The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS)

Abstract Background The prediction of clinical behaviour of breast ductal carcinoma in situ (DCIS) and its progression to invasive disease remains a challenge. Alterations of DNA damage repair mechanisms are associated with invasive breast cancer (BC). This study aims to assess the role of base excision repair (BER) DNA Polymerase Beta (POLβ) in DCIS. Methods A cohort of DCIS comprising pure DCIS (n = 776) and DCIS coexisting with invasive BC (n = 239) were prepared as tissue microarrays. POLβ protein expression was assessed using immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Preclinically, we investigated the impact of POLβ depletion on stem cell markers in representative DCIS cell line models. Results Reduced POLβ expression was associated with aggressive DCIS features including high nuclear grade, comedo necrosis, larger tumour size, hormonal receptor negativity, HER2 overexpression and high Ki67 index. Combined low nuclear/low cytoplasmic POLβ expression showed the strongest association with the features’ characteristics of aggressive behaviour. There was a gradual reduction in the POLβ expression from normal breast tissue, to DCIS, with the lowest expression observed in the invasive BC. Low POLβ expression was an independent predictor of recurrence in DCIS patients treated with breast conserving surgery (BCS). POLβ knockdown was associated with a significant increase in cell stemness markers including SOX2, NANOG and OCT4 levels in MCF10-DCIS cell lines. Conclusion Loss of POLβ in DCIS is associated with aggressive behaviour and it can predict recurrence. POLβ expression in DCIS provides an additional feature for patients’ risk stratification for personalised therapy.

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Responsiveness of adjacent ductal carcinoma in situ and changes in HER2 status after neoadjuvant chemotherapy/trastuzumab treatment in early breast cancer: Results from the GeparQuattro study (GBG 40).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.6 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 6-6

Author(s):

G. Von Minckwitz ◽

S. Darb-Esfahani ◽

S. Loibl ◽

J. B. Huober ◽

H. Tesch ◽

...

Keyword(s):

Neoadjuvant Chemotherapy ◽

Ductal Carcinoma In Situ ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

Her2 Status ◽

Her2 Overexpression ◽

Her2 Expression ◽

Her2 Positive ◽

Complete Eradication

6 Background: Adjacent ductal carcinoma in situ (DCIS) is in found in approximately 45% of invasive ductal carcinomas (IDC) of the breast. Pure DCIS overexpresses HER2 in approximately 45%. There is uncertainty whether adjacent DCIS impacts on the response to neoadjuvant chemotherapy and trastuzumab as well as whether HER2 expression in IDC component or adjacent DCIS changes throughout treatment. Methods: Core biopsies and surgical tissue from participants of the GeparQuattro study with HER2-positive IDC were centrally examined for the area of invasive ductal component and adjacent DCIS before and after receiving neoadjuvant anthracycline-taxane-trastuzumab containing chemotherapy. HER2 overexpression in IDC and adjacent DCIS was quantified separately by immunohistochemistry using the Ventana automated staining system. Pathological complete response (pCR) was defined as no residual invasive or non-invasive tumor tissue. Results: Fifty nine (37.3%) of 158 IDCs presented with adjacent DCIS at diagnosis. These tumors showed lower regression grades than pure IDC (p=0.033). Presence of adjacent DCIS was an independent negative predictor of pCR (odds ratio 0.42 [95% CI 0.2-0.9], p=0.027). Adjacent DCIS area decreased from pre-treatment to surgery (r=0.205) with 30 (50.8%) IDCs with adjacent DCIS showing complete eradication of adjacent DCIS. HER2 status of adjacent DCIS was highly correlated with HER2 status of IDC component before (r=0.892) and after treatment (r=0.676). Degree of HER2 overexpression of the IDC component decreased in 16 (33.3%) out of 49 patients without a pCR. These 16 IDCs showed lower RGs compared to the 33 IDCs with unchanged HER2 expression (p=0.055). Conclusions: HER2-positive IDCs with adjacent DCIS is less responsive to neoadjuvant chemotherapy and trastuzumab compared to pure IDC. However, complete eradication of adjacent DCIS is frequently observed. HER2-overexpression of the invasive ductal component decreases in a subset of tumors, which showed less tumor regression.

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Histiocytoid Ductal Carcinoma In Situ of the Breast: Not All Intraductal Foamy Cells Are Macrophages!

International Journal of Surgical Pathology ◽

10.1177/1066896919864635 ◽

2019 ◽

Vol 27 (8) ◽

pp. 872-875

Author(s):

Hélène Dano ◽

Christine Galant ◽

Maude Coyette ◽

Mieke R. Van Bockstal

Keyword(s):

Ductal Carcinoma In Situ ◽

Carcinoma In Situ ◽

Clear Cell ◽

Ductal Carcinoma ◽

Screening Mammography ◽

Her2 Overexpression ◽

Breast Cancers ◽

Cell Component ◽

Diagnostic Challenge

With the advent of screening mammography, the incidence of ductal carcinoma in situ (DCIS) has increased. DCIS accounts for around 20% of breast cancers diagnosed at present. The histiocytoid variant of clear cell DCIS is a rare subtype of DCIS, characterized by epithelial cells with a clear and foamy cytoplasm. Histiocytoid DCIS serves as a potential diagnostic pitfall, since it can be easily mistaken for intraductal collections of foamy macrophages. In this article, we report a particular case of biphasic DCIS, characterized by an extensive histiocytoid-type clear cell component and a conventional “non-clear” cell component. Both components presented with HER2 protein overexpression. We discuss the diagnostic challenge and differential diagnosis of clear cell DCIS, as well as the role of HER2 overexpression in DCIS pathogenesis.

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Significance of HER2/neu overexpression in pure ductal carcinoma in situ: A clinicopathologic study with long-term follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.26_suppl.85 ◽

2013 ◽

Vol 31 (26_suppl) ◽

pp. 85-85

Author(s):

Zeina Al-Mansour ◽

Thomas Stockl ◽

Ashraf Khan ◽

Richard Horner ◽

Ediz Cosar ◽

...

Keyword(s):

Ductal Carcinoma In Situ ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

Disease Recurrence ◽

Nuclear Grade ◽

Her2 Overexpression ◽

Her2 Positive ◽

High Nuclear Grade

85 Background: The prognostic value of HER2 (c-ERB2) overexpression in invasive breast cancer is well known, and correlates with aggressivene behavior. HER2 overexpression was reported in 13-56% of ductal carcinoma in-situ (DCIS). The significance of HER2 overexpression in DCIS has yet to be elucidated. The aim of this study was to correlate HER2 status with known prognostic indicators of DCIS and to evaluate whether the HER2 overexpression correlates with disease recurrence. Methods: All cases of DCIS diagnosed at our institution between 2000 and 2005 were retrieved. Cases without follow-up, those treated with mastectomy or those with concurrent invasive component were excluded. Clinicopathologic data were collected, including age at time of diagnosis, size of the lesion, nuclear grade, presence of comedo necrosis, margin status, estrogen (ER) and progesterone receptor (PR) status, type of adjuvant treatment received and length of follow-up. A representative block from each case was immunostained using the Hercept test. Slides were reviewed by 2 pathologists and interpreted in accordance with ASCO/CAP guidelines. Equivocal cases were reflexed for FISH testing. Results: A total of 152 cases were examined. Mean follow-up period was 77 months (range 12 to 138 months). HER2 was overexpressed in 49 cases (33%), and was significantly associated with high nuclear grade and presence of comedo necrosis. HER2-positive patients were more likely to be ER and PR negative. HER2 positive and negative patients did not differ significantly with respect to age at presentation or size of DCIS. On univariate analysis, HER2-type DCIS showed a higher risk of recurrence (P=0.037), however, this trend did not reach statistical signifance on multivariate analysis. Conclusions: HER2 overexpression was found to be associated with high nuclear grade, comedo necrosis as well as negativity for ER and PR but not with age or the size of DCIS. Patients with HER2-type DCIS (ER/PR-, HER2+) had a higher risk of disease recurrence than other types. However, after adjusting for all the other clinical variables, the molecular phenotype did not withhold its statistical significance as an independent predictor for recurrence.

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