Abstract P2-10-02: The impact of intrinsic subtypes and molecular features on aromatase inhibitor induced reduction of proliferation marker of Ki67 in primary ER+ breast cancer: A POETIC study (CRUK/07/015)
Authors: Cheang MCU , Morden J , Gao Q , Parker J , López-Knowles E , Detre S , Hills M , Zabaglo L , Tomiczek M , Mallon E , Robertson J , Smith I , Bliss J , Dowsett M ,   On Behalf of the POETIC Trialists
Published: March 2017

Background

Neoadjuvant endocrine therapy (NAE) is often a good option for postmenopausal (PM) women with estrogen receptor positive (ER+) breast cancers(BC). Fall in Ki67 is widely accepted as valid for predicting favorable tumor response to NAE and improved outcome. We report our planned correlative study to investigate if intrinsic subtype impacts on Ki67 changes (ΔKi67) as measured by immunohistochemistry. We also explored the correlation of several ER+ BC relevant molecular features at baseline(B) with ΔKi67.

Patients and methods

POETIC is a phase III, randomized 2:1 study for 4486 PM patients with ER+ BC to determine whether peri-operative aromatase inhibitor (AI) followed by standard adjuvant therapy improves outcome compared with standard adjuvant therapy alone. The proliferation rate was estimated as percentage (%) of cancer cells staining for Ki67. Primary biological endpoint was defined as two-week (2wk) change in Ki67 (2wkΔKi67): ln[(2wk Ki67+0.1)/(B Ki67+0.1)]. Secondary endpoint: “responders”, was % change of Ki67 defined as (2wk Ki67 – B Ki67) *100/B Ki67. “Responder” was defined as follows: reduction &lt;50% as poor (PR), 50-75% moderate and &gt;75% as good responder (GR).

Human whole genome expression(GE) Illumina BeadChips were performed. Data was obtained from 137 paired samples from the treatment group(T) and 49 pairs from the control(C) group with GE data passing quality check and baseline Ki67≥5% to minimise the impact of extreme values based on proportional ΔKi67. Intrinsic subtype and risk of recurrence(ROR) groups were calculated using PAM50. GE scores from Oncotype Dx, MammaPrint, p53 mutation/wildtype(Troester 2006), ER+ early response (ERE)(Hatzis 2011), estrogen-regulated genes subtypes (Oh 2006) and markers for 23 different immune cell types(Bindea 2013) were calculated. Associations of GE scores to endpoints of response were determined by Spearman correlation and chi-square tests. Bonferroni correction was used to control error rate with p&lt;0.0005 deemed significant.

Results

At B of the 137 paired T, 64% were Luminal A (LumA), 22% Luminal B (LumB), 9% as HER-2 enriched (HER2-E), 2% as Basal-like (BLBC) and 3% as Normal-like. Subtypes at B were associated with response, with LumA showing the biggest reduction of Ki67 (p=0.0001) and GR. All GE, except ERE, correlated significantly with 2wkΔKi67 and response: higher risk groups associated with lowest reduction rate. None of immune cell types correlated with 2wkΔKi67, except that tumors enriched with T-helper 1 cell type were associated with PR (p &lt; 0.000001).

Comparing subtypes between time-points, 85% of LumB and 42% of HER2-E were assigned instead as LumA at 2wk regardless of response. Of the 15 ROR defined high-risk group, only 33% were assigned instead as low-risk at 2wk.

Conclusion

Both LumA and LumB are endocrine sensitive. A fall of Ki67 was observed in majority of cases. Most tumors estimated as high-risk by molecular profiling showed less response and most remained moderate or high risk of recurrence on endocrine therapy. Whether molecular profiling at 2wk after starting AI predicts for long-term outcome in PM women with ER+ better than at diagnosis will need to be determined.

Citation Format: Cheang MCU, Morden J, Gao Q, Parker J, López-Knowles E, Detre S, Hills M, Zabaglo L, Tomiczek M, Mallon E, Robertson J, Smith I, Bliss J, Dowsett M, On Behalf of the POETIC Trialists. The impact of intrinsic subtypes and molecular features on aromatase inhibitor induced reduction of proliferation marker of Ki67 in primary ER+ breast cancer: A POETIC study (CRUK/07/015) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-10-02.