Use of primary breast tumor gene analysis to prognosticate risk of recurrence and guide therapy
Overall survival (OS): Alive after diagnosis with breast cancer, prior to death from any cause
Breast cancer-specific survival (BCSS): Alive after diagnosis with breast cancer, prior to death from breast cancer
Disease-free survival (DFS): Alive without any evidence of locoregional recurrence or distant metastasis from breast cancer
Distant metastasis-free survival (DMFS): Alive without any evidence of distant metastasis from breast cancer
Oncotype DX: Calculates 9-year risk of distant recurrence as recurrence score (RS) based on expression of 21 genes (16 cancer-related and 5 reference genes)
Used in estrogen receptor ER(+), HER2(-), T1-2, N0 disease; insufficient evidence for routine use in node-positive disease at present
Genes are involved in pathways of estrogen signaling (ESR1, PGR, BCL2, SCUBE3), HER2 (GRB7 and ERBB2), and proliferation (MKI67, AURKA, BIRC5, CCNBI, and MYBL2)
Continuous risk model: Low recurrence score (RS < 18), intermediate (RS 18-30), and high (RS ≥ 31)
Assumes 5 years of tamoxifen therapy as standard; systemic chemotherapy recommended if high RS
MammaPrint: 70-gene expression signature developed using DNA microarray analysis
Used in ER(+) and ER(-), HER2(-) tumors, T1-3, N0-N1 disease
Validated on both fresh and paraffin-embedded tissue
Binary/dichotomous risk model
Separates breast cancers into those at low- or high-risk of developing distant metastases within first 10 years after diagnosis
BluePrint: Determines intrinsic subtype (luminal A or B; HER2-type; basal-like) based on 80-gene signature
Prosigna = Prediction Analysis of Microarray Risk of Recurrence (PAM50 ROR): Calculated using expression profile of 46-gene subset of 50 selected genes of 4 intrinsic subtypes (PAM50), proliferation score (18-gene subset), and tumor size
Stratifies patients with ER(+) disease into high, medium, and low subsets
Magee equations: Model prediction of Oncotype DX RS using Nottingham score, Ki-67, tumor size, quantitative ER and PR, and HER2 status in ER(+) T1-2, N0 disease
EndoPredict: Gene expression assay, includes 8 cancer-related genes of interest and 3 reference genes, validated using data from 2 ABCSG trials (ABCSG-6 and ABCSG-8)
Used in ER/PR(+), HER2(-), T1-3, N0-1, M0 disease
Classifies patients into 2 recurrence risk groups
Breast cancer index (BCI): Combines HOXB13/IL17BR (H/I) 2-gene ratio and molecular grade index (MGI), which is 5-gene predictor including tumor grade and proliferation
Prognostic factor: Estimates outcomes, such as BCSS or DMFS, in absence of treatment
Predictive factor: Estimates likelihood of response to particular treatment
CLINICAL ISSUES
Natural History & Prognosis
Treatment
Selected References
Bowden AR et al: Clinical implications of germline mutations in breast cancer genes: RECQL. Breast Cancer Res Treat. ePub, 2019
Bhargava R et al: Breast cancers with Magee equation score of less than 18, or 18-25 and mitosis score of 1, do not require Oncotype DX testing: A value study. Am J Clin Pathol. ePub, 2018
Sparano JA et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. ePub, 2018
Sughayer M et al: Applying new Magee equations for predicting the Oncotype DX recurrence score. Breast Cancer. 25(5):597-604, 2018
Krop I et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 35(24):2838-2847, 2017
Mamounas EP et al: 21-gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemo-endocrine therapy. J Natl Cancer Inst. 109(4), 2017
Cardoso F et al: 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 375(8):717-29, 2016
Sestak I et al: Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol. 33(8):916-22, 2015
Sparano JA et al: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. ePub, 2015
Filipits M et al: 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):1298-305, 2014
Gnant M et al: Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 25(2):339-45, 2014
Sapino A et al: MammaPrint molecular diagnostics on formalin-fixed, paraffin-embedded tissue. J Mol Diagn. 16(2):190-7, 2014
Dubsky P et al: The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer. 109(12):2959-64, 2013
Glück S et al: Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat. 139(3):759-67, 2013
Ramsey SD et al: Integrating comparative effectiveness design elements and endpoints into a phase III, randomized clinical trial (SWOG S1007) evaluating oncotypeDX-guided management for women with breast cancer involving lymph nodes. Contemp Clin Trials. 34(1):1-9, 2013
Sgroi DC et al: 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):1067-76, 2013
Dubsky PC et al: Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 30(7):722-8, 2012
Filipits M 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. 17(18):6012-20, 2011
Knauer M et al: The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 120(3):655-61, 2010
Mamounas EP et al: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 28(10):1677-83, 2010
Mook S et al: The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 116(2):295-302, 2009
Parker JS et al: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 27(8):1160-7, 2009
Cardoso F et al: Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 26(5):729-35, 2008
Sparano JA et al: Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 26(5):721-8, 2008
Mook S et al: Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 4(3):147-55, 2007
Cobleigh MA et al: Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res. 11(24 Pt 1):8623-31, 2005
Jakesz R et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 366(9484):455-62, 2005
Paik S et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 351(27):2817-26, 2004
Schmid M et al: Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6. J Clin Oncol. 21(6):984-90, 2003
van’tVeer LJ et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415(6871):530-6, 2002
van de Vijver MJ et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 347(25):1999-2009, 2002
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References
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Tables
KEY FACTS
Terminology
Clinical Issues
TERMINOLOGY
Definitions
Use of primary breast tumor gene analysis to prognosticate risk of recurrence and guide therapy
Overall survival (OS): Alive after diagnosis with breast cancer, prior to death from any cause
Breast cancer-specific survival (BCSS): Alive after diagnosis with breast cancer, prior to death from breast cancer
Disease-free survival (DFS): Alive without any evidence of locoregional recurrence or distant metastasis from breast cancer
Distant metastasis-free survival (DMFS): Alive without any evidence of distant metastasis from breast cancer
Oncotype DX: Calculates 9-year risk of distant recurrence as recurrence score (RS) based on expression of 21 genes (16 cancer-related and 5 reference genes)
Used in estrogen receptor ER(+), HER2(-), T1-2, N0 disease; insufficient evidence for routine use in node-positive disease at present
Genes are involved in pathways of estrogen signaling (ESR1, PGR, BCL2, SCUBE3), HER2 (GRB7 and ERBB2), and proliferation (MKI67, AURKA, BIRC5, CCNBI, and MYBL2)
Continuous risk model: Low recurrence score (RS < 18), intermediate (RS 18-30), and high (RS ≥ 31)
Assumes 5 years of tamoxifen therapy as standard; systemic chemotherapy recommended if high RS
MammaPrint: 70-gene expression signature developed using DNA microarray analysis
Used in ER(+) and ER(-), HER2(-) tumors, T1-3, N0-N1 disease
Validated on both fresh and paraffin-embedded tissue
Binary/dichotomous risk model
Separates breast cancers into those at low- or high-risk of developing distant metastases within first 10 years after diagnosis
BluePrint: Determines intrinsic subtype (luminal A or B; HER2-type; basal-like) based on 80-gene signature
Prosigna = Prediction Analysis of Microarray Risk of Recurrence (PAM50 ROR): Calculated using expression profile of 46-gene subset of 50 selected genes of 4 intrinsic subtypes (PAM50), proliferation score (18-gene subset), and tumor size
Stratifies patients with ER(+) disease into high, medium, and low subsets
Magee equations: Model prediction of Oncotype DX RS using Nottingham score, Ki-67, tumor size, quantitative ER and PR, and HER2 status in ER(+) T1-2, N0 disease
EndoPredict: Gene expression assay, includes 8 cancer-related genes of interest and 3 reference genes, validated using data from 2 ABCSG trials (ABCSG-6 and ABCSG-8)
Used in ER/PR(+), HER2(-), T1-3, N0-1, M0 disease
Classifies patients into 2 recurrence risk groups
Breast cancer index (BCI): Combines HOXB13/IL17BR (H/I) 2-gene ratio and molecular grade index (MGI), which is 5-gene predictor including tumor grade and proliferation
Prognostic factor: Estimates outcomes, such as BCSS or DMFS, in absence of treatment
Predictive factor: Estimates likelihood of response to particular treatment
CLINICAL ISSUES
Natural History & Prognosis
Treatment
Selected References
Bowden AR et al: Clinical implications of germline mutations in breast cancer genes: RECQL. Breast Cancer Res Treat. ePub, 2019
Bhargava R et al: Breast cancers with Magee equation score of less than 18, or 18-25 and mitosis score of 1, do not require Oncotype DX testing: A value study. Am J Clin Pathol. ePub, 2018
Sparano JA et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. ePub, 2018
Sughayer M et al: Applying new Magee equations for predicting the Oncotype DX recurrence score. Breast Cancer. 25(5):597-604, 2018
Krop I et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 35(24):2838-2847, 2017
Mamounas EP et al: 21-gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemo-endocrine therapy. J Natl Cancer Inst. 109(4), 2017
Cardoso F et al: 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 375(8):717-29, 2016
Sestak I et al: Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol. 33(8):916-22, 2015
Sparano JA et al: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. ePub, 2015
Filipits M et al: 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):1298-305, 2014
Gnant M et al: Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 25(2):339-45, 2014
Sapino A et al: MammaPrint molecular diagnostics on formalin-fixed, paraffin-embedded tissue. J Mol Diagn. 16(2):190-7, 2014
Dubsky P et al: The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer. 109(12):2959-64, 2013
Glück S et al: Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Breast Cancer Res Treat. 139(3):759-67, 2013
Ramsey SD et al: Integrating comparative effectiveness design elements and endpoints into a phase III, randomized clinical trial (SWOG S1007) evaluating oncotypeDX-guided management for women with breast cancer involving lymph nodes. Contemp Clin Trials. 34(1):1-9, 2013
Sgroi DC et al: 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):1067-76, 2013
Dubsky PC et al: Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 30(7):722-8, 2012
Filipits M 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. 17(18):6012-20, 2011
Knauer M et al: The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 120(3):655-61, 2010
Mamounas EP et al: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 28(10):1677-83, 2010
Mook S et al: The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 116(2):295-302, 2009
Parker JS et al: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 27(8):1160-7, 2009
Cardoso F et al: Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 26(5):729-35, 2008
Sparano JA et al: Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 26(5):721-8, 2008
Mook S et al: Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 4(3):147-55, 2007
Cobleigh MA et al: Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res. 11(24 Pt 1):8623-31, 2005
Jakesz R et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 366(9484):455-62, 2005
Paik S et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 351(27):2817-26, 2004
Schmid M et al: Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6. J Clin Oncol. 21(6):984-90, 2003
van’tVeer LJ et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415(6871):530-6, 2002
van de Vijver MJ et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 347(25):1999-2009, 2002
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