Abstract P3-07-01: Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial
Authors: Thorat MA , Jones LJ , Levey PM , Elia G , Evagora CA , Bundred NJ , Fentiman IS , Forbes JF , Cuzick J 
Published: May 2016

Background:

Majority of studies investigating prognostic role of ER and PgR expression in ductal carcinoma in situ (DCIS) have failed to show a significant relationship with recurrence. Branched evolutionary tumour growth and resulting intratumour heterogeneity is now increasingly acknowledged in a variety of cancers. DCIS offers the opportunity to investigate relevance of clonal populations in different ducts that may have evolved differently and may impact outcome differently. We investigated prognostic role of ER and PgR expression in DCIS and impact of clonal variation in ER/PgR expression using material from UK/ANZ DCIS trial.

Methods:

Formalin-fixed paraffin embedded tissues (FFPETs) were collected from patients enrolled in the UK/ANZ DCIS trial, a randomised 2X2 factorial design trial investigating role of tamoxifen, radiotherapy or both as adjuvant treatment in DCIS. A nested case-control design was used; cases (patients with recurrence) were matched by treatment arm and age to 2 controls each (no recurrence).

ER and PgR expression was evaluated on whole sections by immunohistochemistry using 1D5, PGR636 antibodies and EnVisionTM FLEX + detection system (Dako). Assays were scored by Allred method (positive if expression &gt;1%) and clonal method. Clonal method documented presence of ducts with complete lack of ER or PgR expression in otherwise ER or PgR positive (Allred method) DCIS. Analyses categorising such multi-clonal DCIS as ER or PgR positive as per current practice (standard) and categorising these as ER or PgR negative DCIS (clonal method) were performed.

Results:

Of 540 samples (180 cases, 360 controls), ER and PgR status was evaluable in 504 and 498 patients respectively. ER expression was absent (ER-) in 148 (29.4%), 356 (70.6%) were ER positive (ER+) with 39 (7.7%) of these displaying multi-clonal expression (ERmulti-clonal). PgR expression was absent in 163 (32.7%), 335 (67.3%) were PgR positive with 84 (16.9%) of these displaying multi-clonal expression.

ER- DCIS showed increased risk (Table) of in situ ipsilateral breast event (DCIS-IBE) and invasive ipsilateral breast event (I-IBE) (borderline significance). Prognostic discrimination was higher when ER status was determined by clonal method (ΔX2 1.57 for I-IBE and 9.05 for DCIS-IBE). Increases in the risk of I-IBE and DCIS-IBE were similar for ER- and ERmulti-clonal DCIS.

TableEndpointComparisonScoring MethodHazard Ratio (95%CI)pI-IBEER- vs. ER+Standard1.75 (0.99-3.09)0.0544 ER- vs. ER+Clonal1.90 (1.10-3.30)0.0224 ER- vs. ER+*Clonal1.89 (1.05-3.41)0.0337 ERmulti-clonal vs. ER+*Clonal1.93 (0.74-5.03)0.1759DCIS-IBEER- vs. ER+Standard2.58 (1.68-3.94)&lt;0.0001 ER- vs. ER+Clonal3.13 (2.02-4.85)&lt;0.0001 ER- vs. ER+*Clonal3.11 (1.97-4.93)&lt;0.0001 ERmulti-clonal vs. ER+*Clonal3.20 (1.62-6.34)0.0008* ER+ DCIS not exhibiting multi-clonal expression

Lack of PgR expression was only associated with increased risk of DCIS-IBE and PgR status did not add to the prognostic information provided by ER status.

Conclusions:

ER expression is prognostic for recurrence in DCIS. ER+ DCIS with distinct ER- clones has a recurrence risk similar to ER- DCIS. ER scoring should take clonality of expression into account.

Citation Format: Thorat MA, Jones LJ, Levey PM, Elia G, Evagora CA, Bundred NJ, Fentiman IS, Forbes JF, Cuzick J. Prognostic role and impact of multi-clonal ER and PgR expression in ductal carcinoma in situ: Results from the UK/ANZ DCIS trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-01.