Construction of a novel multi-gene assay (42-gene classifier) for prediction of late recurrence in ER-positive breast cancer patients
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Prediction models for late (> 5 years) recurrence in ER-positive breast cancer need to be developed for the accurate selection of patients for extended hormonal therapy. We attempted to develop such a prediction model focusing on the differences in gene expression between breast cancers with early and late recurrence.
For the training set, 779 ER-positive breast cancers treated with tamoxifen alone for 5 years were selected from the databases (GSE6532, GSE12093, GSE17705, and GSE26971). For the validation set, 221 ER-positive breast cancers treated with adjuvant hormonal therapy for 5 years with or without chemotherapy at our hospital were included. Gene expression was assayed by DNA microarray analysis (Affymetrix U133 plus 2.0).
With the 42 genes differentially expressed in early and late recurrence breast cancers in the training set, a prediction model (42GC) for late recurrence was constructed. The patients classified by 42GC into the late recurrence-like group showed a significantly (P = 0.006) higher late recurrence rate as expected but a significantly (P = 1.62 × E−13) lower rate for early recurrence than non-late recurrence-like group. These observations were confirmed for the validation set, i.e., P = 0.020 for late recurrence and P = 5.70 × E−5 for early recurrence.
We developed a unique prediction model (42GC) for late recurrence by focusing on the biological differences between breast cancers with early and late recurrence. Interestingly, patients in the late recurrence-like group by 42GC were at low risk for early recurrence.
KeywordsER-positive breast cancer Late recurrence prediction Extended hormonal therapy Multi-gene assay Microarray
Human epidermal growth factor receptor 2
Distant metastasis-free survival
Fluorescence in situ hybridization
This study was supported, in part, by the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology.
Compliance with ethical standards
Conflict of interest
Professor Noguchi has been an advisor for Taiho, AstraZeneca and Novartis, and has received research funding for other studies from Sysmex, AstraZeneca, Novartis, Chugai, Daiichi-Sankyo, Kyowa-Kirin, Takeda, Pfizer, Ono, Taiho, and Eisai, and honoraria from AstraZeneca, Novartis, Pfizer, Chugai, Takeda, Sysmex, Nippon Kayaku, Ono. Dr. Kim has received honoraria from AstraZeneca. Dr. Shimazu has received honoraria from AstraZeneca and Chugai. Dr. Naoi has received research funding from Sysmex and AstraZeneca for other studies.
This study complies with the current relevant laws of and guidelines for Japan.
- 1.Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X et al (2013) Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381(9869):805–816CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97(17):1262–1271CrossRefPubMedGoogle Scholar
- 3.Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, Mlineritsch B, Tausch C, Stierer M, Hofbauer F et al (2007) Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 99(24):1845–1853CrossRefPubMedGoogle Scholar
- 4.Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN et al (2008) Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol 26(12):1965–1971CrossRefPubMedGoogle Scholar
- 5.Strasser-Weippl K, Badovinac-Crnjevic T, Fan L, Goss PE (2013) Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer. Breast 22(Suppl 2):S171–S175Google Scholar
- 10.Yamashita H, Ogiya A, Shien T, Horimoto Y, Masuda N, Inao T, Osako T, Takahashi M, Endo Y, Hosoda M et al (2016) Clinicopathological factors predicting early and late distant recurrence in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer 23(6):830–843CrossRefPubMedGoogle Scholar
- 11.Ahn SG, Lee HM, Cho SH, Bae SJ, Lee SA, Hwang SH, Jeong J, Lee HD (2013) The difference in prognostic factors between early recurrence and late recurrence in estrogen receptor-positive breast cancer: nodal stage differently impacts early and late recurrence. PLoS ONE 8(5):e63510CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Hayes DF (2015) Clinical utility of genetic signatures in selecting adjuvant treatment: risk stratification for early vs. late recurrences. Breast 24 Suppl 2:S6–S10Google Scholar
- 15.Buus R, Sestak I, Kronenwett R, Denkert C, Dubsky P, Krappmann K, Scheer M, Petry C, Cuzick J, Dowsett M (2016) Comparison of EndoPredict and EPclin with oncotype DX recurrence score for prediction of risk of distant recurrence after endocrine therapy. J Natl Cancer Inst https://doi.org/10.1093/jnci/djw149 PubMedCrossRefPubMedCentralGoogle Scholar
- 16.Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, Stal O, Brufsky AM, Sgroi D, Erlander MG (2013) Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin Cancer Res 19(15):4196–4205CrossRefPubMedGoogle Scholar
- 17.Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, Erlander MG, Dunbier A, Sidhu K, Lopez-Knowles E et al (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14(11):1067–1076CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Schroeder B, Zhang Y, Stal O, Fornander T, Brufsky A, Sgroi DC, Schnabel CA (2017) Risk stratification with Breast Cancer Index for late distant recurrence in patients with clinically low-risk (T1N0) estrogen receptor-positive breast cancer. NPJ Breast Cancer 3:28CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Filipits M, Nielsen TO, Rudas M, Greil R, Stoger H, Jakesz R, Bago-Horvath Z, Dietze O, Regitnig P, Gruber-Rossipal C et al (2014) The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer. Clin Cancer Res 20(5):1298–1305CrossRefPubMedGoogle Scholar
- 20.Ogiya A, Yamazaki K, Horii R, Shien T, Horimoto Y, Masuda N, Inao T, Hosoda M, Ishida N, Osako T et al (2017) Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer. Breast Cancer 24(3):473–482CrossRefPubMedGoogle Scholar
- 21.Naoi Y, Kishi K, Tanei T, Tsunashima R, Tominaga N, Baba Y, Kim SJ, Taguchi T, Tamaki Y, Noguchi S (2011) Development of 95-gene classifier as a powerful predictor of recurrences in node-negative and ER-positive breast cancer patients. Breast Cancer Res Treat 128(3):633–641CrossRefPubMedGoogle Scholar
- 26.Naoi Y, Kishi K, Tsunashima R, Shimazu K, Shimomura A, Maruyama N, Shimoda M, Kagara N, Baba Y, Kim SJ et al (2013) Comparison of efficacy of 95-gene and 21-gene classifier (Oncotype DX) for prediction of recurrence in ER-positive and node-negative breast cancer patients. Breast Cancer Res Treat 140(2):299–306CrossRefPubMedGoogle Scholar
- 27.Wolmark N, Mamounas EP, Baehner FL, Butler SM, Tang G, Jamshidian F, Sing AP, Shak S, Paik S (2016) Prognostic impact of the combination of recurrence score and quantitative estrogen receptor expression (ESR1) on predicting late distant recurrence risk in estrogen receptor-positive breast cancer after 5 years of tamoxifen: results from NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14. J Clin Oncol 34(20):2350–2358CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Sota Y, Naoi Y, Tsunashima R, Kagara N, Shimazu K, Maruyama N, Shimomura A, Shimoda M, Kishi K, Baba Y et al (2014) Construction of novel immune-related signature for prediction of pathological complete response to neoadjuvant chemotherapy in human breast cancer. Ann Oncol 25(1):100–106CrossRefPubMedGoogle Scholar
- 36.Zhao D, Guo L, Neves H, Yuen HF, Zhang SD, McCrudden CM, Wen Q, Zhang J, Zeng Q, Kwok HF et al (2015) The prognostic significance of protein tyrosine phosphatase 4A2 in breast cancer. OncoTargets Ther 8:1707–1717Google Scholar