Optimizing Endocrine Therapy for Breast Cancer
http://www.100md.com
《临床肿瘤学》
Dana-Farber Cancer Institute, Boston, MA
Approximately three quarters of all invasive breast tumors are estrogen or progesterone receptor–positive, including at least half of all cancers in premenopausal women. The natural history of hormone receptor–positive disease differs from that of receptor-negative disease in terms of time to recurrence, site of recurrence, and overall pace of the disease. Most notable, however, is the striking sensitivity of hormone receptor–positive tumors to endocrine therapy. Positive hormone receptors are a favorable, albeit relatively weak, prognostic factor. At the same time, hormone receptor status is a powerful predictor of the efficacy of adjuvant endocrine interventions. The widespread use of adjuvant endocrine therapy for women with early-stage breast cancer has dramatically decreased breast cancer mortality.
The following two articles review the status of adjuvant endocrine therapy, detailing the progress that has been made and highlighting many questions that remain to be answered. Investigators from the International Breast Cancer Study Group—Drs Dellapasqua, Colleoni, Gelber, and Goldhirsch—provide a comprehensive history of adjuvant endocrine therapy in premenopausal women.1 The evolution of endocrine therapy in younger women is particularly complex as a result of: (1) the inclusion of patients with both hormone receptor–positive and –negative disease in most early trials; (2) the existence of small, underpowered studies that often can lead to misleading results; and (3) the confounding age-related effect of adjuvant chemotherapy on ovarian function. Many of the unanswered questions regarding optimal endocrine therapy of premenopausal women with receptor-positive tumors will be addressed by three ongoing trials led by the International Breast Cancer Study Group and the North American Intergroup.
Drs Strasser-Weippl and Goss2 detail the recent accomplishments in the treatment of postmenopausal women with receptor-positive disease. Recent trials have demonstrated that the aromatase inhibitors add to the benefit of a standard 5-year course of tamoxifen. What remains unclear is whether the aromatase inhibitors should be given to patients in place of tamoxifen, or as part of a sequential treatment strategy. Further analysis of completed trials, as well as results of ongoing and future studies, will provide critical answers that may translate into further improvements in care for postmenopausal women with receptor-positive disease. More than 2,000 postmenopausal women are diagnosed with receptor-positive disease each week in the United States alone; the impact of any improvements in the care of these patients could have significant public health consequences.
For both premenopausal and postmenopausal women, it is likely that optimal endocrine therapy will not follow a "one size fits all" approach. Breast cancer is a heterogeneous disease, and this heterogeneity is very much apparent within the large population of women with hormone receptor–positive tumors. For decades clinicians have recognized the lack of uniformity across hormone receptor–positive tumors, at least partially based on the highly varied response to endocrine therapy. Over the past several years, studies using gene expression profiling have demonstrated the distinct genetic patterns of different breast tumors, including at least two subtypes of hormone receptor–positive disease, often referred to as luminal A and B.3 More recently, investigators from the National Surgical Adjuvant Breast and Bowel Project and Genomic Health demonstrated that a 21-gene assay can help predict which estrogen receptor–positive, node-negative tumors are at low, intermediate, or high risk of distance recurrence in the setting of tamoxifen therapy.4 The clinical and genetic heterogeneity that is seen across breast tumors will likely lead to new classification systems that will, in turn, provide guidance for therapeutic choices.
Variability is not limited to tumors, but applies to our patients as well. Not all women with breast cancer experience the same side effects profile from treatments. We often worry less about the toxic effects of endocrine therapy than of chemotherapy, but the prolonged administration of hormonal agents can result in adverse effects ranging from symptoms that compromise quality of life (eg, hot flashes) to more serious medical problems (eg, thromboembolic events, fractures). Different treatment approaches are better suited for some patients than for others. The goal is to maximize the therapeutic index for each and every woman with breast cancer.
Endocrine therapy is clearly the most important systemic treatment for women with hormone receptor–positive breast cancer. While the addition of adjuvant chemotherapy to hormonal therapy can further reduce the risk of disease recurrence,5 the benefits of chemotherapy are generally greater in women with hormone receptor–negative than hormone receptor–positive disease, particularly when women with receptor-positive disease receive adjuvant endocrine therapy.6 Among women with receptor-positive disease, retrospective studies suggest that the improvement in outcome from chemotherapy may be limited to a relatively small subset of patients, such as those with HER-2-positive and/or highly proliferative lesions.7-9 For the remaining patients, endocrine therapy is not only the best systemic treatment, it may be the only systemic treatment that significantly alters a woman's risk of developing a recurrence. Optimizing adjuvant endocrine therapy is a major research priority, and one that has great potential to help women with breast cancer.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
REFERENCES
Dellapasqua S, Colleoni M, Gelber RD, et al: Adjuvant Endocrine Therapy for Premenopausal Women With Early Breast Cancer. J Clin Oncol 23:1736-1750, 2005
Strasser-Weippl K, Goss PE: Advances in Adjuvant Hormonal Therapy for Postmenopausal Women. J Clin Oncol 23:1751-1759, 2005
Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003
Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004
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
Berry DA, Cirrincione C, Henderson IC, et al: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB and U.S. Breast Intergroup. Breast Cancer Res Treat 88:S17, 2004 (abstr 29; suppl 1)
Fisher B, Jeong JH, Bryant J, et al: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: Long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364:858-868, 2004
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). Breast Cancer Res Treat 88: 2004 (abstr 37; suppl 1)
Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the recurrence score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. Breast Cancer Res Treat 88: 2004 (abstr 24; suppl 1)(Eric P. Winer)
Approximately three quarters of all invasive breast tumors are estrogen or progesterone receptor–positive, including at least half of all cancers in premenopausal women. The natural history of hormone receptor–positive disease differs from that of receptor-negative disease in terms of time to recurrence, site of recurrence, and overall pace of the disease. Most notable, however, is the striking sensitivity of hormone receptor–positive tumors to endocrine therapy. Positive hormone receptors are a favorable, albeit relatively weak, prognostic factor. At the same time, hormone receptor status is a powerful predictor of the efficacy of adjuvant endocrine interventions. The widespread use of adjuvant endocrine therapy for women with early-stage breast cancer has dramatically decreased breast cancer mortality.
The following two articles review the status of adjuvant endocrine therapy, detailing the progress that has been made and highlighting many questions that remain to be answered. Investigators from the International Breast Cancer Study Group—Drs Dellapasqua, Colleoni, Gelber, and Goldhirsch—provide a comprehensive history of adjuvant endocrine therapy in premenopausal women.1 The evolution of endocrine therapy in younger women is particularly complex as a result of: (1) the inclusion of patients with both hormone receptor–positive and –negative disease in most early trials; (2) the existence of small, underpowered studies that often can lead to misleading results; and (3) the confounding age-related effect of adjuvant chemotherapy on ovarian function. Many of the unanswered questions regarding optimal endocrine therapy of premenopausal women with receptor-positive tumors will be addressed by three ongoing trials led by the International Breast Cancer Study Group and the North American Intergroup.
Drs Strasser-Weippl and Goss2 detail the recent accomplishments in the treatment of postmenopausal women with receptor-positive disease. Recent trials have demonstrated that the aromatase inhibitors add to the benefit of a standard 5-year course of tamoxifen. What remains unclear is whether the aromatase inhibitors should be given to patients in place of tamoxifen, or as part of a sequential treatment strategy. Further analysis of completed trials, as well as results of ongoing and future studies, will provide critical answers that may translate into further improvements in care for postmenopausal women with receptor-positive disease. More than 2,000 postmenopausal women are diagnosed with receptor-positive disease each week in the United States alone; the impact of any improvements in the care of these patients could have significant public health consequences.
For both premenopausal and postmenopausal women, it is likely that optimal endocrine therapy will not follow a "one size fits all" approach. Breast cancer is a heterogeneous disease, and this heterogeneity is very much apparent within the large population of women with hormone receptor–positive tumors. For decades clinicians have recognized the lack of uniformity across hormone receptor–positive tumors, at least partially based on the highly varied response to endocrine therapy. Over the past several years, studies using gene expression profiling have demonstrated the distinct genetic patterns of different breast tumors, including at least two subtypes of hormone receptor–positive disease, often referred to as luminal A and B.3 More recently, investigators from the National Surgical Adjuvant Breast and Bowel Project and Genomic Health demonstrated that a 21-gene assay can help predict which estrogen receptor–positive, node-negative tumors are at low, intermediate, or high risk of distance recurrence in the setting of tamoxifen therapy.4 The clinical and genetic heterogeneity that is seen across breast tumors will likely lead to new classification systems that will, in turn, provide guidance for therapeutic choices.
Variability is not limited to tumors, but applies to our patients as well. Not all women with breast cancer experience the same side effects profile from treatments. We often worry less about the toxic effects of endocrine therapy than of chemotherapy, but the prolonged administration of hormonal agents can result in adverse effects ranging from symptoms that compromise quality of life (eg, hot flashes) to more serious medical problems (eg, thromboembolic events, fractures). Different treatment approaches are better suited for some patients than for others. The goal is to maximize the therapeutic index for each and every woman with breast cancer.
Endocrine therapy is clearly the most important systemic treatment for women with hormone receptor–positive breast cancer. While the addition of adjuvant chemotherapy to hormonal therapy can further reduce the risk of disease recurrence,5 the benefits of chemotherapy are generally greater in women with hormone receptor–negative than hormone receptor–positive disease, particularly when women with receptor-positive disease receive adjuvant endocrine therapy.6 Among women with receptor-positive disease, retrospective studies suggest that the improvement in outcome from chemotherapy may be limited to a relatively small subset of patients, such as those with HER-2-positive and/or highly proliferative lesions.7-9 For the remaining patients, endocrine therapy is not only the best systemic treatment, it may be the only systemic treatment that significantly alters a woman's risk of developing a recurrence. Optimizing adjuvant endocrine therapy is a major research priority, and one that has great potential to help women with breast cancer.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
REFERENCES
Dellapasqua S, Colleoni M, Gelber RD, et al: Adjuvant Endocrine Therapy for Premenopausal Women With Early Breast Cancer. J Clin Oncol 23:1736-1750, 2005
Strasser-Weippl K, Goss PE: Advances in Adjuvant Hormonal Therapy for Postmenopausal Women. J Clin Oncol 23:1751-1759, 2005
Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003
Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004
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
Berry DA, Cirrincione C, Henderson IC, et al: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB and U.S. Breast Intergroup. Breast Cancer Res Treat 88:S17, 2004 (abstr 29; suppl 1)
Fisher B, Jeong JH, Bryant J, et al: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: Long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364:858-868, 2004
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). Breast Cancer Res Treat 88: 2004 (abstr 37; suppl 1)
Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the recurrence score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. Breast Cancer Res Treat 88: 2004 (abstr 24; suppl 1)(Eric P. Winer)