- Email: [email protected]
Radiation-Induced Heart Disease in Early Breast Cancer: Problem Solved?
17. Rubenstein B, McAuliffe J, Cawley S, et al: Machine learning in low-level microarray analysis. SIGKDD Explorations 5:130-139, 2003. 18. Hastie T, Tibshirani R, Friedman J: The Elements of Statistical Learning: Data Mining, Inference, and Prediction. New York, Springer-Verlag, 2001.
Radiation-Induced Heart Disease in Early Breast Cancer: Problem Solved? Gabor Gyenes, MD, PhD Postmastectomy radiotherapy (PMRT) has long been an integral part of treatment protocols for early-stage breast cancer. Large randomized studies in the 1970s showed that PMRT was successful in reducing the incidence of locoregional recurrence; however, whether PMRT led to reduced mortality has remained a more controversial issue for decades. Not only was all-cause mortality in the individual trials not significantly reduced, but a 1987 meta-analysis by Cuzick and colleagues1 showed that overall mortality was improved among patients who were not given PMRT. Moreover, both the meta-analysis and analyses of the individual trials revealed excess cardiac mortality and morbidity in the groups given RT.2-4 These findings suggested that an excess in cardiac mortality might offset any potential benefit from RT with regard to breast cancer mortality. Although the heart was originally thought to be a rather radioresistant organ, by the 1980s it had become well known that patients with Hodgkin’s disease were at risk of developing myocardial infarction and other cardiac side effects if treated with high-dose RT. Breast cancer affects a much larger group of patients, and outcome for those patients could be favorable after proper treatment if they did not suffer potentially lifethreatening long-term cardiac side effects from RT. Several aspects of the need to reduce cardiac morbidity from RT for breast cancer have been addressed. Additional retrospective studies have considered the long-term cardiac side effects of improved RT techniques. Eventually, results from 2 large randomized studies published in 1997 showed that PMRT after modified radical mastectomy not only reduced locoregional recurrence rates but also significantly prolonged diseasefree and overall survival times.5,6 While use of breast-conserving surgery with adjuvant RT to the remaining breast was gradually replacing total mastectomy, several reports were published on the possible cardiac complications of this technique.7-10 All of these studies found very small
19. Somorjai R, Dolenko B, Baumgartner R: Class prediction and discovery using gene microarray and proteomics mass spectroscopy data: Curses, caveats, cautions. Bioinformatics 19:1484-1491, 2003. 20. Lord P, Papoian T: Genomics and drug toxicity. Science 306:575, 2004.
numbers of complications, and only 1 study9 found an increased incidence of myocardial infarction in patients who had undergone RT in comparison with appropriate control subjects. In that study, patients with left-sided cancer were compared to those with right-sided disease, and the absolute incidence of radiationinduced cardiac complications was found to be 2% for those with tumors of the left breast and 1% for those with tumors of the right breast. Although the follow-up period was at least 10 years in most of these studies, that may not have been long enough to detect excess rates of cardiac complications because this problem generally emerges more than 10 years after RT. Other studies have attempted to prospectively consider the potential cardiac side effects of modern RT techniques.11,12 These studies did not assess long-term outcomes; rather, they involved use of sensitive nuclear methods to detect subclinical complications of RT. For patients in whom the heart was included in the radiation field, high rates of irreversible perfusion defects were found. Although coronary angiography was not done in most cases, the likelihood is high that these defects were secondary to small-vessel or myocardial fibrosis rather than stenoses of the major epicardial coronary arteries. It is difficult to know whether these small defects would evolve into clinically significant ischemic heart disease in 10 years. To address this question, Gagliardi and colleagues13 used a biological model with data from 2 prior studies3,14 and found that the average excess cardiac risk for patients with stage I breast cancer treated with tangential 6-MV photon beams was about 2%. In 1 of those 2 studies, the mean heart volume irradiated by at least 50% of the prescribed dose of 50 Gy was found to be approximately 6%. However, about 6% of patients would receive 25 Gy to 15% to 21% of the heart volume, which could translate into an excess cardiac risk of about 9% to 12%. Other studies using different methods confirmed that use of modern RT techniques would lead to irradiation of a smaller part of the heart in a smaller proportion of patients. Nevertheless, cardiac irradiation will remain a problem for a few women receiving PMRT.15-17 Another important lesson learned from these studies was that no obvious risk factors could be found to help identify pa-
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tients at high risk of cardiac complications. The most prudent way to predict cardiac complications is to use 3-dimensional RT planning or to assess the irradiated heart volume by virtual simulation at a level just above the diaphragm, where the heart is closest to the chest wall. This plane is inferior to the mammillary plane, the more commonly used plane in 2-dimensional treatment planning.14,15 Therefore in some cases the heart may seem to be spared on the treatment plan, but a significant proportion of the left ventricle may still be irradiated. Predictions that use of modern RT techniques would cause fewer cardiac complications were eventually confirmed in recent overviews including several of the more modern trials. One such meta-analysis of 40 studies showed a moderate but statistically significant reduction in the annual death rate from breast cancer,18 and a follow-up study of the overview first reported by Cuzick and colleagues also showed improvements in both cardiac and breast cancer mortality after RT.19 In summary, because radiation oncologists and physicists have been increasingly successful in excluding the heart from the radiation treatment field, the incidence of cardiac complications has declined, and consequently breast cancer mortality rates after PMRT have improved. The problem has shifted from being an issue for essentially all patients with early breast cancer to an issue for only a few individuals. However, as newer treatment techniques involving higher radiation doses seem to be showing some benefit for subgroups of patients with breast cancer, 20 the potential cardiac side effects of these techniques may need to be assessed to make sure the short-term benefits of RT are not offset by excess long-term cardiac morbidity and mortality. The risk can be minimized, if not fully prevented, for most patients if computed tomography–based treatment planning is optimized by taking the heart into consideration. The STAndardisation of breast RadioTherapy (START) trial15 is a prime example of how a group of major centers can establish their own guidelines and quality control measures to ensure that such side effects are prevented on an ongoing basis. A plethora of studies offer new techniques for limiting cardiac irradiation. These ongoing efforts should lead to further declines in the incidence of radiation-induced coronary artery disease in early breast cancer, so eventually such disease may become as rare as radiation-induced cardiomyopathy and valvular disease. On the other hand, for cardiologists and general practitioners, a history of left-sided PMRT should probably be considered as a nonmodifiable risk factor for coronary artery disease. Acknowledgment The author is grateful to Prof. Dr. George Gyenes for his helpful comments and criticism.
References 1. Cuzick J, Stewart H, Peto R, et al: Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 71:15-29, 1987.
20 20
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Breast Diseases: A Year Book Quarterly Vol 16 No 1 2005
2. Host H, Brennhovd IO, Loeb M: Postoperative radiotherapy in breast cancer–long-term results from the Oslo study. Int J Radiat Oncol Biol Phys 12:727-732, 1986. 3. Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992. 4. Gyenes G, Fornander T, Carlens P, et al: Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 28:1235-1241, 1994. 5. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997. 6. Ragaz J, Jackson SM, Le N, et al: Adjuvant chemotherapy and radiotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997. 7. Vallis KA, Pintilie M, Chong N, et al: Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol 20:1036-1042, 2002. 8. Nixon AJ, Manola J, Gelman R, et al: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998. 9. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: A population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 43:755-762, 1999. 10. Rutqvist LE, Liedberg A, Hammar N, et al: Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation. Int J Radiat Oncol Biol Phys 40:359-363, 1998. 11. Gyenes G, Fornander T, Carlens P, et al: Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: A prospective study. Int J Radiat Oncol Biol Phys 36:899-905, 1996. 12. Goethals I, Dierckx R, De Meerleer G, et al: The role of nuclear medicine in the prediction and detection of radiationassociated normal pulmonary and cardiac damage. J Nucl Med 44:1531-1539, 2003. 13. Gagliardi G, Lax I, Söderström S, et al: Prediction of longterm cardiac mortality after radiotherapy in stage I breast cancer patients. Radiother Oncol 46:63-71, 1998. 14. Gyenes G, Gagliardi G, Lax I, et al: Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 15:13481353, 1997. 15. Venables K, Miles EA, Deighton A, et al: Irradiation of the heart during tangential breast treatment: A study within the START trial. Br J Radiol 77:137-142, 2004. 16. Fuller SA, Haybittle JL, Smith REA, et al: Cardiac doses in post-operative breast irradiation. Radiother Oncol 25:19-24, 1992.
17. Janjan NA, Gillin MT, Prows J, et al: Dose to the cardiac vascular and conduction systems in primary breast irradiation. Med Dosim 14:81-87, 1989.
19. Cuzick J, Stewart H, Rutqvist LE, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994.
18. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomized trials. Lancet 355:1757-1770, 2000.
20. Bartelink H: Radiotherapy to the conserved breast, chest wall, and the regional nodes: Is there a standard? Breast 12:475-482, 2003.
Using In Vivo Chemosensitivity as a Guide for Further Systemic Therapy: Refining the Target Population
VbMF as opposed to additional adjuvant VACP. The interesting and unique part of this study, however, is that the investigators randomized only those patients who showed a clinical response and were found at surgery to have residual disease larger than 1 cm3. Thus, the randomized patients were relatively chemosensitive or relatively chemoresistant depending on one’s point of view. Randomizing patients who showed a pathologic complete response or residual disease smaller than 1 cm3, and for that matter even those who did not show a clinical response to the initial VACP regimen, would have been ideal. Only by this approach could information have been obtained as to who benefits more and who benefits less from use of a non–cross-resistant regimen. Other randomized trials that have not used clinical or pathologic tumor response as a criterion for assigning patients to the non–cross-resistant regimen might be able to answer some of these questions by using subset analyses.3 In fact, outcome results from the B-27 trial of the National Surgical Adjuvant Breast and Bowel Project presented at the 2004 San Antonio Breast Cancer Symposium4 suggested that most of the benefit in disease-free survival from the sequential administration of preoperative docetaxel after preoperative doxorubicin and cyclophosphamide was observed in patients who showed a partial clinical response to the doxorubicin-pluscyclophosphamide regimen. As we rapidly enter the era of gene expression profiling through the use of high-throughput technology and other novel molecular techniques, clinical and, more importantly, pathologic response to neoadjuvant chemotherapy are becoming important end points for identifying gene profiles that predict for response to a certain chemotherapy agent or drug combination.5-8 If this approach is successful, then clinical or pathologic tumor response as a predictor of chemosensitivity or chemoresistance will eventually be replaced by accurate molecular predictive markers that will guide the selection of up-front and subsequent therapy. Genomic technology is already starting to produce results that allow the identification of patients who will or will not respond to certain chemotherapy regimens.6,9 Moreover, genomic technologies are helping us to better understand tumor
Eleftherios P. Mamounas, MD, MPH Neoadjuvant chemotherapy has been established as the standard approach for patients with locally advanced breast cancer and as a reasonable alternative to adjuvant chemotherapy for patients with large but operable disease who wish to reduce the extent of required breast surgery. Possible reduction in the extent of axillary surgery by using sentinel node biopsy is emerging as another potential benefit of neoadjuvant chemotherapy. One of the original premises for the use of neoadjuvant chemotherapy was that primary breast tumor response could serve as an in vivo chemosensitivity assay to predict which patients would or would not benefit from additional (potentially non–cross-resistant) chemotherapy. However, identifying optimal candidates for additional neoadjuvant or adjuvant chemotherapy based on primary tumor response to the initial neoadjuvant regimen has been a difficult task. Although existing information on the subject is limited, the preliminary conclusions seem to be somewhat counterintuitive to the original hypothesis, i.e., that patients who do not respond to the original neoadjuvant chemotherapy regimen might derive the most benefit from subsequent non–cross-resistant chemotherapy. In fact, the results so far point to the opposite conclusion—that patients who show a clinical response to the first chemotherapy regimen are those who derive the most benefit from non–cross-resistant chemotherapy,1 and those who do not show a clinical response to the first regimen have relatively chemoresistant disease and derive little, if any, benefit from non–cross-resistant regimens.2 The results of the present study by Thomas and colleagues (Abstract 1–36) are consistent with those of previous studies in that they demonstrate that outcome for patients who showed a clinical response to neoadjuvant VACP was improved if those patients were given adjuvant
®
Breast Diseases: A Year Book Quarterly Vol 16 No 1 2005
21 21
Radiation-Induced Heart Disease in Early Breast Cancer: Problem Solved? Gabor Gyenes, MD, PhD Postmastectomy radiotherapy (PMRT) has long been an integral part of treatment protocols for early-stage breast cancer. Large randomized studies in the 1970s showed that PMRT was successful in reducing the incidence of locoregional recurrence; however, whether PMRT led to reduced mortality has remained a more controversial issue for decades. Not only was all-cause mortality in the individual trials not significantly reduced, but a 1987 meta-analysis by Cuzick and colleagues1 showed that overall mortality was improved among patients who were not given PMRT. Moreover, both the meta-analysis and analyses of the individual trials revealed excess cardiac mortality and morbidity in the groups given RT.2-4 These findings suggested that an excess in cardiac mortality might offset any potential benefit from RT with regard to breast cancer mortality. Although the heart was originally thought to be a rather radioresistant organ, by the 1980s it had become well known that patients with Hodgkin’s disease were at risk of developing myocardial infarction and other cardiac side effects if treated with high-dose RT. Breast cancer affects a much larger group of patients, and outcome for those patients could be favorable after proper treatment if they did not suffer potentially lifethreatening long-term cardiac side effects from RT. Several aspects of the need to reduce cardiac morbidity from RT for breast cancer have been addressed. Additional retrospective studies have considered the long-term cardiac side effects of improved RT techniques. Eventually, results from 2 large randomized studies published in 1997 showed that PMRT after modified radical mastectomy not only reduced locoregional recurrence rates but also significantly prolonged diseasefree and overall survival times.5,6 While use of breast-conserving surgery with adjuvant RT to the remaining breast was gradually replacing total mastectomy, several reports were published on the possible cardiac complications of this technique.7-10 All of these studies found very small
19. Somorjai R, Dolenko B, Baumgartner R: Class prediction and discovery using gene microarray and proteomics mass spectroscopy data: Curses, caveats, cautions. Bioinformatics 19:1484-1491, 2003. 20. Lord P, Papoian T: Genomics and drug toxicity. Science 306:575, 2004.
numbers of complications, and only 1 study9 found an increased incidence of myocardial infarction in patients who had undergone RT in comparison with appropriate control subjects. In that study, patients with left-sided cancer were compared to those with right-sided disease, and the absolute incidence of radiationinduced cardiac complications was found to be 2% for those with tumors of the left breast and 1% for those with tumors of the right breast. Although the follow-up period was at least 10 years in most of these studies, that may not have been long enough to detect excess rates of cardiac complications because this problem generally emerges more than 10 years after RT. Other studies have attempted to prospectively consider the potential cardiac side effects of modern RT techniques.11,12 These studies did not assess long-term outcomes; rather, they involved use of sensitive nuclear methods to detect subclinical complications of RT. For patients in whom the heart was included in the radiation field, high rates of irreversible perfusion defects were found. Although coronary angiography was not done in most cases, the likelihood is high that these defects were secondary to small-vessel or myocardial fibrosis rather than stenoses of the major epicardial coronary arteries. It is difficult to know whether these small defects would evolve into clinically significant ischemic heart disease in 10 years. To address this question, Gagliardi and colleagues13 used a biological model with data from 2 prior studies3,14 and found that the average excess cardiac risk for patients with stage I breast cancer treated with tangential 6-MV photon beams was about 2%. In 1 of those 2 studies, the mean heart volume irradiated by at least 50% of the prescribed dose of 50 Gy was found to be approximately 6%. However, about 6% of patients would receive 25 Gy to 15% to 21% of the heart volume, which could translate into an excess cardiac risk of about 9% to 12%. Other studies using different methods confirmed that use of modern RT techniques would lead to irradiation of a smaller part of the heart in a smaller proportion of patients. Nevertheless, cardiac irradiation will remain a problem for a few women receiving PMRT.15-17 Another important lesson learned from these studies was that no obvious risk factors could be found to help identify pa-
®
Breast Diseases: A Year Book Quarterly Vol 16 No 1 2005
19 19
tients at high risk of cardiac complications. The most prudent way to predict cardiac complications is to use 3-dimensional RT planning or to assess the irradiated heart volume by virtual simulation at a level just above the diaphragm, where the heart is closest to the chest wall. This plane is inferior to the mammillary plane, the more commonly used plane in 2-dimensional treatment planning.14,15 Therefore in some cases the heart may seem to be spared on the treatment plan, but a significant proportion of the left ventricle may still be irradiated. Predictions that use of modern RT techniques would cause fewer cardiac complications were eventually confirmed in recent overviews including several of the more modern trials. One such meta-analysis of 40 studies showed a moderate but statistically significant reduction in the annual death rate from breast cancer,18 and a follow-up study of the overview first reported by Cuzick and colleagues also showed improvements in both cardiac and breast cancer mortality after RT.19 In summary, because radiation oncologists and physicists have been increasingly successful in excluding the heart from the radiation treatment field, the incidence of cardiac complications has declined, and consequently breast cancer mortality rates after PMRT have improved. The problem has shifted from being an issue for essentially all patients with early breast cancer to an issue for only a few individuals. However, as newer treatment techniques involving higher radiation doses seem to be showing some benefit for subgroups of patients with breast cancer, 20 the potential cardiac side effects of these techniques may need to be assessed to make sure the short-term benefits of RT are not offset by excess long-term cardiac morbidity and mortality. The risk can be minimized, if not fully prevented, for most patients if computed tomography–based treatment planning is optimized by taking the heart into consideration. The STAndardisation of breast RadioTherapy (START) trial15 is a prime example of how a group of major centers can establish their own guidelines and quality control measures to ensure that such side effects are prevented on an ongoing basis. A plethora of studies offer new techniques for limiting cardiac irradiation. These ongoing efforts should lead to further declines in the incidence of radiation-induced coronary artery disease in early breast cancer, so eventually such disease may become as rare as radiation-induced cardiomyopathy and valvular disease. On the other hand, for cardiologists and general practitioners, a history of left-sided PMRT should probably be considered as a nonmodifiable risk factor for coronary artery disease. Acknowledgment The author is grateful to Prof. Dr. George Gyenes for his helpful comments and criticism.
References 1. Cuzick J, Stewart H, Peto R, et al: Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 71:15-29, 1987.
20 20
®
Breast Diseases: A Year Book Quarterly Vol 16 No 1 2005
2. Host H, Brennhovd IO, Loeb M: Postoperative radiotherapy in breast cancer–long-term results from the Oslo study. Int J Radiat Oncol Biol Phys 12:727-732, 1986. 3. Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992. 4. Gyenes G, Fornander T, Carlens P, et al: Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 28:1235-1241, 1994. 5. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997. 6. Ragaz J, Jackson SM, Le N, et al: Adjuvant chemotherapy and radiotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997. 7. Vallis KA, Pintilie M, Chong N, et al: Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol 20:1036-1042, 2002. 8. Nixon AJ, Manola J, Gelman R, et al: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998. 9. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: A population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 43:755-762, 1999. 10. Rutqvist LE, Liedberg A, Hammar N, et al: Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation. Int J Radiat Oncol Biol Phys 40:359-363, 1998. 11. Gyenes G, Fornander T, Carlens P, et al: Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: A prospective study. Int J Radiat Oncol Biol Phys 36:899-905, 1996. 12. Goethals I, Dierckx R, De Meerleer G, et al: The role of nuclear medicine in the prediction and detection of radiationassociated normal pulmonary and cardiac damage. J Nucl Med 44:1531-1539, 2003. 13. Gagliardi G, Lax I, Söderström S, et al: Prediction of longterm cardiac mortality after radiotherapy in stage I breast cancer patients. Radiother Oncol 46:63-71, 1998. 14. Gyenes G, Gagliardi G, Lax I, et al: Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy. J Clin Oncol 15:13481353, 1997. 15. Venables K, Miles EA, Deighton A, et al: Irradiation of the heart during tangential breast treatment: A study within the START trial. Br J Radiol 77:137-142, 2004. 16. Fuller SA, Haybittle JL, Smith REA, et al: Cardiac doses in post-operative breast irradiation. Radiother Oncol 25:19-24, 1992.
17. Janjan NA, Gillin MT, Prows J, et al: Dose to the cardiac vascular and conduction systems in primary breast irradiation. Med Dosim 14:81-87, 1989.
19. Cuzick J, Stewart H, Rutqvist LE, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994.
18. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomized trials. Lancet 355:1757-1770, 2000.
20. Bartelink H: Radiotherapy to the conserved breast, chest wall, and the regional nodes: Is there a standard? Breast 12:475-482, 2003.
Using In Vivo Chemosensitivity as a Guide for Further Systemic Therapy: Refining the Target Population
VbMF as opposed to additional adjuvant VACP. The interesting and unique part of this study, however, is that the investigators randomized only those patients who showed a clinical response and were found at surgery to have residual disease larger than 1 cm3. Thus, the randomized patients were relatively chemosensitive or relatively chemoresistant depending on one’s point of view. Randomizing patients who showed a pathologic complete response or residual disease smaller than 1 cm3, and for that matter even those who did not show a clinical response to the initial VACP regimen, would have been ideal. Only by this approach could information have been obtained as to who benefits more and who benefits less from use of a non–cross-resistant regimen. Other randomized trials that have not used clinical or pathologic tumor response as a criterion for assigning patients to the non–cross-resistant regimen might be able to answer some of these questions by using subset analyses.3 In fact, outcome results from the B-27 trial of the National Surgical Adjuvant Breast and Bowel Project presented at the 2004 San Antonio Breast Cancer Symposium4 suggested that most of the benefit in disease-free survival from the sequential administration of preoperative docetaxel after preoperative doxorubicin and cyclophosphamide was observed in patients who showed a partial clinical response to the doxorubicin-pluscyclophosphamide regimen. As we rapidly enter the era of gene expression profiling through the use of high-throughput technology and other novel molecular techniques, clinical and, more importantly, pathologic response to neoadjuvant chemotherapy are becoming important end points for identifying gene profiles that predict for response to a certain chemotherapy agent or drug combination.5-8 If this approach is successful, then clinical or pathologic tumor response as a predictor of chemosensitivity or chemoresistance will eventually be replaced by accurate molecular predictive markers that will guide the selection of up-front and subsequent therapy. Genomic technology is already starting to produce results that allow the identification of patients who will or will not respond to certain chemotherapy regimens.6,9 Moreover, genomic technologies are helping us to better understand tumor
Eleftherios P. Mamounas, MD, MPH Neoadjuvant chemotherapy has been established as the standard approach for patients with locally advanced breast cancer and as a reasonable alternative to adjuvant chemotherapy for patients with large but operable disease who wish to reduce the extent of required breast surgery. Possible reduction in the extent of axillary surgery by using sentinel node biopsy is emerging as another potential benefit of neoadjuvant chemotherapy. One of the original premises for the use of neoadjuvant chemotherapy was that primary breast tumor response could serve as an in vivo chemosensitivity assay to predict which patients would or would not benefit from additional (potentially non–cross-resistant) chemotherapy. However, identifying optimal candidates for additional neoadjuvant or adjuvant chemotherapy based on primary tumor response to the initial neoadjuvant regimen has been a difficult task. Although existing information on the subject is limited, the preliminary conclusions seem to be somewhat counterintuitive to the original hypothesis, i.e., that patients who do not respond to the original neoadjuvant chemotherapy regimen might derive the most benefit from subsequent non–cross-resistant chemotherapy. In fact, the results so far point to the opposite conclusion—that patients who show a clinical response to the first chemotherapy regimen are those who derive the most benefit from non–cross-resistant chemotherapy,1 and those who do not show a clinical response to the first regimen have relatively chemoresistant disease and derive little, if any, benefit from non–cross-resistant regimens.2 The results of the present study by Thomas and colleagues (Abstract 1–36) are consistent with those of previous studies in that they demonstrate that outcome for patients who showed a clinical response to neoadjuvant VACP was improved if those patients were given adjuvant
®
Breast Diseases: A Year Book Quarterly Vol 16 No 1 2005
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