Abstract
Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promote breast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NET utility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effective treatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67 (>15% vs ≤15%), and Ki67 (>10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient (pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primary ER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6), (Group 2) NET may be appropriate and a biopsy for on-treatment Ki67 analysis may be considered after 2-4 wks of NET (2A: ER 7 or 8 and PgR <6 and 2B: ER 6 or 7 and PgR ≥6) given that on-treatment Ki67 >10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 and PgR ≥6). The ALTERNATE trial (NCT01953588) randomized postmenopausal women with clinical stage II or III, ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months, unless Ki67 was >10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy (NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar across the treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trial therefore provides a large independent data set to evaluate the NET appropriateness model.
Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HR Allred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of the remaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-study Ki67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141 of 468), and Group 3 17% (104 of 607) (Table 1). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67 ≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 >10% at wk 4, compared to 231 of the 815 (28.3%) who had BL Ki67 >15% and subsequent Ki67 >10% at wk 4. 2% of pts who remained on NET due to on-treatment Ki67 <10% had PD. Response and PEPI-0 rates by group will be reported.
Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be used for the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. When baseline ER Allred scores are >6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is >15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NET appropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67 was <10%. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org; Clinical Trials.gov Identifier: NCT01953588
Table 1 Baseline levels of ER, PR, and Ki67 in Relation to Wk 4 Ki67 (N=1,085)
| . | . | Baseline . | Week 4 . | ||||
|---|---|---|---|---|---|---|---|
| Group . | N . | ERAllred Score . | PRAllred Score . | Ki67 . | Ki67 ≤10%N (%) . | Ki67 >10%N (%) . | |
| 1 | N=2 | 6 | <6 | ≤15% | 0 (0%) | 2 (100%) | 9 (90) |
| N=8 | 6 | <6 | >15% | 1 (12.5%) | 7 (87.5%) | ||
| 2A | N=64 | 7 or 8 | <6 | ≤15% | 61 (95.3%) | 3 (4.7%) | 90 (30.1) |
| N=235 | 7 or 8 | <6 | >15% | 148 (63%) | 87 (37%) | ||
| 2B | N=46 | 6 or 7 | ≥6 | ≤15% | 42 (91.3%) | 4 (8.7%) | 51 (30.2) |
| N=123 | 6 or 7 | ≥6 | >15% | 76 (61.8%) | 47 (38.2%) | ||
| 3 | N=150 | 8 | ≥6 | ≤15% | 143 (95.3%) | 7 (4.7%) | 104 (17.1) |
| N=457 | 8 | ≥6 | >15% | 360 (78.8%) | 97 (21.2%) | ||
| . | . | Baseline . | Week 4 . | ||||
|---|---|---|---|---|---|---|---|
| Group . | N . | ERAllred Score . | PRAllred Score . | Ki67 . | Ki67 ≤10%N (%) . | Ki67 >10%N (%) . | |
| 1 | N=2 | 6 | <6 | ≤15% | 0 (0%) | 2 (100%) | 9 (90) |
| N=8 | 6 | <6 | >15% | 1 (12.5%) | 7 (87.5%) | ||
| 2A | N=64 | 7 or 8 | <6 | ≤15% | 61 (95.3%) | 3 (4.7%) | 90 (30.1) |
| N=235 | 7 or 8 | <6 | >15% | 148 (63%) | 87 (37%) | ||
| 2B | N=46 | 6 or 7 | ≥6 | ≤15% | 42 (91.3%) | 4 (8.7%) | 51 (30.2) |
| N=123 | 6 or 7 | ≥6 | >15% | 76 (61.8%) | 47 (38.2%) | ||
| 3 | N=150 | 8 | ≥6 | ≤15% | 143 (95.3%) | 7 (4.7%) | 104 (17.1) |
| N=457 | 8 | ≥6 | >15% | 360 (78.8%) | 97 (21.2%) | ||
Citation Format: Matthew J Ellis, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Mitch Dowsett, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Clifford Hudis, Eric P Winer, Kelly Hunt, Ann H Partridge, Cynthia X Ma, Lisa A Carey. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): An ALTERNATE trial analysis (Alliance A011106) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-10.
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