Abstract P6-16-04: IL6ST, a biomarker of endocrine therapy response, has potential in identifying a subgroup of women with ER+ DCIS who are more likely to benefit from adjuvant endocrine therapy
Authors: Carlos Martinez-Perez, Charlene Kay, Rebecca Swan, Gregory E Ekatah, Laura M Arthur, James Meehan, Mark Gray, Andrew H Sims, Olga Oikonomidou, Arran K Turnbull, J Michael Dixon
Journal: Cancer Research (2020)

Abstract Background: Ductal carcinoma in situ (DCIS) lesions are non-obligate precursors to invasive breast cancer (IBC). With the ultimate goal of preventing the development of invasive disease, DCIS is typically treated by breast-conserving surgery (BCS). Adjuvant radiotherapy (RT) is given for high-grade disease to reduce the risk of in-breast tumour recurrence (IBTR). The use of endocrine therapy (ET) for DCIS varies, as studies show a modest benefit but no survival improvement; in the UK, guidelines recommend ET for DCIS in some scenarios but only instead of, rather than in addition to, RT. This project sought to characterise the biology of ER+ DCIS and identify a group of women who are likely to gain the most benefit from the addition of adjuvant ET. Patients: Cohort A - 77 women with ER+ (Allred 7/8) high-grade DCIS treated with BCS plus RT, 20 of whom developed IBTR.Cohort B - 70 women with ER+ (Allred 7/8) low/intermediate-grade DCIS treated with BCS alone, 12 of whom developed IBTR.Cohort C - 68 women with ER+ (Allred 7/8) DCIS treated with BCS plus ET. All patients were treated locally between 2000 and 2016 and the median follow-up is 6 years. Methods: We performed whole-genome transcriptomic QuantSeq sequencing of samples from cohort A. Sequencing of cohort B and C is currently underway. IL6ST levels were validated using immunohistochemistry and RNAScope. Results: In cohort A, only a subset (34/77) of tumours had gene expression profiles consistent with active ER signalling. Levels of IL6ST, a biomarker for ET response, could differentiate these two subgroups and this was validated at protein level using immunohistochemistry. The low ER signalling subgroup were associated with higher levels of EGFR, HER2 and MAPK signalling. 20/77 high-grade DCIS cases recurred within 10 years. 50% of these recurred as IBC (rather than DCIS) and these were associated with higher levels of IL6ST, had active ER signalling and higher levels of proliferation-associated and estrogen receptor target genes, known to be decreased by ET, in the primary DCIS lesion. Discussion: Our findings suggest that some high-grade ER+ DCIS patients have active ER signalling while in others ER signalling remains low despite highly expressing the ER protein. IL6ST, a biomarker of endocrine therapy response can be used to differentiate these two groups of ER+ DCIS. DCIS lesions which recurred as IBC had active ER signalling and also higher levels of proliferation genes known to be decreased by ET compared with DCIS which recurred as further DCIS. These findings suggest that IL6ST may have a role in identifying a subset of ER+ DCIS which are at a higher risk of developing advanced disease and are also more likely to benefit from the addition of adjuvant ET, with a better risk-to-benefit ratio than observed in previous studies that considered a less targeted use of this treatment strategy, thus potentially reducing the risk of IBC recurrence. These findings will be validated in a cohort of low/intermediate-grade DCIS who received no adjuvant RT (cohort B) and a cohort of patients who received adjuvant ET as part of their treatment (cohort C). Citation Format: Carlos Martinez-Perez, Charlene Kay, Rebecca Swan, Gregory E Ekatah, Laura M Arthur, James Meehan, Mark Gray, Andrew H Sims, Olga Oikonomidou, Arran K Turnbull, J Michael Dixon. IL6ST, a biomarker of endocrine therapy response, has potential in identifying a subgroup of women with ER+ DCIS who are more likely to benefit from adjuvant endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-04.