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Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer
the early benefit in relapse-free survival (within 5 years) and the longer benefit in overall survival (after 5 years) are in agreement with published data.2,4-7 Although the results of this trial will not change current treatment paradigms, the suggestion that polychemotherapy and hormonal therapy are beneficial in premenopausal women who are not undergoing ovarian suppression is hypothesis-generating and will be further addressed in ongoing clinical trials. Current research is directed at using molecular profiles to determine which ER-positive tumors benefit from the addition of chemotherapy. C. S. Denlinger, MD L. J. Goldstein, MD
References 1. Bonadonna G, Moliterni A, Zambetti M, et al: 30 years’ follow up of randomized studies of adjuvant CMF in operable breast cancer: Cohort study. Br J Med 330:217-222, 2005. 2. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005. 3. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003. 4. Albain K, Barlow W, O’Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG 8814) (abstract LBA37). Presented at the 27th Annual San Antonio Breast Cancer Symposium, 2004. Available at http://www.sabcs.org. Accessed August 22, 2007. 5. Davidson NE, O’Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph nodepositive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 23:5973-5982, 2005. 6. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990. 7. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997.
Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer Haffty BG, Yang Q, Reiss M, et al J Clin Oncol 24:5652-5657, 2006 Molecular profiling studies have identified several subtypes of breast cancer with distinct clinical outcomes. The basal-like or “triple-negative” subtype is in part characterized by a lack of hormone and HER2-neu receptors. In multiple studies, this subtype has been identified as one of the breast cancers having the worst outcome. Interestingly, in several neoadjuvant studies, basal-like and HER2-neu-amplified tumors demonstrated significant chemosensitivity, and the highest pathologic complete response rates were seen with these subtypes.1,2 Despite this demonstrated sensitivity, among those who do not experience a pathologic complete response, relapse rates are high and survival durations are short. In this article, Haffty and colleagues studied whether highrisk, triple-negative breast cancers have a higher propensity for local-regional failure after breast-conserving therapy, which might negatively affect patients’ disease-free and overall survivals. Compared to patients with other breast cancer subtypes, localregional failure was not increased in patients with triple-negative disease who underwent breast-conserving surgery and radiation therapy, but they did have a higher distant failure rate. Of interest, BRACA-1 gene mutation–related tumors are generally found to segregate with basal-like tumors in gene microarray studies and may therefore have similar biologic drivers. Foulkes and colleagues3 observed an interesting disruption in the expected relationship between primary tumor size and nodal positivity in BRCA-1 tumors, postulating that other factors, such as increased expression of angiogenesis factors, may predispose BRACA-1 tumors to preferentially metastasize hematogenously and, in part, contribute to worse outcomes. In breast cancer, the greatest improvements in outcome have been achieved when we have been able to identify a biologic driver, such as a hormone receptor or the HER2-neu receptor, and interfere with its function. To date, the biologic drivers for basal-like tumors have yet to be defined, making this an especially difficult cancer to treat. C. R. Osborne, MD
References 1. Fernández-Morales LA, Sequí MA, Andreu X, et al: Analysis of the pathologic response to primary chemotherapy in patients with locally advanced breast cancer grouped according to estrogen receptor, progesterone receptor, and HER2 status. Clin Breast Cancer 7:559-564, 2007. 2. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329-2334, 2007. 3. Foulkes WD, Metcalfe K, Hanna W, et al: Disruption of the expected positive correlation between breast tumor size and
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Breast Diseases: A Year Book Quarterly Vol 18 No 4 2008
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lymph node status in BRCA1-related breast carcinoma. Cancer 98:1569-1577, 2003.
Protein Expression Profiling in High-Risk Breast Cancer Patients Treated with High-Dose or Conventional DoseDense Chemotherapy Diallo-Danebrock R, Ting E, Gluz O, et al Clin Cancer Res 13:488-497, 2007 This interesting paper examines the results of a previously reported trial of the use of adjuvant high-dose chemotherapy (HDCT) to treat breast cancer subtypes identified by immunohistochemical profiling. The original study, the West German Study Group AM01 trial, randomized approximately 400 patients who were at very high risk for recurrence (at least 9 involved lymph nodes) to receive adjuvant chemotherapy at dense but conventional doses or tandem HDCT.1 The trial was well performed and balanced, and an intent-to-treat, 4-year event-free analysis reported in 2005 significantly favored HDCT (60% vs 44%). The current report used panels of proteins selected to identify molecular subtypes and applied them to a tissue microarray from 236 study subjects. In post-hoc subset analysis of the clinical trial results, the benefit of HDCT appeared largely in the HER2-positive/estrogen receptor (ER)negative, basal-like, and possibly “multiple marker negative” subtypes. When treated with HDCT, outcomes in those subtypes approached that of their better-prognosis cousins, the luminal cancers. This result is not surprising, because the tumors were hormone receptor–low subtypes, and others have noted that ER-negative breast cancers derive greater benefit from chemotherapy advances than do ER-positive tumors.2 ER–negative breast cancers are also at higher risk for early relapse. Given that at the time of this report patients had been followed for fewer than 5 years, this apparent interaction may not hold up as the data mature. This level III-IV biomarker evidence has generated a hypothesis for prospective testing. However, even with better patient selection, the future of HDCT in breast cancer is debatable. Most of us hope that, in the future, there will be better use of smarter drugs, although, as suggested here, there may also be a role for smarter use of dumber drugs, too. L. A. Carey, MD
References 1. Nitz UA, Mohrmann S, Fischer J, et al: Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: Results of a multicentre phase III trial. Lancet 366:1935-1944, 2005. 2. Berry DA, Cirrincione C, Henderson IC, et al: Estrogenreceptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:16581667, 2006.
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Breast Diseases: A Year Book Quarterly Vol 18 No 4 2008
Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis from INT-0137 (S9313) Linden HM, Haskell CM, Green SJ, et al J Clin Oncol 25:656-661, 2007 The Southwest Oncology Group (SWOG) 9313 trial showed no difference between high-dose, sequential therapy using doxorubicin followed by cyclophosphamide compared with lower doses of these agents given concurrently. Each regimen delivered the same total doses over the same total time, but the number of doses and timing varied. Now more than 10 years after the study was planned, we have good evidence that dose-escalation of doxorubicin above 60 mg/m2 and of cyclophosphamide above 600 mg/m2 is of little or no value. We also have evidence that the timing of chemotherapy (dose-density), independent of dose size or number, is important. On the basis of these data, we can reconsider the SWOG 9313 trial as a comparison of a fixed-dose regimen of doxorubicin every 3 weeks for 4 cycles followed by cyclophosphamide every 2 weeks for 3 cycles with the concurrent administration of doxorubicin and cyclophosphamide every 3 weeks for 6 cycles. These data in turn suggest that the dose-dense scheduling of cyclophosphamide “makes up” for the reduction in dose number for both agents. This finding is similar to that of the Arbeitsgemeinschaft Gynäkologische Onkologie trial, which compared sequential, dosedense high-dose epirubicin, paclitaxel, and cyclophosphamide against conventional epirubicin and cyclophosphamide followed by paclitaxel.1 C. A. Hudis
Reference 1. Moebus VJ, Lueck HJ, Thomssen C, et al: Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) in comparison to conventional schedule chemotherapy in high-risk breast cancer patients (≥ 4+ LN). Mature results of an AGO-trial (abstract 43). Breast Cancer Res Treat 100:S20, 2001.
Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancer Limentani SA, Brufsky AM, Erban JK, et al J Clin Oncol 25:1232-1238, 2007 Neoadjuvant chemotherapy (systemic treatment prior to surgery) for primary breast cancer is a rapidly evolving treatment approach. A position paper recently published in the Journal of Clinical Oncology clearly stated that more effective chemotherapy regimens are needed that do not unnecessarily increase toxicity.
References 1. Bonadonna G, Moliterni A, Zambetti M, et al: 30 years’ follow up of randomized studies of adjuvant CMF in operable breast cancer: Cohort study. Br J Med 330:217-222, 2005. 2. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005. 3. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003. 4. Albain K, Barlow W, O’Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG 8814) (abstract LBA37). Presented at the 27th Annual San Antonio Breast Cancer Symposium, 2004. Available at http://www.sabcs.org. Accessed August 22, 2007. 5. Davidson NE, O’Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph nodepositive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 23:5973-5982, 2005. 6. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990. 7. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997.
Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer Haffty BG, Yang Q, Reiss M, et al J Clin Oncol 24:5652-5657, 2006 Molecular profiling studies have identified several subtypes of breast cancer with distinct clinical outcomes. The basal-like or “triple-negative” subtype is in part characterized by a lack of hormone and HER2-neu receptors. In multiple studies, this subtype has been identified as one of the breast cancers having the worst outcome. Interestingly, in several neoadjuvant studies, basal-like and HER2-neu-amplified tumors demonstrated significant chemosensitivity, and the highest pathologic complete response rates were seen with these subtypes.1,2 Despite this demonstrated sensitivity, among those who do not experience a pathologic complete response, relapse rates are high and survival durations are short. In this article, Haffty and colleagues studied whether highrisk, triple-negative breast cancers have a higher propensity for local-regional failure after breast-conserving therapy, which might negatively affect patients’ disease-free and overall survivals. Compared to patients with other breast cancer subtypes, localregional failure was not increased in patients with triple-negative disease who underwent breast-conserving surgery and radiation therapy, but they did have a higher distant failure rate. Of interest, BRACA-1 gene mutation–related tumors are generally found to segregate with basal-like tumors in gene microarray studies and may therefore have similar biologic drivers. Foulkes and colleagues3 observed an interesting disruption in the expected relationship between primary tumor size and nodal positivity in BRCA-1 tumors, postulating that other factors, such as increased expression of angiogenesis factors, may predispose BRACA-1 tumors to preferentially metastasize hematogenously and, in part, contribute to worse outcomes. In breast cancer, the greatest improvements in outcome have been achieved when we have been able to identify a biologic driver, such as a hormone receptor or the HER2-neu receptor, and interfere with its function. To date, the biologic drivers for basal-like tumors have yet to be defined, making this an especially difficult cancer to treat. C. R. Osborne, MD
References 1. Fernández-Morales LA, Sequí MA, Andreu X, et al: Analysis of the pathologic response to primary chemotherapy in patients with locally advanced breast cancer grouped according to estrogen receptor, progesterone receptor, and HER2 status. Clin Breast Cancer 7:559-564, 2007. 2. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329-2334, 2007. 3. Foulkes WD, Metcalfe K, Hanna W, et al: Disruption of the expected positive correlation between breast tumor size and
®
Breast Diseases: A Year Book Quarterly Vol 18 No 4 2008
401 401
lymph node status in BRCA1-related breast carcinoma. Cancer 98:1569-1577, 2003.
Protein Expression Profiling in High-Risk Breast Cancer Patients Treated with High-Dose or Conventional DoseDense Chemotherapy Diallo-Danebrock R, Ting E, Gluz O, et al Clin Cancer Res 13:488-497, 2007 This interesting paper examines the results of a previously reported trial of the use of adjuvant high-dose chemotherapy (HDCT) to treat breast cancer subtypes identified by immunohistochemical profiling. The original study, the West German Study Group AM01 trial, randomized approximately 400 patients who were at very high risk for recurrence (at least 9 involved lymph nodes) to receive adjuvant chemotherapy at dense but conventional doses or tandem HDCT.1 The trial was well performed and balanced, and an intent-to-treat, 4-year event-free analysis reported in 2005 significantly favored HDCT (60% vs 44%). The current report used panels of proteins selected to identify molecular subtypes and applied them to a tissue microarray from 236 study subjects. In post-hoc subset analysis of the clinical trial results, the benefit of HDCT appeared largely in the HER2-positive/estrogen receptor (ER)negative, basal-like, and possibly “multiple marker negative” subtypes. When treated with HDCT, outcomes in those subtypes approached that of their better-prognosis cousins, the luminal cancers. This result is not surprising, because the tumors were hormone receptor–low subtypes, and others have noted that ER-negative breast cancers derive greater benefit from chemotherapy advances than do ER-positive tumors.2 ER–negative breast cancers are also at higher risk for early relapse. Given that at the time of this report patients had been followed for fewer than 5 years, this apparent interaction may not hold up as the data mature. This level III-IV biomarker evidence has generated a hypothesis for prospective testing. However, even with better patient selection, the future of HDCT in breast cancer is debatable. Most of us hope that, in the future, there will be better use of smarter drugs, although, as suggested here, there may also be a role for smarter use of dumber drugs, too. L. A. Carey, MD
References 1. Nitz UA, Mohrmann S, Fischer J, et al: Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: Results of a multicentre phase III trial. Lancet 366:1935-1944, 2005. 2. Berry DA, Cirrincione C, Henderson IC, et al: Estrogenreceptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:16581667, 2006.
402 402
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Breast Diseases: A Year Book Quarterly Vol 18 No 4 2008
Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis from INT-0137 (S9313) Linden HM, Haskell CM, Green SJ, et al J Clin Oncol 25:656-661, 2007 The Southwest Oncology Group (SWOG) 9313 trial showed no difference between high-dose, sequential therapy using doxorubicin followed by cyclophosphamide compared with lower doses of these agents given concurrently. Each regimen delivered the same total doses over the same total time, but the number of doses and timing varied. Now more than 10 years after the study was planned, we have good evidence that dose-escalation of doxorubicin above 60 mg/m2 and of cyclophosphamide above 600 mg/m2 is of little or no value. We also have evidence that the timing of chemotherapy (dose-density), independent of dose size or number, is important. On the basis of these data, we can reconsider the SWOG 9313 trial as a comparison of a fixed-dose regimen of doxorubicin every 3 weeks for 4 cycles followed by cyclophosphamide every 2 weeks for 3 cycles with the concurrent administration of doxorubicin and cyclophosphamide every 3 weeks for 6 cycles. These data in turn suggest that the dose-dense scheduling of cyclophosphamide “makes up” for the reduction in dose number for both agents. This finding is similar to that of the Arbeitsgemeinschaft Gynäkologische Onkologie trial, which compared sequential, dosedense high-dose epirubicin, paclitaxel, and cyclophosphamide against conventional epirubicin and cyclophosphamide followed by paclitaxel.1 C. A. Hudis
Reference 1. Moebus VJ, Lueck HJ, Thomssen C, et al: Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) in comparison to conventional schedule chemotherapy in high-risk breast cancer patients (≥ 4+ LN). Mature results of an AGO-trial (abstract 43). Breast Cancer Res Treat 100:S20, 2001.
Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancer Limentani SA, Brufsky AM, Erban JK, et al J Clin Oncol 25:1232-1238, 2007 Neoadjuvant chemotherapy (systemic treatment prior to surgery) for primary breast cancer is a rapidly evolving treatment approach. A position paper recently published in the Journal of Clinical Oncology clearly stated that more effective chemotherapy regimens are needed that do not unnecessarily increase toxicity.