Journal Article
. 2018 Sep;173(1).
doi: 10.1007/s10549-018-4964-y.

Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study

Hiroji Iwata 1 Norikazu Masuda 2 Yutaka Yamamoto 3 Tomomi Fujisawa 4 Tatsuya Toyama 5 Masahiro Kashiwaba 6 Shoichiro Ohtani 7 Naruto Taira 8 Takehiko Sakai 9 Yoshie Hasegawa 10 Rikiya Nakamura 11 Hiromitsu Akabane 12 Yukiko Shibahara 13 Hironobu Sasano 13 Takuhiro Yamaguchi 13 Kentaro Sakamaki 14 Helen Bailey 15 Diana B Cherbavaz 15 Debbie M Jakubowski 15 Naoko Sugiyama 15 Calvin Chao 15 Yasuo Ohashi 16 
  • PMID: 30242578
  •     36 References
  •     10 citations


Purpose: The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole.

Methods: NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result, ESR1 and PGR single-gene scores, and ER gene-group score.

Results: Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18-30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18-30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (p < 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (p < 0.001), ESR1 score (p = 0.049), PGR score (p < 0.001), and ER gene-group score (p < 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31, p = 0.010).

Conclusion: The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer.

Keywords: Breast cancer; Hormonal therapy; Neoadjuvant; Oncotype DX; Recurrence score.

Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonié Bordeaux Groupe Sein (IBBGS).
L Mauriac, G MacGrogan, +5 authors, F Bonichon.
Ann Oncol, 1999 Mar 17; 10(1). PMID: 10076721
Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients.
J Chang, T J Powles, +5 authors, M Dowsett.
Clin Cancer Res, 2000 Feb 26; 6(2). PMID: 10690547
Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.
M J Ellis, A Coop, +9 authors, M Borgs.
J Clin Oncol, 2001 Sep 18; 19(18). PMID: 11559718
Highly Cited.
Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study.
W Eiermann, S Paepke, +10 authors, Letrozole Neo-Adjuvant Breast Cancer Study Group.
Ann Oncol, 2002 Feb 02; 12(11). PMID: 11822750
Highly Cited.
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.
Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis.
Davide Mauri, Nicholas Pavlidis, John P A Ioannidis.
J Natl Cancer Inst, 2005 Feb 03; 97(3). PMID: 15687361
Highly Cited.
Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial.
Ian E Smith, Mitch Dowsett, +8 authors, IMPACT Trialists Group.
J Clin Oncol, 2005 Jul 07; 23(22). PMID: 15998903
Highly Cited.
Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.
Luca Gianni, Milvia Zambetti, +14 authors, Steven Shak.
J Clin Oncol, 2005 Sep 08; 23(29). PMID: 16145055
Highly Cited.
Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial.
Luigi Cataliotti, Aman U Buzdar, +5 authors, Celia Tosello de Oliveira.
Cancer, 2006 Apr 07; 106(10). PMID: 16598749
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.
A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
Laurel A Habel, Steven Shak, +12 authors, Charles P Quesenberry.
Breast Cancer Res, 2006 Jun 02; 8(3). PMID: 16737553    Free PMC article.
Highly Cited.
Favorable outcome in patients with breast cancer in the presence of pathological response after neoadjuvant endocrine therapy.
Sadako Akashi-Tanaka, Mutsuko Omatsu, +8 authors, Takashi Fukutomi.
Breast, 2007 Apr 10; 16(5). PMID: 17418576
Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.
Jenny C Chang, Andreas Makris, +14 authors, Steven Shak.
Breast Cancer Res Treat, 2007 May 01; 108(2). PMID: 17468949
Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer.
Vladimir F Semiglazov, Vladislav V Semiglazov, +7 authors, Lev M Berstein.
Cancer, 2007 Jun 01; 110(2). PMID: 17538978
Locally advanced and inflammatory breast cancer.
Stephen Chia, Sandra M Swain, David R Byrd, David A Mankoff.
J Clin Oncol, 2008 Feb 09; 26(5). PMID: 18258987
Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy.
Ute E Krainick-Strobel, Werner Lichtenegger, +6 authors, Stefan Paepke.
BMC Cancer, 2008 Feb 28; 8. PMID: 18302747    Free PMC article.
21-Gene expression profile assay on core needle biopsies predicts responses to neoadjuvant endocrine therapy in breast cancer patients.
Sadako Akashi-Tanaka, Chikako Shimizu, +10 authors, Kenichi Yoshimura.
Breast, 2009 May 05; 18(3). PMID: 19410462
Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial.
John A Olson, G Thomas Budd, +10 authors, Matthew J Ellis.
J Am Coll Surg, 2009 May 30; 208(5). PMID: 19476859    Free PMC article.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
Mitch Dowsett, Jack Cuzick, +11 authors, Steven Shak.
J Clin Oncol, 2010 Mar 10; 28(11). PMID: 20212256
Highly Cited.
Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition.
Masakazu Toi, Shigehira Saji, +15 authors, Hironobu Sasano.
Cancer Sci, 2011 Jan 15; 102(4). PMID: 21231986
Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031.
Matthew J Ellis, Vera J Suman, +17 authors, John A Olson.
J Clin Oncol, 2011 May 11; 29(17). PMID: 21555689    Free PMC article.
Highly Cited.
Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer.
Antonio Llombart-Cussac, Ángel Guerrero, +6 authors, Vicente Guillem Porta.
Clin Transl Oncol, 2012 Feb 04; 14(2). PMID: 22301401
Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.
Gunter von Minckwitz, Michael Untch, +14 authors, Sibylle Loibl.
J Clin Oncol, 2012 Apr 18; 30(15). PMID: 22508812
Highly Cited.
Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy.
Stefan Glück, Femke de Snoo, +2 authors, George Somlo.
Breast Cancer Res Treat, 2013 Jun 13; 139(3). PMID: 23756626
Evaluating the 21-gene assay Recurrence Score® as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer.
Takayuki Ueno, Norikazu Masuda, +12 authors, Masakazu Toi.
Int J Clin Oncol, 2013 Oct 09; 19(4). PMID: 24101215
In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?
Xavier Pivot, Laura Mansi, +14 authors, Christian Villanueva.
Oncologist, 2015 Mar 22; 20(4). PMID: 25795632    Free PMC article.
A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene recurrence score.
Denise A Yardley, Nancy W Peacock, +6 authors, John D Hainsworth.
Breast Cancer Res Treat, 2015 Oct 29; 154(2). PMID: 26507191
Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis.
Laura M Spring, Arjun Gupta, +5 authors, Aditya Bardia.
JAMA Oncol, 2016 Jul 02; 2(11). PMID: 27367583    Free PMC article.
Highly Cited. Systematic Review.
The impact of Oncotype DX® recurrence score of paraffin-embedded core biopsy tissues in predicting response to neoadjuvant chemotherapy in women with breast cancer.
Atilla Soran, Rohit Bhargava, +8 authors, Kandace P McGuire.
Breast Dis, 2016 Sep 24; 36(2-3). PMID: 27662272
Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial.
Harry D Bear, Wen Wan, +8 authors, Amy P Sing.
J Surg Oncol, 2017 Apr 14; 115(8). PMID: 28407247    Free PMC article.
Impacts of Early Guideline-Directed 21-Gene Recurrence Score Testing on Adjuvant Therapy Decision Making.
Hannah Dzimitrowicz, Sarah Mougalian, +17 authors, Tara B Sanft.
J Oncol Pract, 2017 Oct 20; 13(12). PMID: 29048991
Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).
Lancet Oncol, 2017 Dec 16; 19(1). PMID: 29242041    Free PMC article.
Highly Cited. Review.
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.
Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.
B Fisher, A Brown, +11 authors, N V Dimitrov.
J Clin Oncol, 1997 Jul 01; 15(7). PMID: 9215816
Highly Cited.
A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer.
A Makris, T J Powles, +5 authors, H T Ford.
Ann Oncol, 1998 Dec 23; 9(11). PMID: 9862047
Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.
Jill R Dietz, Meena S Moran, +16 authors, Katharine A Yao.
Breast Cancer Res Treat, 2020 Apr 26; 181(3). PMID: 32333293    Free PMC article.
Highly Cited.
Case 22-2020: A 62-Year-Old Woman with Early Breast Cancer during the Covid-19 Pandemic.
Laura M Spring, Michelle C Specht, +6 authors, Beverly Moy.
N Engl J Med, 2020 Jul 02; 383(3). PMID: 32610007    Free PMC article.
Can multigene assays widen their clinical usefulness in early breast cancer treatment choice during the current COVID-19 outbreak in Italy?
Alberto Zambelli, Carlo Alberto Tondini.
ESMO Open, 2020 Jul 15; 5(Suppl 3). PMID: 32661020    Free PMC article.
Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women-a literature review and proposed guidelines.
Lauren I Madigan, Phuong Dinh, J Dinny Graham.
Breast Cancer Res, 2020 Jul 22; 22(1). PMID: 32690069    Free PMC article.
A system for risk stratification and prioritization of breast cancer surgeries delayed by the COVID-19 pandemic: preparing for re-entry.
Barbara L Smith, Anvy Nguyen, +6 authors, Michele A Gadd.
Breast Cancer Res Treat, 2020 Jul 28; 183(3). PMID: 32712878    Free PMC article.
Evaluating ZNF217 mRNA Expression Levels as a Predictor of Response to Endocrine Therapy in ER+ Breast Cancer.
Julie A Vendrell, Jérôme Solassol, +7 authors, Pascale A Cohen.
Front Pharmacol, 2019 Feb 12; 9. PMID: 30740056    Free PMC article.
Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer.
Li-Tong Yao, Mo-Zhi Wang, +5 authors, Ying-Ying Xu.
World J Clin Cases, 2019 Aug 20; 7(15). PMID: 31423426    Free PMC article.
Molecular characterization of breast cancer needle core biopsy specimens by the 21-gene Breast Recurrence Score test.
Debbie M Jakubowski, Helen Bailey, +7 authors, Frederick L Baehner.
J Surg Oncol, 2020 Jun 05;. PMID: 32497318    Free PMC article.
Breast Cancer Management During COVID-19 Pandemic in Madrid: Surgical Strategy.
Juana María Brenes Sánchez, Amanda López Picado, +3 authors, María Herrera De La Muela.
Clin Breast Cancer, 2020 Nov 24; 21(1). PMID: 33223393    Free PMC article.
Identification of DHX36 as a tumour suppressor through modulating the activities of the stress-associated proteins and cyclin-dependent kinases in breast cancer.
Yinduo Zeng, Tao Qin, +7 authors, Yuxin Cui.
Am J Cancer Res, 2021 Jan 09; 10(12). PMID: 33414996    Free PMC article.