- Email: [email protected]
Predictive Models: The Art and the Science
rapidly expanding activities on preventable and curable inherited disorders, including the right to know (see www.phgen.eu). Because 0.5–1.0 million healthy European women are BRCA mutation carriers, the condition may become known as a public health issue rather than a rare genetic disorder.
3. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804-7810.
References
4. Møller P, Hagen AI, Apold J, et al. Genetic epidemiology of BRCA mutation—family history identifies less than 50% of mutation carriers. Eur J Cancer. 2007;43:1713-1717.
1. Moller P, Evans DG, Reis MM, et al. Surveillance for familial breast cancer: differences in outcome according to BRCA mutation status. Int J Cancer. 2007;121:1017-1020. 2. Hagen AI, Kvistad KA, Maehle L, et al. Sensitivity of MRI versus mammography to diagnose BRCA-associated breast cancer validated in a national prospective series. Breast. 2007;16:367-374.
Predictive Models: The Art and the Science Kimberly J. Van Zee, MS, MD In the art and science of medicine, the “art” has long dominated the “science.” Until the past century, there was actually very little science at all in the practice of medicine. However, in the past few decades, an exponentially increasing abundance of scientific investigations have been conducted with resultant data that answer particular clinical questions. The current generation of surgeons and physicians has gone through medical school, residency, and years of practice with the perception that the actual practice of medicine is guided by science. Although this is certainly true in many cases, there remain many aspects of medicine that are managed by tradition established long ago by clinicians observing individual patients. A great advance in recent years is the development of prediction tools to help patients and clinicians estimate the chance that a particular outcome will happen to a patient in a particular situation. In the field of breast cancer medicine, Adjuvant!,1 an online tool used to predict risk for distant disease and mortality, has proved to be a revolutionary resource for clinicians. In the field of breast cancer surgery, the Memorial Sloan-Kettering nomogram,2 which predicts the likelihood that a woman with a positive sentinel lymph node (SLN) will have additional nonSLN metastases, is a prediction tool for women and clinicians
118 118
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Breast Diseases: A Year Book Quarterly Vol 19 No 2 2008
5. Norum J, Hagen AI, Mæhle L, Apold J, Burn J, Møller P. Prophylactic bilateral salpingo-oophorectomy (PBSO) with or without prophylactic bilateral mastectomy (PBM) or no intervention in BRCA1 mutation carriers. a cost-effectiveness analysis. Eur J Cancer. 2008;44;963-971.
who are considering avoidance of completion axillary lymph node dissection (ALND) in the setting of a positive SLN. Adjuvant! and the Memorial Sloan-Kettering nomogram both utilize data obtained from large populations of women with breast cancer to create a prediction tool that improves risk estimation for clinicians and patients. We and others have shown that prediction models based on actual patient data provide more accurate estimates than expert clinicians’ “guesstimations.”3,4 Recently, we published a second prediction tool, for use after a woman’s diagnosis of breast cancer but before her definitive SLN biopsy procedure.5 As the modern patient seeks more and more information regarding her future risks, we have found that she often presents to the breast cancer surgeon with numerous questions. First on the list is often, “Doctor, what are my chances of having a positive sentinel node?” Our new tool, a nomogram, allows the clinician to generate individual risk estimates that are clearly more accurate than using an overall proportion applicable to the general population. For example, although overall, about 1 in 3 women with breast cancer has lymph node metastases, our new nomogram can identify a patient with an approximate 10% chance or someone with greater than a 50% risk of having nodal metastases. Our tool is also more accurate than an estimate based solely on primary tumor size. Furthermore, like the first Memorial SloanKettering nomogram, which predicts the likelihood of nonSLN metastases, the variables necessary for our new nomo-
gram are commonly available, and the graphical component as well as the online calculator are easy to use. Because many institutions determine hormone-receptor status only on the definitive surgical specimen, 2 models were created: one that includes ER and PR status and another that includes neither. As the use of such models is adopted by clinicians, I expect to see with increasing frequency the development of more statistical prediction models to assist patients and clinicians with estimating future outcomes. Although this approach should be viewed as a clear advance in our ability to make decisions on the basis of actual data, I also fear its misuse. Great caution should be used when making decisions on the basis of a mathematical model. These are simply formulas that estimate probabilities, but no mathematical model can actually make decisions. For example, many clinicians have contacted me to ask what the “threshold” of risk is below which I would not do a completion ALND in a woman with a positive SLN. I have a lengthy discussion with them, pointing out that there is no threshold—there is simply a risk estimate. I still maintain that completion ALND is the standard for a woman with a positive node, and if a woman or her clinician is considering avoidance of ALND, the nomogram can give them some estimate of risk of leaving behind hematoxylin and eosin–detectable disease. An estimate of 10% might be completely acceptable for an elderly woman with multiple comorbidities but completely unacceptable for a young woman with young children. Similarly, I fear that some patients or clinicians will misuse estimates of risk derived using our new nomogram by not proceeding with an SLN biopsy in the face of a low calculated risk. I cannot emphasize enough how wrong this would be. SLN biopsy is a low-risk, highly accurate procedure that is associated with very low morbidity.6,7 If a patient with a low calculated risk of having a positive SLN biopsy actually did have SLN metastasis, it would dramatically change her situation. Staging and systemic therapy recommendations would generally move from stage I and no chemotherapy to stage II with systemic chemotherapy. The risk/benefit ratio for staging the axilla is extremely low for the majority of patients. Clinicians and patients should always consider staging the axilla as preferable to a risk estimate that cannot, by its very nature, ever be as accurate for an individual as the actual SLN biopsy.
In closing, I offer a note of caution to clinicians. The art of medicine remains essential in the application and interpretation of various scientific tools. These tools should be used wisely and with careful attention to risks and benefits, should the low-risk event actually be true. Clinicians must remember the “art” of medicine while using the “science” of medicine.
References 1. 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;19:980991. 2. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol. 2003;10:1140-1151. 3. Specht MC, Kattan MW, Gonen M, Fey J, Van Zee KJ. Predicting nonsentinel node status after positive sentinel lymph biopsy for breast cancer: clinicians versus nomogram. Ann Surg Oncol. 2005;12:654-659. 4. Smidt M, Strobbe LJ, Groenewoud HM, Van der Wilt GJ, Van Zee KJ, Wobbes T. Can surgical oncologists reliably predict the likelihood for non-SLN metastases in breast cancer patients? Ann Surg Oncol. 2007;14:615-620. 5. Bevilacqua JLB, Kattan MW, Fey JV, Cody HS, Borgen PI, Van Zee KJ. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J Clin Oncol. 2007;25:3670-3679. 6. Baron RH, Fey JV, Borgen PI, Stempel MM, Hardick KR, Van Zee KJ. Eighteen sensations after breast cancer surgery: a 5-year comparison of sentinel lymph node biopsy and axillary lymph node dissection. Ann Surg Oncol. 2007;14:16531661. 7. McLaughlin SA, Wright MJ, Morris K, et al. Prevalence of lymphedema in 903 women with breast cancer 5 years after sentinel node biopsy or axillary dissection: measurements and patient perceptions (abstract 145). Presented at the 2007 American Society of Clinical Oncology Breast Cancer Symposium. http://www.asco.org. Accessed January 11, 2008.
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3. Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804-7810.
References
4. Møller P, Hagen AI, Apold J, et al. Genetic epidemiology of BRCA mutation—family history identifies less than 50% of mutation carriers. Eur J Cancer. 2007;43:1713-1717.
1. Moller P, Evans DG, Reis MM, et al. Surveillance for familial breast cancer: differences in outcome according to BRCA mutation status. Int J Cancer. 2007;121:1017-1020. 2. Hagen AI, Kvistad KA, Maehle L, et al. Sensitivity of MRI versus mammography to diagnose BRCA-associated breast cancer validated in a national prospective series. Breast. 2007;16:367-374.
Predictive Models: The Art and the Science Kimberly J. Van Zee, MS, MD In the art and science of medicine, the “art” has long dominated the “science.” Until the past century, there was actually very little science at all in the practice of medicine. However, in the past few decades, an exponentially increasing abundance of scientific investigations have been conducted with resultant data that answer particular clinical questions. The current generation of surgeons and physicians has gone through medical school, residency, and years of practice with the perception that the actual practice of medicine is guided by science. Although this is certainly true in many cases, there remain many aspects of medicine that are managed by tradition established long ago by clinicians observing individual patients. A great advance in recent years is the development of prediction tools to help patients and clinicians estimate the chance that a particular outcome will happen to a patient in a particular situation. In the field of breast cancer medicine, Adjuvant!,1 an online tool used to predict risk for distant disease and mortality, has proved to be a revolutionary resource for clinicians. In the field of breast cancer surgery, the Memorial Sloan-Kettering nomogram,2 which predicts the likelihood that a woman with a positive sentinel lymph node (SLN) will have additional nonSLN metastases, is a prediction tool for women and clinicians
118 118
®
Breast Diseases: A Year Book Quarterly Vol 19 No 2 2008
5. Norum J, Hagen AI, Mæhle L, Apold J, Burn J, Møller P. Prophylactic bilateral salpingo-oophorectomy (PBSO) with or without prophylactic bilateral mastectomy (PBM) or no intervention in BRCA1 mutation carriers. a cost-effectiveness analysis. Eur J Cancer. 2008;44;963-971.
who are considering avoidance of completion axillary lymph node dissection (ALND) in the setting of a positive SLN. Adjuvant! and the Memorial Sloan-Kettering nomogram both utilize data obtained from large populations of women with breast cancer to create a prediction tool that improves risk estimation for clinicians and patients. We and others have shown that prediction models based on actual patient data provide more accurate estimates than expert clinicians’ “guesstimations.”3,4 Recently, we published a second prediction tool, for use after a woman’s diagnosis of breast cancer but before her definitive SLN biopsy procedure.5 As the modern patient seeks more and more information regarding her future risks, we have found that she often presents to the breast cancer surgeon with numerous questions. First on the list is often, “Doctor, what are my chances of having a positive sentinel node?” Our new tool, a nomogram, allows the clinician to generate individual risk estimates that are clearly more accurate than using an overall proportion applicable to the general population. For example, although overall, about 1 in 3 women with breast cancer has lymph node metastases, our new nomogram can identify a patient with an approximate 10% chance or someone with greater than a 50% risk of having nodal metastases. Our tool is also more accurate than an estimate based solely on primary tumor size. Furthermore, like the first Memorial SloanKettering nomogram, which predicts the likelihood of nonSLN metastases, the variables necessary for our new nomo-
gram are commonly available, and the graphical component as well as the online calculator are easy to use. Because many institutions determine hormone-receptor status only on the definitive surgical specimen, 2 models were created: one that includes ER and PR status and another that includes neither. As the use of such models is adopted by clinicians, I expect to see with increasing frequency the development of more statistical prediction models to assist patients and clinicians with estimating future outcomes. Although this approach should be viewed as a clear advance in our ability to make decisions on the basis of actual data, I also fear its misuse. Great caution should be used when making decisions on the basis of a mathematical model. These are simply formulas that estimate probabilities, but no mathematical model can actually make decisions. For example, many clinicians have contacted me to ask what the “threshold” of risk is below which I would not do a completion ALND in a woman with a positive SLN. I have a lengthy discussion with them, pointing out that there is no threshold—there is simply a risk estimate. I still maintain that completion ALND is the standard for a woman with a positive node, and if a woman or her clinician is considering avoidance of ALND, the nomogram can give them some estimate of risk of leaving behind hematoxylin and eosin–detectable disease. An estimate of 10% might be completely acceptable for an elderly woman with multiple comorbidities but completely unacceptable for a young woman with young children. Similarly, I fear that some patients or clinicians will misuse estimates of risk derived using our new nomogram by not proceeding with an SLN biopsy in the face of a low calculated risk. I cannot emphasize enough how wrong this would be. SLN biopsy is a low-risk, highly accurate procedure that is associated with very low morbidity.6,7 If a patient with a low calculated risk of having a positive SLN biopsy actually did have SLN metastasis, it would dramatically change her situation. Staging and systemic therapy recommendations would generally move from stage I and no chemotherapy to stage II with systemic chemotherapy. The risk/benefit ratio for staging the axilla is extremely low for the majority of patients. Clinicians and patients should always consider staging the axilla as preferable to a risk estimate that cannot, by its very nature, ever be as accurate for an individual as the actual SLN biopsy.
In closing, I offer a note of caution to clinicians. The art of medicine remains essential in the application and interpretation of various scientific tools. These tools should be used wisely and with careful attention to risks and benefits, should the low-risk event actually be true. Clinicians must remember the “art” of medicine while using the “science” of medicine.
References 1. 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;19:980991. 2. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol. 2003;10:1140-1151. 3. Specht MC, Kattan MW, Gonen M, Fey J, Van Zee KJ. Predicting nonsentinel node status after positive sentinel lymph biopsy for breast cancer: clinicians versus nomogram. Ann Surg Oncol. 2005;12:654-659. 4. Smidt M, Strobbe LJ, Groenewoud HM, Van der Wilt GJ, Van Zee KJ, Wobbes T. Can surgical oncologists reliably predict the likelihood for non-SLN metastases in breast cancer patients? Ann Surg Oncol. 2007;14:615-620. 5. Bevilacqua JLB, Kattan MW, Fey JV, Cody HS, Borgen PI, Van Zee KJ. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J Clin Oncol. 2007;25:3670-3679. 6. Baron RH, Fey JV, Borgen PI, Stempel MM, Hardick KR, Van Zee KJ. Eighteen sensations after breast cancer surgery: a 5-year comparison of sentinel lymph node biopsy and axillary lymph node dissection. Ann Surg Oncol. 2007;14:16531661. 7. McLaughlin SA, Wright MJ, Morris K, et al. Prevalence of lymphedema in 903 women with breast cancer 5 years after sentinel node biopsy or axillary dissection: measurements and patient perceptions (abstract 145). Presented at the 2007 American Society of Clinical Oncology Breast Cancer Symposium. http://www.asco.org. Accessed January 11, 2008.
®
Breast Diseases: A Year Book Quarterly Vol 19 No 2 2008
119 119