Decision of Adjuvant Systemic Treatment in HR+ HER2- Early Invasive Breast Cancer: Which Biomarkers Could Help?

Figures & data

Table 1 Prognostic Value of Oncotype DX^® (Only HR+, HER2- Tumors)

Reference	N	Population	Systemic Treatment	Median Follow-Up (Months)	Primary Endpoint(s)	Results		Comments
Univariate Analysis	Multivariate Analysis
Adjuvant, prospective studies
Sparano et al, 2015^Citation56	1626	HR+ (ER+, n = 1621), HER2-, N0, 1.1–5 cm or 0.6–1.0 cm and intermediate or high grade, RS 0 to 10	-ET alone: AI (n = 963, 59%), Tam (n = 560, 34%), Tam + AI (n = 13, 0.8%), ovarian-function suppression (n = 44, 2.7%), other or unknown therapy (n = 46, 2.8%)	69	5y-DFS (%, 95% CI)	93.8 (92.4–94.9)	NR	- Prospective randomized trial - Modification of the LR group (RS ≤ 10)
Sparano et al, 2018^Citation59	6711	HR+ (ER+, n = 6702), HER2-, N0, 1.1–5 cm or 0.6–1.0 cm and intermediate or high grade, RS 11 to 25	-ET alone (n = 3399) -ET + CT (n = 3312)	90	9y-DFS (%)	● ET alone 83.3±0.9 ● ET + CT: 84.3±0.8	NR
Glutz et al, 2016^Citation57	2642	N+ or high-risk N- (T2, grade 2 and 3, high uPA/PAI-1, or age < 35y), HR + HER2- ER + = 2390 (90.5%) LR = 459 (17.4%) IR = 1544 (58.4%) HgR = 550 (20.8%) Unknown = 89 (3.4%)	No CT if RS ≤ 11 (n = 348, 15.3%)	35	3y-DFS (%, 95% CI)	HgR: 91.9 (89.0–94.8) IR: 97.8 (96.8–98.8) LR: 97.4 (95.6–99.1) p< 0.001		- Prospective trial - LR defined by RS ≤ 11 HgR defined by RS > 25
RS fractionally ranked (75th-25th percentile) HR = 2.31 (1.52–3.52), p< 0.001	HR = 1.68 (1.04–2.74), p = 0.035
Adjuvant, retrospective studies
Le Du et al, 2015^Citation52	1030	ER+ HER2- T1 LR = 571 (55.5%) IR = 370 (35.9%) HgR = 89 (8.6%)	ET (n = 722, 70%), CT (n = 2, 0.2%) both (n = 266, 26%), none (n = 17, 1.7%), missing data (n = 23, 2%)	38.4	5y-DMFS (%)	HgR: 76.4, (59.2–87.1) LR: 95.9 (93.0–97.6) p< 0.0001	NS	Retrospective study
Wen et al, 2017^Citation53	1406	N0, ER+, HER2- RS < 18	ET (n = 1361, 97%), CT (n = 170, 12%)	46	5y-DMFS (%)	99.6	NR	Retrospective single-institution study
Barcenas et al, 2017^Citation51	1424	HR+, HER2-, N0 LR = 297 (20.8%) IR = 894 (62.8%) HgR = 233 (16.4%)	CT (n = 310, 22%), ET (n = 1302, 91%)	58	5y-IDFS (%, 95% CI)	IR group: 92.6 (89.6–94.7)		- Retrospective single-institution study - HRs of the effect of chemotherapy in IR group were NS: 1.64 for DFS (95% CI, 0.73–3.71), 1.46 for RFS (95% CI, 0.41–5.23), 1.25 for DMFS (95% CI, 0.32–4.92), and 2.19 for OS (95% CI, 0.44–11.0) - cutoffs:LR: RS ≤ 10, IR: RS 11–25, HgR: RS > 25
Neoadjuvant
Soran et al, 2016^Citation104	60	ER+ HER2- T1-3 N0-1 LR =27 (45%) IR =10 (17%) HgR =23 (38%)	AC-T	NA	Clinical response rate	NS (categorical RS: p = 0.21, continuous RS: p = 0.7)	NA

Notes: The bolded data in the population column indicate the inclusion criteria for the population in the study, while the data in conventional characters indicate the observed characteristics of the population.

Abbreviations: RS, recurrence score; HR, hormone receptor; ER, estrogen receptor; LR., low risk; IR, intermediate risk; HgR, high risk; N0, node negative; N+, node positive; CT, chemotherapy; ET, endocrine therapy; Tam, Tamoxifen; y, year; DFS, disease-free survival; RFS, recurrence-free survival; DRFS, distant recurrence-free survival; OS, overall survival; MFS, metastasis-free survival; BCSS, breast cancer-specific survival; DMFS, distant metastasis-free survival; DMFI, distant metastasis-free interval; IDFS, invasive disease-free survival; TTDR, time to distant recurrence; LRR, loco-regional recurrence; pCR, pathological complete response; NR, not reported; NS, no significant; NA, not applicable; NSABP, National Surgical Adjuvant Breast and Bowel Project; ATAC, Arimidex Tamoxifen Alone or in Combination.

Table 2 Evaluable Multivariate Analysis of Biomarkers for Prognosis in Adjuvant Studies in HR+, HER2- Patient

A. Oncotype DX^®
Number of unique patients
Total	3672
Number of multivariate models	2
Biomarker is significant (p< 0.05)	1
Adjustment factors (%)
● Tumor grade	100%
● Tumor size	50%
● Nodal status/number of nodes	50%
● ER level	50%
● PR level	50%
● Ki-67	100%
B. EndoPredict^®
Number of unique patients
Total	4509
Number of multivariate models	4
Biomarker is significant (p< 0.05)	4
Adjustment factor (%)
● Tumor size	100%
● Nodal status/number of nodes	100%
● Tumor grade	100%
● Age	100%
● ER status	25%
● PR status	50%
● Ki-67	50%
● Type of endocrine therapy	75%
● Systemic treatment	25%

Table 3 Prognostic Value of Endopredict^® (Only HR+, HER2-)

Reference	N	Population	Systemic Treatment	Median Follow-Up (Months)	Primary Endpoint(s)	Results		Comments
Univariate	Multivariate
Adjuvant
Filipits et al, 2011^Citation73	1702	ER+, HER2- (ABCSG-6: n = 378, ABCSG-8: n = 1324, postmenopausal) LR = 832 (48.9%) HgR = 870 (51.1%)	ET alone - Tam 5y (ABCSG-6) - Tam 5 or 2y + anastrozole 3y (ABCSG-8)	- 97.4 (ABCSG-6) - 72.3 (ABCSG-8)	10y-DMFS (%)	- ABCSG-6: LR: 8 (3–13), HgR: 22 (15–29) p< 0.001 - ABCSG-8: LR: 6 (2–9), HgR: 15 (11–20) p< 0.001 EPclin: - ABCSG-6: LR: 4 (1–8), HgR: 28 (20–36) p< 0.001 - ABCSG-8: LR: 4 (2–5), HgR: 22 (15–29) p< 0.001	- ABCSG-6 HR = 1.19 (1.04–1.36), p = 0.010 - ABCSG-8 HR = 1.26 (1.15–1.38), p<0.001	- Patients from prospective trials - Description training set: 964 ER+, HER2- tumors from patients treated with adjuvant Tamoxifen only - long-term data in Dubsky et al^Citation105. EP, 0–5y: HR (multivariateanalysis) = 1.20 (1.10–1.31), p< 0.001. EP, >5y: HR (multivariateanalysis) = 1.28 (1.10–1.48), p< 0.001. EPclin, 0-5y: HR = 4.82 (3.12–7.44), p < 0.001. EPclin, >5y: HR = 6.25 (2.72–14.36), p < 0.001. EPclin 10y DMFS: LR 98.20% (96.54–99.85), HgR 87.69 (82.86–92.52)
Martin et al, 2014^Citation76	555	ER+, HER2-, N+ LR = 141 (25%) HgR = 414 (75%) EPclin LR = 74 (13%)	CT (FEC x 6 or FEC x 4 + paclitaxel x 8) 5-y ET (Tam, AI or both)	104.4	10y-DMFS	LR: 93%, HgR: 70% HR = 4.8 (2.5–9.5); p< 0.0001	HR = 1.126 (1.041–1.219) p = 0.0031	- Patients from a prospective trial (GEICAM 9906 trial) - Interaction test chemotherapy arm (FEC vs FEC-T) and EP score: NS (p = 0.71)
Fitzal et al, 2015^Citation106	1324	ER+, HER2- postmenopausal LR = 641 (48.4%) HgR = 683 (51.6%)	Tam 5y or 2y + anastrozole 3y	72.3	10y-local recurrence free survival (%)	LR: 98.4, HgR: 96.2 p = 0.008 EPclin LR: 98.3, HgR: 95.3	p< 0.005	Patients from a prospective trial (ABCSG-8)
Buus et al, 2016^Citation77	928	ER+ HER2- N0 = 680 (73.3%) LR = 386 (41.6%) HgR = 542 (58.4%) EPclin LR = 546 (58.8%)	Anastrozole or Tam 5y No CT	120	DMFS	EPclin 0-10y:χ^2 = 139.3; p < 0.001 0-5y:χ^2 = 80.0; p < 0.001 5-10y: χ^2 = 59.3; p < 0.001 EP 0-10y:χ^2 49.3; p < 0.001 0-5y:χ^2 25.7; p < 0.001 5-10y: χ^2 23.6; p < 0.001	EP clin 0-10y: χ^2 = 20.3; p < 0.001 0-5y: χ^2 = 10.5; p = 0.001 5–10:χ^2 = 9.9; p = 0.002 EP 0-10y: χ^2 16.4; p < 0.001 0-5y: χ^2 6.9; p = 0.009 5-10y: χ^2 9.8; p = 0.002	- Patients from a prospective trial (ATAC trial) - Comparison RS
Neoadjuvant
Bertucci et al, 2014 ^Citation78	553	ER+, HER2- cN+ = 336 (65%) LR = 283 (51%) HgR = 270 (49%)	anthracycline-based CT	40	pCR rate (%)	LR: 7, HgR: 17 p < 0.001	OR = 1.13 (1.04–1.24) p = 0.02	HgR 5y-DFS equal to 73% (95% CI 63–85) vs LR 88% (95% CI 81–95) p = 0.015

Notes: The bolded data in the population column indicate the inclusion criteria for the population in the study, while the data in conventional characters indicate the observed characteristics of the population.

Abbreviations: EP, EndoPredict score; EP, Clin EP based on tumor size and nodal status; ER, estrogen receptor; LR, low risk; HgR, high risk; N0, node negative; N+, node positive; CT, chemotherapy; ET, endocrine therapy; Tam, Tamoxifen; FEC, fluorouracil + epirubicin + cyclophosphamide; DMFS, distant metastasis-free survival; DFS, disease-free survival; pCR, pathological complete response; NR, not reported; NS, no significant; ABCSG, Austrian Breast and Colorectal Cancer Study Group; ATAC, Arimidex Tamoxifen Alone or in Combination.

Table 4 Prognostic Value of PAM50 ROR (Only HR+, HER2-)

Reference	N	Population	Systemic Treatment	Median Follow-Up (Months)	Primary Endpoint(s)	Results		Comments
Univariate Analysis	Multivariate Analysis
Adjuvant, retrospective studies in prospective trials
Martin et al, 2016^Citation86	555	N+, ER+, HER2- (GEICAM 9906 trial) ROR-S: LR =173 (32.3%) IR =233 (43.5%) HgR = 130 (25.2%)	CT (6 FEC or FEC X 4 + 8 weekly paclitaxel) 5-y ET (Tam, AI or both)	104.4	DMFS	- ROR-S:LR vs IR: HR = 2.3, LR vsHgR: HR = 3.2 - ROR-P:LR vs IR: HR = 2.5, LR vsHgR: HR = 4 - ROR-T:LR vs IR: HR = 2.3, LR vsHgR: HR = 3.7 - ROR-PT: LR vs IR: HR = 4.5, LR vsHgR: HR = 5.8 -p< 0.001 for all		Cutoffs: ROR-S (<24; 24–53; >53), ROR-P (<12; 12–53; >53), ROR-T (<29; 29–65; >65), PAM50 ROR-PT (<18; 18–65; >65).
Adjuvant, retrospective studies
Cockburn et al, 2016^Citation88		ER+, HER2- (GSE6532-A and GSE6532-2) %LR, IR, HgR: NR	- Tam 5y - No detail about CT	120	DMFS	N0: HR = 0.48, p = 8.07E-04 N+: HR = 0.65, p = 1.34E-02	NR	Cohort study
Neoadjuvant
Prat et al, 2016^Citation91	180	HR+ (ER+ 99.4%), HER2- N0 = 67 (37.2%) continuous ROR-S	8 to 10 cycles of anthracyclines and taxanes	NA	Residual breast cancer burden 0/I: response rate	Continuous ROR score was a significant predictor of response to CT (p = 0.047)	NR	Every 20 point increase in ROR score, a patient was 59.1% more likely to respond to CT in the neoadjuvant setting

Notes: The bolded data in the population column indicate the inclusion criteria for the population in the study, while the data in conventional characters indicate the observed characteristics of the population.

Abbreviations: ROR, risk of recurrence; ROR-S, ROR based on subtype; ROR-P, ROR based on subtype and proliferation; ROR-T, ROR based on subtype and tumor size; ROR-PT, ROR based on subtype, proliferation, and tumor size; HR, hormone receptor; ER, estrogen receptor; LR, low risk; IR, intermediate risk; HgR, high risk; N0, node negative; N+, node positive; CT, chemotherapy; ET, endocrine therapy; Tam, Tamoxifen; DMFS, distant metastasis-free survival; NR, not reported.

Table 5 Correlation Between Signatures

	upA/PAI-1	Oncotype DX^®	Mammaprint^®	PAM50 ROR
Oncotype DX^®	NR
Mammaprint^®	NR	- Cramer’s V statistic = 0.6^Citation41,Citation98 - r = 0.68^Citation44 - Pearson correlation = 0.65^Citation80 - Kappa =0.40 (0.30 to 0.49)^Citation101
PAM50 ROR	NR	- r = 0.39^Citation84 - r = 0.76^Citation44 - r = 0.08^Citation99 -Pearson correlation = 0.78^Citation80 - kappa = 0.44 (0.33 to 0.54)^Citation101	- r = 0.64^Citation44 - Pearson correlation = 0.68^Citation80 - kappa = 0.53 (0.43 to 0.63)^Citation101
Endopredict^®	-EPclinvs uPA: kappa = 0.313 (p < 0.001) -EPclinvs PAI-1 kappa = 0.176 (p = 0.066)^Citation102	- kappa = 0.41 (EPclin)^Citation77 - Pearson correlation = 0.82^Citation80 - r = 0.65^Citation100	- Pearson correlation = 0.68^Citation80	- r = 0.72^Citation86 - Pearson correlation = 0.81^Citation80

Abbreviation: NR not reported.

Figure 1 Flowchart of eligible studies.

Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005–2014. doi:10.1056/NEJMoa151076426412349

 PubMed Web of Science ®Google Scholar

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111–121. doi:10.1056/NEJMoa180471029860917

 PubMed Web of Science ®Google Scholar

Gluz O, Nitz UA, Christgen M, et al. West German Study Group Phase III planb trial: first prospective outcome data for the 21-gene recurrence score assay and concordance of prognostic markers by central and local pathology assessment. J Clin Oncol off J Am Soc Clin Oncol. 2016;34(20):2341–2349. doi:10.1200/JCO.2015.63.5383

 PubMed Web of Science ®Google Scholar

Le Du F, Gonzalez-Angulo AM, Park M, Liu DD, Hortobagyi GN, Ueno NT. Effect of 21-gene RT-PCR assay on adjuvant therapy and outcomes in patients with stage I breast cancer. Clin Breast Cancer. 2015;15(6):458–466. doi:10.1016/j.clbc.2015.06.00626233757

 PubMed Web of Science ®Google Scholar

Wen HY, Krystel-Whittemore M, Patil S, et al. Breast carcinoma with an oncotype Dx recurrence score <18: rate of distant metastases in a large series with clinical follow-up. Cancer. 2017;123(1):131–137. doi:10.1002/cncr.3027127526056

 PubMed Web of Science ®Google Scholar

Barcenas CH, Raghavendra A, Sinha AK, et al. Outcomes in patients with early-stage breast cancer who underwent a 21-gene expression assay. Cancer. 2017;123:2422–2431. doi:10.1002/cncr.3061828199747

 PubMed Web of Science ®Google Scholar

Soran A, Bhargava R, Johnson R, et al. The impact of Oncotype DX® recurrence score of paraffin-embedded core biopsy tissues in predicting response to neoadjuvant chemotherapy in women with breast cancer. Breast Dis. 2016;36(2–3):65–71. doi:10.3233/BD-15019927662272

 PubMedGoogle Scholar

Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res off J Am Assoc Cancer Res. 2011;17(18):6012–6020. doi:10.1158/1078-0432.CCR-11-0926

 PubMed Web of Science ®Google Scholar

Dubsky P, Filipits M, Jakesz R, et al. EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. Ann Oncol off J Eur Soc Med Oncol. 2013;24(3):640–647. doi:10.1093/annonc/mds334

 PubMed Web of Science ®Google Scholar

Martin M, Brase JC, Calvo L, et al. Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2- breast cancer patients: results from the GEICAM 9906 trial. Breast Cancer Res BCR. 2014;16(2):R38. doi:10.1186/bcr364224725534

 PubMed Web of Science ®Google Scholar

Fitzal F, Filipits M, Rudas M, et al. The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial. Br J Cancer. 2015;112(8):1405–1410. doi:10.1038/bjc.2015.9825867274

 PubMed Web of Science ®Google Scholar

Buus R, Sestak I, Kronenwett R, et al. Comparison of endopredict and epclin with oncotype DX recurrence score for prediction of risk of distant recurrence after endocrine therapy. J Natl Cancer Inst. 2016;108(11). doi:10.1093/jnci/djw149

 PubMedGoogle Scholar

Bertucci F, Finetti P, Viens P, Birnbaum D. EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive, HER2-negative breast cancer. Cancer Lett. 2014;355(1):70–75. doi:10.1016/j.canlet.2014.09.01425218596

 PubMed Web of Science ®Google Scholar

Martin M, Brase JC, Ruiz A, et al. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study. Breast Cancer Res Treat. 2016;156(1):81–89. doi:10.1007/s10549-016-3725-z26909792

 PubMed Web of Science ®Google Scholar

Cockburn JG, Hallett RM, Gillgrass AE, et al. The effects of lymph node status on predicting outcome in ER+/HER2- tamoxifen treated breast cancer patients using gene signatures. BMC Cancer. 2016;16:555. doi:10.1186/s12885-016-2501-027469239

 PubMed Web of Science ®Google Scholar

Prat A, Galván P, Jimenez B, et al. Prediction of response to neoadjuvant chemotherapy using core needle biopsy samples with the prosigna assay. Clin Cancer Res off J Am Assoc Cancer Res. 2016;22(3):560–566. doi:10.1158/1078-0432.CCR-15-0630

 PubMed Web of Science ®Google Scholar

Espinosa E, Sánchez-Navarro I, Gámez-Pozo A, et al. Comparison of prognostic gene profiles using qRT-PCR in paraffin samples: a retrospective study in patients with early breast cancer. PLoS One. 2009;4(6):e5911. doi:10.1371/journal.pone.000591119547727

 PubMed Web of Science ®Google Scholar

Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med. 2006;355(6):560–569. doi:10.1056/NEJMoa05293316899776

 PubMed Web of Science ®Google Scholar

Prat A, Parker JS, Fan C, et al. Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen. Ann Oncol off J Eur Soc Med Oncol. 2012;23(11):2866–2873. doi:10.1093/annonc/mds080

 PubMed Web of Science ®Google Scholar

Zhao X, Rødland EA, Sørlie T, et al. Systematic assessment of prognostic gene signatures for breast cancer shows distinct influence of time and ER status. BMC Cancer. 2014;14:211. doi:10.1186/1471-2407-14-21124645668

 PubMed Web of Science ®Google Scholar

Bartlett JMS, Bayani J, Marshall A, et al. Comparing breast cancer multiparameter tests in the OPTIMA prelim trial: no test is more equal than the others. J Natl Cancer Inst. 2016;108(9). doi:10.1093/jnci/djw050

 PubMedGoogle Scholar

Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol off J Am Soc Clin Oncol. 2013;31(22):2783–2790. doi:10.1200/JCO.2012.46.1558

 PubMed Web of Science ®Google Scholar

Alvarado MD, Prasad C, Rothney M, et al. A prospective comparison of the 21-gene recurrence score and the PAM50-based prosigna in estrogen receptor-positive early-stage breast cancer. Adv Ther. 2015;32(12):1237–1247. doi:10.1007/s12325-015-0269-226610383

 PubMed Web of Science ®Google Scholar

Ettl J, Klein E, Hapfelmeier A, et al. Decision impact and feasibility of different ASCO-recommended biomarkers in early breast cancer: prospective comparison of molecular marker EndoPredict and protein marker uPA/PAI-1. PLoS One. 2017;12(9):e0183917. doi:10.1371/journal.pone.018391728877230

 PubMed Web of Science ®Google Scholar

Varga Z, Sinn P, Fritzsche F, et al. Comparison of endopredict and oncotype DX test results in hormone receptor positive invasive breast cancer. PLoS One. 2013;8(3):e58483. doi:10.1371/journal.pone.005848323505515

 PubMed Web of Science ®Google Scholar