Journal Article
. 2020 Dec;12().
doi: 10.1177/1758835920973130.

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

Ulrike Nitz 1 Oleg Gluz 1 Hans H Kreipe 2 Matthias Christgen 2 Sherko Kuemmel 1 Frederick L Baehner 3 Steven Shak 3 Bahriye Aktas 4 Michael Braun 5 Kerstin Lüdtke-Heckenkamp 6 Helmut Forstbauer 7 Eva-Maria Grischke 8 Benno Nuding 9 Maren Darsow 10 Claudia Schumacher 11 Katja Krauss 12 Wolfram Malter 13 Marc Thill 14 Mathias Warm 15 Rachel Wuerstlein 16 Ronald E Kates 1 Nadia Harbeck 17 
Affiliations
  • PMID: 33281950
  •     14 References

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.

A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial.
Daniel Hofmann, Ulrike Nitz, +4 authors, Nadia Harbeck.
Trials, 2013 Aug 21; 14. PMID: 23958221    Free PMC article.
Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27.
K Strasser-Weippl, G Sudan, +6 authors, P E Goss.
Eur J Cancer, 2017 Dec 24; 90. PMID: 29274617
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
Joseph A Sparano, Robert J Gray, +27 authors, George W Sledge.
N Engl J Med, 2018 Jun 05; 379(2). PMID: 29860917    Free PMC article.
Highly Cited.
Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.
John M S Bartlett, Cassandra L Brookes, +15 authors, Daniel Rea.
J Clin Oncol, 2011 Mar 23; 29(12). PMID: 21422407    Free PMC article.
Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.
Matthew J Ellis, Andrew Coop, +8 authors, William R Miller.
Cancer Res, 2003 Oct 16; 63(19). PMID: 14559846
Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.
Giuseppe Viale, Anita Giobbie-Hurder, +18 authors, Breast International Group Trial 1-98.
J Clin Oncol, 2008 Nov 05; 26(34). PMID: 18981464    Free PMC article.
Highly Cited.
Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.
Prudence A Francis, Olivia Pagani, +34 authors, SOFT and TEXT Investigators and the International Breast Cancer Study Group.
N Engl J Med, 2018 Jun 05; 379(2). PMID: 29863451    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics.
Matthew J Ellis, Yu Tao, +9 authors, Mitch Dowsett.
J Natl Cancer Inst, 2008 Sep 25; 100(19). PMID: 18812550    Free PMC article.
Highly Cited.
Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.
Mitch Dowsett, Ian E Smith, +8 authors, IMPACT Trialists Group.
J Natl Cancer Inst, 2007 Jan 18; 99(2). PMID: 17228000
Highly Cited.
Endocrine therapy, new biologicals, and new study designs for presurgical studies in breast cancer.
Mitch Dowsett, Ian Smith, +13 authors, Judith Bliss.
J Natl Cancer Inst Monogr, 2011 Nov 02; 2011(43). PMID: 22043057
Letrozole in the neoadjuvant setting: the P024 trial.
Matthew J Ellis, Cynthia Ma.
Breast Cancer Res Treat, 2007 Nov 21; 105 Suppl 1. PMID: 17912634    Free PMC article.
Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.
Chungyeul Kim, Gong Tang, +18 authors, Soonmyung Paik.
J Clin Oncol, 2011 Sep 29; 29(31). PMID: 21947828    Free PMC article.