Citations

Abstract Introduction: Current models to predict breast cancer risk do not differentiate risk for estrogen receptor (ER) positive and negative breast cancer (BC), despite growing evidence that these tumors are biologically very different. We hypothesized that women with ER+ BC cancers have different clinical risk factors and histologic findings on prior benign breast biopsies than those with ER- BC. Methods: After IRB approval, we examined associations of age at benign biopsy and histologic features of the benign biopsy with ER status of incident BCs within the Mayo Benign Breast Disease Cohort. Benign biopsy slides were reviewed for extent of lobular involution and degree of epithelial proliferation by a single breast pathologist blinded to BC events. Invasive BCs occurring within 15 years after benign biopsy were classified as ER+ if ER staining was >1%. BC case-only associations with ER status were evaluated using multivariate logistic regression. Full-cohort hazard ratios (HR) and 95% confidence intervals (CI) for risk of ER-specific subtypes were estimated using Cox proportion hazards regression. Results: Among 13,410 women undergoing a benign breast biopsy from 1967-2001, 656 invasive BCs (459 ER+, 106 ER, 106 unknown) occurred within 15 years. Women who developed ER+ and ER- BCs were similar in age at the time of their prior benign breast biopsy (p=0.34). Although benign biopsies in women who later developed ER+ BC were more likely to show complete involution (23% vs 15% for ER- BC), this was not statistically significant (p=0.06). However, the degree of epithelial proliferation was significantly associated with ER status of later BCs (p=0.001), with ER+ BCs more likely than ER- BCs to have had a prior biopsy with atypical hyperplasia (16% vs 8%), and ER+ BCs less likely than ER- BCs to have had a prior biopsy with proliferative disease without atypia (33% vs 52%); this association remained after multivariate adjustment (p=0.003). We further pursued the association of epithelial proliferation with differential risk of ER+ and ER- BC in our overall cohort of 13,410 women (Table 1). Compared to women with non-proliferative disease, women with proliferative disease +/- atypia had ∼2-fold hazard ratios for ER- BC, whereas hazard ratios for ER+ BC were higher in women with atypical hyperplasia (∼4-fold) compared to proliferative disease. Hazard Ratio of ER+ and ER- BC within 15 years of BBD based upon degree of epithelial proliferation at benign biopsyCancer TypeGroupNN EventsHazard Ratio (95% CI)p-valueInvasive ER- ≤15 yearsNP8478421.00 (ref)<0.0001 PD4229542.63 (1.76, 3.93) AH70382.60 (1.22, 5.54) Invasive ER+ ≤15 yearsNP84782321.00 (ref)<0.0001 PD42291511.33 (1.09, 1.64) AH703744.41 (3.39, 5.73) NP=nonproliferative disease, PD=proliferative disease without atypia; AH=atypical hyperplasia Conclusion: ER+ and ER- breast cancers appear to have different features on prior benign breast biopsy, with atypical hyperplasia showing increased risk for both types of breast cancer, but a greater risk for ER+ tumors. Citation Format: Amy C Degnim, Derek C Radisky, Robert A Vierkant, Ryan D Frank, Marlene H Frost, Vernon S Pankratz, Celine M Vachon, Tanya L Hoskin, Julie M Cunningham, Chen Wang, Jean-Pierre Kocher, Teresa M Allers, Joanne L Johnson, Tina J Hieken, Karthik Ghosh, Lynn C Hartmann, Daniel W Visscher. Histologic features of benign breast biopsy tissue and association with ER positive and ER negative breast cancer in the Mayo BBD cohort study [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 P6-10-06.

Abstract Background: Many newly diagnosed breast cancer patients undergo preoperative breast MRI which includes visualization of some degree of the axilla. The impact of patient characteristics and tumor biology on the fidelity of MRI imaging of the axilla in these cases is not well-studied. We sought to examine the correlation between nodal findings on breast MRI and pathologic nodal status in newly diagnosed breast cancer patients. Methods: With IRB approval, we identified 1868 consecutive breasts with invasive cancer in 1803 patients undergoing primary operation with axillary surgery from 1/2010-7/2013. Patients undergoing neoadjuvant chemotherapy (348) were excluded leaving 1510 breasts with cancer in 1455 patients. Preoperative MRI was performed in 763 patients (52%). We evaluated patient, imaging and pathology data. Results: Patients evaluated with MRI were median age 57 years. The majority of tumors were T1 (63%) and T2 (28%). MRI identified suspicious axillary nodes in 240 cases (31%), of which 123 (51%) were node positive at operation. Suspicious axillary findings on MRI predicted both nodal status and pN stage at operation (both p<0.0001). The sensitivity, specificity, accuracy, positive (PPV) and negative predictive value (NPV) of MRI for nodal disease across tumor types is shown. Pathologic Node PositiveSensitivity (95% CI)Specificity (95% CI)NPV (95% CI)PPV (95% CI)Accuracy (95% CI)All Cases (n=763)234 (31%)52.6 (46-59.1)77.9 (74.1-81.3)78.8 (75-82.1)51.3 (44.8-57.7)70.1 (66.7-73.3)Approximated Biologic Subtype (missing=24)ER+/HER2- (n=609)194 (32%)51.0 (43.8-58.2)80.0 (75.8-83.7)77.8 (73.4-81.5)54.4 (46.9-61.7)70.8 (67-74.3)HER2+ (n=69)20 (29%)65.0 (40.9-83.7)71.4 (56.5-83)83.3 (68-92.5)48.1 (29.2-67.6)69.6 (57.2-79.8)ER-/HER2- (n=61)17 (28%)58.8 (33.5-80.6)75.0 (59.4-86.3)82.5 (66.6-92.1)47.6 (26.4-70)70.5 (57.3-81.1)p value0.740.430.330.560.730.98Tumor Grade (missing=5)1 (n=259)58 (22%)32.8 (21.4-46.5)79.6 (73.2-84.8)80.4 (74.1-85.5)31.7 (20.6-45.1)69.1 (63.0-74.6)2 (n=351)124 (35%)55.6 (46.5-64.5)79.7 (73.8-84.6)76.7 (70.7-81.8)60.0 (50.4-68.9)71.2 (66.1-75.9)3 (n=148)51 (34%)66.7 (52.0-79.0)70.1 (59.8-78.8)80.0 (69.6-87.6)54.0 (41.0-66.4)68.9 (60.7-76.1)p value0.0010.00030.110.720.020.93 Diagnostic performance did not vary significantly based on patient body mass index (BMI) or approximated biologic subtype, but specificity was better for patients >age 50 (p=0.007) and sensitivity and PPV both were worse for grade 1 vs grade 2/3 tumors. Node positivity rate at operation was 48% (51/106) for patients with a solitary abnormal node on MRI and 54% (72/134) when >1 suspicious node was seen (p=0.39). However, multiple vs solitary MRI suspicious nodes correlated with ≥3 positive nodes at operation (40 [30%] vs 19 [18%], p=0.03) and pN2/pN3 disease (29 [22%] vs 12 [11%], p=0.03). Conclusion: Axillary lymph node findings on MRI for breast cancer predict nodal status and disease volume in invasive breast cancer patients. Tumor biologic subtype did not affect performance characteristics of preoperative MRI, but tumor grade did influence the sensitivity and PPV of MRI. When MRI is performed in the evaluation of newly diagnosed breast cancer, axillary findings inform pathologic nodal stage at operation regardless of tumor subtype. Citation Format: Sean C Dupont, Judy C Boughey, Tanya L Hoskin, Katrina N Glazebrook, Tina J Hieken. Value of breast MRI for preoperative axillary assessment of breast cancer patients [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 P1-01-03.

Purpose Optimal early detection and prevention for breast cancer depend on accurate identification of women at increased risk. We present a risk prediction model that incorporates histologic features of biopsy tissues from women with benign breast disease (BBD) and compare its performance to the Breast Cancer Risk Assessment Tool (BCRAT). Methods We estimated the age-specific incidence of breast cancer and death from the Mayo BBD cohort and then combined these estimates with a relative risk model derived from 377 patient cases with breast cancer and 734 matched controls sampled from the Mayo BBD cohort to develop the BBD–to–breast cancer (BBD-BC) risk assessment tool. We validated the model using an independent set of 378 patient cases with breast cancer and 728 matched controls from the Mayo BBD cohort and compared the risk predictions from our model with those from the BCRAT. Results The BBD-BC model predicts the probability of breast cancer in women with BBD using tissue-based and other risk factors. The concordance statistic from the BBD-BC model was 0.665 in the model development series and 0.629 in the validation series; these values were higher than those from the BCRAT (0.567 and 0.472, respectively). The BCRAT significantly underpredicted breast cancer risk after benign biopsy (P = .004), whereas the BBD-BC predictions were appropriately calibrated to observed cancers (P = .247). Conclusion We developed a model using both demographic and histologic features to predict breast cancer risk in women with BBD. Our model more accurately classifies a woman's breast cancer risk after a benign biopsy than the BCRAT.

Abstract Background: The prognosis for stage III melanoma is variable, with the 5-year survival ranging from 23-87%. Previous studies have demonstrated both immune cell activation and dysfunction within the sentinel lymph node (SLN) of melanoma patients. We hypothesize that differences within the host response, specifically the immune cell profile of the SLN, may predict the heterogeneous behavior of stage III melanoma. Methods: A retrospective review of clinically node negative patients undergoing a SLN biopsy at our institution was undertaken. Thirty four SLN positive cases in which the patients also underwent a complete lymph node dissection were identified and the archived FFPE SLN blocks were obtained. A single tumor positive SLN was selected and immunohistochemistry was performed for dendritic cell markers (CD123, CD86, CD11c and HLA-DR), cytotoxic T cells (CD8), anergic T cells (PD-1) and regulatory T cells (Foxp3). Slides were digitized and analyzed for percent of the SLN staining positive for each respective marker using IHCscore. These findings were correlated with risk of further non-SLN disease in the same nodal basin as well as effect on disease-free and overall survival. Results: The SLN exhibited expression of both immune activation (CD8, CD86, and CD11c) and immune suppressive (CD123, PD-1 and Foxp3) markers. HLA-DR expression was significantly higher in females (52.07% vs. 42.32%, p=0.02). No other immune marker was associated with any baseline demographic or clinical variable. Median disease-free survival and overall survival was 6 months and not yet reached and 16 months and not yet reached for patients with and without non-SLN involvement, respectively; however, no difference was noted in any of the SLN immune markers between patients with and without non-SLN involvement. Increased CD8 expression in the SLN was associated with an improvement in disease-free survival (HR 0.94 p = 0.048) but not overall survival (HR 0.93 p = 0.07). In two variable multivariate analyses, CD8 expression remained independent for disease-free survival when adjusted for Breslow depth but not non-SLN involvement. The median disease-free survival for patients with low CD8 expression within the SLN was 19.5 months and median disease-free survival has not been reached in those with high CD8 expression in the SLN after a median of 59 months follow up (log-rank p = 0.05). Conclusion: Previous reports suggest T cell infiltration of melanoma tumors is an important prognostic factor. In this study we found that CD8 T cell accumulation within the SLN was associated with a disease-free survival advantage. Cytotoxic T cell accumulation within the SLN declines early in melanoma and the degree of CD8 depletion corresponds to the risk of disease recurrence. These findings support a key role for effector T cells in the control of melanoma progression. Citation Format: Travis E. Grotz, Aaron S. Mansfield, James W. Jakub, Svetomir N. Markovic, Tina J. Hieken. Immune cell profile of the SLN has prognostic value in stage III melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2013-1266

Abstract The view of eosinophils (Eos) as solely effector cells involved in host parasite defense and in the pathophysiology of allergic diseases has been challenged in recent years. In fact, there is a growing realization that these cells interact with other components of innate and adaptive immunity. For example, mouse Eos were recently demonstrated to promote plasma cell retention in the bone marrow. However, it remains unknown whether Eos influence the biology of normal B lymphocytes. In this study, we specifically assessed the effect of Eos on B cell survival, proliferation, and Ig secretion. Our data first revealed that the genetic deletion of Eos from NJ1638 IL-5 transgenic hypereosinophilic mice (previously shown to display profound B cell expansion) resulted in the near abolishment of the B cell lymphocytosis. In vitro studies using human tissues demonstrated Eos’ proximity to B cell follicles and their ability to promote B cell survival, proliferation, and Ig secretion via a contact-independent mechanism. Additionally, this ability of Eos to enhance B cell responsiveness was observed in both T-independent and T-dependent B cell activation and appears to be independent of the activation state of Eos. Finally, a retrospective clinical study of hypereosinophilic patients revealed a direct correlation between peripheral blood eosinophil levels and B cell numbers. Taken together, our study identifies a novel role for Eos in the regulation of humoral immunity via their impact on B cell homeostasis and proliferation upon activation.

Background and Objectives. While excisional biopsy is recommended to diagnose cutaneous melanoma, various biopsy techniques are used in practice. We undertook this study to identify how frequently final tumor stage and treatment recommendations changed from diagnostic biopsy to final histopathology after wide local excision (WLE).Methods. We compared the histopathology of the dermatopathologist-reviewed diagnostic biopsy and final WLE in 332 cutaneous melanoma patients.Results. Tumor sites were extremity (51%), trunk (33%), and head/neck (16%). Initial biopsy types were excisional (56%), punch (21%), shave (18%), and incisional (5%). Most diagnostic biopsies were margin positive regardless of technique, and 36% of patients had residual melanoma on WLE. T-stage changed in 8% of patients, of whom 59% were diagnosed by punch biopsy, 15% by incisional biopsy, 15% by shave biopsy, and 11% by excisional biopsy (P<0.0001). Treatment recommendations changed in 6%: 2% after excisional biopsy, 5% after shave biopsy, 18% after punch biopsy, and 18% after incisional biopsy (P<0.0001).Conclusions. Although most biopsy margins were positive, T-stage and treatment changed for only a minority of melanoma patients. Our data provide valuable information to inform patient discussion regarding the likelihood of a change in prognosis and the need for secondary procedures after WLE. These data support the superiority of dermatopathologist-reviewed excisional biopsy when feasible.

Background: Current recommendations for surgical management of early-stage breast cancer include breast-conserving surgery with postoperative irradiation. However, studies show that mastectomy is still being used by women with early-stage breast cancer. Methods: Review of the medical literature published between 2000 and 2010 to determine the factors associated with the decision of patients for surgical treatment in early-stage breast cancer. Results: The following patient characteristics affect the surgical decision-making process in early-stage breast cancer: age, socioeconomic factors, geographic area in which the patient lives, proximity to a radiation therapy center, testing for BRCA gene, breast imaging, and decision aids. Conclusions: Of increasing importance in the decision making about treatment of women with early-stage breast cancer are the woman's perception of having a surgical choice and the influence of that choice on postoperative quality of life.