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Background: I-SPY 2 is a neoadjuvant platform trial open to patients with locally advanced, molecular high-risk breast cancer. In a concerted pursuit of mid-therapy response biomarkers, we evaluated inter-regimen biopsies, to identify patients who may be candidates for treatment de-escalation. In a pilot study, we observed that absence of carcinoma in an inter-regimen biopsy may predict pathologic complete response (pCR). In this expanded study of 100 participants, we sought to confirm that finding and assess pathologic features of the inter-regimen biopsy as predictors of tumor response to neoadjuvant therapy. Methods: Digital H&E images of 100 inter-regimen (12 week) image-guided breast biopsies +/- ancillary immunohistochemistry (p63 and/or cytokeratin) were reviewed by 9 I-SPY affiliated pathologists to record 1) tumor bed and 2) presence/absence of residual invasive carcinoma (IC) (with tumor cellularity scored as 0-100%). The data set included 393 cores (mean 3.9 (2-4) cores/biopsy). Fisher’s exact t-test was used for association of presence/absence of IC with pCR, and tumoral hormone receptor (HR) and HER2 status. Association between biopsy tumor cellularity and residual cancer burden (RCB) indices used Pearson’s correlation. Results: In the biopsy set, 84 (84%) had ≥80% inter-observer diagnostic agreement on both 1) presence of tumor bed and 2) presence/absence of IC (53 IC+ /31 IC-). IC+/IC- biopsies had equal numbers of evaluable tissue cores. The primary tumors were 63% HR+/37% HR-. The presence of IC in the biopsy correlated with tumoral HR/HER2 status (p=0.0014: 74%: HR+HER2-; 62%: TN; 60%: HR+HER2+; 10%: HR-HER2+). Of 31 patients with IC- biopsies, 25 (80%) went on to pCR, whereas only 7/53 (13%) of patients with IC+ biopsies had pCR, conferring an odds ratio for pCR of 26, Fisher p=7.5E-10. Overall, IC- biopsies had a positive predictive value (PPV) for pCR of 81%, with a PPV for HR- tumors of 94% vs. 67% for HR+ tumors (Table 1). In the 6 IC- biopsies from patients with non-pCR (“false-negatives”), most were HR+ (5/6, Table 1), and tumor bed size in the resection specimen was smaller than for IC+ biopsies with non-pCR: 276 mm2 (0.4-1000 mm2) vs. 1166 mm2 (1-11960 mm2). In contrast, the 46/53 IC+ biopsies in patients with non-pCR had a PPV for predicting non-pCR of 86%, (PPV for HR+ tumors: 94% vs. PPV for HR- tumors: 66%. Tumor cellularity in the biopsy (mean 37%, [2.5-93%]) did not correlate with RCB index (p=0.57) or RCB breast-only index (p = 0.17) at resection. Conclusion: In this 100 biopsy set from the I-SPY2 trial, the absence of residual carcinoma in inter-regimen biopsies was highly predictive of pCR, particularly for HR- tumors. The “false-negative” biopsies (IC-/non-pCR) were predominantly HR+ tumors with small residual tumor beds at resection. Conversely, the presence of carcinoma in inter-regimen biopsies was highly predictive of non-pCR, particularly for HR+ tumors. These data demonstrate the utility, and the limitations, of the inter-regimen biopsy as one tool to identify patients who may benefit from therapeutic de-escalation. Table 1: PPV for pCR/non-PCR by Inter-regimen Biopsy StatusInter-regimen biopsy with or without Invasive carcinoma (IC+/-)pCRnon-pCRPPV (Sensitivity) for pCR(IC- Biopsies)PPV (Sensitivity) for non-pCR(IC+ biopsies)IC- biopsiesAll25681% (78%)-HR+10567% (83%)-HR-15194% (75%)-IC+ biopsiesAll746-86% (88%)HR+236-94% (88%)HR-510-66% (91%) Citation Format: Jodi M Carter, Molly E Klein, Sara J Venters, Kimmie Rabe, I Tolgay Ocal, Kamaljeet Singh, Denise M Wolf, Sunati Sahoo, Shuko Harada, Laila Khazai, Malini Harigopal, Alexander D Borowsky, Gregor Krings, Ronald Balassanian, Yunn-Yi Chen, Kimberley Cole, Sonal Shad, Amy Delson, Lamorna Brown-Swigart, I-SPY 2 TRIAL Consortium, Laura Esserman, Laura van ‘t Veer, W Fraser Symmans. Pathologic features of the inter-regimen biopsy predict response to neoadjuvant therapy in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-09.

Background: The I-SPY 2 TRIAL, open to patients with locally advanced, molecular high-risk breast cancer, aims to bring each patient to pathologic complete response (pCR) with a minimum of toxicity. Here we test the hypothesis that imaging (MR volume predictors) combined with core biopsy may be used to accurately select candidates who show early response and provide an option of treatment de-escalation at mid-therapy (12 weeks). Methods: Of 100 I-SPY 2 patients with pathologist-assessed core biopsies at the inter-regimen time point (~12 weeks through treatment) and pCR data, 87 also had serial MR images and were considered in this study. Eleven I-SPY 2 TRIAL pathologists independently provided a digital assessment of the presence or absence of residual invasive cancer from H&E stained, and any requested ancillary IHC, images from imaging-guided core biopsies. Pathology predicts pCR if there is a consensus of no invasive residual disease. We generated predictions for all (55) unique pairs over the 11 pathologists, where pCR is predicted if both pathologists find no invasive cells. MRI pCR prediction models were previously developed on an independent dataset of ~990 I-SPY 2 patients, and applied to this cohort. Volume-based prediction models were previously optimized within each subtype and predicted probability thresholds were selected over a range of positive predictive value (PPV). In this study, MR predicts pCR (positive test) if the predicted probability is above a threshold that yields a given PPV value. For each pathologist pair, we combined pathology-based and MR-based predictors into a predictive-RCB (pre-RCB); and pre-RCB predicts a patient as pCR (RCB0) if both MR and pathology predicts pCR. Predictive performance is assessed by calculating the mean and range of PPV and sensitivity.Results: 39% (34/87) of the patients in this study achieved pCR. Over all pairs of pathologists, on average 80% of pathology-only predicted pCRs were true pCRs (mean PPV = 80% [range: 69-92%]), and 74% of patients who achieved pCR were predicted pCR by pathology alone (mean sensitivity = 74% [65-82%]). We assessed combinations with MR probability thresholds at PPV levels 50%-70%; and observed the best balance of PPV and sensitivity for the pre-RCB when MR thresholds were set at 50% PPV level. At this threshold setting, the pre-RCB achieved a PPV = 92% [83-100%], meaning on average 92% of predicted pCRs were true pCRs, and this improvement in positive predictive performance over pathology alone is achieved with a lower but still-reasonable 53% sensitivity [33-62%]. Conclusion: Pre-RCB, which predicts a patient as pCR if both MR and inter-regimen pathology predicts pCR, provides clinically actionable accuracy for treatment de-escalation for early responders (PPV>90%). Adding a final MR review at the time of early surgery may further improve performance. Resulting from data presented in this abstract, the pre-RCB algorithm, including the final MR review, has been operationalized and will be used prospectively to identify patients who are highly likely to have already achieved pCR by the inter-regimen timepoint. Citation Format: Sara J Venters, Wen Li, Denise M Wolf, Jodi M Carter, Molly E Klein, Kamaljeet Singh, Kimmie Rabe, I Tolgay Ocal, David Newitt, Christina Yau, Natsuko Onishi, Jessica Gibbs, Sunati Sahoo, Shuko Harada, Laila Khazai, Malini Harigopal, Alexander D Borowsky, Gregor Krings, Ronald Balassanian, Yunn-Yi Chen, Kimberley Cole, Sonal Shad, Barbara LeStage, Amy Delson, Sandra Finestone, Lamorna Brown-Swigart, I-SPY 2 Imaging Working Group, I-SPY 2 TRIAL Consortium, Laura Esserman, Laura van ‘t Veer, W Fraser Symmans, Nola M Hylton. Serial MRI and pathology combined to select candidates for therapy de-escalation in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-10.

We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of “intrinsic” molecular breast cancer (BC) subtypes. We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group. All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women

Each Gleason score category of prostatic adenocarcinoma (or Grade Group) may encompass a diverse group of architectural patterns such as well-formed glands, poorly formed glands, cribriform structures, single cells, and/or solid sheets. We have noted heterogeneity within the single-cell subtype of Gleason pattern 5 prostatic adenocarcinoma that has not been fully addressed. Therefore, we retrospectively reviewed a series of radical prostatectomies with high-grade prostatic adenocarcinoma (Grade Group 4 or 5), identifying tumors with a component of single-cell infiltration. Additional cases identified prospectively were also included. TNM status, association with other histologic patterns, and clinical follow-up status were determined. Immunohistochemistry for NKX3.1, E-cadherin, p120 catenin, and prostate-specific antigen (PSA) were performed in each case. Eighteen cases with a component of well-developed Gleason pattern 5 characterized by single infiltrative cells that comprised ≥5% of the tumor were identified (15/202 retrospective radical prostatectomies with the high-grade disease [7.5%]). The single-cell pattern ranged from 5% to 50% of the tumor volume, with 5 cases containing ≥40%, and variable secondary architecture included diffuse infiltrating single cells with targetoid growth pattern around benign glands, solid expansive nests of noncohesive cells, and corded/single file growth pattern. Further morphologic analysis demonstrated 2 distinct histologic subtypes: (1) (subtype 1; n=9) monomorphic "plasmacytoid" tumor cells with eccentrically placed nuclei and variable intracytoplasmic vacuoles with bland cytology and discohesion and (2) (subtype 2; n=9) more cohesive tumor cells with greater cytologic atypia characterized by prominent nucleoli, greater variability in nuclear size/shape, occasional mitotic figures, and more irregular infiltration. By immunohistochemistry, NKX3.1 nuclear expression and PSA cytoplasmic expression was retained in all cases. Concomitant membranous E-cadherin loss and strong cytoplasmic p120 catenin expression were present in 5 of the 18 (28%) cases, all in subtype 1 (5/9, 56%). Overall, 56% (10/18) of patients had advanced-stage disease (≥pT3b), and 70% (7/10) of these patients had associated lymphovascular invasion. All patients had concomitant cribriform patterns of carcinoma. The outcome was available for 14 patients: 4 died of unknown cause; 6 had biochemical recurrence with distant bone metastasis in 5 of the 6; and 4 patients with

Pleomorphic invasive lobular carcinoma (ILC) has long been thought to have worse outcomes than classic ILC and is therefore often treated with chemotherapy. However, recent data question the utility of the pleomorphic designation, as the poor outcomes seen may be related to other associated high-risk features. Importantly, mitotic count may better define a subset of ILC with high risk of recurrence. We sought to determine the impact of pleomorphic histology versus mitotic count on disease-free survival (DFS) in pure ILC. Additionally, we evaluated whether pleomorphic histology was associated with receipt of chemotherapy when adjusting for other factors. We analyzed a cohort of 475 patients with stage I–III pure ILC. We used Kaplan–Meier estimates, and Cox proportional hazards and logistic regression for multivariate analyses. Pleomorphic histology was confirmed by central pathology review. In a multivariate model, pleomorphic histology was not associated with reduced DFS. Only mitotic score, receptor subtype, and pathologic stage were independently and significantly associated with DFS. Patients with pleomorphic ILC were significantly more likely to receive chemotherapy than patients with classic ILC (adjusted odds ratio 2.96, p = 0.026). The pleomorphic designation in ILC does not have clinical utility and should not be used to determine therapy. Rather, mitotic count identified clear prognostic groups in this cohort of pure ILC.

Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

Background: The I-SPY 2 TRIAL enrolls women with locally advanced, molecular high-risk breast cancer. An integrated Residual Cancer Burden (iRCB), based on MRI volume change through treatment, is used to predict pathologic complete response (pCR) in the randomization/evaluation Bayesian engine. With the goal of effective de-escalation of treatment for patients exhibiting an early response, biomarkers are being assessed for their ability to predict pCR, alone or with MR data, during treatment. Here, we present the results of a pilot study to examine if invasive tumor cellularity in mid-treatment tissue core biopsies predicts pCR in a 40-patient cohort of I-SPY 2 patients. Other pathologic variables evaluated include Ki67, tumoral histologic features, and stromal tumor-infiltrating lymphocytes (sTILs). Methods: I-SPY 2 TRIAL pathologists (N=4) were provided images of H&E-stained and Ki67 IHC- labelled (DAKO/Agilent, clone MIB-1) core biopsy sections from 40 patients at the inter-regimen time point, ~12-weeks into treatment. Of the 40 patients, 35 had 4 cores, 3 had 3 cores, and 2 had 2 cores assessed. In total, images from 153 cores were evaluated. For each core, pathologists were asked to score the % area occupied by tumor bed (treatment changes and/or residual cancer), % of viable invasive tumor (0-100%) within tumor bed (with Nottingham grading, % Ki67 labelled, and % sTILs, using standardized guidelines). As decided by the pathologist group, only cores with identified tumor bed were included in the initial analysis. Concordance between pathologists was assessed for all scored criteria, using % agreement for dichotomous variables, and Pearson correlation (r)/standard deviation (sd) for continuous variables. The maximum and average cellularity recorded over all cores/patient, averaged over all pathologists, were analyzed for association with pCR using t- tests (significance threshold: p Results: Pathologist were in general agreement about the presence or absence of tumor bed, with greater than 82% agreement between any two (83-96%), and an overall agreement of 77%. For scoring the % of the tumor bed involved by invasive cancer, correlations between pairs of pathologists ranged from 0.79-0.95 (mean(r)=0.87, sd=5%), and agreement on a binary presence/absence of invasive cancer was 78%. Both the mean (t-test: p=7.59E-05) and maximum (t-test: p=0.0012) %invasive tumor at 12 weeks, scored as an average over all pathologists, were significantly higher in patients who did not achieve pCR than in responders. We also treated %invasive cellularity as a dichotomous variable (present/absent). 90% (9/10) of patients scored by all pathologists as 0% invasive tumor cells (absent) achieved a pCR, vs only 20% (6/30) of patients scored as >0% invasive cellularity by one or more pathologists (present) (OR=32, Fisher p=0.0005); yielding a positive predictive value for pCR of 0.9. Ki67 and sTILS at 12 weeks were fairly concordant across pathologists ((r,sd)=(0.92, 8.45%) and (0.82,5.5%), respectively), but did not associate with response (p>0.05 for pCR, RCB01, or RCB index). Tumor histologic grade at 12 weeks, assessed in 29/30 patients with non-zero cellularity, trended toward association (Fisher p=0.078): 44% (4/9) with Grade 3 went on to have a pCR, vs. 15% (2/13) with Grade 2 and 0 with Grade 1. These data demonstrate the utility of invasive tumor cellularity as a predictor of pCR in a clinical setting. Conclusion: In this pilot study we demonstrate that the absence of invasive cancer cells within identified tumor bed in mid-treatment core biopsy samples is highly predictive of pCR. Citation Format: Sara J Venters, Denise M Wolf, Lamorna Brown-Swigart, Christina Yau, Amy L Delson, Bev Parker, Ron Balassanian, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Jane Wei, I-SPY 2 TRIAL Consortium, Laura J Esserman, Laura J van't Veer, W Fraser Symmans. Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR in the I-SPY 2 Trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-02.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

Soft extracellular matrix protects breast cancer cells from apoptosis and reduces the efficacy of chemo- and radiation therapies through enhanced NF-κB signaling and diminished proapoptotic JNK activity. Therapeutic targeting of the NF-κB–JNK axis may thwart treatment resistance in breast cancer., Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.

Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in

The natural history and optimal treatment of pleomorphic (PLCIS) and florid (FLCIS) lobular carcinoma in situ variants remains uncertain. We reviewed the clinicopathologic features and management of LCIS variants at our institution over a 20-year period. Of 85 cases (61 PLCIS, 24 FLCIS), 77% were associated with invasive carcinoma (84% lobular, 13% ductal/lobular, 3% ductal) and only 17% (9 PLCIS, 5 FLCIS) were pure. Most (81%) invasive carcinomas were grade 2, with all grade 3/pleomorphic invasive lobular carcinomas (ILC) associated with PLCIS, and all grade 1 tumors associated with FLCIS. PLCIS-associated invasive carcinomas were more often ER- (21%) or HER2+ (14%) than FLCIS-associated tumors (100% ER+, 6% HER2+). LCIS variants were unifocal and co-localized with invasive carcinoma in 20/20 selected spatially mapped cases, whereas classic LCIS (CLCIS) was multifocal with wider distribution (10/17). Of 21 pure LCIS variants on core biopsy, all represented the radiographic (95%) or palpable (5%) target. The excisional upgrade rate was similar for PLCIS (38%) and FLCIS (33%). Pure LCIS variants on core biopsy were often (20%) HER2+ and had a higher Ki-67-index than synchronous CLCIS (P=0.002). Lower ER expression in LCIS variants versus CLCIS was due to ER- apocrine PLCIS. ER and HER2 were consistently concordant between LCIS variants and upgraded ILC but discordant between synchronous CLCIS and LCIS variants in 5/14 (36%). Pure LCIS variants were excised to negative margins and frequently (58%) treated with endocrine but not radiation therapy without recurrences. In summary, PLCIS and FLCIS demonstrate features of direct precursor lesions warranting surgical excision.

PURPOSE Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)–positive DCIS. PATIENTS AND METHODS A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline. RESULTS Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm3. Median reductions from baseline MRI volume (1.4 cm3) were 0.6 cm3 (61.0%) at 3 months ( P < .001) and 0.8 cm3 (71.7%) at 6 months ( P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%). CONCLUSIONS In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.

This review reflects a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is part of a series of expert recommendations on topics encountered in daily practice. The authors, 4 pathologists with expertise in breast pathology and a breast surgeon with a clinical and research interest in lobular carcinoma in situ (LCIS), met by conference call in September 2019 to develop recommendations for evaluating and reporting LCIS. Herein, we summarize the diagnostic criteria of classic LCIS and LCIS subtypes according to the most recent WHO criteria, discuss how best to distinguish LCIS from ductal carcinoma in situ in problematic cases (including the uses and limitations of E-cadherin immunohistochemistry), and review outcome and management issues for patients with LCIS.

We present a case of low-grade endometrial stromal sarcoma (ESS) that metastasized to the breast 25 years after the original diagnosis, with clinical, radiographic and pathologic follow-up data. The diagnosis of metastatic ESS was supported by the morphologic features of the breast tumor and its immunohistochemical profile, which included positive staining for CD10, WT1, estrogen receptor (ER) and progesterone receptor (PR). The diagnosis of metastatic ESS was confirmed by fluorescence in situ hybridization (FISH) testing, which revealed a characteristic JAZF1 gene rearrangement. The unusual clinical presentation raised a differential diagnosis that included mammary myofibroblastoma of the breast. We compared the morphologic characteristics and immunohistochemical profile of 15 low-grade ESS cases (8 primary and 7 metastatic) to eight cases of mammary myofibroblastoma. Immunostains that differentiated between these entities included CD34, retinoblastoma protein (Rb) and FOXL2. The pathologist can play a key role in the recognition of uncommon metastases to breast, and although rare, metastatic low-grade ESS should be included in the differential diagnosis of spindle cell tumors of the breast.

Importance Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence–free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures Pathologic complete response and 3-year EFS and DRFS. Results Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3,392 cases (1,105 premenopausal) and 8,882 (3,192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER−), progesterone receptor (PR+/PR−), and HER2 (HER2+/HER2−). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated=11–27%, p≤0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+, PR+, and HER2− breast cancer; percent MD partially mediated these associations (percent mediated≥31%, p≤0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated=16%, p≤0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression. Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age. Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

Fibroepithelial lesions of the breast comprise a morphologically and biologically heterogeneous group of biphasic tumors with epithelial and stromal components that demonstrate widely variable clinical behavior. Fibroadenomas are common benign tumors with a number of histologic variants, most of which pose no diagnostic challenge. Cellular and juvenile fibroadenomas can have overlapping features with phyllodes tumors and should be recognized. Phyllodes tumors constitute a spectrum of lesions with varying clinical behavior and are graded as benign, borderline or malignant based on a set of histologic features according to recommendations by the World Health Organization (WHO). Recent developments have significantly expanded our understanding of the pathogenesis of fibroepithelial lesions, highlighting fibroadenomas as true neoplasms and underscoring a commonality with phyllodes tumors in the form of recurrent MED12 exon 2 mutations. In addition, sequencing studies have elucidated pathways associated with phyllodes tumor progression. Accurate diagnosis and grading of phyllodes tumors are important for patient management and prognosis, as grade broadly correlates with increasing local recurrence risk, and essentially only malignant tumors metastasize. However, classification of fibroepithelial lesions in many cases remains challenging on both core biopsy and excision specimens. A commonly encountered problem at the benign end of the spectrum is the distinction of benign phyllodes tumor from cellular fibroadenoma, which is largely due to the subjective nature of histologic features used in diagnosis and histologic overlap between lesions. Grading is further complicated by the requirement to integrate multiple subjective and ill-defined parameters. On the opposite end of the histologic spectrum, malignant phyllodes tumors must be distinguished from more common metaplastic carcinomas and from primary or metastatic sarcomas, which can be especially difficult in core biopsies. Immunohistochemistry can be useful in the differential diagnosis but should be interpreted with attention to caveats. This review provides an overview and update on the spectrum of fibroepithelial lesions, with special emphasis on common problems and practical issues in diagnosis.

Purpose: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging���residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)���have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. Methods: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. Results: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. Conclusions: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case–control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses’ Health Study, Nurses’ Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11–25% OR 2.50, 95% CI 1.94–3.22 vs. OR 2.03, 95% CI 1.70–2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41–0.70 vs. OR 0.71, 95% CI 0.59–0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11–25% OR 3.24, 95% CI 1.75–6.00 vs. OR 1.93, 95% CI 1.25–2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21–0.85 vs. OR 0.56, 95% CI 0.35–0.89, p-heterogeneity = 0.01), even though the interaction was not significant. Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

This chapter encompasses four uncommon types of triple negative breast cancer, which include adenoid cystic carcinoma (ACC), apocrine carcinoma, metaplastic carcinoma, and medullary carcinoma. Also included in the discussion for differential diagnosis are three additional rare subtypes: acinic cell carcinoma, oncocytic carcinoma, and mucoepidermoid carcinoma. Most of these tumors are “basal-like cancers,” as defined by gene expression analysis. Although sharing the triple negative and basal-like phenotype, these tumors demonstrate remarkably different clinical behaviors, which range along a spectrum from indolent to aggressive, emphasizing the notion that triple negative or basal-like breast cancer comprises a heterogeneous group of diseases. While ACC has well-defined histopathologic features and unique molecular alterations, metaplastic carcinomas represent a morphologically and genetically diverse group of tumors. Furthermore, uniform agreement on diagnostic criteria is lacking for medullary carcinoma and apocrine carcinoma. Accordingly, diagnosis of these uncommon lesions can be challenging, especially in core needle biopsy (CNB) specimens.

To evaluate the feasibility of dual-energy CT (DECT) for monitoring dynamic changes in the renal corticomedullary sodium gradient in swine.This study was approved by our Institutional Animal Care and Use Committee. Four water-restricted pigs were CT-scanned at 80 and 140 kVp at baseline and at 5 min intervals for 30 min during saline or furosemide diuresis. The renal cortical and medullary CT numbers were recorded. A DECT basis material decomposition method was used to quantify renal cortical and medullary sodium concentrations and medulla-to-cortex sodium ratios at each time point based on the measured CT numbers. The sodium concentrations and medulla-to-cortex sodium ratios were compared between baseline and at 30 min diuresis using paired Student t-tests. The medulla-to-cortex sodium ratios were considered to reflect the corticomedullary sodium gradient.At baseline prior to saline diuresis, the mean medullary and cortical sodium concentrations were 103.8±8.7 and 65.3±1.7 mmol/l, respectively, corresponding to a medulla-to-cortex sodium ratio of 1.59. At 30 min of saline diuresis, the medullary and cortical sodium concentrations decreased to 72.3±1.0 and 56.0±1.4 mmol/l, respectively, corresponding to a significantly reduced medulla-to-cortex sodium ratio of 1.29 (P0.05). At baseline prior to furosemide diuresis, the mean medullary and cortical sodium concentrations were 110.5±3.6 and 66.7±4.1 mmol/l, respectively, corresponding to a medulla-to-cortex sodium ratio of 1.66. At 30 min of furosemide diuresis, the medullary and cortical sodium concentrations decreased to 68.5±0.3 and 58.9±4.0 mmol/l, respectively, corresponding to a significantly reduced medulla-to-cortex sodium ratio of 1.16 (P0.05). One of the 4 pigs developed acute tubular necrosis likely related to prolonged hypoxia during intubation prior to the furosemide diuresis experiment. The medulla-to-cortex sodium ratio for this pig, which was excluded from the mean medulla-to-cortex ratio above, was 1.07 at baseline and 1.15 at 30 min following the administration of furosemide.DECT monitoring of dynamic changes in the renal corticomedullary sodium gradient after physiologic challenges is feasible in swine.

520Background: I-SPY2 is a multicenter phase 2 trial in high risk stage II/III breast cancer (BC) using adaptive randomization within biomarker subtypes to evaluate novel treatment agents added to ...

Lobular carcinoma in situ (LCIS) of the breast may exhibit a spectrum of morphologic growth patterns and may also colonize underlying benign breast lesions. This diversity in appearance can create diagnostic challenges, especially in core needle biopsy specimens. Some LCIS variants may mimic ductal carcinoma in situ or invasive carcinoma. Furthermore, some LCIS variants are frequently associated with adjacent invasive lobular carcinoma. Therefore, familiarity with this morphologic spectrum is essential when evaluating LCIS in core needle biopsies. This review focuses on histologic and immunohistochemical features that help to distinguish unusual patterns of LCIS from the lesions they mimic.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers.

Purpose Magnetic resonance imaging (MRI) is an important tool for characterizing invasive breast cancer but has proven to be more challenging in the setting of ductal carcinoma in situ (DCIS). We investigated whether MRI features of DCIS reflect differences in biology and pathology. Patients and Methods Forty five of 100 patients with biopsy-proven DCIS who underwent MRI and had sufficient tissue to be characterized by pathologic (nuclear grade, presence of comedo necrosis, size, and density of disease) and immunohistochemical (IHC) findings (proliferation, Ki67; angiogenesis, CD34; and inflammation, CD68). Pathology and MRI features (enhancement patterns, distribution, size, and density) were analyzed using pairwise and canonical correlations. Results Histopathologic and IHC variables correlated with MRI features (r = 0.73). The correlation was largely due to size, density (by either MRI or pathology), and inflammation (P < .05). Most small focal masses were estrogen receptor-positive. MRI enhancement patterns that were clumped were more likely than heterogeneous patterns to be high-grade lesions. Homogenous lesions were large, high grade, and rich in macrophages. Presence of comedo necrosis and size could be distinguished on MRI (P < .05). MRI was most likely to over-represent the size of less dense, diffuse DCIS lesions. Conclusion The heterogeneous presentation of DCIS on MRI reflects underlying histopathologic differences.

Imaging patterns of benign proliferative processes often complicate the assessment of ductal carcinoma in situ (DCIS) by magnetic resonance imaging (MRI). We investigated the pathologic and biologic characteristics of false positive enhancement by breast MRI.DCIS (n = 45), benign (n = 5), and false-positive (MRI enhancement and nonmalignant pathology) (n = 10) cases were characterized by immunohistochemistry and MRI features.For DCIS cases, images that overestimated pathologic size had heterogeneous enhancement on MR, were estrogen receptor positive, and were low grade by pathology. False-positives had higher rates of proliferation, angiogenesis, and inflammation compared with benign tissue but lower values than DCIS. Benign proliferative processes accounted for all false-positive and size overestimated cases.Lesions that enhance on MRI have higher proliferation, angiogenesis, and inflammation compared with nonproliferative breast tissue. Benign proliferative processes often enhance on MRI and are difficult to differentiate from low-grade, ER+ DCIS lesions. False-positive MRI enhancement may reflect a spectrum of change within high-risk tissue.

Reported are the clinical and pathologic features of glycogenic hepatopathy, a pathologic overloading of hepatocytes with glycogen that is associated with poorly controlled diabetes mellitus. Fourteen cases were studied by stains, including hematoxylin and eosin, trichrome, periodic acid-Schiff, and periodic acid-Schiff with diastase. Ultrastructural analysis was performed in 2 cases. Medical records were reviewed for clinical presentations, laboratory findings, and clinical outcomes. The individuals ranged from 8 to 25 years of age. All had type I diabetes mellitus with poor glycemic control. The clinical presentations included hepatomegaly, abdominal pain, and elevated transaminases (range, 50-1600 IU/L). The transaminases were dramatically elevated in 3 cases to greater than 10 times the upper limit of normal. All biopsies showed diffusely pale staining hepatocytes on hematoxylin and eosin stains, with excessive glycogen accumulation demonstrated by periodic acid-Schiff stains. Ultrastructural examination revealed marked glycogen accumulation in the cytoplasm and nuclei. Most cases showed no evidence for fatty liver disease: steatosis was absent in 12 of 14 cases, simple steatosis was seen in 1 of 14 cases, and mild steatohepatitis was present in 1 of 14 cases. Mallory hyaline was absent in all cases, acidophil bodies were only rarely seen, and inflammation was absent or minimally present. Fibrosis was typically absent, with only 2 cases demonstrating focal mild fibrosis. Three patients had adequate follow-up and demonstrated improvement of liver enzyme levels with control of blood glucose. We conclude that glycogenic hepatopathy can cause hepatomegaly and significant transaminase elevations in individuals with type I diabetes mellitus. The pathology is distinct from steatohepatitis.

Fibroepithelial lesions with cellular stroma (FELCS) in breast core needle biopsy (CNB) specimens may result in either fibroadenoma or phyllodes tumor at excision. We evaluated histologic features, proliferation indices (by Ki-67 and topoisomerase II α immunostaining) and p53 expression in 29 cases of FELCS in CNB specimens and correlated these with excision findings in a blinded manner. On excision, 16 patients had fibroadenomas and 12 had phyllodes tumors. All CNB specimens with mildly increased stromal cellularity were fibroadenomas on excision (n = 4), and all with markedly cellular stroma were phyllodes tumors (n = 4). Among CNB specimens with moderate cellularity (12 fibroadenomas and 8 phyllodes tumors), only stromal mitoses were discriminatory histologically. Stromal proliferation indices were significantly higher in CNB that were phyllodes tumors vs fibroadenomas. Assessment of stromal cellularity, mitoses, and proliferation indices might help determine the probability of phyllodes tumor occurring and guide management of these cases.

Objective The gross extent of ulcerative colitis (UC) is a recognized risk factor for the development of colitis-related dysplasia and colorectal cancer (CRC). The risk of neoplasia associated with the microscopic extent of colitis is unknown. The aim of this study was to describe the gross and microscopic extent of colitis in patients with UC-related dysplasia/CRC. Methods All patients who underwent colectomy at our institution between 1992-2001 with colitis-related dysplasia/CRC were identified. Histological sections from each colectomy specimen were reviewed for the microscopic extent of colitis and the location of all lesions with dysplasia/CRC. Results Thirty-six patients with colitis-related dysplasia/CRC were identified of whom 30 had slides available for review. Gross pancolitis was identified in 19 patients, though microscopic pancolitis was evident in all 30 patients. Among the 11 patients with only distal gross colitis, 4/15 neoplastic lesions were proximal to the area of gross involvement. Conclusions UC-related neoplasia can occur in areas of the colon not grossly involved with colitis, though it did not occur in any patients without microscopic pancolitis. To devise rational cancer surveillance guidelines, further studies are needed to determine the risk of colitis-related neoplasia in patients with microscopic pancolitis but limited gross disease.

Purpose: The evidence on associations of mammographic breast density with breast cancer risk by combination of tumor aggressiveness features is limited. We examined associations of breast density phenotypes with risk of aggressive breast tumor features by menopausal status, and current postmenopausal hormone therapy. Methods: This study included 2,635 invasive breast cancer cases and 4,059 controls from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses Health Study, Nurses Health Study II, and San Francisco Mammography Registry. Percent breast density, absolute dense and non-dense areas were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density measures with risk of breast tumor aggressiveness (defined as presence of 2 or more of the following tumor characteristics: size ≥2cm, grade 2 or 3, or positive nodes), stratified by menopausal status and current hormone therapy (i.e., premenopausal, postmenopausal/estrogen therapy, postmenopausal/combined therapy, and postmenopausal/no hormones). We also evaluated differences in the strength of associations across categories. In a secondary analysis, we examined these associations while excluding cases with mammogram date within 2 years of diagnosis. Results: Positive associations of percent density and dense area and inverse associations of non-dense area with breast cancer risk were stronger in aggressive vs. non-aggressive tumors (OR=2.62, 95%CI 2.08-3.31 vs. OR=1.94, 95%CI 1.62-2.33 for percent density≥51% vs. 11-25%, p-heterogeneity=0.001; OR=1.89, 95%CI 1.54-2.31 vs. OR=1.65, 95%CI 1.41-1.93 for dense area 4th vs. 2nd quartile, p-heterogeneity=0.015; OR=0.56, 95%CI 0.44-0.72 vs. OR=0.71, 95%CI 0.59-0.86 for non-dense area 4th vs 2nd quartile, p-heterogeneity=0.007, respectively). These patterns were similar across all menopausal and hormone therapy groups (P-interactions=0.62, 0.76, and 0.23, for percent density, dense area and non-dense area, respectively). Excluding cases diagnosed within 2 years of mammography resulted in similar findings. Conclusion: Mammographic density phenotypes were more strongly associated with aggressive cancer (having two or more of the following: size ≥2cm, grade 2 or 3, or positive nodes) vs. non-aggressive types of breast cancer across categories of menopause and hormone therapy types. Citation Format: Lusine Yaghjyan, Rulla Tamimi, Kimberly Bertrand, Christopher G. Scott, Matthew R. Jensen, Shane Pankratz, Kathleen Brandt, Daniel Visscher, Aaron Norman, Fergus Cough, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew H. Beck, Steven R. Cummings, Karla Kerlikowske, Celine Vachon. Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B27.

High mammographic density (MD) is associated with a greater risk of breast cancer and is characterized by high extracellular matrix (ECM) collagen. Elevated collagen increases ECM stiffness and can promote the malignant transformation of oncogenically-primed mammary epithelial cells in culture and in vivo. Whether or not high MD reflects a breast stroma that is stiff and if ECM stiffness accounts for the elevated breast cancer risk in high MD tissue and how has yet to be resolved. To address this question we are conducting a comprehensive biophysical and molecular analysis of BIRADS status in prophylactic mastectomies in women with low (BIRADS 1) versus high MD (BIRADS 4). Data revealed that the intra-lobular ECM associated with the terminal end-buds contains anisotropic compliant and relaxed collagen fibrils. By contrast, the inter-lobular ECM contains stiff, oriented collagen fibrils. Preliminary data suggest that the ECM associated with the terminal end-buds in the upper outer quadrant may be stiffer in women with high MD as compared to low MD. These same tissues also expressed lower levels of the microRNA miR-203, which has been implicated in epithelial-to-mesenchymal transition (EMT) inhibition. Consistently, in vitro studies revealed that miR-203 was repressed in MECs cultured on a stiff ECM. We also found that a stiffened mammary ECM decreases miR-203 expression and promotes an EMT. Additionally, inhibiting ECM stiffening restored miR-203 levels and reduced an EMT. Moreover and importantly, we showed that triple negative breast tumors that often express EMT markers have reduced miR-203 levels. Studies are underway to elaborate these preliminary findings and to assess their clinical relevance. (This work is supported by the: NIH NSRA T32 CA 108462-11 to Ivory Dean, Susan G Komen PDF12230246 to Irene Acerbi, W81XWH-13-1-0216, USMRAA DOD-BCRP BC122990, NIH R01 CA138818-01A1 and NIH R01 CA192914-01 to Valerie Weaver.) Citation Format: Ivory Dean, Irene Acerbi, Janna Mouw, Quanming Shi, Yunn-Yi Chen, Jan Liphardt, Shelley Hwang, Valerie Weaver. Interplay between ECM stiffness, miR-203 and mammographic density. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C24.

GATA3 is implicated in mammary epithelial development and breast cancer progression and is an evolving immunohistochemical marker in breast cancer. Often associated with estrogen receptor (ER) signaling, GATA3 expression has been reported in ER-negative breast cancers, but systematic evaluation of GATA3 expression in a large set of triple-negative breast cancers (TNBC) is lacking. Given low sensitivities of mammaglobin (MGB) and GCDFP15 in metastatic TNBC, additional markers for site of origin identification would be useful in this context. We examined immunohistochemical expression of GATA3 in a large group of treatment-naive TNBC (n = 111) and ER-positive (n = 39) and HER2-positive (n = 31) breast cancers with commonly used antibody clones, HG3-31 (GATA3-H) and L50-823 (GATA3-L), and compared GATA3, MGB, and GCDFP15. Respectively, GATA3-L and GATA3-H were positive in 66% and 44% of TNBC (P = .002), 93% and 79% of ER-/HER2+ tumors (P = .596), and 100% of ER+/HER2- and ER+/HER2+ tumors (P = 1.00 each). GATA3-L was technically and diagnostically more sensitive than GATA3-H in TNBC and was technically more sensitive in other subtypes. MGB (26%) and GCDFP15 (16%) were less sensitive for TNBC than other subtypes (P.001). Notably, 56% and 36% of MGB-/GCDFP15- TNBC were positive with GATA3-L and GATA3-H, respectively (P = .027). Seventy percent of TNBC were positive for GATA3-L, MGB, or GCDFP15 compared with 49% using GATA3-H in the panel. GATA3 is a diagnostically useful marker for TNBC and is more sensitive than MGB and GCDFP15 combined. GATA3-L is more sensitive for TNBC than GATA3-H, and an immunopanel of GATA3-L, MGB, and GCDFP15 provides optimal diagnostic sensitivity for TNBC.

The widespread use of mammography has resulted in the detection of an increasing number of small invasive breast cancers, i.e. those that are 1cm and smaller. Patients with these small cancers generally have a low incidence of axillary lymph node metastases, and this has led some to question the routine use of axillary dissection in these patients. In addition, the prognosis of these patients is generally favorable, and the routine use of adjuvant systemic therapy is difficult to justify. Nonetheless, some patients with these small invasive cancers will have axillary nodal involvement and/or develop metastatic disease. The identification of this prognostically unfavorable subset of patients within this otherwise favorable group is an important goal of clinical research. In this article, we review the available literature on prognostic factors for patients with breast cancers 1cm and smaller to help determine which of these features might be of value in the identification of patients at risk for axillary lymph node involvement and/or metastatic disease.

Introduction Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models. Methods Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (51%) versus average density (11-25%). Women ages 2.1 cm) versus small tumors and positive versus negative lymph node status (P’s

Percent mammographic density (PMD) is a risk factor for estrogen receptor (ER)-positive and ER-negative invasive breast cancer (BC). Gene expression profiling has identified molecular signatures that classify invasive BC into distinct subtypes that vary in their clinical behavior, response to treatment and likely, etiology. Immunohistochemical (IHC) staining of tumor sections using antibody panels can be used to classify these ‘intrinsic’ molecular subtypes. We evaluated whether density measures [PMD, absolute dense area (DA) and non-dense area (NDA)], are associated equally with all ‘intrinsic’ molecular subtypes. Pooled analysis of six cohort or case-control studies included 3492 women with invasive BC and 10,148 without, who underwent screening mammography a median 4 years prior to diagnosis (for cases). PMD, DA, and NDA were assessed from digitized film-screen mammograms using a computer-assisted thresholding technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+ (PMD) or into quartiles (DA and NDA). Receptor status was abstracted from pathology records and supplemented by IHC staining. We classified tumors as Luminal A (ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (TN) (ER-/PR-/HER2-). For TN, we also differentiated basal-like tumors (positive for EGFR and/or CK 5/6) from unclassified (negative on both markers). We used polytomous logistic regression to calculate the odds ratio (OR) of each ‘intrinsic’ subtype of BC by categories of PMD, DA or NDA, adjusting for age, body mass index and study. We tested for statistical heterogeneity of associations by subtype. Of 3492 invasive BC cases, 2217 (63%) were classified as Luminal A, 747 (21%) as Luminal B, 159 (5%) as HER2 expressing, and 369 (11%) as TN. Of TN, 203 were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) unclassified. PMD was associated with BC risk across all subtypes. For Luminal A, compared to women with 11-25% PMD (reference), women with 0-10% had a reduced risk of BC (OR = 0.63 [95% confidence interval: 0.55, 0.74]) while women with 26-50% had an OR = 1.5 [1.3, 1.7] and women with 51%+ had the highest risk, OR = 2.3 [2.0, 2.7]. Similar BC associations were seen across PMD categories when comparing the five subtypes (P-heterogeneity = 0.63). Similar trends were seen for DA and BC across the five subtypes (P-het = 0.25). NDA was inversely associated with BC across subtypes, and there was suggestion of a stronger inverse trend among HER2-expressing BC compared to other subtypes (P-het = 0.09). Our results suggest mammographic density measures are associated with all ‘intrinsic’ molecular subtypes. However, NDA may be more strongly inversely associated with HER2-expressing than other subtypes. Understanding the importance of density measures for BC subtypes has significance for subtype-specific risk models. Citation Format: Aaron D. Norman, Rulla M. Tamimi, Christopher G. Scott, Kimberly A. Bertrand, Matthew R. Jensen, Daniel W. Visscher, Fergus J. Couch, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew Beck, Vernon S. Pankratz, Karla Kerlikowske, Celine M. Vachon. Association of mammographic density measures and breast cancer ‘intrinsic’ molecular subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2593.

Gene expression profiling has identified molecular subtypes that classify invasive breast cancers into distinct categories that vary in their clinical behavior and response to treatment. These subtypes highlight the many possible biologically and clinically distinct types of breast cancer. Immunohistochemical (IHC) staining of tumor sections using antibody panels has been used as a surrogate for the molecular subtypes identified through gene expression profiling, resulting in a set of intrinsic molecular subtypes. Given the heterogeneity within breast cancer, one might expect that different risk factors influence specific subtypes of breast cancer through various etiologic pathways. We evaluated whether percent mammographic density (MD), the proportion of fibroglandular or white tissue on a mammogram and one of the strongest and most consistent risk factors for breast cancer, is associated equally with all intrinsic molecular subtypes. Data were pooled from six cohort or case-control studies including 3389 women with invasive breast cancer and 9860 without, who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms (for cases, at a median 4 years prior to diagnosis) using a computer-assisted threshold technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+. Receptor status was abstracted from clinical pathology records and supplemented by IHC staining of tumor sections or microarrays. With estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) information, we classified tumors into the intrinsic molecular subtypes: Luminal A ( ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (ER-/PR-/HER2-). For cancers found to be triple negative (TN), we also stained for epidermal growth factor receptor (EGFR) and cytokeratins (CK) 5/6 to differentiate basal-like tumors (positive for EGFR and/or CK 5/6) from the unclassifieds (negative on both EGFR and CK 5/6). We used polytomous logistic regression to calculate the odds (OR) of each of the intrinsic subtypes of breast cancer by categories of percent MD, adjusting for age, BMI and study. Contrasts were constructed and tested within the polytomous model framework to investigate differences in the strength of association of percent MD across subtypes. On average, cases were slightly older (56.4 years [SD=11.3]) than controls (55.8 [10.9]). Of the 3389 invasive breast cancer cases, 2146 (63%) were classified as Luminal A, 709 (21%) as Luminal B, 169 (5%) as HER-2 expressing, and 365(11%) as triple negative (TN). Of the TN tumors, 203 had tumor tissue available and were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) as unclassified. Percent (%) MD was associated with breast cancer risk across all intrinsic subtypes. For Luminal A, compared to women with 11-25% MD (reference), women with 0-10% MD had a reduced risk of breast cancer (OR=0.64 [95% confidence interval (CI): 0.55, 0.74]) while women with 26-50% MD had an OR=1.5 (1.3,1.7) and women with 51%+ MD had the highest risk, OR=2.4 (2.0, 2.8). Similar associations were seen for Luminal B, HER2 expressing, and TN across percent MD categories. The small differences among the percent MD-breast cancer associations observed for the different subtypes were not statistically significant, either when comparing the four (Luminal A, Luminal B, HER-2 expressing and TN; p=0.61) or five categories of subtypes (Luminal A, Luminal B, HER-2 expressing, basal-like, unclassified; p=0.66). Our results suggest percent MD is a risk factor for all intrinsic molecular subtypes. Additional study is needed to examine whether these results hold for younger and older aged women. Understanding the importance of mammographic density measures for subtypes of breast cancer has significance for development of subtype-specific risk models. Citation Format: Celine Vachon, Rulla Tamimi, Yunn-Yi Chen, Christopher Scott, Kimberly Bertrand, Matthew Jensen, Daniel Visscher, Aaron Norman, Fergus Couch, John Shepherd, Bo Fan, Fang-Fang Wu, Lin Ma, Andrew Beck, Steve Cummings, V. Shane Pankratz, Karla Kerlikowske. Mammographic density: A risk factor for all breast cancers or only specific subtypes? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA22.

Purpose Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers. Patients and Methods Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets. Results In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets. Conclusion In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.

Neoadjuvant chemotherapy is standard of care for patients with locally advanced breast cancer. Patients who achieve a pathologic complete response have a more favorable outcome than those who do not; however, a standard system for classifying residual disease has not been adopted. Various definitions of complete response exist, some of which allow for minimal residual invasive or in situ carcinoma. The pattern of residual carcinoma restricted to lymphatic spaces without stromal invasion, herein called pure intralymphatic carcinoma, has not been well addressed. Neither has the pattern of minimal residual stromal invasive cancer accompanied by an extensive intralymphatic component, herein called predominantly pure intralymphatic carcinoma. We report the incidence, clinicopathologic features, and clinical significance of pure and predominantly pure intralymphatic carcinoma in a cohort of 146 neoadjuvant-treated breast cancer patients. We also evaluate the use of the immunohistochemical lymphatic marker D2-40 in these tissues exposed to neoadjuvant chemotherapy. Six patients (4%) had residual pure intralymphatic carcinoma. No gross abnormalities were present in the mastectomy specimens except for 1 case that had a discrete mass, corresponding to residual in situ carcinoma. Residual intralymphatic tumor size ranged from 0.2 to 6 cm. All but one had residual positive lymph nodes. Residual predominantly pure intralymphatic carcinoma was found in 5/146 (4%) patients. A discrete gross mass was observed in 3/5 specimens. Whereas residual stromal invasive carcinoma ranged in size from 0.1 to 1.8 cm, the intralymphatic component ranged from 6 to 9.3 cm. All had residual positive lymph nodes. D2-40 adequately marked lymphatic endothelium in all cases tested. Death occurred in 6/11 (55%) versus 17/135 (13%) patients with or without pure/predominantly pure intralymphatic carcinoma, respectively. After controlling for tumor stage, the presence of either of these residual intralymphatic patterns was associated with a 3-fold increase in death (Cox proportional hazards ratio=3.59, 95% confidence interval, 1.29, 9.99, P=0.014). Elevated risk for disease progression was also observed but this was not statistically significant. We conclude that pure/predominantly pure intralymphatic carcinoma is a clinically significant pattern of residual disease. This may be an underrecognized pattern because of the discordance between gross and microscopic findings and because of challenges in diagnosing intralymphatic carcinoma. D2-40 immunostaining is useful in this setting. Current staging criteria should be clarified to define whether extensive intralymphatic tumor should be incorporated in tumor stage assignment.

Objective To determine the value of histology in identifying Lynch syndrome among those patients with early onset of colorectal cancer (CRC). Methods Demographic, clinical and cancer history data from patients diagnosed with CRC before 60 years of age, and treated at our institution between 1997 and 2005, were collected from medical records and direct interview. Their tumors were assessed to identify histological features suggestive of high frequency microsatellite instability (MSI-H): tumor infiltrating lymphocytes, Crohn’s like inflammatory reaction, mucinous, signet ring cells, medullary growth pattern and then, tested for microsatellite instability (MSI) and MLH1/ MSH2 protein expression. Results Sixty-five patients were included in the study. The mean age at diagnosis was 48 ± 9.9 years. Overall, 28 (43%) patients, including 13 of 35 diagnosed between ages 50 and 60, had tumor demonstrating one or more histological features suggestive of MSI-H. These patients were younger (45 vs. 50 years, P = 0.02) and more commonly had family history of Lynch syndrome-related cancers (36 vs. 19%), though the latter feature did not reach statistical significance (P = 0.07). Eleven of 25 tumors with MSI-H histology, but only 1 of 29 tumors without special histological features were found to be MSI-H (P < 0.0001). Histology had a positive predictive value of 44% and a negative predictive value of 97% for identifying MSI-H tumors. Conclusions Limiting MSI analysis only to those tumors with suggestive histology would have reduced the need for testing by nearly 60% of all tumors from patients that met the revised Bethesda guidelines.

Aberrant microenvironments and loss of balance in cell-extracellular matrix signaling are associated with breast cancer invasion, metastasis, and resistance to therapy. We have recently shown that increased β1 integrin signaling is involved in malignant progression and that inhibitory antibody to β1 integrin leads to selective apoptosis and decreased proliferation in three-dimensional cultures and in xenograft models of breast cancer in vivo. To investigate the clinical importance of these findings, in the present study we examined the expression of β1 integrin and extracellular β1 integrin ligands fibronectin and laminin-1 in a cohort of 249 breast cancer patients who had a median follow-up of 8.4 years. Among the 149 scorable cases, the highest β1 integrin intensity score (3+ versus 0–2+) was associated with significantly decreased 10-year overall survival of 48% versus 71% (P < 0.03) and decreased disease-free survival of 50% versus 80% (P < 0.05). Importantly, high fibronectin expression was associated with decreased overall and disease-free survival on univariate analysis (P < 0.04) and β1 integrin intensity score was significantly correlated with fibronectin expression (Kendall's tau-b = 0.19; P = 0.03). In a multivariate Cox proportional hazards model, β1 integrin intensity score remained a significant independent predictor of overall survival [hazard ratio (HR), 1.69; 95% confidence interval (95% CI), 1.19–2.38; P < 0.003] and disease-free survival (HR, 1.87; 95% CI, 1.21–2.88; P < 0.005). These findings show that β1 integrin expression has potential prognostic value in invasive breast cancer and that coexpression of fibronectin may help identify patients with more aggressive tumors who may benefit from targeted therapy. [Cancer Res 2007;67(2):659–64]

Introduction: We recently reported the percentage of mammographic density (MD) to be a breast cancer risk factor across tumor characteristics and age groups. Yet, we noted stronger associations for tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages Methods: Data were pooled from six studies including 3517 women with invasive breast cancer and 8558 without. Dense area and non-dense area were assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We standardized dense and non-dense area measurements made within each study and categorized into quartiles based on the control distribution for pooled analyses. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (ER, PR) status by age ( Results: Absolute dense area was associated with increased breast cancer risk [odds ratios (ORs) Q1 vs Q2: 0.67, Q3 vs Q2: 1.25, Q4 vs Q2: 1.62] and non-dense area was associated with decreased breast cancer risk (ORs: Q1 vs Q2: 1.44, Q3 vs Q2: 0.89, Q4 vs Q2: 0.71) overall and across all age groups. Positive associations for absolute dense area were observed across all invasive tumor characteristics. Stronger associations were noted for larger tumors across all ages (p-trend Conclusion: These results suggest the strong association we previously observed of high percent MD and ER-negative disease in women Citation Format: Kimberly A. Bertrand, Christopher G. Scott, Rulla M. Tamimi, Matthew R. Jensen, V. Shane Pankratz, Aaron Norman, John Shepherd, Yunn-Yi Chen, Karla Kerlikowske, Celine M. Vachon. Dense and non-dense mammographic area and risk of breast cancer by age and tumor characteristics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2014-3279

e12029 Background: DCIS diagnosed on needle biopsy may underestimate the presence of invasive cancer identified on subsequent excision. This study aims to identify clinicopathologic factors from pr...

Intraabdominal coccidioidomycosis is a very rare entity and usually responds to medical therapy. Operative intervention is reserved for diagnosis or drainage of localized collections. With biliary coccidioidomycosis, medical treatment appears to be ineffective, and biliary tract drainage is necessary for optimal management. A case of coccidioidomycosis in the gallbladder and biliary tree is described and the literature reviewed.

80 Background: Breast cancer treatment depends on the accurate analysis of immunohistochemical biomarkers (IHC4): estrogen and progesterone receptors, Ki-67, HER2. The Athena Harmonization project was undertaken to reduce technical and scoring variances between different laboratories and different pathologists. Methods: Initial assessment: Five breast cancer samples were sectioned and distributed to 5 UC campuses, where IHC4 and HER2 FISH tests were done per usual methods. Samples were selected to cover the range of negative, positive, and moderate for each antigen. Stained slides were circulated to 10 pathologists for scoring. Digital whole slide images (WSI) were made and scored. Technical variance reduction: A Delphi voting process identified an ideal histology slide for each IHC4 antigen. Laboratories adjusted techniques to match the appearance of the ideal slides, followed by pathologist and quantitative image analysis (QIA) validation. Scoring variance reduction: A digital pathology training tool was created where pathologists scored breast cancer tissue microarrays with known scores for the IHC4 antigens. Results: Scoring variance did not exceed clinical thresholds, although there were significant technical and scoring variances between laboratories that could affect research outcomes. The mean values and variance were similar for WSI and glass slides, except for HER2 (higher scores on WSI but without benefit of workstation calibration). Each laboratory adjusted technical parameters to more closely match the ideal IHC4. Early QIA data indicate reduced variance between adjusted and ideal histology slides. Conclusions: Considerable and significant technical and interpretational variances between five University of California laboratories can be overcome by harmonizing protocols, setting new inter-institutional standards for pathology and histology best practices. Quantitative image analysis and whole slide imaging were instrumental. Subsequent harmonization will include cases near thresholds for clinical treatment guidelines.

Background: Data on breast cancer FDG uptake in relation to clinically relevant molecular subtypes and their interaction is scarce. Some have shown higher standardized uptake values (SUV) in triple negative (TN) and HER2+ than hormone receptor (HR)+ disease. We hypothesize that FDG uptake in HER2+ disease depends on HR status. Methods: We identified 186 invasive breast cancer patients with a whole body FDG-PET/CT scan between 2005 and 2010 at UCSF (within 6 months prior to or after diagnosis but before therapy). Receptor expression was assessed on adjuvant therapy naïve specimens using IHC (HR [ER and PR], HER2) and FISH (HER2) according to clinical practice. We related routinely assessed (log-transformed) SUVmax to receptor expression with linear regression and analysis of covariance (ANCOVA), and adjusted for tumor grade. Results: SUVmax was reported for 160 primary breast cancers and 154 had complete data for HR and HER2. Median age at diagnosis was 52 years (range 21-87), and 34% had localized, 52% regional, and 14% distant disease. Average tumor size was 3.9 cm (SD 2.2), and 12% had good, 51% moderate and 37% poor grade. FDG uptake strongly depended on molecular subtype (Table). Uptake was lowest in HER2-HR+ and somewhat - but not significantly - higher in HER2+HR- disease. The highest SUVmax was found in HER2+HR+, followed by TN disease (both significantly higher than HER2-HR+). The interaction between HR and HER2 in relation to FDG uptake was significant (P=0.003). ANCOVA showed that the higher TN uptake could largely be explained by differences in grade, whereas SUVmax in HER2+HR+ disease remained significantly higher than in HER2-HR+ disease. Conclusion: This large series of advanced primary breast cancer showed FDG uptake to be comparably low in HER2-HR+ and HER2+HR- disease, but significantly higher in HER2+HR+ and TN disease. Tumor grade largely explained the higher FDG uptake in TN disease but not the results for HER2+HR+. FDG-PET may need evaluation at different settings taking into account uptake variation due to tumor biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4558. doi:1538-7445.AM2012-4558