Targeted therapies in breast cancer

Introduction

Our approach to the classification and treatment of breast cancer patients has fundamentally changed over the last few decades due to the significant progress in our understanding of the molecular alterations that underlie these tumors. Breast cancer is a disease with significant biologic diversity resulting in a wide spectrum of morphologic subtypes and vastly different clinical behaviors.¹ As a result, it has become increasingly clear that the “one size fits all” approach to treatment that has been used in the past works well for some patients, but not at all for others, necessitating a more individualized approach to management. A major challenge in breast cancer treatment is to identify the subgroups of patients who will benefit from a particular adjuvant therapy regimen, with the goal of providing the right treatment based on the patient’s underlying tumor biology.^2,3

Currently, the initial treatment strategy for clinical decision-making involves careful consideration of a group of key clinicopathological factors, which include the patient’s age, menopausal status, tumor size, histologic type, tumor grade, lymphovascular invasion, lymph node staging, and evidence of distant metastasis. In addition, three predictive markers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) are routinely utilized to help define therapy in breast cancer. These factors are used to help identify patients who are appropriate candidates for specific treatments that target key underlying molecular drivers of disease progression. The use of these predictive markers as an adjuvant to treatment decisions requires that the results be as accurate as possible, given their role in determining optimal and effective therapy.

Estrogen receptor (ER) and progesterone receptor (PR)

ER is a member of a family of intracellular steroid hormone receptors that are activated by interaction with the ligand, estrogen. Two different forms exist, ER alpha and ER beta, each encoded by a separate gene (ESR1 and ESR2, respectively). ER alpha is the most important ER in breast cancer. After binding to its ligand, estrogen, ER is transported to the nucleus of the cell. In the nucleus, ER functions as a transcription factor and regulates the expression of a number of genes that are important in breast cancer biology, including genes associated with proliferation.

The analysis of ER in breast tumors is perhaps the most successful example of the use of a biomarker in guiding therapy for cancer patients. The expression of ER by breast cancer has been shown to be highly predictive for a clinical benefit from a variety of endocrine therapies, and this benefit is seen only in tumors that are ER and/or PR positive. Endocrine therapy with tamoxifen or aromatase inhibitors has been shown to be the most effective and available targeted therapy for ER-positive breast cancer, being used in neoadjuvant, adjuvant, palliative, and preventive settings.⁴ A five-year course of tamoxifen adjuvant therapy after surgery significantly decreases disease recurrence rates and reduces breast cancer mortality for both pre- and postmenopausal women with ER-positive tumors.⁵ Due to the clinical importance of accurate assessment of these receptors, the ASCO/CAP task force provided new guidelines for standardized testing and reporting for ER and PR in 2010.⁶

Human epidermal growth factor receptor 2 (HER2)

HER2 is a 185 Kd transmembrane glycoprotein with tyrosine kinase activity and is a member of the HER family of growth factor receptors involved in the complex regulation of cell proliferation, angiogenesis, and enhancing cell survival pathways. The HER2 gene is located on chromosome 17 and is amplified as an early event in breast cancer carcinogenesis for a subset of tumors, occurring in about 15%-20% of breast cancers.^7,8 Gene amplification is the primary mechanism that drives HER2 overexpression in this subset of breast cancers. HER2 overexpression resulting from this gene amplification dramatically increases the likelihood of receptor activation and signaling, contributing to a more aggressive tumor biology, and is associated with higher rates of recurrence and mortality.

Targeted therapies against HER2 positive disease have been developed and are remarkably effective in both metastatic and adjuvant settings for patients with HER2 positive tumors. The drug trastuzumab is a humanized monoclonal antibody that combines the mouse recognition sequence of a monoclonal antibody (clone 4D5) against an extracellular epitope of the receptors with a human IgG1. Trastuzumab demonstrates a high affinity and specificity for the HER2 receptor, and in preclinical studies it was shown to be effective at inhibiting the growth of HER2 overexpressing breast cancer cells. Trastuzumab has been shown to improve response rates, time to progression, and even survival when used alone⁹ or added to chemotherapy in metastatic settings.¹⁰ In addition, prospective randomized trials have demonstrated that adjuvant trastuzumab significantly reduces the relative risk of recurrence in early-stage HER2 positive breast cancer.^11-13 The data from these clinical trials highlights the importance of accurate HER2 testing for every newly diagnosed breast cancer patient in order to help select those patients who will be the most suitable candidates for HER2 targeted therapy.¹⁴ Clinical assays to assess the HER2 status include immunohistochemistry (IHC), which detects protein overexpression, or fluorescence in situ hybridization (FISH), which detects gene amplification.¹⁵ Both assays have been clinically validated in prospective randomized trials to help predict which patients will benefit from treatment that targets HER2 overexpression.

The ASCO/CAP task force has provided comprehensive HER2 testing guidelines.¹⁶ The guidelines did not recommend one test over another and, based on clinical trial data, concluded that both IHC and FISH could be used to assess the HER2 status of breast cancer if the test had been appropriately validated and the laboratory had a rigorous Quality Assurance program. Patients with evidence either of gene amplification by FISH or protein overexpression by IHC are considered suitable for HER2 targeted therapy. The guidelines also recognized that there are equivocal categories that are occasionally encountered when interpreting the results from both IHC and FISH testing for HER2. These equivocal categories recognize that the HER2 test results represent a continuous rather than a categorical variable and can no longer be reported simply as binary. The equivocal category for immunohistochemical assays must be confirmed by reflex FISH analysis of the sample, whereas equivocal FISH results can be confirmed by counting additional cells, repeating the FISH assay, or confirmatory immunohistochemical testing.

Multigene assay

As the treatment options for breast cancer have grown progressively more complex, the clinical decisions regarding the suitability of adjuvant systemic therapy for individual patients increasingly require a more comprehensive assessment of the underlying biology of the tumor, necessitating the development of new ways to characterize, profile and classify breast cancer. To address this need, the application of new molecular approaches and multigene assays for predicting prognosis and treatment response in breast cancer has begun to move into the clinical arena with the introduction of clinically available assays, such as the Genomic Health, Inc. Oncotype DX™ test (Redwood City, CA). The Oncotype test is a validated 21-gene quantitative RT-PCR assay that has been developed for use in formalin-fixed paraffin embedded breast cancer samples that are estrogen receptor positive and node negative. The test results provide additional information about prognosis and the likelihood of benefit of chemotherapy in this subgroup of breast cancer patients.^17,18

Conclusion

The most clinically relevant, practical, affordable, and broadly available ancillary testing to help determine the prognosis for breast cancer patients, as well as testing to help guide the selection of the most beneficial treatment regimens, will continue to be an area of active research. Moving forward, it will be necessary to evaluate new, potentially useful prognostic assays in a prospective fashion, in uniformly treated patient populations using standardized assay procedures and state-of-the-art statistical methods. By combining morphological, immunohistochemical, and molecular techniques, the pathology community is rapidly moving toward providing clinicians with a more clinically meaningful diagnosis for breast cancer patients.

David G. Hicks, MD, is Director of Surgical Pathology, Department of Pathology and Laboratory Medicine, at the University of Rochester Medical Center in Rochester, New York. Dr. Hicks previously worked with the Department of Anatomic Pathology at the Cleveland Clinic Foundation (CCF) and the Roswell Park Cancer Institute. Active in research throughout his career, Dr. Hicks has recently been involved in the search for new molecular genetic markers that provide information useful in guiding the therapeutic management of breast cancer.

References

1. Simpson PT, Reis-Filho JS, Gale T, Lakhani SR. Molecular evolution of breast cancer. J Pathol. 2005;205:248-254.
2. Bergh J, Holmquist M. Who should not receive adjuvant chemotherapy? International databases. J Natl Cancer Inst Monogr. 2001;(30):103-108.
3. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19:980-991.
4. Jordan VC, Brodie AM. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids. 2007;72:7-25.
5. 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;365:1687-1717.
6. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784-2795.
7. Yaziji H, Goldstein LC, Barry TS, et al. HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004;291:1972-1977.
8. Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004;5:63-69.
9. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648.
10. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.
11. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354:809-820.
12. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.
13. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672.
14. Hicks DG, Kulkarni S. Trastuzumab as adjuvant therapy for early breast cancer: the importance of accurate human epidermal growth factor receptor 2 testing. Arch Pathol Lab Med. 2008;132:1008-1015.
15. Hicks DG, Kulkarni S. HER2+ breast cancer: review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.
16. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118-145.
17. 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;351:2817-2826.
18. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734.