Long-term outcome and prognostic value of Ki67
after perioperative endocrine therapy in postmenopausal women with
hormone-sensitive early breast cancer (POETIC): an open-label, multicentre,
parallel-group, randomised, phase 3 trial
by Ian Smith, John Robertson, Lucy Kilburn, Maggie Wilcox,
Abigail Evans, Chris Holcombe, Kieran Horgan, Cliona Kirwan, Elizabeth Mallon,
Mark Sibbering, Anthony Skene, Raghavan Vidya, Maggie Cheang, Jane Banerji,
James Morden, Kally Sidhu, Andrew Dodson, Judith M Bliss, Mitch Dowsett
The Lancet Oncology:
ARTICLES| VOLUME
21, ISSUE 11, P1443-1454, NOVEMBER 01, 2020
Background
Preoperative and perioperative aromatase inhibitor (POAI)
therapy has the potential to improve outcomes in women with operable oestrogen
receptor-positive primary breast cancer. It has also been suggested that tumour
Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome
better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two
hypotheses.
Methods
POETIC was an open-label, multicentre, parallel-group,
randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal
women aged at least 50 years with WHO performance status 0–1 and hormone
receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI
(letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14
days before and following surgery or no POAI (control). Adjuvant treatment was
given as per UK standard local practice. Randomisation was done centrally by
computer-generated permuted block method (variable block size of six or nine)
and was stratified by hospital. Treatment allocation was not masked. The
primary endpoint was time to recurrence. A key second objective explored
association between Ki67 (dichotomised at 10%) and disease outcomes. The
primary analysis for clinical endpoints was by modified intention to treat (excluding
patients who withdrew consent). For Ki67 biomarker association and endpoint
analysis, the evaluable population included all randomly assigned patients who
had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310;
the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN
registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is
ongoing.
Findings
Between Oct 13, 2008, and April 16, 2014, 4480 women were
recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6,
2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women
had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio
0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer
recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI
group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated
HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and
Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and
low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high).
Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in
the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low
group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported
grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI
group vs six [<1%] of 1400 in the control group) and
musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related
deaths were reported.
Interpretation
POAI has not been shown to improve treatment outcome, but
can be used without detriment to help select appropriate adjuvant therapy based
on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do
well with adjuvant standard endocrine therapy (giving consideration to
clinical–pathological factors), whereas those whose POAI-induced Ki672W remains
high might benefit from further adjuvant treatment or trials of new therapies.
Funding
Cancer Research UK.
