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Tumor Genomic Testing: e.g., Oncotype DX, MammaPrint
Erin Roesch, MD
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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

          1. Bowden AR et al: Clinical implications of germline mutations in breast cancer genes: RECQL. Breast Cancer Res Treat. ePub, 2019
          2. 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
          3. Sparano JA et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. ePub, 2018
          4. Sughayer M et al: Applying new Magee equations for predicting the Oncotype DX recurrence score. Breast Cancer. 25(5):597-604, 2018
          5. 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
          6. 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
          7. 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
          8. 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
          9. Sparano JA et al: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. ePub, 2015
          10. 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
          11. 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
          12. Sapino A et al: MammaPrint molecular diagnostics on formalin-fixed, paraffin-embedded tissue. J Mol Diagn. 16(2):190-7, 2014
          13. 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
          14. 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
          15. 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
          16. 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
          17. 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
          18. 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
          19. 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
          20. 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
          21. 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
          22. Parker JS et al: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 27(8):1160-7, 2009
          23. Cardoso F et al: Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 26(5):729-35, 2008
          24. 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
          25. Mook S et al: Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 4(3):147-55, 2007
          26. 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
          27. 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
          28. 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
          29. 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
          30. van’tVeer LJ et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415(6871):530-6, 2002
          31. 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
          Tables

          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

                  1. Bowden AR et al: Clinical implications of germline mutations in breast cancer genes: RECQL. Breast Cancer Res Treat. ePub, 2019
                  2. 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
                  3. Sparano JA et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. ePub, 2018
                  4. Sughayer M et al: Applying new Magee equations for predicting the Oncotype DX recurrence score. Breast Cancer. 25(5):597-604, 2018
                  5. 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
                  6. 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
                  7. 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
                  8. 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
                  9. Sparano JA et al: Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. ePub, 2015
                  10. 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
                  11. 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
                  12. Sapino A et al: MammaPrint molecular diagnostics on formalin-fixed, paraffin-embedded tissue. J Mol Diagn. 16(2):190-7, 2014
                  13. 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
                  14. 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
                  15. 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
                  16. 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
                  17. 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
                  18. 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
                  19. 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
                  20. 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
                  21. 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
                  22. Parker JS et al: Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 27(8):1160-7, 2009
                  23. Cardoso F et al: Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 26(5):729-35, 2008
                  24. 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
                  25. Mook S et al: Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 4(3):147-55, 2007
                  26. 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
                  27. 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
                  28. 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
                  29. 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
                  30. van’tVeer LJ et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 415(6871):530-6, 2002
                  31. 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