- Email: [email protected]
Breast surgery in advanced breast cancer: Local control in the presence of metastases
ARTICLE IN PRESS THE BREAST The Breast 16 (2007) S63–S66 www.elsevier.com/locate/breast
Original Article
Breast surgery in advanced breast cancer: Local control in the presence of metastases William C. Wooda,b, a
Department of Surgery, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA b Winship Cancer Institute, USA
Abstract Recent reports have associated improved survival with surgical resection of primary breast cancer in patients presenting with synchronous metastases. These series can be criticized for selection bias as an explanation for improved outcome. Mutlivariate analysis attempting to address selection is still compatible with an associated benefit. Until a prospective randomized trial answers this question with solid evidence, what treatment gives the patient the benefit of the doubt? It would appear to favor resection of the primary in selected patients in whom the metastatic disease has a chance of control with systemic therapy. Once the barrier of surgery in the presence of metastases is breached, questions regarding more frequent application of surgery and ablative irradiation for metachronous metastasis in selected patients arise. The time has come to address this issue as well. r 2007 Elsevier Ltd. All rights reserved. Keywords: Local control; Stage M1 breast cancer; Surgery for breast cancer metastases; Prospective trials; Surgery in advanced breast cancer
Introduction
Review
In generally accepted practice women who present with distant metastases of breast cancer are not considered candidates for surgical management of the primary tumor. Several recent publications (Table 1) have suggested that surgery for the primary tumor in such women is associated with improved survival.1–5 This raises two questions. The first is the role of surgical management of the primary in the presence of metastatic disease. The second is the associated question of the role of surgery and/or irradiation in ablating all evident breast cancer, primary or metastatic, and attempting by producing complete clinical remission to achieve a long-term, even lifetime, remission of disease.
The presence of metastases [Stage IV, M1 disease] has long been considered a firm contraindication to ablative surgery for primary breast cancer. The management of breast cancer has changed dramatically from the time when this principle arose. First, the ablative surgery that was being prevented was radical mastectomy. Today, excision of the tumor by limited surgery, often after significant reduction in volume by neoadjuvant therapy, is part of a combined approach to breast conserving therapy (BCT). Second, M1 disease was detected by symptoms or clinical findings or relatively crude radiographic techniques. Today many of the patients with M1 disease found at presentation of the primary breast cancer have smaller metastases, detected by PET scans or bone scans. Third, the therapy available for treating metastatic breast cancer was rarely capable of producing long-term remission. Management was focused on the control of the metastatic disease. Response of the distant metastases was often reflected in response of the primary tumor. Radiation therapy was available to assist in control of the primary breast cancer. Mastectomy was reserved for the complications of
Corresponding author at: Department of Surgery, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA. Tel.: +1 404 727 5800; fax: +1 404 727 4716. E-mail address: [email protected]
0960-9776/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2007.07.008
ARTICLE IN PRESS W.C. Wood / The Breast 16 (2007) S63–S66
S64 Table 1 Breast surgery in M1 breast cancer. First author
Primary untreated
1
Khan et al.
Primary resected
N
Med survival
5-year survival
N
6861
11.9 mos
6.7%
9162
Carmichael et al.5
Med survival
5-year survival
p-value MultiV+
3369 Marg Marg+ 20
24 mos 19 mos 23 mos
19% 11% (41% 3 years)
Rapiti et al.2
173
18 mos
12%
61 Marg
26 mos
27%
p ¼ .049
Blanchard et al.3
169
16.8 mos
10%
33 Marg+ 258
14 mos 27 mos
16% 22%
po.0001
142
Not reached
70% (7% DM free)
82
NR
70% (27% DM free)
p ¼ .0007
4
Babiera et al.
uncontrolled local disease, including ulceration, bleeding, and tumor necrosis. Today numerous active cytotoxic agents are available, as are tamoxifen and aromatase inhibitors for appropriate patients. Newer agents targeted to specific receptors offer further gains in tumor cell kill and consequent response duration. In 2002, Khan et al.1 reported a retrospective review of 16,023 patients from the National Cancer Data Bank (USA) with metastatic breast cancer found at their initial presentation. They considered the outcome in three groups of patients. Those who had no resection of the primary tumor had 17.3% 3-year survival, those who had resection but with margin involvement had 26% and those who had clear margins of resection a 35% 3-year survival. This outcome was significantly better (po.0001). In 2006, Rapiti et al.2 reported a population based review of 300 breast cancer patients presenting with M1 disease. The 3-year survival for the group whose primary tumor was resected with clear margins was similar to that reported by Khan. The group excised with involved margins was not significantly better than the group not resected. The hazard ratio for risk of death with resection to clear margins was .6 compared to the group that was not resected (p ¼ .049). This report was published with a superb editorial by Morrow and Goldstein.6 They discussed this topic in detail, raising the very appropriate concern that conclusions drawn from treating different populations of metastatic breast cancer patients differently cannot be considered convincing evidence of treatment effect. Blanchard et al.3 reviewed 807 patients who had Stage IV disease at presentation. They analyzed 427 patients who survived more than 90 days, a major initial selection bias, although appropriate. They were unable to group by margin status, but 78% of the patients had mastectomy as their surgical procedure. The 3-year survivals of the two resulting groups are similar to those in Khan’s report. The authors attempted to minimize selection bias by multivariate analysis. The hazard ratio for definitive surgery compared to no surgery to the primary was .71 (p ¼ .0059 by multivariate analysis). Charmichael et al.5 reported on
20 patients with the primary resected for a 41% 3-year survival, remarkably similar to the outcome in the other reports. Babiera et al.4 compared 142 patients with untreated primaries with 82 with resected primaries. These all received contemporary systemic therapy and both groups have a 70% 5-year actuarial survival. Only 7% of those with untreated primary tumors are free of distant metastases, but 27% of those with resected primary cancers are free. Although it is interesting that all five of these reviews of different populations produced similar results, the presumption of bias in favor of those who were selected for surgical therapy leaves the hypothesis of benefit open to conjecture. This is a question that requires the confidence of similar populations that can only be achieved by randomization in a prospective clinical trial. A legitimate question regards the treatment of women who present with Stage IV breast cancer until the time that the decision can be based on prospective evidence. The basis on which the prohibition of treatment of the primary in this circumstance arose is not applicable for many of these women. Just as that decision was based on the application of primary principles, those principles must be applied to each individual today. We lack data from the modern era that would support failing to provide definitive control of the primary tumor when the extent and biology of the metastasis suggest a possibility of control. When there seems to be an opportunity to control a limited metastatic focus, the patient warrants receiving the benefit of the doubt, i.e. to have surgical control of the primary tumor. We must confess that the value of surgery for the primary in the face of metastatic disease has long been known and accepted under a different guise. Nodal metastases [N1,2] are clearly quantitatively, not qualitatively, different from M1 metastases. We routinely treat ‘‘for cure’’ patients who present with metastases to their axillary nodes. We know that these are metastatic deposits and that they are associated with a variable burden of distant metastatic disease that relates to the number of the lymph nodes containing metastases. The prohibition of
ARTICLE IN PRESS W.C. Wood / The Breast 16 (2007) S63–S66
surgery for metastatic breast cancer is related to the letter of the alphabet that we have assigned, M vs. N, not to the presence of distant metastases. It can be argued, then, that patients presenting with a limited volume of metastatic disease that responds to initial therapy deserve definitive treatment of their primary in the expectation of long-term remission. Although a definitive answer will require a prospective trial, decisions regarding patient management are required in the meantime. The default position can be defended that there are no data suggesting that control of the primary tumor in the presence of metastatic tumor that may respond or has responded to contemporary systemic therapy is not most appropriate. The goal of resection of the primary tumor would be the removal of a source of tumor stem cells resistant to systemic therapy that could serve as a source of new metastases. The last decades have been associated with great pessimism that the quality of local control has any effect on ultimate survival. This despite the reality that in the era prior to mammographic screening and adjuvant therapy, surgery and radiation alone achieved a 10-year survival rate of 450% of operable patients.7 The overview of radiation or not after breast conserving surgery demonstrates clearly that prevention of local failure, i.e. definitive local control, results in a significant survival advantage.8 These data demonstrate a survival advantage accruing to patients with improved local control. The obverse is also true. Lack of optimal local control is associated with a diminished survival from breast cancer. This was seen in each of the reports in which surgical ablation of the primary was attempted, presumably with a similar selection bias, if the surgical resection margins were not clear. Survival was not improved despite reduction in tumor volume. Once the taboo of surgery for M1 disease has been broached, a much larger question arises. Has progress in breast cancer therapy, both systemic and local-regional, reached the point that patients with metachronous metastatic breast cancer should be considered for a comprehensive approach designed to produce freedom from all clinically apparent tumor? If clinical NED (no evident disease) status can be achieved, should not ‘‘adjuvant therapy’’ then be tested for the identification of those patient groups selected by clinical/pathological and by genomic techniques that would benefit? Particularly those subgroups presenting with M1 disease that have a real chance of lifetime remission (called ‘‘cure’’ in a less skeptical era). Several areas of clinical oncology support such a conclusion (Table 2). Local or regional recurrence of breast cancer has long been considered appropriate for attempting ablation of all apparent disease, in the absence of demonstrated distant metastases. Survival has been related to the nodal status of the initial primary (a surrogate for the burden of distant metastatic disease) and the addition of some systemic therapy to the surgery and radiation.9 Isolated metastases
S65
Table 2 Resection of breast cancer metastases. First author
Dates
N
5-year survivors
Lung Wilkins et al.17 Morrow et al.18 Mountain et al.19 Lanza et al.20 Staren et al.21 Livartowski et al.22 Ludwig et al.23 Girard et al.24 Friedel et al.25
1933–74 1939–78 1963–83 1981–90 1972–90 1987–95 1989–98 1969–84 1960–94
9 10 30 44 33 52 21 186 467
53% 20% 27% 50% 36% 54% 53% 32% (23% 10 years) 38% (22% 10 years)
Liver Elias et al.26 Pocard et al.27 Selzner et al.28
1986–94 –95 1987–99
21 21 17
24% 60% 22%
d’Annibale et al.29
1984–99
18
25% DFI o3 years 40% DFI 43 years
have been treated by resection and reported as small series for many years. Resection of pulmonary metastases is associated with prolonged survival as illustrated in Table 2.10,12 Incomplete resection is associated with minimal or no benefit, providing further evidence that the quality of local-regional control, even of isolated metastases, relates to superior survival. Intensified local treatment (resection or boost irradiation) of brain metastases appears to confer benefit as well.11,12 Resection of hepatic metastases of breast cancer has also been proposed based on retrospective reviews of resection in selected patients (Table 2).12,13 Breast cancer is not the only tumor type that has been treated by resection of metastatic disease in selected patients. Among the most common indications for hepatic resection in the United States is metastasis from colorectal carcinoma. This is associated with 5-year survival rates of about 30% in various series, depending on the extent and number of the metastases resected and upon complete ablation of apparent tumor.14 The resection of metastases in malignant melanoma has also been associated with prolonged survival.15 These reviews stretch back to patients treated over 40 years ago. The progress in staging distant metastases, the wide use of minimally invasive surgical techniques, and the availability of more effective hormonal, cytotoxic, and biological agents offer the hope of treating many patients selected for favorable presentations of breast cancer metastases today. Consequently, a more apt analogy to another disease may be gastrointestinal stromal tumors (GIST). The availability of imatinib [Gleevacs] gives a specific, very effective biological therapy for treating metastatic or recurrent GIST’s. The expression of c-KIT proto-oncogene mutations provides a predictive marker. Patients treated with complete clinical remission have an ongoing recurrence rate over time. Early data suggest that
ARTICLE IN PRESS S66
W.C. Wood / The Breast 16 (2007) S63–S66
resection of the recurrence prior to treatment, or after partial response, is associated with a superior disease free survival. Such analogies are intriguing, but fail to provide definitive evidence on which to base treatment recommendations. All evidence points to the existence of a group of patients with metastatic breast cancer that can be rendered Stage IV NED by surgery and/or radiation accompanied by tailored systemic therapy. Prospective clinical trials designed to improve our ability to select such patients are needed. Genomic profiling offers more specific tumor classification than has ever been possible previously. It is time to seriously address the question raised 5 years ago in an editorial by Professor Gabriel Hortobagyi, ‘‘Can we cure limited metastatic breast cancer?’’16 Conflict of Interest Statement None declared. References 1. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 2002;132: 620–7. 2. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006;24:2743–9. 3. Blanchard DK, Bhatia P, Hilsenbeck SG, Elledge RM. Does surgical management of Stage IV breast cancer affect outcome? Breast Cancer Res Treat 2006;100:A2110. 4. Babiera GV, Rao R, Feng L, Meric-Bernstam F, et al. Effect of primary tumor extirpation in breast cancer patients who present with Stage IV disease and an intact primary tumor. Ann Surg Oncol 2006; 13:776–82. 5. Carmichael AR, Anderson EDC, Chetty U, Dixon JM. Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol 2003;29:17–9. 6. Morrow M, Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol 2006;24:2694–6. 7. Haagensen CD. Diseases of the breast. 2nd ed. Philadelphia: WB Saunders Co.; 1971. p. 456–7. 8. Clarke M, Collins R, Darby S. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;366:2087–106. 9. Juan O, Luch A, dePaz L, et al. Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED). Breast Cancer Res Treat 1999;53:105–12.
10. Girard P, Baldeyrou P, Le Chevalier T, et al. Surgery for pulmonary metastases. Who are the 10-year survivors? Cancer 1994;74:2791–7. 11. Bartsch R, Fromm S, Rudas M, et al. Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer—a retrospective analysis. Radiother Oncol 2006;80:313–7. 12. Singletary SE, Walsh G, Vauthey J-N, et al. A role for curative surgery in the treatment of selected patients with metastatic breast cancer. Oncologist 2003;8:241–51. 13. Selzner M, Morse MA, Vredenburgh JJ, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000;127:383–9. 14. Kemeny NE, Kemeny M, Lawrence TS. Liver metastases. In: Abeloff MD, Armitage JO, Niederhuber JE, et al., editors. Clinical oncology. 3rd ed. Philadelphia: Elsevier, Churchill Livingstone; 2004. p. 1141. 15. Faries MB, Morton DL. Editorial: the promise of metastasectomy in melanoma. Ann Surg Oncol 2006;13:607–9. 16. Hortobagyi G. Editorial: can we cure limited metastatic breast cancer? J Clin Oncol 2002;20:620–3. 17. Wilkins EWJ, Head JM, Burke JF. Pulmonary resection for metastatic neoplasms in the lung; experience at the Massachusetts General Hospital. Am J Surg 1979;135:480–3. 18. Morrow CE, Vassilopoulos PP, Grage TB. Surgical resection for metastatic neoplasms of the lung: experience of the University of Minnesota hospitals. Cancer 1980;45(12):2981–5. 19. Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastasis: a 20-year experience. Ann Thorac Surg 1984;38(4): 323–30. 20. Lanza LA, Natarajan G, Roth JA, Putnam JB. Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Ann Thorac Surg 1992;54:244–8. 21. Staren ED, Salerno C, Rongione A, Witt TR, Faber P. Pulmonary resection for metastatic breast cancer. Arch Surg 1992;127:1282–4. 22. Livartowski A, Chapelier A, Beuzedoc P, Dierick A, Asselain B, Dartevelle P, et al. Bull Cancer 1998;85(9):800. 23. Ludwig C, Stoelben E, Hasse I. Disease-free survival after resection of lung metastases in patients with breast cancer. Eur J Surg Oncol 2003; 29:532–5. 24. Girard P, Baldeyrou P, Le Chevalier T, et al. Surgery for pulmonary metastases: who are the 10-year survivors? Cancer 1994;74(10): 2791–7. 25. Fiedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer; prognostic criteria on the basis of 467 cases of the international registry of lung metastases. Eur J Cardiothorac Surg 2002;22:335–44. 26. Elias D, Lasser PH, Monrucolli D, et al. Hepatectomy for liver metastases from breast cancer. Eur J Surg Oncol 1995;21:510–3. 27. Pocard M, Salmon RJ. Hepatic resection for breast cancer metastasis. The concept of adjuvant surgery. Bull Cancer 1997;84:47–50. 28. Selzner M, Morse MA, Vredenburgh JJ, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000;127:383–9. 29. d’Annabale M, Piovanello P, Cerasoli V, Campioni N. Liver metastases from breast cancer: the role of surgical treatment. Hepatogastroenterology 2005;52:1858–62.
Original Article
Breast surgery in advanced breast cancer: Local control in the presence of metastases William C. Wooda,b, a
Department of Surgery, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA b Winship Cancer Institute, USA
Abstract Recent reports have associated improved survival with surgical resection of primary breast cancer in patients presenting with synchronous metastases. These series can be criticized for selection bias as an explanation for improved outcome. Mutlivariate analysis attempting to address selection is still compatible with an associated benefit. Until a prospective randomized trial answers this question with solid evidence, what treatment gives the patient the benefit of the doubt? It would appear to favor resection of the primary in selected patients in whom the metastatic disease has a chance of control with systemic therapy. Once the barrier of surgery in the presence of metastases is breached, questions regarding more frequent application of surgery and ablative irradiation for metachronous metastasis in selected patients arise. The time has come to address this issue as well. r 2007 Elsevier Ltd. All rights reserved. Keywords: Local control; Stage M1 breast cancer; Surgery for breast cancer metastases; Prospective trials; Surgery in advanced breast cancer
Introduction
Review
In generally accepted practice women who present with distant metastases of breast cancer are not considered candidates for surgical management of the primary tumor. Several recent publications (Table 1) have suggested that surgery for the primary tumor in such women is associated with improved survival.1–5 This raises two questions. The first is the role of surgical management of the primary in the presence of metastatic disease. The second is the associated question of the role of surgery and/or irradiation in ablating all evident breast cancer, primary or metastatic, and attempting by producing complete clinical remission to achieve a long-term, even lifetime, remission of disease.
The presence of metastases [Stage IV, M1 disease] has long been considered a firm contraindication to ablative surgery for primary breast cancer. The management of breast cancer has changed dramatically from the time when this principle arose. First, the ablative surgery that was being prevented was radical mastectomy. Today, excision of the tumor by limited surgery, often after significant reduction in volume by neoadjuvant therapy, is part of a combined approach to breast conserving therapy (BCT). Second, M1 disease was detected by symptoms or clinical findings or relatively crude radiographic techniques. Today many of the patients with M1 disease found at presentation of the primary breast cancer have smaller metastases, detected by PET scans or bone scans. Third, the therapy available for treating metastatic breast cancer was rarely capable of producing long-term remission. Management was focused on the control of the metastatic disease. Response of the distant metastases was often reflected in response of the primary tumor. Radiation therapy was available to assist in control of the primary breast cancer. Mastectomy was reserved for the complications of
Corresponding author at: Department of Surgery, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA. Tel.: +1 404 727 5800; fax: +1 404 727 4716. E-mail address: [email protected]
0960-9776/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2007.07.008
ARTICLE IN PRESS W.C. Wood / The Breast 16 (2007) S63–S66
S64 Table 1 Breast surgery in M1 breast cancer. First author
Primary untreated
1
Khan et al.
Primary resected
N
Med survival
5-year survival
N
6861
11.9 mos
6.7%
9162
Carmichael et al.5
Med survival
5-year survival
p-value MultiV+
3369 Marg Marg+ 20
24 mos 19 mos 23 mos
19% 11% (41% 3 years)
Rapiti et al.2
173
18 mos
12%
61 Marg
26 mos
27%
p ¼ .049
Blanchard et al.3
169
16.8 mos
10%
33 Marg+ 258
14 mos 27 mos
16% 22%
po.0001
142
Not reached
70% (7% DM free)
82
NR
70% (27% DM free)
p ¼ .0007
4
Babiera et al.
uncontrolled local disease, including ulceration, bleeding, and tumor necrosis. Today numerous active cytotoxic agents are available, as are tamoxifen and aromatase inhibitors for appropriate patients. Newer agents targeted to specific receptors offer further gains in tumor cell kill and consequent response duration. In 2002, Khan et al.1 reported a retrospective review of 16,023 patients from the National Cancer Data Bank (USA) with metastatic breast cancer found at their initial presentation. They considered the outcome in three groups of patients. Those who had no resection of the primary tumor had 17.3% 3-year survival, those who had resection but with margin involvement had 26% and those who had clear margins of resection a 35% 3-year survival. This outcome was significantly better (po.0001). In 2006, Rapiti et al.2 reported a population based review of 300 breast cancer patients presenting with M1 disease. The 3-year survival for the group whose primary tumor was resected with clear margins was similar to that reported by Khan. The group excised with involved margins was not significantly better than the group not resected. The hazard ratio for risk of death with resection to clear margins was .6 compared to the group that was not resected (p ¼ .049). This report was published with a superb editorial by Morrow and Goldstein.6 They discussed this topic in detail, raising the very appropriate concern that conclusions drawn from treating different populations of metastatic breast cancer patients differently cannot be considered convincing evidence of treatment effect. Blanchard et al.3 reviewed 807 patients who had Stage IV disease at presentation. They analyzed 427 patients who survived more than 90 days, a major initial selection bias, although appropriate. They were unable to group by margin status, but 78% of the patients had mastectomy as their surgical procedure. The 3-year survivals of the two resulting groups are similar to those in Khan’s report. The authors attempted to minimize selection bias by multivariate analysis. The hazard ratio for definitive surgery compared to no surgery to the primary was .71 (p ¼ .0059 by multivariate analysis). Charmichael et al.5 reported on
20 patients with the primary resected for a 41% 3-year survival, remarkably similar to the outcome in the other reports. Babiera et al.4 compared 142 patients with untreated primaries with 82 with resected primaries. These all received contemporary systemic therapy and both groups have a 70% 5-year actuarial survival. Only 7% of those with untreated primary tumors are free of distant metastases, but 27% of those with resected primary cancers are free. Although it is interesting that all five of these reviews of different populations produced similar results, the presumption of bias in favor of those who were selected for surgical therapy leaves the hypothesis of benefit open to conjecture. This is a question that requires the confidence of similar populations that can only be achieved by randomization in a prospective clinical trial. A legitimate question regards the treatment of women who present with Stage IV breast cancer until the time that the decision can be based on prospective evidence. The basis on which the prohibition of treatment of the primary in this circumstance arose is not applicable for many of these women. Just as that decision was based on the application of primary principles, those principles must be applied to each individual today. We lack data from the modern era that would support failing to provide definitive control of the primary tumor when the extent and biology of the metastasis suggest a possibility of control. When there seems to be an opportunity to control a limited metastatic focus, the patient warrants receiving the benefit of the doubt, i.e. to have surgical control of the primary tumor. We must confess that the value of surgery for the primary in the face of metastatic disease has long been known and accepted under a different guise. Nodal metastases [N1,2] are clearly quantitatively, not qualitatively, different from M1 metastases. We routinely treat ‘‘for cure’’ patients who present with metastases to their axillary nodes. We know that these are metastatic deposits and that they are associated with a variable burden of distant metastatic disease that relates to the number of the lymph nodes containing metastases. The prohibition of
ARTICLE IN PRESS W.C. Wood / The Breast 16 (2007) S63–S66
surgery for metastatic breast cancer is related to the letter of the alphabet that we have assigned, M vs. N, not to the presence of distant metastases. It can be argued, then, that patients presenting with a limited volume of metastatic disease that responds to initial therapy deserve definitive treatment of their primary in the expectation of long-term remission. Although a definitive answer will require a prospective trial, decisions regarding patient management are required in the meantime. The default position can be defended that there are no data suggesting that control of the primary tumor in the presence of metastatic tumor that may respond or has responded to contemporary systemic therapy is not most appropriate. The goal of resection of the primary tumor would be the removal of a source of tumor stem cells resistant to systemic therapy that could serve as a source of new metastases. The last decades have been associated with great pessimism that the quality of local control has any effect on ultimate survival. This despite the reality that in the era prior to mammographic screening and adjuvant therapy, surgery and radiation alone achieved a 10-year survival rate of 450% of operable patients.7 The overview of radiation or not after breast conserving surgery demonstrates clearly that prevention of local failure, i.e. definitive local control, results in a significant survival advantage.8 These data demonstrate a survival advantage accruing to patients with improved local control. The obverse is also true. Lack of optimal local control is associated with a diminished survival from breast cancer. This was seen in each of the reports in which surgical ablation of the primary was attempted, presumably with a similar selection bias, if the surgical resection margins were not clear. Survival was not improved despite reduction in tumor volume. Once the taboo of surgery for M1 disease has been broached, a much larger question arises. Has progress in breast cancer therapy, both systemic and local-regional, reached the point that patients with metachronous metastatic breast cancer should be considered for a comprehensive approach designed to produce freedom from all clinically apparent tumor? If clinical NED (no evident disease) status can be achieved, should not ‘‘adjuvant therapy’’ then be tested for the identification of those patient groups selected by clinical/pathological and by genomic techniques that would benefit? Particularly those subgroups presenting with M1 disease that have a real chance of lifetime remission (called ‘‘cure’’ in a less skeptical era). Several areas of clinical oncology support such a conclusion (Table 2). Local or regional recurrence of breast cancer has long been considered appropriate for attempting ablation of all apparent disease, in the absence of demonstrated distant metastases. Survival has been related to the nodal status of the initial primary (a surrogate for the burden of distant metastatic disease) and the addition of some systemic therapy to the surgery and radiation.9 Isolated metastases
S65
Table 2 Resection of breast cancer metastases. First author
Dates
N
5-year survivors
Lung Wilkins et al.17 Morrow et al.18 Mountain et al.19 Lanza et al.20 Staren et al.21 Livartowski et al.22 Ludwig et al.23 Girard et al.24 Friedel et al.25
1933–74 1939–78 1963–83 1981–90 1972–90 1987–95 1989–98 1969–84 1960–94
9 10 30 44 33 52 21 186 467
53% 20% 27% 50% 36% 54% 53% 32% (23% 10 years) 38% (22% 10 years)
Liver Elias et al.26 Pocard et al.27 Selzner et al.28
1986–94 –95 1987–99
21 21 17
24% 60% 22%
d’Annibale et al.29
1984–99
18
25% DFI o3 years 40% DFI 43 years
have been treated by resection and reported as small series for many years. Resection of pulmonary metastases is associated with prolonged survival as illustrated in Table 2.10,12 Incomplete resection is associated with minimal or no benefit, providing further evidence that the quality of local-regional control, even of isolated metastases, relates to superior survival. Intensified local treatment (resection or boost irradiation) of brain metastases appears to confer benefit as well.11,12 Resection of hepatic metastases of breast cancer has also been proposed based on retrospective reviews of resection in selected patients (Table 2).12,13 Breast cancer is not the only tumor type that has been treated by resection of metastatic disease in selected patients. Among the most common indications for hepatic resection in the United States is metastasis from colorectal carcinoma. This is associated with 5-year survival rates of about 30% in various series, depending on the extent and number of the metastases resected and upon complete ablation of apparent tumor.14 The resection of metastases in malignant melanoma has also been associated with prolonged survival.15 These reviews stretch back to patients treated over 40 years ago. The progress in staging distant metastases, the wide use of minimally invasive surgical techniques, and the availability of more effective hormonal, cytotoxic, and biological agents offer the hope of treating many patients selected for favorable presentations of breast cancer metastases today. Consequently, a more apt analogy to another disease may be gastrointestinal stromal tumors (GIST). The availability of imatinib [Gleevacs] gives a specific, very effective biological therapy for treating metastatic or recurrent GIST’s. The expression of c-KIT proto-oncogene mutations provides a predictive marker. Patients treated with complete clinical remission have an ongoing recurrence rate over time. Early data suggest that
ARTICLE IN PRESS S66
W.C. Wood / The Breast 16 (2007) S63–S66
resection of the recurrence prior to treatment, or after partial response, is associated with a superior disease free survival. Such analogies are intriguing, but fail to provide definitive evidence on which to base treatment recommendations. All evidence points to the existence of a group of patients with metastatic breast cancer that can be rendered Stage IV NED by surgery and/or radiation accompanied by tailored systemic therapy. Prospective clinical trials designed to improve our ability to select such patients are needed. Genomic profiling offers more specific tumor classification than has ever been possible previously. It is time to seriously address the question raised 5 years ago in an editorial by Professor Gabriel Hortobagyi, ‘‘Can we cure limited metastatic breast cancer?’’16 Conflict of Interest Statement None declared. References 1. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 2002;132: 620–7. 2. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006;24:2743–9. 3. Blanchard DK, Bhatia P, Hilsenbeck SG, Elledge RM. Does surgical management of Stage IV breast cancer affect outcome? Breast Cancer Res Treat 2006;100:A2110. 4. Babiera GV, Rao R, Feng L, Meric-Bernstam F, et al. Effect of primary tumor extirpation in breast cancer patients who present with Stage IV disease and an intact primary tumor. Ann Surg Oncol 2006; 13:776–82. 5. Carmichael AR, Anderson EDC, Chetty U, Dixon JM. Does local surgery have a role in the management of stage IV breast cancer? Eur J Surg Oncol 2003;29:17–9. 6. Morrow M, Goldstein L. Surgery of the primary tumor in metastatic breast cancer: closing the barn door after the horse has bolted? J Clin Oncol 2006;24:2694–6. 7. Haagensen CD. Diseases of the breast. 2nd ed. Philadelphia: WB Saunders Co.; 1971. p. 456–7. 8. Clarke M, Collins R, Darby S. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;366:2087–106. 9. Juan O, Luch A, dePaz L, et al. Prognostic factors in patients with isolated recurrences of breast cancer (stage IV-NED). Breast Cancer Res Treat 1999;53:105–12.
10. Girard P, Baldeyrou P, Le Chevalier T, et al. Surgery for pulmonary metastases. Who are the 10-year survivors? Cancer 1994;74:2791–7. 11. Bartsch R, Fromm S, Rudas M, et al. Intensified local treatment and systemic therapy significantly increase survival in patients with brain metastases from advanced breast cancer—a retrospective analysis. Radiother Oncol 2006;80:313–7. 12. Singletary SE, Walsh G, Vauthey J-N, et al. A role for curative surgery in the treatment of selected patients with metastatic breast cancer. Oncologist 2003;8:241–51. 13. Selzner M, Morse MA, Vredenburgh JJ, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000;127:383–9. 14. Kemeny NE, Kemeny M, Lawrence TS. Liver metastases. In: Abeloff MD, Armitage JO, Niederhuber JE, et al., editors. Clinical oncology. 3rd ed. Philadelphia: Elsevier, Churchill Livingstone; 2004. p. 1141. 15. Faries MB, Morton DL. Editorial: the promise of metastasectomy in melanoma. Ann Surg Oncol 2006;13:607–9. 16. Hortobagyi G. Editorial: can we cure limited metastatic breast cancer? J Clin Oncol 2002;20:620–3. 17. Wilkins EWJ, Head JM, Burke JF. Pulmonary resection for metastatic neoplasms in the lung; experience at the Massachusetts General Hospital. Am J Surg 1979;135:480–3. 18. Morrow CE, Vassilopoulos PP, Grage TB. Surgical resection for metastatic neoplasms of the lung: experience of the University of Minnesota hospitals. Cancer 1980;45(12):2981–5. 19. Mountain CF, McMurtrey MJ, Hermes KE. Surgery for pulmonary metastasis: a 20-year experience. Ann Thorac Surg 1984;38(4): 323–30. 20. Lanza LA, Natarajan G, Roth JA, Putnam JB. Long-term survival after resection of pulmonary metastases from carcinoma of the breast. Ann Thorac Surg 1992;54:244–8. 21. Staren ED, Salerno C, Rongione A, Witt TR, Faber P. Pulmonary resection for metastatic breast cancer. Arch Surg 1992;127:1282–4. 22. Livartowski A, Chapelier A, Beuzedoc P, Dierick A, Asselain B, Dartevelle P, et al. Bull Cancer 1998;85(9):800. 23. Ludwig C, Stoelben E, Hasse I. Disease-free survival after resection of lung metastases in patients with breast cancer. Eur J Surg Oncol 2003; 29:532–5. 24. Girard P, Baldeyrou P, Le Chevalier T, et al. Surgery for pulmonary metastases: who are the 10-year survivors? Cancer 1994;74(10): 2791–7. 25. Fiedel G, Pastorino U, Ginsberg RJ, et al. Results of lung metastasectomy from breast cancer; prognostic criteria on the basis of 467 cases of the international registry of lung metastases. Eur J Cardiothorac Surg 2002;22:335–44. 26. Elias D, Lasser PH, Monrucolli D, et al. Hepatectomy for liver metastases from breast cancer. Eur J Surg Oncol 1995;21:510–3. 27. Pocard M, Salmon RJ. Hepatic resection for breast cancer metastasis. The concept of adjuvant surgery. Bull Cancer 1997;84:47–50. 28. Selzner M, Morse MA, Vredenburgh JJ, et al. Liver metastases from breast cancer: long-term survival after curative resection. Surgery 2000;127:383–9. 29. d’Annabale M, Piovanello P, Cerasoli V, Campioni N. Liver metastases from breast cancer: the role of surgical treatment. Hepatogastroenterology 2005;52:1858–62.