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.

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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.

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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.

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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.

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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.

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MammaPrint

Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.¹⁶ The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.¹⁷ This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.

The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.¹⁸ The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.^19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.¹⁷

Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.^18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.^18,22

A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.²² The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.²² In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.

THE SURGEON’S PERSPECTIVE

To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.^24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.

Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.⁸ A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.

In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.

In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.²⁶