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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 4  |  Page : 1249-1256

Prediction of heterogeneity in breast cancer immunophenotype at ductal carcinoma in situ stage?


1 Department of Histopathology, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India
2 Department of General Surgery, Post Graduate Institute of Medical Sciences and Research, Chandigarh, India

Date of Web Publication7-Feb-2017

Correspondence Address:
Amanjit Bal
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Sector 2, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.199541

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 > Abstract 

Introduction: Ductal carcinoma in situ (DCIS) is considered a heterogeneous lesion at the molecular level. However, there is a paucity of literature about the existence of molecular subtypes in DCIS which can predict their biological behavior at the preinvasive stage.
Materials and Methods: Precise prevalence of molecular subtypes of pure DCIS and DCIS component of infiltrating duct carcinoma (IDC) was evaluated using immunohistochemistry and correlated with known prognostic factors.
Results: DCIS cases were classified as luminal A (46.6% in each group), luminal B (pure DCIS 20% and DCIS component of IDC 13.3%), HER2 overexpressing, basal and nonbasal (pure DCIS 3.3% and 26.6% and DCIS component of IDC 3.3% and 33.3%, respectively), and triple negative, nonbasal (pure DCIS and DCIS component of IDC 3.3% each). The molecular phenotype of DCIS correlated well with that of the coexisting IDC.
Conclusions: This study demonstrated molecular heterogeneity in DCIS; however, similar molecular phenotypes were seen in the coexisting IDC suggesting that DCIS is a precursor lesion and can predict phenotype of the invasive component. This also suggests that the invasiveness of DCIS is not dependent solely on the molecular character of the tumor epithelial cells, but factors such as tumor microenvironment may play a role.

Keywords: Ductal carcinoma in situ, immunohistochemistry, molecular subtypes


How to cite this article:
Rohilla M, Bal A, Singh G, Joshi K. Prediction of heterogeneity in breast cancer immunophenotype at ductal carcinoma in situ stage?. J Can Res Ther 2016;12:1249-56

How to cite this URL:
Rohilla M, Bal A, Singh G, Joshi K. Prediction of heterogeneity in breast cancer immunophenotype at ductal carcinoma in situ stage?. J Can Res Ther [serial online] 2016 [cited 2017 Dec 11];12:1249-56. Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1249/199541


 > Introduction Top


Breast carcinoma is a heterogeneous disease encompassing many morphological and molecular entities. Currently, it is classified as luminal A, luminal B, HER2 overexpressing, and triple negative (basal and nonbasal).[1],[2] Each molecular subtype exhibits distinct clinical behavior. Ductal carcinoma in situ (DCIS) is a precursor to invasive breast carcinoma and constitutes approximately 5% of breast cancers in the absence of screening; but within screening programs, it comprises approximately 20–25% of these tumors.[3] There is a general consensus that DCIS represents an intermediate step between normal breast tissue and invasive breast cancer and if untreated develops into invasive carcinoma in a significant proportion of cases within 10 years of diagnosis.[4],[5],[6] The microscopic heterogeneity of DCIS has led to the development of a number of systems for classification. Historically, DCIS has been classified on the basis of architectural pattern of epithelial proliferation, however, the reproducibility of this system of categorization is problematic as lesions most frequently show a mixture of architectures.[7],[8] Therefore, newer systems are based on nuclear grade and the presence or absence of luminal necrosis.[9],[10]

Similar to invasive breast carcinoma, the concept that DCIS is not one entity but a heterogeneous group of lesions is now generally accepted.[11] While new information regarding the molecular heterogeneity of invasive breast cancers is rapidly emerging, there is a paucity of literature about the existence of similar molecular subtypes in DCIS which can predict molecular heterogeneity and biological behavior at the preinvasive stage of breast cancer. In this study, we aim to evaluate heterogeneity in DCIS using immunohistochemistry.


 > Materials and Methods Top


This study included lumpectomies or mastectomies with a diagnosis of pure DCIS and invasive breast cancer with DCIS component >70% and were reviewed as per our Institutional Review Board Ethics Committee. All cases treated by chemotherapy before the surgery and with the previous history of lumpectomy followed by mastectomy for residual disease were excluded from the study.

Light microscopy

Detailed morphological features, histological type, grade, and necrosis were noted on light microscopic examination of hematoxylin and eosin-stained sections. Histological grading of infiltrating component of the tumor was done using the Elston and Ellis modification of Bloom–Richardson score while grading of the DCIS component of the tumor was done using the Van Nuys classification and Van Nuys Prognostic Index (VNPI).[10]

Immunohistochemistry and assessment of immunostains

All cases were stained for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, CK5/6, CK8/18, and CK14. Details of antibodies used in the study are listed in [Table 1]. Normal breast tissue adjacent to the tumor was used as an internal positive control. Negative controls were obtained by omitting the primary antibodies. Allred scoring system was used for the assessment for ER and PR immunostaining. Interpretation for HER2/neu was done as described in literature. For CK8/18, 5/6, and 14, cytoplasmic immunoreactivity in tumor cells was taken as positive. A proportion score (PS) was assigned from 0 to 3 (score 0 - <10%, score 1-11–33%, score 2-34–66%, and score 3 - >66%) representing the proportion of tumor cells, and an intensity score (IS) was assigned from 0 to 3 (score 0 - absent, score 1 - weak, score 2 - moderate, and score 3 - strong) representing the average staining intensity of tumor cells. A total score was calculated by multiplying PS and IS (ranging from 0 to 9).
Table 1: Details of antibodies used in the study

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Molecular classification

Molecular classification of the tumors (invasive and DCIS components) was done as follows:[12] luminal A: ER+/PR±/HER2−, CK8/18+, CK5/6−, CK14−; luminal B: ER+/PR±/HER2+, CK8/18+, CK5/6−, CK14−; HER2 overexpressing, basal: ER−/PR−/HER2+, CK8/18±, CK5/6+, CK14+; HER2 overexpressing, nonbasal: ER−/PR−/HER2+, CK8/18+, CK5/6−, CK14−; and triple negative, basal: ER−/PR−/HER2−, CK8/18±, CK5/6+, CK14+; triple negative, nonbasal: ER−/PR−/HER2−, CK8/18+, CK5/6−, CK14−.

Statistical analysis

Data were analyzed using statistical package SPSS version 17.0 for MS-Windows (SPSS Inc., Chicago, IL, USA). Correlations among categorical variables in the multivariate and bivariate analysis were determined using the Mann–Whitney test, Wilcoxon signed-ranks test and Pearson's Chi-square test. Significance was assumed at P < 0.05.


 > Results Top


Clinicopathological parameters

Pure ductal carcinoma in situ (n = 30)

The age of the patients ranged from 27 to 70 years with a mean of 48.6 years. Majority of cases (66.6%) were above 40 years of age and 33.3% were below 40 years of age. The size of tumor ranged from 0.5 to 8 cm in the largest dimensions. The maximum number of patients had tumor size of ≤2 cm (10 cases, 43.4%) followed by >2–5 cm in 8 (34.7%) patients. In 21.7% tumors, the size was >5 cm in largest dimensions. Out of thirty patients, the size of tumor was not known in seven patients as slides and blocks were submitted for review.

Infiltrating duct carcinoma with >70% ductal carcinoma in situ (n = 30)

The age of the patients ranged from 27 to 86 years with a mean of 46.9 years. Majority of cases (60%) were above 40 years and 40% were below 40 years of age. The size of tumor ranged from 1.2 to 7 cm in the largest dimensions. The maximum number of patients had tumor size ranging from 2 to 5 cm, i.e., 16 cases (57.1%) followed by ≤2 cm in 7 (25%) patients. More than 5 cm tumor size was seen in 5 cases (17.8%). The size of tumor was not known in 2 patients as slides and blocks were submitted for review.

Van Nuys classification

Pure ductal carcinoma in situ

The various architectural patterns observed in pure DCIS cases were solid, papillary, clinging, cribriform, comedo, and micropapillary [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d,[Figure 1]e,[Figure 1]f. Most of the cases had more than one architectural pattern. Comedo pattern was the most common (10 cases, 33.3%) primary architectural pattern followed by cribriform pattern (7 cases, 23.3%). Microcalcification was seen in only 9 (30%) cases. Based on the Van Nuys classification, sixteen (53.3%) cases were classified morphologically as high grade with or without necrosis (Grade III), and seven cases (23.3%) each as nonhigh-grade with necrosis (Grade II) and nonhigh-grade without necrosis (Grade I). Out of 30 cases, 23 cases were graded on the basis of VNPI scoring system as Grade I (5 cases, 21.7%), Grade II (14 cases, 60.8%), and Grade III (4 cases, 17.3%).
Figure 1: Ductal carcinoma in situ(a) cribriform pattern (H and E, ×200), (b) solid pattern (H and E, ×200), (c) micropapillary pattern (H and E, ×200), (d) comedo pattern with central necrosis (H and E, ×200), (e) high-grade nuclei with marked pleomorphism (H and E, ×200), and (f) invasive duct carcinoma with ductal carcinoma in situ(H and E, ×200)

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Infiltrating duct carcinoma with >70% ductal carcinoma in situ

The architectural patterns observed in DCIS component in infiltrating duct carcinoma (IDC) with >70% DCIS cases were similar to pure DCIS and had more than one architectural pattern. Comedo pattern (14 cases, 46.6%) was the most common primary pattern followed by cribriform pattern (10 cases, 33.3%). Out of 30 cases, microcalcification was seen in 19 (63.3%) cases. Based on Van Nuys classification, high-grade DCIS with or without necrosis comprised the maximum number (17 cases, 56.6%), followed by 9 cases (30%) of nonhigh-grade DCIS with necrosis. Nonhigh-grade cases without necrosis (4 cases, 13.3%) were least frequent.

Lymph node status

Out of 30 cases of pure DCIS, lymph nodes were received in only 18 cases and none showed lymph node metastasis. Out of 30 cases of IDC with >70% DCIS, lymph nodes were received in 27 cases of which lymph node metastasis was seen in only 9 cases.

Classification of cases based on hormone receptors and HER2 expression

Pure ductal carcinoma in situ

Maximum number of pure DCIS cases were ER+ and/or PR+ and HER2− (14 cases, 46.6%) while only one case (3.3%) was ER−/PR−/HER2− (triple negative). Six cases (20%) were ER+ and/or PR+ and HER2+ and 9 cases (30%) were HER2 overexpressing [Figure 2]a,[Figure 2]b,[Figure 2]c.
Figure 2: Pure ductal carcinoma in situ(a) estrogen receptor immunostaining shows uniformly positive tumor cells (estrogen receptor immunostain), (b) progesterone receptor immunostaining show uniformly positive tumor cells (progesterone receptor immunostain), (c) HER2 immunostain 3+, complete membranous staining (HER2 immunostain), (d) CK8/18 strong cytoplasmic and membranous positivity in tumor epithelial cells in ductal carcinoma in situ(CK8/18 immunostain), (e) CK5/6 immunostain shows strong cytoplasmic and membranous positivity in >10% of tumor epithelial cells in pure ductal carcinoma in situ, basal type (CK5/6 immunostain), and (f) negative CK14 in ductal carcinoma in situ(CK14 immunostain)

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Infiltrating duct carcinoma cases with >70% ductal carcinoma in situ

In DCIS component of IDC, 14 cases (46.6%) were ER+ and/or PR+/HER2−, 4 cases (13.3%) were ER+ and/or PR+/HER2+; 11 cases were ER− and/or PR−/HER2 + while 1 case was triple negative. In IDC component, 15 cases (50%) were ER+ and/or PR+/HER2−, 3 cases (10%) were ER+ and/or PR+/HER2+, 11 cases (36.6%) were ER− and/or PR−/HER2+ while 1 case was triple negative [Figure 3]a,[Figure 3]b,[Figure 3]c.
Figure 3: Ductal carcinoma in situ component of infiltrating duct carcinoma: (a-c) estrogen receptor, progesterone receptor, and HER2 immunostaining show uniformly positive tumor cells in in situ and invasive component (estrogen receptor and progesterone receptor immunostain). (d) CK8/18 shows strong cytoplasmic and membranous positivity in tumor epithelial cells in in situ and invasive component (CK8/18 immunostain), (e) CK14 immunostain shows strong cytoplasmic and membranous positivity in > 10% of tumor epithelial cells in ductal carcinoma in situ component only (CK14 immunostain), and (f) negative CK5/6 in ductal carcinoma in situ and invasive component (CK5/6 immunostain)

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Classification of cases based on cytokeratin expression

Pure ductal carcinoma in situ

All cases demonstrated positivity for the luminal cytokeratins 8/18. Twenty-nine cases (96.6%) had a luminal phenotype (CK8/18+, CK5/6−, and CK14−). Of these, 28 cases had strong CK8/18 expression (score 9) and 2 cases (6.6%) showed score of 6 (one case showed decrease in PS and other showed decrease in IS). None of the case was positive (i.e., expression in >10% epithelial cells) for CK14; however, one case (3.3%) was weakly positive for CK5/6 in the epithelial cells indicative of basal phenotype [Figure 2]d,[Figure 2]e,[Figure 2]f.

Infiltrating duct carcinoma cases with >70% ductal carcinoma in situ

All cases demonstrated positivity for the luminal cytokeratins 8/18 in DCIS component. Six (20%) cases showed score of <9 (due to decrease in PS or decrease in IS). However, remaining cases expressed CK8/18 strongly (score 9). One case (3.3%) showed epithelial positivity for CK14, and none was positive for CK5/6 in the epithelial cells. In the invasive component, all the cases showed positivity for CK8/18 in the epithelial cells; however, 6 cases showed score of <9 (due to decrease in PS or decrease in IS) while the rest of the cases expressed CK8/18 strongly (score 9). None of the case showed positivity for CK14 and CK5/6 in the epithelial cells. In DCIS component, 29 cases (96.6%) were luminal type and 1 case was basal type; whereas in IDC component all the cases were luminal type [Figure 3]d,[Figure 3]e,[Figure 3]f.

Combined ER/PR/HER2 and cytokeratin classification [Table 2]
Table 2: Molecular classification of pure ductal carcinoma in situ and intraductal and invasive component of infiltrating duct carcinoma with >70% ductal carcinoma in situ

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Maximum number (14 cases, 46.6%) of pure DCIS cases were luminal A type, and 6 cases (20%) were luminal B phenotype. Eight cases (26.6%) were HER2 overexpressing, nonbasal type, and one case (3.3%) was HER2 overexpressing basal type. There was only one case of triple negative nonbasal phenotype (3.3%). In DCIS component of IDC, 14 cases (46.6%) were luminal A type, 4 cases (13.3%) were luminal B type, 10 cases (33.3%) were HER2+ overexpressing nonbasal, one case (3.3%) was HER2 overexpressing basal type, and one case (3.3%) was triple negative nonbasal type.

Comparison of molecular classification of ductal carcinomain situ component with coexisting infiltrating duct carcinoma component

Twenty-six cases (86.6%) of IDC with >70% DCIS had similar molecular classification of DCIS component and coexisting IDC component. In the remaining 4 cases, there was difference in molecular classification between DCIS and IDC component. In 2 cases, DCIS component was luminal B while IDC was luminal A type, i.e., in IDC component, there was loss of HER2 expression. In one case, DCIS component was luminal A while IDC was luminal B type and in another case, DCIS component was HER2 expressing, basal type and IDC was HER2 expressing nonbasal type.

Van Nuys classification and molecular classification

Pure ductal carcinoma in situ

All Grade I tumors (7 cases) were luminal A type. Of 7 cases of Grade II tumors, two cases (28.5%) each were luminal A, luminal B, and HER2 overexpressing, nonbasal type while one case was triple negative, nonbasal. Six cases (37.5%) of Grade III tumors were HER2 overexpressing, nonbasal type, and 1 case (6.2%) was HER2 overexpressing, basal type. Five cases (29.4%) of Grade III tumors were luminal A and 4 cases (25%) were luminal B type. The correlation between molecular classification and Van Nuys morphological grade in pure DCIS was statistically significant with P value of 0.025 [Table 3].
Table 3: Comparison of morphological (Van Nuys classification) grading and molecular classification of pure ductal carcinoma in situ and ductal carcinoma in situ component in cases of infiltrating duct carcinoma with >70% ductal carcinoma in situ

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Infiltrating duct carcinoma cases with >70% ductal carcinoma in situ

All cases with morphological Grade I were luminal A type. Morphological Grade II tumors were luminal A in four cases (44.4%) and luminal B and HER2 overexpressing nonbasal type in 2 cases (22.2%) each, while one case was triple negative (nonbasal). Forty-seven percent Grade III tumors were HER2 overexpressing nonbasal type and 1 case (5.8%) was HER2 overexpressing-basal type. Grade III tumors were luminal A in 35.2% cases and luminal B in 11.7% cases. The correlation between molecular classification and Van Nuys morphological grade in DCIS component was statistically insignificant with P value of 0.085 [Table 3].


 > Discussion Top


DCIS is characterized by the proliferation of malignant epithelial cells within the ductolobular system of the breast without evidence of invasion through the basement membrane into the surrounding stroma.[9] Although information concerning the molecular heterogeneity of invasive breast cancer is gradually accumulating, the same is not true for DCIS. DCIS of the breast is a heterogeneous group of preinvasive breast tumors with variable malignant potential. Hence, it is still challenging to accurately determine the risk of progression to invasive cancer. This is limited by the lack of information about molecular alterations in DCIS. Only few studies have attempted to evaluate whether the same molecular subtypes, as identified in invasive breast cancer, are also seen in DCIS.[13],[14],[15],[16],[17]

In the present study, 30 cases each of pure DCIS and IDC with more than 70% DCIS were studied for molecular subtyping. ER was positive in 63.3% pure DCIS cases and 56.6% cases of DCIS component of IDC. The highest percentage of ER positivity was seen in Grade I tumors (100%) and least in Grade III tumors (50%) in both DCIS and DCIS component of IDC in our study. Various studies have shown that ER is expressed in 50–60% of patients with DCIS or invasive cancer.[18],[19],[20] Zafrani et al.[21] found ER expression in 83% of well-differentiated DCIS, in 74% of poorly differentiated DCIS, in 91% of DCIS lesions with no necrosis, and in 37% of DCIS lesions with massive necrosis. There was similar ER and PR expression in pure DCIS, IDC component, and DCIS component of IDC in our study. Zhang et al.[22] also showed that ER and PR expression were similar in DCIS, DCIS with microinvasion, and IDC and suggested that hormone receptor status was determined at the stage of in situ carcinoma.

In the present study, HER2 expression in IDC component was seen less frequently (46.6%) as compared to the DCIS component of IDC (56.6%) and pure DCIS (50%) although this was not statistically significant. The maximum numbers of HER2/neu positive cases among both groups were Grade III tumors. The studies have demonstrated HER2 expression in more than 40% of DCIS patients, with a much higher percentage of patients being with comedo/high-grade DCIS than patients with noncomedo/low-grade DCIS.[23] In addition, studies have observed that HER2-positivity was found more often in patients with pure DCIS compared to those with microinvasive DCIS and DCIS with IDC.[24] In our study, there was no statistically significant difference in HER2 expression in DCIS, DCIS with IDC, or morphologic grades of DCIS in either group. Women with invasive cancer, whose tumors express HER2 have a poorer prognosis than those whose tumors do not express HER2, and the higher incidence of expression found in DCIS may therefore seem paradoxical. Some researchers postulated that HER2 expression was due to the process of atypical hyperplasia in DCIS, and loss of HER2 expression occurs as DCIS develops into IDC. Another hypothesis is that the HER2− IDC does not develop from DCIS but from the atypical hyperplasia.[25],[26] Another theory explaining this phenomenon is that most invasive cancers develop from DCIS tumors that have low expression of HER2 but high proliferative rates. Because such tumors progress rapidly, they are in the DCIS stage for only a short period and would therefore be underrepresented in population samples.[27] A recent study found overexpression of HER2 in DCIS to be the only significant predictor of invasive disease in a multivariate analysis and suggested that HER2 may be important in promoting invasion.[28] This has clear clinical implications, and further studies are needed to establish the prognostic value of HER2 in DCIS.

Earlier studies have shown that DCIS can also be classified into the five molecular phenotypes that were initially described for invasive breast carcinoma. However, these studies showed a difference in prevalence of the molecular phenotypes between DCIS and IDC. An increased prevalence of luminal B and HER2 overexpressing molecular subtypes was noted in DCIS compared with invasive carcinomas.[15],[16] Clark et al.[2] proposed that each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups. In the present study, in both pure DCIS cases and DCIS component of IDC, the maximum number of cases were luminal A type followed by HER2 overexpressing, nonbasal type, luminal B type, and HER2 overexpressing, basal and triple negative, nonbasal type. The most common molecular phenotype reported by Gupta et al. in DCIS cases was luminal A (45.3%) followed by HER2-expressing type (24%), luminal B (21.3%), and unclassified (9.3%) type. There was no case of basal-like phenotype in their study.[13]

Meijnen et al.[29] carried out an immunohistochemical study on 163 cases of DCIS and showed no evidence of CK14 or EGFR expression, with CK5/6 being expressed in only 3 cases. In an unsupervised cluster analysis, they identified two major groups, an ER+/Bcl-2+ group designated as luminal and an ER–/Bcl-2– group designated as nonluminal. The luminal subgroup was further subdivided on the basis of androgen receptor (AR) into AR+, AR–, and mixed groups while the nonluminal group was subdivided into HER2+ and HER2− subsets. There was a significant relationship between grade and distribution between subsets, with well and intermediate grade DCIS clustering to the luminal groups compared to nonluminal groups. Livasy et al.,[15] in an analysis of 245 pure DCIS cases, identified 8% as basal (defined as ER–, HER2–, EGFR+, and/or CK5/6+), and a further 6% fell into the TN category. Studies have demonstrated a relationship between morphological grade and molecular phenotype for DCIS lesions.[13],[16] In our study, the correlation between morphological grade and molecular classification was statistically significant in pure DCIS cases while it was not significant in DCIS component of IDC. All cases of morphological Grade I tumors in both pure DCIS and DCIS component of IDC were luminal A type while in morphological Grade III tumors, the maximum number (pure DCIS: 37.1% and DCIS component of IDC: 47%) were of HER2 overexpressing type.

Tamimi et al.[16] showed that the prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249); however, Gupta et al.[13] reported that in all cases, the molecular phenotype was identical in DCIS component and the invasive component. In our study also, the correlation between molecular classification of IDC and DCIS component of IDC was statistically significant, and only four cases showed difference in molecular subtypes. Steinman et al.[17] have proposed that in most cases, there is a high degree of coexpression of the markers between DCIS and the coexisting IDC, suggesting that DCIS is frequently a precursor lesion for coexisting IDC. He also suggested that the rate of discordant expression of these markers is low and is more frequently associated with high-grade carcinoma, suggesting that other molecular pathways also may also be present. DCIS and IDC frequently coexist within the same tumor and have the same nuclear features and genetic alternations.[30] The expression of ER is strongly associated with low-grade DCIS while HER2 overexpression is strongly associated with high-grade disease.[29],[31] The pattern of receptor expression may be important in predicting disease behavior is suggested in a study by Kepple et al.,[32] who found that ER+, PR–, HER2 + DCIS was significantly more likely to recur than other DCIS types, and this receptor profile was associated with significantly reduced disease-free survival.


 > Conclusions Top


The molecular heterogeneity of invasive breast cancer is well known and has been put into the practice of clinical oncology as a molecular classification, which has both prognostic and predictive value in guiding therapy. This study demonstrated molecular heterogeneity in DCIS; however, similar molecular phenotypes were seen in DCIS and the coexisting IDC suggesting that DCIS is a precursor lesion of IDC. The similar molecular phenotypes of the proliferating tumor (epithelial) cells also suggest that the invasiveness of the lesion is not dependent solely on the molecular character of the tumor epithelial cells, but other factors such as myoepithelial cells and microenvironment may be playing a significant role.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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    Tables

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