The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer

Abstract

Background: Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC).

Methods: The prospective WSG-ADAPT HR+/HER2- trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical-pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0-11 or RS 12-25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy.

Results: The ADAPT HR+/HER2- trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0-11, 58.3% RS 12-25, and 18.7% RS 26-100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26-100 versus others, RS 0-11 versus others) were significant (both p < 0.001); Ki-67 quotients were higher for RS 26-100 (p = 0.02, Mann-Whitney). In premenopausal women (n = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women (n = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry (p = 0.002) or real-time polymerase chain reaction (p < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (RS = 0.7, n = 181).

Conclusions: This phase of the WSG-ADAPT HR+/HER2- trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%.

Clinicaltrialsgov identifier: NCT01779206.

Keywords: Ki-67; Recurrence Score; biomarker; breast cancer; endocrine therapy.

Conflict of interest statement

Conflict of interest statement: U Nitz has minority non-profit ownership at WSG Study Group; received honoraria from Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Zodiac Pharma; has a consulting/advisory board role at Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Seattle Genetics, received research funding from Lilly (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), Pfizer (Inst), Roche/Genentech (Inst), provided expert testimony for Genomic Health; and received travel accommodations/expenses from Roche, Genomic Health, Pfizer, Celgene. O Gluz has minority non-profit ownership at WSG Study Group; received honoraria from Genomic Health, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, AstraZeneca; has a consulting/advisory board role at Amgen, Roche, Daiichi Sankyo, Genomic Health, Merck Sharp & Dohme; and received travel accommodations/expenses from Roche, Celgene, Daiichi Sankyo. HH Kreipe received honoraria from Roche, Novartis, AstraZeneca, Genomic Health; has a consulting/advisory board role at Roche, Novartis, AstraZeneca, Genomic Health; and received travel accommodations/expenses from Genomic Health, Roche Pharma, Novartis, AstraZeneca. S Kuemmel has minority non-profit ownership at WSG Study Group; has a consulting/advisory board role at Roche, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX Medical Technologies, Daiichi Sankyo, pfm medical, Pfizer, MSD, Lilly, Sonoscape; and received travel accommodations/expenses from Roche, Daiichi Sankyo, Sonoscope. FL Baehner was an employee at Genomic Health. S Shak was an employee, had a leadership role, had stock, and PI related to Genomic Health. M Christgen, H Forstbauer, E Grischke, M Darsow, M Warm, and RE Kates declare no conflict of interest. B Aktas received honoraria from Pfizer, Roche Pharma, Novartis Pharma, AstraZeneca, Amgen, Tesaro Bio Germany, PharmaMar, Eisai; has a consulting/advisory board role at Novartis Pharma, Roche Pharma, Pfizer, Tesaro Bio; and received travel accommodations/expenses from AstraZeneca, Amgen, Roche Pharma, Pfizer, Novartis Pharma, Tesaro Bio Germany, PharmaMar, Eisai. M Braun received honoraria from AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva; has a consulting/advisory board role at AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva; and received travel accommodations/expenses from AstraZeneca, Celgene, Eisai, Genomic Health, GlaxoSmithKline, Medac, Novatis, Pfizer, Roche, RTI Surgical, Teva. K Lüdtke-Heckenkamp has a consulting/advisory board role at Roche, Lilly, Novartis, Celgene; received research funding from Roche (Inst), Lilly (Inst), Novartis (Inst), Pfizer (Inst); and received travel accommodations/expenses from Roche, Celgene, Pfizer, Novartis. B Nuding has a consulting/advisory board role at Roche, Novartis, Pfizer; and received travel accommodations/expenses from Novartis. C Schumacher received research funding from Roche (Inst), Novartis (Inst), Boehringer (Inst); and serves on the Speaker’s bureau of Roche. K Krauss has stock/interest at Fresenius (Fam); received honoraria from Roche, Celgene; received research funding from Novartis, Pfizer; and received travel accommodations/expenses from Medtronic. W Malter received honoraria from Nanostring, Celgene, Roche; and has a consulting/advisory board role at Genomic Health, Pfizer, Novartis, Hologic. M Thill received honoraria from Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Eisai, Exact Sciences, Daiichi Sanyko, Gedeon Richter, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Novartis, onkowissen.de, Omniamed, Pfizer, pfm Medical, Roche, RTI Surgical; has a consulting/advisory board role at Amgen, AstraZeneca, Biom‘Up, Celgene, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, Lilly, MSD, Norgine, Neodynamics, Novartis, onkowissen.de, Pfizer, pfm Medical, Pierre-Fabre, Roche, RTI Surgical, Sysmex, Tesaro; received research funding from Exact Sciences; received travel accommodation/expenses from Amgen, Art Tempi, AstraZeneca, Celgene, Clovis, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MCI, Medtronic, MSD, Norgine, Novartis, Omniamed, Pfizer, pfm Medical, Roche, RTI Surgical, Tesaro. R Wuerstlein has a consulting/advisory board role at Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva; received travel accommodation/expenses from Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva; and is on the Speaker’s bureau of Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi-Sankyo, Eisai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. N Harbeck has minority non-profit ownership at WSG Study Group; received honoraria for consulting and/or lectures from Agendia, Amgen, AstraZeneca, BMS, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Samsung, Sandoz/Hexal, Seattle Genetics.

© The Author(s), 2020.

Figures

Figure 1.

WSG-ADAPT HR+/HER2− trial design. Reprinted from Hofmann et al. HR, hormone receptor; HER2, human epidermal growth-factor receptor 2; q1w, weekly; pCR, pathologic complete response; q2w, every second week; RS, Recurrence Score.