Triple Negative Ductal Carcinoma In Situ Research Articles

Spectrum of Ductal Carcinoma In Situ (DCIS) Lesions of the Breast: From Morphology to Molecular Characteristics.

Background Specific molecular characteristics of invasive breast cancer have been linked to an increased risk of early relapse. Similarly, ductal carcinoma in situ (DCIS) displays a comparable molecular profile, although their prevalence and implications are not yet fully understood. Aims and objectives The study design defined a multivariable statistical approach aimed at describing the interplay between the histopathological features of ductal carcinoma in situ (DCIS) and their molecular profile. The objective was to explore the correlations between the histopathological features of DCIS (tumor location, DCIS grade, DCIS type, and presence or absence of comedo necrosis) and various biomarkers like estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2/neu), androgen receptor (AR), and epidermal growth factor receptor (EGFR), in addition to the Ki-67 labeling index. Methods In this retrospective study, we selected and analyzed 100 diagnosed cases of ductal carcinoma in situ (DCIS) to represent various subtypes, grades, and morphological characteristics. A detailed histopathological review and immunohistopathological staining for ER, PR, HER2/neu, AR, EGFR, and Ki-67 were performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks. Molecular subtyping was done based on the biomarker analysis into luminal A, luminal B, luminal HER2/neu, HER2/neu enriched, and triple-negative subtypes. Statistical analysis was done to examine the correlation between tumor location, histopathological features of ductal carcinoma in situ (DCIS), and the expression of the immunohistochemical markers and the molecular subtypes. Results The majority of cases exhibited positivity for estrogen receptor (ER) and progesterone receptor (PR). A strong association was observed between histopathological features (DCIS grade, type, and comedo necrosis) of DCIS and ER/PR status. Additionally, a significant correlation was found between ductal carcinoma in situ (DCIS) grade and HER2/neu status. However, no association was identified between histopathological features and AR or EGFR status. Contrary to expectations, triple-negative DCIS did not show the most aggressive behavior, whereas HER2/neu-positive tumors, particularly high-grade ones, exhibited more aggressive features. No low-grade cases of luminal HER2/neu and HER2/neu-enriched tumors were found. A higher Ki-67 labeling index was found in cases with grade 3 and solid and comedo architectural types of DCIS, while low-grade tumors had a lower Ki-67 labeling index. Conclusion These findings suggest that hormone pathways play a crucial role in ductal carcinoma in situ (DCIS) progression, but the molecular interactions are complex and extend beyond simple binary associations. The complex relationship between the histopathological features of ductal carcinoma in situ (DCIS) and its hormone receptor status warrants further investigation with a larger sample size to fully understand the underlying mechanisms. The results challenge the expectation that triple-negative DCIS is the most aggressive subtype, highlighting the need for further research into the prognostic significance of different DCIS subtypes.

Abstract B021: Canine CAR T-cells therapy for mammary carcinoma in dogs

Abstract In women, ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease that is widely considered to be a nonobligate precursor of invasive carcinoma. TNBC is the most aggressive and lethal form of breast cancer and predominantly occurs in women at high genetic risk including those with mutated BRCA1 genes. We provide for the first time an immunocompetent animal model for triple-negative DCIS (TN-DCIS) that will facilitate molecular analysis of preinvasive TNBC and will provide an invaluable resource for identifying and selecting targets for TNBC vaccine immunoprevention or immunotherapeutic intervention. Unlike most studied rodent models, dogs develop TN-DCIS spontaneously without genetic or chemical manipulation. We have shown that canine DCIS resembles human DCIS with shared histopathologic and molecular features and with similar imaging and behavioral characteristics. Dogs are much more outbred than laboratory rodents, yet certain breeds are at increased risk for developing mammary tumors. Indeed, we have found that 50% of randomly screened asymptomatic hound dogs have premalignant mammary lesions and that mammary TN-DCIS often progresses to invasive carcinoma within one year. Given the many common features of canine breast cancer and the high homology between the canine and human genome, the dog model offers an outstanding opportunity for exploiting TNBC immunoprevention and immunotherapeutic strategies. Moreover, the prevalence and rapid progression of canine TN-DCIS provides a much more rapid and cost-effective alternative to human trials for evaluation of the clinical effectiveness of cancer vaccine strategies. One immunotherapeutic strategy we are testing using our canine TN-DCIS model is chimeric antigen receptor (CAR) T-cells. CAR T-cells have shown promise in treating many malignancies, but in solid tumors have been hindered by many limitations. To overcome these limitations, we designed genetically engineered universal canine CAR T-cells that must be activated and targeted by a small-molecule adaptor before it can kill cancer cells. Our results showed that universal CAR T cells are functional and killed canine mammary tumor cell lines in vitro. Citation Format: Xavier E. Ramos-Cardona, Sulma I. Mohammed, Yong Gu Lee, Phillip Low. Canine CAR T-cells therapy for mammary carcinoma in dogs [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B021.

Relationship of the breast ductal carcinoma in situ (DCIS) immune microenvironment with clinicopathological features: An institutional experience.

e12565 Background: DCIS is usually treated with resection followed by 5 years of adjuvant endocrine therapy for hormone receptor (HR) + DCIS. Endocrine therapy is not used in HR- DCIS. Although DCIS is considered a precursor lesion to invasive breast cancer, the different molecular subtypes confer variable clinical outcomes. The host immune response plays a key role in breast cancer progression and response to therapy. However, relative to invasive breast cancer, the immune milieu of DCIS is less understood. This retrospective study compares the clinical outcomes and tumor microenvironment of HR+ and HR- DCIS in order to identify clinical and immunological features in HR- DCIS that may predict an increased risk of recurrence or progression to invasive breast cancer. Methods: A single institution retrospective chart review was performed to identify patients diagnosed with DCIS between 2012 and 2017. A clinico-pathologic data set, as well as the PD-L1 expression of the DCIS and TILs were collected and correlated with various outcomes. Results: Our cohort consisted of 20 cases of HR- DCIS and 50 cases of HR+ DCIS. Overall, 56% were Caucasian, 20% Asian, 18% Hispanic, and 6% African American. Of the HR- patients, 70% were Caucasian, 15% Hispanic, and 15% Asian. Of the 17 HR- patients with available HER2 data, 76% had HER2+, and 24% triple negative (TN) DCIS. 18% of the HR+ patients and 38% of the HR- patients were PD-L1+. 25% of the HR-/HER2+ patients, and 75% of the TN patients were PD-L1+. 6% of the HR+ patients developed recurrent disease, 2 with DCIS and 1 with invasive ductal carcinoma. 20% of the HR- patients had recurrent disease, all of whom were HER2+. Of the HR- patients that recurred, 2 recurred with metastatic disease, 1 with ipsilateral invasive ductal carcinoma, and 1 with DCIS. All 7 patients that recurred had original DCIS pathology showing a high nuclear grade. Our future results at the time of the meeting will expand on this cohort. Conclusions: This retrospective analysis showed that HR- DCIS conferred higher rates of local and distant recurrence. Therefore, there is a need for treatments to reduce the recurrence rates of HR- DCIS. There are ongoing clinical trials for the high risk, HR-/HER2+ DCIS subtype. TN DCIS is also an aggressive phenotype. Given the high rate of PD-L1 positivity we detected in TN DCIS, immune-based therapy may be useful in the adjuvant setting to reduce the risk of recurrence in this cohort of patients.

Higher densities of tumour-infiltrating lymphocytes and CD4+ T cells predict recurrence and progression of ductal carcinoma in situ of the breast.

Host immunity influences cancer progression and therapeutic response. We investigated the potential of tumour-infiltrating lymphocytes (TILs) around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. CD4, CD8, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in DCIS from 198 patients was determined by immunohistochemistry. We correlated disease-free survival (DFS), clinicopathological parameters and biomarker expression with TIL density and CD4/CD8 ratio. High TIL density was associated with high nuclear grade (P<0.001), DCIS PD-L1 expression (P=0.008), TIL PD-L1 expression (P<0.001), oestrogen (ER) negativity (P<0.001), progesterone (PR) negativity (P<0.001), human epidermal growth factor receptor 2 (HER2) positivity (P=0.002) and triple negativity (P=0.001). TIL PD-L1 expression was associated with triple-negative DCIS (P=0.028). TIL density was associated with molecular subtypes (P<0.001). High CD4+ T cell density was associated with high nuclear grade (P=0.001), microinvasion (P=0.037), ER negativity (P<0.001), PR negativity (P=0.001), HER2 positivity (P=0.004), triple negativity (P=0.023) and PD-L1 expression in TILs (P<0.011). High CD4/CD8 ratio was associated with PD-L1 expression in DCIS (P=0.035) and TILs (P<0.001). DCIS with higher TIL density disclosed worse DFS (P=0.012) and was affirmed with multivariate analysis [95% confidence interval (CI)=1.109-2.554, hazard ratio (HR)=1.683, P=0.014]. Poorer DFS for ipsilateral invasive recurrence was found for DCIS with higher CD4+ T cell density (P=0.006) or CD4/CD8 ratio (P=0.02), confirmed by multivariate analysis for the former (95% CI=1.369-10.196, HR=3.736, P=0.01) and latter (95% CI=1.311-7.935, HR=3.225, P=0.011). DCIS with higher TIL density was associated with poorer prognostic parameters and predicted recurrence, while both CD4+ T cell density and CD4/CD8 ratio were associated with both recurrence and ipsilateral invasive recurrence.

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer unresponsive to traditional receptor-targeted treatments, leading to a disproportionate number of deaths. Invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DCIS). Detection of triple-negative DCIS (TN-DCIS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive TN-DCIS to invasive TNBC are needed. Here, we study a canine TN-DCIS progression and investigate the DNA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DCIS and invasive breast cancer. We report hypo- and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DNA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DCIS. Changes in DNA methylation during TN-DCIS progression in this canine model correspond with gene expression patterns in human breast tissues. This study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DCIS stage only of TN-DCIS progression.

Abstract P5-07-07: The immune microenvironment of ductal carcinoma in situ of the breast

Abstract Background: The importance of tumor-infiltrating lymphocytes (TIL) in invasive breast carcinoma for tumor development and therapeutic response is widely accepted. However, the immune microenvironment of breast ductal carcinoma in situ (DCIS) has not been fully elucidated. Evasion of immune surveillance is a necessary step in tumor evolution. In DCIS, the tumor cells are relatively protected from the immune system due to an myoepithelial cell layer and basement membrane, and intraductal immune cells are rarely detected. In contrast, in invasive disease, cancer cells and immune cells are often intermingled. Thus, understanding the immune microenviroment of in situ to invasive carcinoma transition might be particularly important to identify novel targets for early stage of tumor invasion. Aims: The aim of this study is to evaluate the clinical importance of TILs in DCIS. Methods: TILs were assessed in 133 DCIS samples with or without microinvasive disease according to the proposed method from the International Immuno-Oncology Working Group on Breast Cancer. In addition, the relationship between TILs in DCIS and clinicopathological features was evaluated. Results: TILs are present in most DCIS in varying levels. The median proportion of TILs in DCIS was 14%. Only a minority of DCIS showed &amp;gt;50% TILs, which represented only 12.8% of all cases. High TILs in DCIS was significantly associated with comedo necrosis (p&amp;lt;0.0001), high nuclear grade (p=0.0030), ER negativity (p&amp;lt;0.0001), PR negativity (p&amp;lt;0.0001), HER2 positivity (p=0.0030). Triple negative DCIS and HER2 positive DCIS had significantly higher level of TILs (p=0.0008). No correlation was demonstrated between TILs and recurrence risk. Conclusions: High TILs in DCIS was significantly associated with adverse histopathologic features. Further characterization of immune environment of DCIS may be essential for immunotherapy and breast cancer prevention. Citation Format: Yamashita N, Hisamatsu Y, Shigechi T, Tokunaga E, Saeki H, Oki E, Maehara Y. The immune microenvironment of ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-07.

Triple-negative and HER2 positive ductal carcinoma in situ of the breast: characteristics, behavior, and biomarker profile.

We compared the characteristics, clinical behavior, and biomarker profile between HER2 positive (HER2+) and triple-negative (TN) ductal carcinoma in situ (DCIS) which are considered more aggressive than other DCIS subtypes. In addition, we explored the impact of these features on its potential of progression to invasive breast carcinomas. Cases of DCIS diagnosed at the Department of Pathology, Singapore General Hospital from 1994 to 2010 were identified. TN and HER2+ DCIS cases formed the study cohort. Immunohistochemistry (IHC) was performed for ER, PR, HER2, CK14, EGFR, and p53. Comparisons of clinicopathological features, IHC results, and clinical outcomes were performed between the two groups. We evaluated 145 HER2+ and 85 TN DCIS cases. HER2 positive DCIS had significantly higher nuclear grade (p < 0.001) and more frequent necrosis (p < 0.001) than TN DCIS. HER2 positive DCIS also harbored significantly higher rates of nuclear p53 immunoreactivity (p = 0.002) than TN DCIS. Younger patients (age < 40) with HER2+ and TN DCIS demonstrated statistically significant worse invasive DFS than older women (p < 0.001). Multivariate cox regression analysis (HR 15.08, 95% CI 12.79-81.45, p = 0.002) also confirmed these findings. In addition, younger patients (age < 40) with HER2+ DCIS experienced significantly poorer prognosis when p53 was also positive (p = 0.033). HER2+ DCIS had more aggressive pathological characteristics compared to TN DCIS; accumulation of mutant p53 could possibly be contributory. Age was an independent predictor of aggressive biological behavior of HER2+ and TN DCIS. We demonstrated that younger patients with p53 positive HER2+ DCIS had significantly adverse clinical outcome.

Abstract 2357: CDK4/6 inhibition in early stage triple negative breast cancer

Abstract Palbociclib (PD), a CDK4/6 inhibitor, has recently been approved for use in advanced ER positive breast cancer, demonstrating significant benefit in combination with endocrine therapies. Ductal carcinoma in situ (DCIS) is an inobligate precursor to invasive ductal carcinoma with anywhere from 14-53% of cases progressing. Progression is unpredictable and driven by poorly understood mechanisms. In this study, we assess the efficacy of PD in the context of this early stage disease using a triple negative DCIS model(MCF10DCIS), not only in inhibiting cell cycle but also in hindering the progression from in situ to invasive lesion. We demonstrate similar efficacy of PD in 2D on MCF10DCIS and immortal mammary epithelial cells (MCF10As) in preventing proliferation, inhibiting phosphorylation of RB and stopping cell cycle progression. Yet in 3D, MCF10DCIS cells form smaller, more organized spheres in the presence of drug while MCF10As appear unaffected, highlighting potential disease selectivity in vivo. Interestingly, when a cDNA array is performed on MCF10DCIS cells grown in 3D +/- PD, the most regulated genes are not well characterized cell cycle genes as one might predict based on previously published data and 2D response to treatment, suggesting alternative CDK4/6 targets may be responsible for the phenotype observed in 3D. We also demonstrate in a nude mouse xenograft model of MCF10DCIS that PD is able to significantly reduce overall tumor burden while simultaneously delaying the progression of lesions to invasive disease. Though the growth of PD treated MCF10DCIS lesions is delayed we demonstrate that proliferation is unaffected in vivo by the presence of the drug, based on equivalent Ki67 signal within the lesions. This reiterates the possibility that in 3D and in vivo contexts PD targets mechanisms outside of cell cycle regulation in order to slow tumor growth and delay invasive transition. We believe that investigation into alternative targets of CDK4/6 altered by PD in 3D and in vivo may provide insights on important mechanisms of DCIS progression in DCIS models and human patients. Citation Format: William B. Kietzman, Virginie Ory, Fransisco Saenz, Ghada Sharif, Anton Wellstein, Anna T. Riegel. CDK4/6 inhibition in early stage triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2357. doi:10.1158/1538-7445.AM2017-2357

The immune microenvironment of breast ductal carcinoma in situ

The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ (DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1−tumor infiltrating lymphocytes were seen only in ER+/HER-2−DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention.

Screening mammography-detected ductal carcinoma in situ: mammographic features based on breast cancer subtypes

We evaluated the mammographic and histopathologic features of screening mammography-detected ductal carcinoma in situ (DCIS) based on the breast cancer subtypes determined by immunohistochemistry. A total of 94 patients with 94 screening mammography-detected DCIS were included in this study. Mammographically, human epidermal growth factor receptor 2 (HER2)-positive DCIS was more commonly associated with calcifications than estrogen receptor (ER)-positive and triple-negative DCIS (P=.003). Histopathologically, HER2-positive DCIS and triple-negative DCIS were associated with high nuclear grade (P≤.001) and comedo necrosis (P≤.001) than ER-positive DCIS.

Carcinoma in situ to invasive breast cancer.

Invasive breast cancer (IBC) is a heterogeneous disease which can be divided in several molecular subtypes [1] with distinct biological behavior and clinical outcome. Although these subtypes are based on microarray-based gene expression studies, each molecular subtype has an immunohistochemical surrogate: luminal A (ER+ and PR+/Her2−, low Ki-67 index), luminal B (ER+, Her2−, PR− or low and/or high Ki-67 index or ER+, Her2+ with any PR expression and Ki-67 index), basal-like (ER−, PR− and Her2−) and Her2-overexpressed (ER−, PR− and Her2+) [2], which has been further refi ned with the addition of CK5/6 and EGFR [3]. The DNA mutation spectrum across these different breast cancer subtypes varies widely [4] and there is increased evidence that genetic alterations, and their prognostic and predictive signifi cance, differ among them. Ductal carcinoma in situ (DCIS) is regarded as a nonobligate precursor lesion of IBC, sharing a great degree of agreement regarding morphology and genetics [5]. In other words: ER+ and ER− DCIS correlate with respectively ER+ and ER− IBC. Reported incidences of DCIS subtypes suggest that progression of DCIS to IBC differs among subtypes [6]: Triple-negative DCIS seems to have the fastest progression. Luminal A type DCIS seems to progress slower to IBC than luminal B type DCIS. The high incidence of pure Her2+ DCIS compared with Her2+ IBC and the association of Her2+ IBC with an extensive DCIS component might indicate that Her2 amplifi cation does not play a key role in DCIS progression to IBC. The recent manuscript by Kim et al. [7] focuses on genomic differences between pure DCIS and synchronous DCIS with IBC in order to better understand the mechanisms of DCIS progression. In this interesting study, they compared 6 cases with pure DCIS and 5 pairs of synchronous DCIS and IBC by whole-exome sequencing and copy number profi ling. They concluded that pure DCIS harbored wellknown mutations (e.g. TP53, PIK3CA and AKT1), copy number alterations and chromothripsis, but had significantly fewer driver genes and co-occurrence of mutation/copy number alterations compared with synchronous DCIS with IBC. The authors proposed that although pure DCIS already has some driver mutations, additional changes are needed to progress to IBC. They stated that pure DCIS seems to have a less aggressive genome compared with synchronous DCIS and IBC. However, the study is based on a limited number of cases of different molecular subtypes. All six cases with pure DCIS were ER+, the majority (4 out of 6) was Her2− and all showed low or intermediate Ki-67 index. In conclusion: all pure DCIS cases were of the luminal type, mostly luminal A. On the contrary, the synchronous DCIS-IBC group included a total of fi ve cases, mainly (3 out of 5) ER−. The majority (4 out of 5) showed Her2 amplifi cation and all showed intermediate or high Ki-67 index, which means that this synchronous DCIS-IBC group includes only luminal B and Her2+ cases. Obviously, the pure DCIS group and the DCIS-IBC group consist of cases with a different molecular subtype; the pure DCIS group mostly luminal A, the DCIS− IBC group mostly luminal B and Her2+. Therefore, the question arises whether the reported genetic differences between these groups are a true refl ection of biological behavior (progression to IBC or not) or that these differences are the result of comparing different DCIS subtypes. In other words, in case one would compare luminal A type pure DCIS to luminal B type or Her2+ pure DCIS, would the results not be similar? In line with this, Kim et al. [7] reported that the ER− and PR− group harbored a higher number of somatic mutations and copy number alterations compared with the ER+ and PR+ group respectively, although this difference was only signifi cant for PR. In addition, the Her2+ cases seem to have more copy number alterations compared with the Her2− cases. Therefore, in our opinion, comparing different molecular DCIS subtypes with different biological behavior (progression or not) does not answer the question whether the reported molecular alterations of the DCIS component are truly responsible for progression since these differences could also be the result of comparing different DCIS subtypes. In order to study true progression-related alterations, we believe it might be preferable to do either paired analyses of synchronous DCIS-IBC or perform analyses of pure DCIS with molecular subtype matched cases with synchronous DCIS-IBC.

Abstract P2-11-19: Expression of folate receptor alpha in ductal carcinoma in situ of the breast and comparison with that of invasive ductal carcinoma

Abstract Background: We have previously shown that the expression of Folate receptor alpha (FRA) is associated with high grade ER-/PR- or triple negative (TN) invasive ductal carcinoma of the breast. The aim of the current study is to investigate the expression pattern of FRA in a cohort of ductal carcinoma in situ (DCIS), analyze its relationship with different clinicopathological features and expression of several key biomarkers, and compare these findings to our previous data on invasive ductal carcinoma (IDC). Methods: Ninety-eight cases of DCIS of the breast diagnosed between 1997 and 2008 in our institution were identified, reviewed and 6 blocks of tissue microassays (TMA) were constructed. The association between the expression of FRA (≥10% designed as positive expression) and the clinicopathologic features, the expression of ER, PR, HER2 and Ki-67, and the clinical outcome were evaluated, and these results were compared to those from IDC (399/430 cases with informative data). Results: Among the 98 cases of DCIS in TMA, 88 cases were informative. The expression rate of FRA was 21% for DCIS, less than the 29% seen in IDC. Expression of FRA was associated with high nuclear grades (42%), though less frequently than with IDC (52%). FRA expression was also associated with ER negativity (46%), PR negativity (33%) and high Ki-67 expression (50%) in DCIS, although significantly less than in IDC (75%, 63%, and 56%, respectively for negative ER and PR, and high Ki-67). Also, only 50% of ER/PR negative, TN and basal-like DCIS expressed FRA, significantly lower than that of IDC (74%, 80% and 80%, respectively). Due to the limited cases of DCIS, we did not demonstrate a significant difference in disease-free survival between FRA positive and negative tumors (p-value = 0.1792), although we did observe that IDC with FRA expression was significantly associated with a worse disease-free survival (p-value = 0.04). Comparison between FRA expression between DCIS and IDC FRA≥10% in DCISFRA≥10% in IDCp-value 88 cases399 cases Nuclear 342%52%0.0185ER negative46%75%0.0442PR negative33%63%0.0214HER2 3+31%37%0.7003ER-/PR-50%74%0.0973Triple Negative50%80%0.1622Basal-Like50%80%0.1739 Conclusion: Our data demonstrates that FRA expression is associated with high nuclear grade, ER/PR negative and TN DCIS, though at a significantly lower rate than was observed in IDC, suggesting a possible role for this receptor in early breast carcinogenesis. There are differences in the rates of FRA expression between DCIS and IDC, suggesting that FRA may be one of the key molecules involved in progression of DCIS to IDC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-19.

Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study

BackgroundDifferent molecular subtypes of breast cancer have been identified based on gene expression profiling. Treatment suggestions based on an approximation of these subtypes by immunohistochemical criteria have been published by the St Gallen international expert consensus panel. Ductal carcinoma in situ (DCIS) can be classified into the same molecular subtypes. Our aim was to study the relation between these newly defined subtypes and prognosis in DCIS.MethodsTMA including 458 women from a population-based cohort with DCIS diagnosed 1986–2004 was used. Stainings for ER, PR, HER2 and Ki67 were used to classify the surrogate molecular subtypes according to the St Gallen criteria from 2011. The associations with prognosis were examined using Kaplan-Meier analyses and Cox proportional hazards regression models.ResultsSurrogate molecular subtyping could be done in 381 cases. Mean follow up was 164 months. Of the classified DCIS 186 were Luminal A (48.8%), 33 Luminal B/HER2- (8.7%), 74 Luminal B/HER2+ (17.4%), 61 HER2+/ER- (16.0%) and 27 Triple Negative (7.1%). One hundred and two women had a local recurrence of which 58 were invasive. Twenty-two women had generalised disease, 8 without a prior local recurrence. We could not find a prognostic significance of the molecular subtypes other than a higher risk of developing breast cancer after more than 10 years of follow-up among women with a Triple Negative DCIS (OR 3.2; 95% CI 1.1-9.8).ConclusionsThe results from this large population-based cohort, with long-term follow up failed to demonstrate a prognostic value for the surrogate molecular subtyping of DCIS using the St Gallen criteria up to ten years after diagnosis. More than ten years after diagnosis Triple Negative DCIS had an elevated risk of recurrence.

Triple‐negative breast cancer: Histological subtypes and immunohistochemical and clinicopathological features

To reveal heterogeneous properties of triple-negative (TN) breast cancers (estrogen receptor negative, progesterone receptor negative and HER2 negative) and to clarify whether the developmental pathways to TN breast cancer are single or multiple, we conducted clinicopathological and immunohistochemical studies on TN breast cancers, with special reference to comparison of the invasive component (iIC) and the ductal component (dcIC) of invasive TN breast cancer and pure TN ductal carcinoma in situ (TNDCIS). Tumor tissues were obtained from 97 patients with TN invasive carcinoma and 10 patients with TNDCIS. Two histological subclassifications, "atypical" medullary carcinoma (type A, n=16) and carcinoma with a central acellular zone (type B, n=11), were distinguished from conventional ductal carcinoma. Other invasive ductal carcinomas were classified as type C (n=64) and special types were classified as type D (n=5). The follow-up period for the 96 patients ranged from 5 to 147.8 months (mean, 47.6 months). Out of 97 cases, dcIC was present in 29 (30%) cases and type A and B had significantly few ductal components, 0% and 18%, respectively. There were only six (6%) cases with non-TN cells in dcIC and TN cells in iIC and five of them were type C. In 13 (13%) cases, epidermal growth factor receptor (EGFR) expression existed only in iIC. Therefore, most of the TN carcinoma develops originally and rapidly invades at the early stage, especially in types A and B. The relapse rate of type B was the highest (36.4%) and the overall survival of patients with type B was the shortest (P=0.02), which indicates that the prognosis of type B is significantly worse than the other types.