Prognostic and Predictive Factors for Breast Cancer: Translating Technology to Oncology
http://www.100md.com
《临床肿瘤学》
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
In medical school, we were taught that clinical decision making requires a consideration of the balance of benefits and risks to provide optimal care for the patient. As we train and then practice medicine, understanding and conveying the risks and benefits of a given treatment are constantly refined by personal experience, interactions with patients, our colleagues and experts in the field, and availability of evidence derived from well-designed and -analyzed clinical trials.
Management of patients with breast cancer is a great illustration of this complex and iterative process. In the preventive, primary care, and adjuvant settings, decisions are made for individuals based on our hope that, in general, we help more patients than we harm. For women with relatively low risk of developing metastatic disease, such as those with high-risk but benign breast findings or women with small, hormone-dependent, node-negative breast cancers, we never actually know if we have helped an individual patient. Indeed, a majority of such patients will not recur despite our care, not because of it. On the other hand, treatment of patients with metastatic disease, although ultimately almost always associated with a tragic outcome, can be extraordinarily rewarding. In this setting, we can observe a highly symptomatic patient regain her quality of life as a clear-cut consequence of judiciously applied local and systemic therapies, including endocrine and chemotherapies and, more recently, novel therapy such as trastuzumab.
Arguably, prognostic and predictive factors have been of value to help individualize therapy of breast cancer more than for any other solid tumors. The substantial benefits of adjuvant systemic therapy have been well documented for over 30 years.1,2 Furthermore, it is a disease for which disparate therapies are beneficial in different subgroups. For example, it appears that adjuvant chemotherapy reduces the annual odds of recurrence by approximately 25% to 30% for all patients.2 In those with an initially poor prognosis (for example, with positive axillary lymph nodes), this proportional reduction may result in an absolute improvement of 10% to 20% or more in the likelihood of being disease free after 10 to 15 years of follow-up. This same proportional reduction, when applied to a group of patients with small, node-negative, and estrogen receptor (ER) -positive cancers may only improve their odds of being disease free by a small percentage during that same period.1 Furthermore, the "grandmother" of all predictive factors, ER, exquisitely separates patients who will or will not benefit from endocrine therapy, to the extent that, despite having such a favorable profile, tamoxifen is rarely, if ever, used in ER-negative patients. Likewise, the value of HER-2 amplification and/or overexpression is clearly recognized for selection of patients who are likely or not likely to benefit from trastuzumab in the metastatic setting.3,4
However, even in breast cancer, molecular markers of prognosis and prediction are less than ideal, resulting in inefficient application of therapy that is either not needed, or worse, needed but ineffective. In the last 4 years, three major areas of research have been directed towards this dilemma, and each is discussed in various reviews within this issue. Drs Paik and van't Veer5 provide an overview of the exciting field of gene expression array pattern recognition as a means of developing new tumor markers that are, in effect, amalgamations of several markers. They discuss the remarkable laboratory and statistical advances that they and their colleagues have championed. These advances have permitted, in a very short time, development of potentially clinically applicable assays that are now the subject of large validation studies. Drs Braun and Naume6 discuss a different strategy: identification of rare metastatic cells present in bone marrow and/or blood. They discuss the technical pitfalls as well as the incredible promise of detecting micrometastases as harbingers of future recurrence. Perhaps more importantly, they review efforts to genotype and phenotype these cells, which should lead to further benefit to monitoring these rare events in the adjuvant and metastatic settings.
Finally, regardless of these mind-boggling technical advances, there is still a patient (often anxious and confused) in the chair across from us that needs to have this complicated information distilled into understandable language. Drs Whelan and Loprinzi7 provide an overview of the patient decision aids that are available as "laboratory-to-patient" dictionaries. These aids have been developed to help patients who often find themselves in a world of scientific—and often confusing—techno-babble make informed and intelligent decisions that fit their needs at what is, of course, an incredibly stressful time in their lives.
Mortality from breast cancer is dropping in the Western world as a result of widespread and early application of better and safer therapies.8 Understanding these scientific advances, and being able to convey them to our patients, is essential as we strive to provide them with even longer and better lives after the diagnosis of breast cancer.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
Acknowledgment
Supported by a grant from the National Institutes of Health (RO1 CA092461) and by Fashion Footwear Foundation/QVC Presents Shoes on Sale.
REFERENCES
Early Breast Cancer Trialist's Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
Early Breast Cancer Trialist's Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930-942, 1998
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 344:783-792, 2001
Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002
van't Veer LJ, Paik S, Hayes DF: Gene expression profiling of breast cancer: A new tumor marker. J Clin Oncol 23:1631-1635, 2005
Braun S, Name B: Circulating and disseminated tumor cells. J Clin Oncol 23:1623-1626, 2005
Whelan TJ, Loprinzi C: Physician/patient decision aids for adjuvant therapy. J Clin Oncol 23:1627-1630, 2005
Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355:1822, 2000(Daniel F. Hayes)
In medical school, we were taught that clinical decision making requires a consideration of the balance of benefits and risks to provide optimal care for the patient. As we train and then practice medicine, understanding and conveying the risks and benefits of a given treatment are constantly refined by personal experience, interactions with patients, our colleagues and experts in the field, and availability of evidence derived from well-designed and -analyzed clinical trials.
Management of patients with breast cancer is a great illustration of this complex and iterative process. In the preventive, primary care, and adjuvant settings, decisions are made for individuals based on our hope that, in general, we help more patients than we harm. For women with relatively low risk of developing metastatic disease, such as those with high-risk but benign breast findings or women with small, hormone-dependent, node-negative breast cancers, we never actually know if we have helped an individual patient. Indeed, a majority of such patients will not recur despite our care, not because of it. On the other hand, treatment of patients with metastatic disease, although ultimately almost always associated with a tragic outcome, can be extraordinarily rewarding. In this setting, we can observe a highly symptomatic patient regain her quality of life as a clear-cut consequence of judiciously applied local and systemic therapies, including endocrine and chemotherapies and, more recently, novel therapy such as trastuzumab.
Arguably, prognostic and predictive factors have been of value to help individualize therapy of breast cancer more than for any other solid tumors. The substantial benefits of adjuvant systemic therapy have been well documented for over 30 years.1,2 Furthermore, it is a disease for which disparate therapies are beneficial in different subgroups. For example, it appears that adjuvant chemotherapy reduces the annual odds of recurrence by approximately 25% to 30% for all patients.2 In those with an initially poor prognosis (for example, with positive axillary lymph nodes), this proportional reduction may result in an absolute improvement of 10% to 20% or more in the likelihood of being disease free after 10 to 15 years of follow-up. This same proportional reduction, when applied to a group of patients with small, node-negative, and estrogen receptor (ER) -positive cancers may only improve their odds of being disease free by a small percentage during that same period.1 Furthermore, the "grandmother" of all predictive factors, ER, exquisitely separates patients who will or will not benefit from endocrine therapy, to the extent that, despite having such a favorable profile, tamoxifen is rarely, if ever, used in ER-negative patients. Likewise, the value of HER-2 amplification and/or overexpression is clearly recognized for selection of patients who are likely or not likely to benefit from trastuzumab in the metastatic setting.3,4
However, even in breast cancer, molecular markers of prognosis and prediction are less than ideal, resulting in inefficient application of therapy that is either not needed, or worse, needed but ineffective. In the last 4 years, three major areas of research have been directed towards this dilemma, and each is discussed in various reviews within this issue. Drs Paik and van't Veer5 provide an overview of the exciting field of gene expression array pattern recognition as a means of developing new tumor markers that are, in effect, amalgamations of several markers. They discuss the remarkable laboratory and statistical advances that they and their colleagues have championed. These advances have permitted, in a very short time, development of potentially clinically applicable assays that are now the subject of large validation studies. Drs Braun and Naume6 discuss a different strategy: identification of rare metastatic cells present in bone marrow and/or blood. They discuss the technical pitfalls as well as the incredible promise of detecting micrometastases as harbingers of future recurrence. Perhaps more importantly, they review efforts to genotype and phenotype these cells, which should lead to further benefit to monitoring these rare events in the adjuvant and metastatic settings.
Finally, regardless of these mind-boggling technical advances, there is still a patient (often anxious and confused) in the chair across from us that needs to have this complicated information distilled into understandable language. Drs Whelan and Loprinzi7 provide an overview of the patient decision aids that are available as "laboratory-to-patient" dictionaries. These aids have been developed to help patients who often find themselves in a world of scientific—and often confusing—techno-babble make informed and intelligent decisions that fit their needs at what is, of course, an incredibly stressful time in their lives.
Mortality from breast cancer is dropping in the Western world as a result of widespread and early application of better and safer therapies.8 Understanding these scientific advances, and being able to convey them to our patients, is essential as we strive to provide them with even longer and better lives after the diagnosis of breast cancer.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
Acknowledgment
Supported by a grant from the National Institutes of Health (RO1 CA092461) and by Fashion Footwear Foundation/QVC Presents Shoes on Sale.
REFERENCES
Early Breast Cancer Trialist's Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
Early Breast Cancer Trialist's Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930-942, 1998
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 344:783-792, 2001
Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002
van't Veer LJ, Paik S, Hayes DF: Gene expression profiling of breast cancer: A new tumor marker. J Clin Oncol 23:1631-1635, 2005
Braun S, Name B: Circulating and disseminated tumor cells. J Clin Oncol 23:1623-1626, 2005
Whelan TJ, Loprinzi C: Physician/patient decision aids for adjuvant therapy. J Clin Oncol 23:1627-1630, 2005
Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355:1822, 2000(Daniel F. Hayes)