was 30%, which was not associated with resident involvement. Interns assisting from July to September had significantly lower rates of positive margins. Margins were more likely to be positive following any given residents first 3 cases on their breast rotation than throughout the remainder of their rotation. CONCLUSION Although resident level alone does not influence the adequacy of BCS, experience gained over time does appear to be associated with lower rates of positive margins.

Abstract PD10-02: Metabolic syndrome and recurrence within the 21-gene recurrence score assay risk categories in lymph node negative breast cancer

Background: The incidence of the metabolic syndrome (MS) has been increasing in the United States and elsewhere. The interaction of MS with breast cancer (BC) incidence, tumor biology and outcomes are under study. We hypothesized that the presence of MS would predict BC recurrence to a variable degree across the diverse BC biology as defined by the risk categories of the 21-gene recurrence score (RS) assay. Patients and Methods: We studied consecutive patients (pts) with newly diagnosed, estrogen receptor (ER) positive, lymph node (LN) negative BC treated in our institution between 2006–2011 who had a 21-gene RS assay done on their tumors. All pts were treated with standard systemic and local therapy. The electronic medical record was queried for key diagnoses including MS and its constituent parts. The WHO definition was used to categorize pts as having MS defined as diabetes mellitus (DM) or glucose intolerance, plus at least 2 of the following: hypertension (HTN), dyslipidemia (HL), central obesity and microalbuminemia. Tumor characteristics including Ki67 index, grade, tumor size, HER2/neu status; and pt characteristics including age, race, menopausal status, body mass index were recorded. The association of MS and the tumor and patient characteristics with the RS tertiles of low, intermediate and high risk was analyzed. Results: We identified 332 pts, median age 62 years, of whom 88 (27%) had MS. There was no significant association between the MS and any of the patient or tumor variables including the 21-gene RS assay, except for race (p = 0.004). Eleven of 21 (52%) African-American women had MS, 68 of 284 (24%) Caucasian women had MS, and 9 of 21 (43%) others including Hispanic and Asian women had MS. However, there was a significant association between recurrence and MS (p = 0.0002) independent of other factors. Of the 21 pts who recurred, 13 (61.9%) had MS. There was an association of recurrence and MS within RS tertiles. For pts with low risk scores, 7/44 (15.9%) with MS vs. 1/126 (0.79%) without MS had recurrence (p = 0.0003). For pts with intermediate risk scores, 5/30 (16.67%) with MS vs. 4/83 (4.82%) without MS had recurrence (p = 0.05). For patients with high risk scores, 1/9 (11.11%) with MS vs. 2/15 (13.33%) without MS had recurrence (p = 1). Conclusion: MS is an independent risk factor for BC recurrence among women with LN negative, ER positive BC treated with standard adjuvant therapy. There is a striking impact of MS on recurrence in pts with tumor biologies defined by low (and to a lesser degree) intermediate risk 21-gene RS assay scores. However, there is no difference in recurrence risk by MS among those pts with high RS. This implies that interventions directed at modifying MS in newly diagnosed pts with early BC may potentially favorably impact survival in those with specific tumor biologies as defined by multigene assays. Thus, long-term prospective studies should be conducted to further evaluate both the short and long term effects of MS on BC outcomes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-02.

Considerations for sentinel lymph node biopsy in breast cancer patients with biopsy proven axillary disease prior to neoadjuvant treatment

BACKGROUND Axillary disease can be downstaged with neoadjuvant treatment for breast cancer. We attempted to identify factors to consider in determining whether to perform a sentinel lymph node biopsy in patients with biopsy proven axillary metastases (cN+) prior to neoadjuvant treatment. METHODS A retrospective chart review was conducted on patients at a single tertiary care center who underwent neoadjuvant treatment followed by surgery between 9/2013 and 2/2017. RESULTS 47% of patients with node positive disease prior to neoadjuvant treatment were downstaged to node negative (ypN0) disease. These patients were more likely to have triple negative or Her2 positive disease than those patients who remained node positive (ypN+) as these were more likely to have hormone receptor positive disease. These patients were also more likely to demonstrate complete clinical imaging response of the primary tumor and axilla on preoperative breast MRI. CONCLUSIONS Tumor biology and clinical response noted on breast MRI can help guide the decision to perform sentinel lymph node biopsy in patients with axillary node positive disease prior to neoadjuvant treatment.

Abstract P1-10-04: Post-operative imaging after atypical ductal hyperplasia excision: The findings and costs

Introduction: With a reported incidence of 2-12% in breast biopsy specimens, the appropriate management of atypical ductal hyperplasia (ADH) remains in evolution. At present, the optimal screening guidelines for patients with high-risk breast lesions such as ADH remain unclear. Current practices often parallel the surveillance of cancer patients and include a 6 month interval mammogram prior to resuming annual screening, which may result in unnecessary procedures and financial costs. This interval mammogram is typically a diagnostic study, which is an additional cost to the patient and healthcare system. The purpose of this study was to identify interval pathology following initial surgical resection and review associated costs. Methods: Following institutional review board approval, the pathology database from a single institution was queried for patients who underwent surgical excision for ‘atypical ductal hyperplasia’ from 2008 to 2013. Those who did not have follow-up data available were excluded. Subsequent clinical care was reviewed, including interval imaging and need for additional intervention. Based on a review of hospital charges from 2013, the average charge for a unilateral diagnostic mammogram (out-patient, digital) was

Abstract P1-02-01: Flat epithelial atypia diagnosed on breast core biopsy: what next?

382. Results: There were 55 patients who underwent an excisional biopsy that were diagnosed with ADH and had subsequent follow-up. The median age was 57 years (range 38-82 years), and the median breast cancer risk assessment score was 2.3% at 5 years (range 0.5-17.9%) and 12.5% lifetime risk (range 2.2-37.6%). Pathology included concurrent lobular carcinoma in situ (n=1), atypical lobular hyperplasia (n=3), flat epithelial atypia (n=14), and papillary lesions (n=19). In addition to a routine clinical breast exam, a short-term follow-up diagnostic (ipsilateral) mammogram was performed in 35 patients. Of the 35 interval mammograms obtained, 31 yielded benign findings on initial imaging, while 4 patients required additional imaging that ultimately resulted in benign findings. The overall hospital charges for the 35 short interval mammograms alone during this 6 year period were roughly

Abstract 3135: Notch 1 and notch 4 biomarker expression in triple-negative invasive breast cancer

13,370. For the patients that resumed annual surveillance, 3 had abnormal mammograms requiring additional imaging, and no malignancies were identified in this subset of patients. To date, the median physician follow-up is 3 years, and 52 patients have undergone at least one mammogram since their initial imaging; all subsequent findings have been benign for all patients. When extrapolated to national data, cost savings to the healthcare system from eliminating short interval mammograms would exceed

Positron Emission Tomography-avid Adrenal Mass and Incidental Renal Mass in a 70-Year-Old Woman With Newly Diagnosed Breast Cancer

12 million annually without compromising clinical outcomes. Conclusions: Based on our findings, a 6 month follow-up mammogram is not recommended and incurs unnecessary costs to the patient and healthcare system. In the post-surgical breast, imaging may be misleading and result in additional procedures and significant charges that ultimately do not affect clinical outcomes. Although a clinical exam is still recommended at 6 months following surgical excision for a diagnosis of ADH, patients should forego short interval (6 month) imaging and resume annual mammogram surveillance. Citation Format: Jennifer K Plichta, Adrienne N Cobb, Gerard J Abood, Constantine Godellas, Claudia B Perez. Post-operative imaging after atypical ductal hyperplasia excision: The findings and costs [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 P1-10-04.

Results from a pilot of an innovative 4R Cancer Care Delivery Model: Impact on patient self-management.

Background: Historically, atypical ductal hyperplasia (ADH) identified on breast core biopsy has been associated with a 20% upgrade to malignancy at surgical excision. Recent literature has suggested a downward trend in such upgrade rates, possibly related to the use of larger gauge core biopsy devices. It is still unclear if this applies to other high-risk lesions, such as flat epithelial atypia (FEA). As core biopsy techniques and imaging have improved, it is critical to review the correlation between FEA diagnosed on core biopsy and malignancy at final surgical excision. Methods: We performed a retrospective chart review of our institution9s medical record from 2009 to 2011 to identify all patients who (1) underwent breast core biopsy, (2) were initially diagnosed with FEA without malignancy (in situ or invasive carcinoma), and (3) proceeded with surgical excision at our institution. Results: Of the 726 breast core biopsies performed between 2009 and 2011, we identified 14 patients who met our inclusion criteria. Three patients were upgraded to malignancy following surgical excision (21%). The median age was 53.5 years, and the average breast cancer risk assessment scores were 3.5% 5-year and 18.9% lifetime. All patients underwent pre-biopsy mammogram, and four were further evaluated with ultrasound; no patients underwent a breast MRI. All of the imaging abnormalities were initially classified as BI-RADS 4, including five masses/densities and nine with suspicious calcifications. Only one patient reported the lesion as palpable on presentation and this was eventually upgraded to malignancy. All patients underwent image-guided core biopsies, including 13 stereotactic, vacuum-assisted and one ultrasound-guided, vacuum-assisted. Nine patients had 9-gauge core needle biopsies, while the remaining four patients had 11, 12, or 14-gauge needle biopsies, and this did not vary between years. Following surgical excision, three of the 14 patients (21%) were upgraded pathologically to ductal carcinoma in situ (DCIS; n=1) or invasive ductal carcinoma (n = 2). All three of these patients had 9-gauge core biopsies prior to surgical excision. Of note, four patients also had concurrent ADH on initial biopsy, although none of these were pathologically upgraded to malignancy. Of the upgrades, one patient proceeded with a definitive lumpectomy (negative sentinel lymph node biopsy) and one underwent bilateral mastectomy. The third patient is planning to undergo ipsilateral mastectomy for a subsequent diagnosis of multi-centric breast disease, including identification of an ipsilateral DCIS lesion distant from the primary lesion. Conclusions: The use of a larger gauge core biopsy needle (e.g. 9-gauge) may yield superior tissue sampling and should likely be considered as the standard of care in the evaluation of image-detected breast abnormalities. In addition, biopsy results should not be considered definitively non-malignant when a high-risk lesion is identified. While there may be a trend towards not excising some of these high-risk lesions, we believe that a core biopsy demonstrating FEA still warrants surgical excision. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-02-01.

Results from a pilot of an innovative 4R Cancer Care Delivery Model in early breast cancer: Impact on timing and sequencing of guideline recommended care.

BACKGROUND: Triple-negative breast cancer (TNBC) is a high-grade tumor showing lack of expression of estrogen and progesterone receptors and human epidermal growth factor receptor (HER-2/neu). Unlike hormone receptor and HER-2/neu positive breast carcinomas, there is no targeted therapy for TNBC. The objective of this study is to investigate Notch 1 and Notch 4 biomarker expression in TNBC and to correlate the expression with known prognostic factors. DESIGN: We performed a retrospective chart review of 29 TNBC during 1998-2007. Data collected included age at diagnosis, histological type and grade, Ki67 proliferation rate, and patient survival status. Formalin-fixed paraffin embedded tissue blocks from each TNBC was selected. Notch 1 and Notch 4 expression were analyzed by immunohistochemical method (Santa Cruz Biotechnology Inc, USA). The intensity of staining for Notch 1 and 4 expressions and the sub-cellular localization of these receptors (cytoplasmic or nuclear) in tumor epithelial cells and vascular endothelial cells were noted. Only strong cytoplasmic and/or nuclear staining was documented as positive for Notch expression. Student9s t test and chi-square test were applied for data analysis. RESULTS: Age of the patients ranged from 37 to 83 years (mean 57.7). Twenty-seven tumors were infiltrating ductal carcinomas (93.1%) and 2 were infiltrating papillary carcinomas (6.9%). Twenty-one cases were grade 3 (72.4%), 7 were grade 2 (24.2%) and one was grade 1 (3.4%). Unfavorable Ki67 proliferation rate (>20%) was seen in 26 (90%), borderline rate (10-20%) in 2 (6.9%) and favorable rate ( CONCLUSION: This study demonstrates that (1) majority of triple-negative invasive breast cancers are morphologically high grade infiltrating ductal carcinomas with high Ki 67 proliferation rate, (2) both Notch 1 and Notch 4 receptors are over-expressed in tumor cells and in vascular endothelial cells in majority of this molecular subset of breast carcinoma, and (3) this subtype is associated with high overall survival rate with the currently available treatment. Targeting Notch signaling with gamma secretase inhibitors needs to be explored to further improve the survival rate of TNBC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3135. doi:10.1158/1538-7445.AM2011-3135