ABSTRACT
Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promotebreast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NETutility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effectivetreatments. 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 primaryER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER <6or ER 6 and PgR <6), (Group 2) NET may be appropriate and a biopsy for on-treatment Ki67 analysis may beconsidered 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 andPgR ≥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 acrossthe treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trialtherefore 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 HRAllred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of theremaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-studyKi67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141of 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-treatmentKi67 <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 usedfor the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. Whenbaseline 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 NETappropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67was <10%. (Table Presented).