Over a 30-year period in the 20th century, human flight evolved from the propeller to the jet engine and then managed to send us to the moon and back. The changes over the past 30 years in our understanding of the biology of breastcancer and its application to treatment are no less startling. Since 1975, we have witnessed an astounding evolution in our strategies to prevent, diagnose, and manage a disease that affects the lives of so many in the United States and around the world. These efforts have generated many headlines and an occasional stumble. Nonetheless, they have had a dramatic impact on the lives of millions of people, and it is hoped that the rate of improvement will further accelerate in years to come. Historical Background
Randomized trials that were started in the 1970s disproved long-established dogmas emphasizing aggressive local therapy as the key for controlling breastcancer and preventing recurrence. As a consequence, most women with earlystage breast cancer are now able to preserve their breasts[6,7] and often undergo removal of just a few sentinel nodes from the axilla. Further, a generation of studies starting with seminal trials published in the mid-1970s confirmed that adjuvant systemic therapy significantly reduces the risk of breast cancer recurrence, thereby confirming that invasive breast cancer must be viewed as a systemic disease from its inception.[9,10] A key tool underlying these accomplishments was the concept of the controlled clinical trial first introduced by Sir Richard Doll almost 60 years ago.[11,12] While many of the initialadjuvant breast cancer trials were too small to detect the small improvements that might be clinically significant, the systematic review exercises held by the Early Breast Cancer Trialists Collaborative Group every 5 years since 1985 have proven invaluable to confirm the survival benefit offered by adjuvant chemotherapy for the average patient with early-stage disease (especially younger women) and by tamoxifen for any patient with estrogen receptor alpha (ER)-positive disease regardless of age. In fact, National Surgical Adjuvant Breast and Bowel Project investigators have suggested that some form of adjuvant therapy should be considered for even women with invasive tumors of 1 cm or less and negative axillary lymph nodes, although such recommendations have been considered too broad by many and do not account for individual variability. Evolving Guidelines
In this issue of ONCOLOGY, Mina and Sledge chronicle the development of adjuvant systemic therapy for breast cancer since the 1985 National Institutes of Health Consensus Development Conference on early-stage breast cancer and provide a comprehensive summary of critical advances in the last 20 years. Many of these developments have been distilled into expert panel consensus recommendations and clinical practice guidelines like those released every 2 years following the St. Gallen meetings and at least yearly by the National Comprehensive Cancer Network (NCCN). As a result, most clinicians have been exposed to the principles of evidencebased medicine,[16,17] and cancer specialists have become quite familiar with the concept of relative and absolute risk reduction. Medical oncologists often employ validated online instruments[18,19] for real-time discussions with patients regarding the actual average improvement in 10- year risk of cancer-related recurrence and mortality offered by various chemotherapy and endocrine regimens. Treatment guidelines and software tools have proven invaluable in clinicalpractice, but their use highlights some of the challenges oncologists face while translating population and clinical trial evidence into recommendations for individual patients. In most cases, we have information about the average risk and average benefit for a group of patients with similar riskstratification features who were given the same or similar therapy, when in fact the actual variability within such a group can be substantial. But it is now clear that breast cancer is actually a collection of diseases that share a common name but have an extremely diverse biologic behavior. This is unquestionably a disease for which onesize treatment will not fit all patients. Practitioners should therefore enthusiastically welcome the most recent update of the algorithms for adjuvant therapy selection issued by the 2005 St. Gallen consensus panel and the NCCN.[20,21] These panels have now placed primary emphasis on measures of potential response to therapy rather than risk stratification. The impact of these seemingly subtle changes goes beyond a simple switch in their order of consideration. Rather, these new guidelines reflect our increasing ability to move beyond prognostic factors to focus on individual predictive factors, ie, those unique features that could potentially determine an individual's likelihood of benefiting (or not) from specific therapies. Only then do the traditional markers-such as tumor size and lymph node status-that aid in prognostic but not predictive assessment come into play. Recent Advances
Seven years ago, the American Society of Clinical Oncology annual meeting was dominated by presentations of adjuvant high-dose chemotherapy trials that emphasized dose-intensification strategies for high-risk patients without much attention to individual biologic features. Fast forward a few years. Factors long thought to carry a modest prognostic value like expression of ER and the human epidermal growth factor receptor 2 (HER2) are now fully validated as strong predictive markers of response to specific therapies thatcould potentially provide a substantial survival benefit for the right patients.[ 3,22-24] Perhaps equally important, patients whose tumors lack expression of these specific markers and who are unlikely to be helped by these therapies can be spared from exposure to a costly "placebo." These types of studies are now accelerating in the molecular era as geneexpression profile assays appear to identify several major breast cancer subtypes with prognostic implications.[ 25] At least one commercial assay using paraffin-embedded tissue has undergone strict assay standardization, and was shown in retrospective validation studies to have strong prognostic[ 26] and predictive value for patients with lymph node-negative, ER-positive disease. The same assay also predicted the likelihood of pathologic complete response in patients treated with preoperative chemotherapy for locally advanced disease, an area that merits further study. Looking Ahead
In 2006, the promise of selecting therapy based on tumor characteristics is now an established part of clinical practice. Until now, the reliability, accuracy, and reporting standards for many assays used in clinical practice have often not been given much needed attention. In many cases, immunohistochemistry assays have not been used as stand-alone tests. Rather, they have often been used to complement conventional pathology evaluation and confirm a specific diagnosis or to stratify patients among various prognostic groups. As new assays are introduced in clinical practice to serve as the sole determinant of therapy selection, pathologists and labs performing these assays will bear a much higher degree of responsibility for patient outcome. Equally important, clinicians using these results must understand the nuances of their use, going beyond a simple interpretation of a positive or negative test result. They must understand how the test was done, be familiar with potential variables that may affect results, and know what ques-tions to ask the pathologist. Concerns about the accuracy and reproducibility of assays of hormone receptor[29,30] and HER2[31,32] expression have been well documented, and we now understand that both presence and intensity of expression are critical features for determining benefit to biologically based therapy with tamoxifen, aromatase inhibitors, and trastuzumab (Herceptin). In addition, much of our focus thus far has been on specific tumor characteristics, but there is now increasing recognition that individual host factors can influence response and toxicity to individual therapies. In other words, proper assay performance by labs and pathologists and interpretation of results by oncologists is crucial, and the need to address platform standardization and reproducibility issues is expected to be further compounded as we introduce more complex gene array and pharmacogenetic assays into routine breast cancer clinical practice. Addressing these technical issues[ 36,37] and disseminating this information to all end users is a big challenge, but these are indeed exciting times for us and for our patients. We look forward to the next 30 years!
—Antonio C. Wolff, MD, FACP
—Nancy E. Davidson, MD
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97:1652-1662, 2005.
2. Berry DA, Cronin KA, Plevritis SK, et al, for the Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784- 1792, 2005.
3. 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 365:1687-1717, 2005.
4. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.
5. Hortobagyi GN, Salazar J de L, Pritchard K, et al: The global breast cancer burden: Variations in epidemiology and survival. Clin Breast Cancer 6:391-401, 2005.
6. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567-575, 2002.
7. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233- 1241, 2002.
8. Lyman GH, Giuliano AE, Somerfield MR, et al: American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer. J Clin Oncol 23:7703-7720, 2005.
9. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up [see comments]. N Engl J Med 332:901-906, 1995.
10. Fisher B, Jeong JH, Dignam J, et al: Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr (30):62-66, 2001.
11. Medical Research Council Streptomycin in Tuberculosis Trials Committee: Streptomycin treatment for pulmonary tuberculosis. BMJ 2:769-782, 1948.
12. Doll R: Controlled trials: The 1948 watershed. BMJ 317:1217-1220, 1998.
13. Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93:112- 120, 2001.
14. Lippman ME, Hayes DF: Adjuvant therapy for all patients with breast cancer? J Natl Cancer Inst 93:80-82, 2001.
15. Consensus conference. Adjuvant chemotherapy for breast cancer. JAMA 254:3461-3463, 1985.
16. Cochrane AL: Archie Cochrane in his own words. Selections arranged from his 1972 introduction to “Effectiveness and Efficiency: Random Reflections on the Health Services” 1972. Control Clin Trials 10:428-433, 1989.
17. Sackett DL, Rosenberg WMC, Gray JAM, et al: Evidence based medicine: what it is and what it isn’t. BMJ 312:71-72, 1996.
18. 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 19:980-991, 2001.
19. Olivotto IA, Bajdik CD, Ravdin PM, et al: Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 23:2716-2725, 2005.
20. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005.
21. National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines— version 2.2006. Available at www.nccn.org/professionals/ physician_gls/PDF/breast.pdf. Accessed Jan 2, 2006.
22. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.
23. Piccart-Gebhart MJ, Procter M, Leyland- Jones B, et al, and the Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005.
24. Slamon D, Eiermann W, Robert N, et al, on behalf of the BCIRG 006 Investigators: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study (abstract 1). Breast Cancer Res Treat 94(suppl 1):S5, 2005.
25. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869- 10874, 2001.
26. Paik S, Shak S, Tang G, et al: Multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004.
27. Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the recurrence score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20 (abstract 24). Breast Cancer Res Treat 88(suppl 1):S15, 2004.
28. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23:7265-7277, 2005.
29. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474- 1481, 1999.
30. Mohsin SK, Weiss H, Havighurst T, et al: Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: A validation study. Mod Pathol 17:1545-1554, 2004.
31. Roche PC, Suman VJ, Jenkins RB, et al: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 94:855-857, 2002.
32. Paik S, Bryant J, Tan-Chiu E, et al: Realworld performance of HER2 testing: National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 94:852-854, 2002.
33. Stearns V, Davidson NE, Flockhart DA: Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J 4:143-153, 2004.
34. Simon R: Diagnostic and prognostic prediction using gene expression profiles in highdimensional microarray data. Br J Cancer 89:1599-1604, 2003.
35. Marsh S, Kwok P, McLeod HL: SNP databases and pharmacogenetics: Great start, but a long way to go. Hum Mutat 20:174-179, 2002.
36. Zarbo RJ, Hammond ME: Conference summary, Strategic Science symposium. HER-2/neu testing of breast cancer patients in clinical practice. Arch Pathol Lab Med 127:549-553, 2003.
37. Bammler T, Beyer RP, Bhattacharya S, et al: Standardizing global gene expression analysis between laboratories and across platforms. Nat Methods 2:351-356, 2005.
38. Wolff AC, Desch CE: Clinical practice guidelines in oncology: Translating evidence into practice (and back). Journal of Oncology Practice 1:160-161, 2005. Available at www.jopasco.org. Accessed Jan 2, 2006.