Clinical Topics & News

Gene Expression Signatures in Breast Cancer: A Surgical Oncologist’s Perspective

Fed Pract. 2014 August;31(8):53-57

References

1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.

2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.

3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.

4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.

5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.

6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.

7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.

8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.

9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.

10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.

11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.

12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.

13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.

14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.

15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.

16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.

17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.

18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.

19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.

20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.

21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.

22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.

23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. 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. 2009;116(2):295-302.

24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.

25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.

26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.

Oncotype DX

The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.

The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).^10,11

Clinical Trials

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.¹¹ In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.¹²

The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.¹⁰ This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.

In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.¹³

Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.

Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.¹³

Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.^14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.¹³

The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.¹⁰