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Introduction: Non-classic lobular carcinoma in situ (NC-LCIS) is a rare pathologic entity which encompasses a variety of histologic diagnoses. As such its natural history, including upgrade rates to invasive cancer (IC) or ductal carcinoma in situ (DCIS) on excision, is poorly characterized. We sought to evaluate the risk of upgrade to IC or DCIS when NC-LCIS is diagnosed on core biopsy. Methods: After obtaining IRB approval, institutional pathology databases were searched for NC-LCIS core biopsy diagnoses (carcinoma in situ (CIS), carcinoma in situ with ductal and lobular features (CIS/DLF), pleomorphic LCIS (P-LCIS), variant LCIS (V-LCIS), LCIS with necrosis). Cases with a NC-LCIS core biopsy diagnosis and with available pathology results from subsequent surgery were included. Cases with known concurrent ipsilateral IC, DCIS and/or atypical ductal hyperplasia were excluded. Results: 107 cases with NC-LCIS in any pathology report were identified (1998-2016); 44 were excluded due to concurrent ipsilateral IC, the remaining 62 patients with 63 core biopsy diagnoses of NC-LCIS all underwent surgical excision and formed our study cohort. Median age was 56 years (range 43-83); 43 (68%) were postmenopausal. NC-LCIS was diagnosed on core biopsy for mammographic findings in 57 (90%) cases and for MRI findings in 6 (9%). All were BI-RADS 4 lesions; calcifications were the most common biopsy indication (50 (78%)). CIS/DLF was the most common term used for NC-LCIS (28 (44%)), followed by CIS (18 (29%)), V-LCIS (14 (22%)) and P-LCIS (3 (5%)). On core biopsy, 36/44 (82%) of NC-LCIS cases were E-cadherin negative, 38/41 (93%) were ER positive, and 6/34 (18%) were HER2 positive. IC and/or DCIS were diagnosed on subsequent surgery in 22 (33%) of patients, of which 14 (67%) were IC and 8 (18%) had DCIS only. LesionTotalE-cadherin negativeUpgraded, N (%)Invasive cancer, N (%)DCIS only, N (%)CIS188/10 (80%)3 (16%)2 (67%)1 (33%)CIS/DLF2819/23 (83%)12 (43%)7 (58%)5 (42%)P-LCIS31/1 (100%)3 (100%)2 (67%)1 (33%)V-LCIS148/10 (80%)4 (29%)3 (75%)1 (25%) Median IC size was 0.2 cm (0.06-1.1 cm). IC histology was ductal in n=4 (29%), lobular in n=7 (50%), and ductal and lobular in n=3 (21%). Among the 14 invasive lesions, 5 (36%) were grade I, 5 (36%) were grade II and 2(13%) were grade III, (grade was not reported for 2 remaining ICs); 12/14 (86%) were ER positive and 1/14 (7%) was HER2 positive; none had LVI or positive nodes. Among the 42 cases not upgraded, 13 (31%) had mastectomy, 9 (21%) had excision and radiation, 20 had excision only, all had negative margins. At median follow-up of 60 months (1-224 months), 1/20 patients treated with excision only was diagnosed with DCIS, 14 months after surgery for CIS/DLF on core biopsy. Conclusions: In this large series of NC-LCIS diagnosed on core biopsy, the upgrade rate to carcinoma was 33% supporting the recommendation for routine excision of these lesions. The cancers found at excision were all stage I and the majority were grade I or II. At a median follow-up of 60 months only 1/20 patients with pure NC-LCIS treated with excision alone developed a future ipsilateral cancer. Further study of the natural history of these rare lesions is warranted. Citation Format: Nakhlis F, Harrison BT, Lester SC, Hughes KS, Coopey SB, King TA. Evaluating the risk of upgrade to invasive breast cancer and/or DCIS on excision following a diagnosis of non-classic lobular carcinoma in situ [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-01.

Background: Response to neoadjuvant chemotherapy in breast cancer serves as an important prognostic indicator, as patients whose estrogen receptor (ER) negative and/or HER2 positive cancers undergo a pathologic complete response (pCR) have an excellent outcome. Guidelines on classification of treatment response are available, but data is lacking for the rare event where lymph-vascular invasion (LVI) is the only residual disease in the breast. Only one study (Rabban JT et al, Am J Surg Pathol, 2009) has investigated the significance of this pattern of residual disease. These authors reported 6 patients with residual LVI in the breast in the absence of stromal invasion. Five of the patients also had residual disease in lymph nodes. Prognosis was poor with four of the patients dying in less than 4 years and an additional patient dying at 10 years. The aim of our study was to gather more data on this rare pattern of residual disease, with a focus on node negative cases. Design: We retrospectively identified from our pathology database all cases in which LVI was the only residual disease in the breast after neoadjuvant therapy. Results: A total of 16 cases were identified, yielding an incidence of 1.6% of all cancers undergoing neoadjuvant chemotherapy over a 10 year period. All patients were females with a mean age of 54 years (range 40-69 years). Eight cancers initially presented as a palpable breast mass, 4 as vague breast symptoms, 2 as inflammatory carcinoma and 1 was detected on screening mammogram. In twelve cases the axillary lymph nodes were either suspicious by imaging or proven positive by needle biopsy. The mean pre-neoadjuvant tumor size was 2.7cm (range 0.5-8.0cm). Six cancers were negative for hormone receptors and HER2, eight cancers were positive for HER2 and 4 cancers were positive for ER. After neoadjuvant chemotherapy, nine patients had no residual disease in lymph nodes. The remaining seven patients had residual disease in lymph nodes, although minimal in the majority. The mean follow-up was 65 months for the node negative group (range 9-125 months) and 44 months for the node positive group (range 7-102 months). One death occurred in each group (at 12 months and 67 months respectively), two patients are alive with metastatic disease in the node negative group and the remaining 12 patients are alive without disease. Conclusions: Pure residual LVI after neoadjuvant chemotherapy is a rare event. Our findings show that the outcome associated with residual LVI, with or without residual cancer in nodes, might not be as dismal as previously reported, although longer follow-up will be required. The more favorable outcome observed is in contrast to the single study previously published. Although the difference may be due to details in the type of chemotherapy or stage at presentation, it is difficult to compare the 2 groups of patients due to limited information about the earlier cases. More data is needed to draw conclusions on the prognostic significance of this type of residual disease. The lack of a current AJCC/UICC T category for this finding will make identification of these patients difficult in large databases. Citation Format: Guilbert M-C, Lester SC. Lymph-vascular invasion in the absence of stomal invasion after neoadjuvant therapy: A rare pattern of residual carcinoma that lacks an AJCC/UICC T category [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-15.

Background: The need for radiation therapy (RT) in conservatively managed DCIS is a source of ongoing debate. This is an updated analysis of a phase II prospective study of wide excision alone for DCIS. The study was activated in May 1995 and closed in July 2002 following accrual of 158 patients because the number of local recurrences (LR) met the predetermined stopping rules. The objective of the analysis is to update the distribution and cumulative incidence of events (LR, contralateral breast cancer [CBC], second malignancy and death from other causes). Materials and Methods: A total of 158 patients had DCIS with predominant nuclear grade 1 or 2, a mammographic extent of ≥2.5 cm, and excision with final microscopic margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The results presented are from the 8-year analysis (8-year minimum potential follow-up time). Twenty-six patients without recurrence who were followed less than 8 years were excluded from the analysis as were 7 first events (4 LR) that occurred beyond 8 years of follow-up; the analysis thus includes 132 patients and 36 first events. Cumulative incidence curves were generated to assess the rates of LR or other events. Median follow up time was 10 years. Results: Overall, 36/132 patients (27%) had a first event as of April 2010. Of these 36 events, 19 were LR, 13 were CBC, 1 was a second malignancy, and 3 were deaths from other causes. Of the 19 LR, 13 (68%) were DCIS only and 6 (32%) were invasive. Fourteen occurred in the same quadrant and 5 were elsewhere in the ipsilateral breast. The 8-year estimated cumulative incidence of LR was 14.4% (95% CI: 8.4-20.4%). For all other events, the 8-year estimated cumulative incidence was 12.9% (95% CI: 3.6-13.1%). The estimated annual percentage rates of LR, CBC, and other events were 2.1%, 1.5% and 0.4%, respectively. Discussion: The results of this prospective study demonstrate a substantial and ongoing risk of LR and CBC in patients with small, nuclear grade 1 or 2 DCIS treated with wide excision with margins of ≥1cm in the absence of RT. Most LRs occurred in the same quadrant, rather than elsewhere in the breast, suggesting that excision alone is inadequate even for this highly selected population. Further study is warranted to determine if there is a subgroup of DCIS patients with nuclear grade 1 or 2 disease who are at low enough risk of LR following wide excision that RT can be omitted safely. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-03.

Background: There is increasing evidence that the presence of a host inflammatory response to breast cancer may influence outcomes. Utilizing inflammation scores on the histology of breast cancer samples submitted for comprehensive molecular analyses for The Cancer Genome Atlas (TCGA), we provide an updated look at associations between the presence of host inflammation and breast cancer molecular and pathologic features. Design: Experts in breast pathology reviewed the digital slides of breast cancer samples submitted for comprehensive molecular profiling to the TCGA and scored each case for the level of inflammation present (high/moderate vs mild/minimal). We tested pairwise associations between host inflammation and molecular subtypes (DNA copy-number, RNA expression, RPPA defined subtypes, miRNA subtypes, methylation subtypes) and pathological features by performing Chi-Square analyses. Multiple hypothesis testing correction was performed using the Bonferroni method. Results: 598 breast cancer cases with TCGA molecular profiling data were scored by the expert breast pathologists for morphological features (including inflammation). 195 (33%) of these were scored as high/moderate inflammation. Cases with inflammation had a significantly higher rate of TP53 mutations (p = 9.0e-8) with 64 of 118 (54.2%) p53 mutant cases with inflammation. Inflammation was also significantly associated with PAM50 molecular subtypes (p = 2.2e-11), with the greatest enrichment among basal-like (64.5% of 70 basal-like cases had inflammation) and the greatest depletion among Luminal A (18.1% of 166 Luminal A cases had inflammation). Cases with inflammation were significantly less likely to be lobular (p = 1.5e-7), had less tubule formation (p = 0.0006), increased mitoses (p Conclusions: There are strong associations between breast cancer molecular and pathological features and the host inflammatory response. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-06.

Background: Previous studies have found that particular pathologic features are more common in breast cancers arising in BRCA mutation carriers. However, the biologic and molecular bases for the morphologic associations are not clear. This study is conducted to analyze pathologic and molecular features in tumors stratified by BRCA1 or BRCA2 mutation status using the breast cancer samples that have comprehensive molecular portraits characterized by the Cancer Genome Atlas (TCGA). Methods: The digital slides of breast cancer samples submitted for comprehensive molecular profiling to the TCGA were reviewed by expert breast pathologists, who were unaware of the BRCA status or other molecular signatures. Each tumor was evaluated and scored for histologic type, nuclear pleomorphism, tubule formation, mitosis, stromal inflammation, and necrosis. 562 cases had both pathology and tumor exome sequencing data available and constituted the current study population. We determined the association of somatic BRCA1 and BRCA2 mutation status with pathologic features and molecular characteristics (mutation of PIK3CA and TP53, and molecular subtypes defined by PAM50 mRNA data) using the Fisher exact test for categorical variables and the Wilcoxon test for ordinal variables. Results: Of the 562 tumors, 514 had no BRCA1 or BRCA2 mutation, while 48 (8.5%) of tumors were found to harbor a BRCA1 mutation (n = 16, 3%), BRCA2 mutation (n = 30, 5%), or mutation in both (n = 2, 0.3%). BRCA1 and BRCA2 mutational status showed no significant association with lobular features, tubule formation, nuclear pleomorphism, or stromal inflammation (all p > 0.05), although there was a trend for increased nuclear pleomorphism in BRCA2 mutant cases (p = 0.07). The lack of significant association of BRCA1/2 mutational status with these features may be due to our study's relatively small number of BRCA1/2 mutant cases. Both BRCA1 and BRCA2 mutations were associated with a higher mitotic count (p = 0.03 and 0.04, respectively). BRCA2 mutation showed no association with necrosis (p = 1), while BRCA1 mutation status was associated with increased necrosis (OR = 2.7, p = 0.04). BRCA2 mutation status showed no significant association with PAM50 subtype (p = 0.37), while BRCA1 mutation status was significantly associated with PAM50 molecular subtype (p = 0.005), with the greatest enrichment among Basal-like (7/70 Basal-like with BRCA1 mutation, 10%) and depletion among Luminal-B (0/79 Luminal-B with BRCA1 mutation, 0%). Neither BRCA1 nor BRCA2 mutations were significantly association with PIK3CA mutations (p = 0.39, 0.08, respectively). BRCA2 mutation status was not associated with TP53 mutations (p = 0.65), while BRCA1 mutation status was associated with increased TP53 mutations (OR = 4.0, p = 0.005). Conclusion: Tumors with BRCA1 and BRCA2 alterations are associated with specific pathologic and molecular features. However, there is molecular and morphologic heterogeneity within these cancers. These factors need to be considered when designing algorithms for BRCA testing and targeted therapy in BRCA-related cancers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-15.

Abstract #1072 Background We have previously reported two complementary prognostic markers in breast cancer for predicting risk of recurrence (Ma et al, Clin Cancer Res, 2008): a molecular grade index (MGI) that recapitulates grade 1 and 3 tumors and stratifies grade 2 tumors, and a gene expression index (HOXB13/IL17BR or H/I) that predicts clinical outcome in estrogen receptor positive (ER+) patients and endocrine benefit (Jerevell et al, Breast Cancer Res Treat, 2007). In combination, MGI and H/I define three risk groups: Low risk (low MGI), intermediate risk (low H/I, high MGI) and high risk (high H/I, high MGI). We conducted a study to compare risk stratification by MGI and H/I within samples for which a previous recurrence score (RS) by Oncotype Dx was reported. Materials and Methods RNA was extracted from formalin-fixed paraffin-embedded sections from all obtainable samples of patients (pts) from five institutions in which a RS was reported MGH, 77pts; Brigham, 48pts; IU, 19pts; UAB, 13pts; Scripps, 9pts. Real-time RT-PCR assays for MGI and H/I were completed and binary results of low and high for both were determined using pre-defined cutpoints. Risk stratification via MGI + H/I for each sample was compared to previously reported RS's (low, intermediate or high). Results For the 166 pts, 48% had a low, 45% intermediate and 7% high RS's. Overall, risk stratifications by RS versus MGI + H/I were significantly correlated (p < 0.001) with 81% of patients with low RS also having low risk (low MGI). Risk stratification by H/I + MGI reduced intermediate risk via RS by 2.5-fold (45% versus 18%). Discussion In ER+ pts, MGI + H/I produces a significantly smaller group of patients with intermediate risk by re-stratifying a large number of patients with intermediate RS into low and high risk groups. Risk stratification by H/I + MGI in ER+ pts is by measurement of two discrete parameters: endocrine responsiveness (H/I) and proliferative status (MGI). This may allow for more informed treatment decisions by the treating oncologist. Further studies with clinical outcome are required to establish the clinical significance of these different risk stratification methods. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1072.