- Email: [email protected]
Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT
boost therapy than after external beam boost therapy in patients with laterally/centrally located tumors (hazard ratio, 3.25; 95% confidence interval, 0.91-11.65). Conclusion.—Tumor location, interval between surgery and RT, and boost technique might influence local control of breast cancer treated by breast-conserving surgery and RT. Knauerhase and colleagues reported the results of 263 women with stages I-II breast carcinoma after breast-conserving surgery followed by breast radiation. With a median follow-up of 94 months, the 10-year rate of local recurrence was 9.9%. On
multivariate analysis, significantly increased risks of local recurrence were associated with (1) medial tumor location (compared with lateral/ central location) and (2) an interval greater than 2 months between surgery and the start of radiation therapy. Of borderline statistical significance on multivariate analysis were negative hormone receptor status (compared with positive status) and an external-beam boost technique (compared with an interstitial highdose rate technique). The radiation boost to the primary tumor bed was delivered by using 1 of 3 techniques: (a) electron boost, (b) interstitial boost, or (c) photon boost. Similar to
other studies, an interval to the start of radiation therapy greater than 2 months was associated with an increased risk of local recurrence when compared to a longer interval (adjusted hazard ratio ¼ 2.485; P ¼ 0.037). The results from this study confirm that the long-term results of breast-conserving surgery followed by radiation therapy achieve high rates of local control and that attention to technical radiation treatment is important to optimize local control.
many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods.—Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results.—A total of 693 women were randomly assigned to fulvestrant (n ¼ 351) or exemestane (n ¼342).
Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio ¼ 0.963; 95% CI, 0.819 to 1.133; P ¼ .6531). The overall response rate (7.4% v 6.7%; P ¼ .736) and clinical benefit rate (32.2% v 31.5%; P ¼ .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion.—Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced
L. J. Solin, MD
CHEMOTHERAPY Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT Chia S, Gradishar W, Mauriac L, et al (Univ of British Columbia, Vancouver, Canada) J Clin Oncol 26:1664-1670, 2008
Purpose.—The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor– positive (HR+) breast cancer. Because
94
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 1 2009
progression or recurrence during treatment with a nonsteroidal AI. As third-generation AIs are increasingly being prescribed for adjuvant therapy and first-line therapy for metastatic disease in postmenopausal women with HRpositive breast cancer, one of the major challenges faced by oncologists today is the selection of an optimum therapeutic strategy after disease progression on an AI. There are currently multiple options for continuing endocrine therapy, including receiving an alternative AI, such as switching from a nonsteroidal AI to a steroidal AI or vice versa, receiving a selective estrogen receptor modulator (eg, tamoxifen), receiving a pure estrogen antagonist (eg, fulvestrant), or receiving steroid hormones (eg, progestins, androgens, or estrogens). Among these choices, fulvestrant and AIs are frequently chosen, as they are generally well tolerated. Until the publication of the EFECT trial, there had been no head-
Impact of Raloxifene or Tamoxifen Use on Endometrial Cancer Risk: A PopulationBased Case-Control Study DeMichele A, Troxel AB, Berlin JA, et al (Univ of Pennsylvania; Abramson Cancer Ctr, PA; Children's Hosp of Philadelphia, PA; et al) J Clin Oncol 26:4151-4159, 2008
Purpose.—Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estro-
to-head comparisons between the different agents in the setting of AI treatment failure. The EFECT trial is a double-blind, placebo-controlled phase III trial comparing fulvestrant to exemestane, a steroidal AI, in postmenopausal women with HRpositive breast cancer that had progressed on nonsteroidal AIs. The trial demonstrated equivalent efficacy for fulvestrant and exemestane, with an overall response rate of 7.4% versus 6.7% and a clinical benefit rate of 32.2% versus 31.5% for fulvestrant and exemestane, respectively. However, the median TTP of 3.7 months in both groups was short. Though the study supports the current practice of using 1 of these 2 agents in postmenopausal women with HR-positive breast cancer that progresses while on a nonsteroidal AI, many questions remain. Close to 70% of the patients in EFECT, including some who were thought to have endocrine-sensitive tumors based on the duration of response to previous AI therapy, did not benefit from either
agent. Strategies to better predict whether an HR-positive tumor would still be responsive to additional endocrine therapy, as well as strategies to overcome endocrine therapy resistance, are desperately needed. It has been increasingly recognized that the mechanisms of AI resistance involve other signaling pathways, providing the rationale for combining endocrine therapy with targeted agents. In this regard, ongoing clinical trials are evaluating the combination of endocrine therapy with inhibitors of growth factor receptor signaling pathways or tumor angiogenesis. A deeper understanding of the mechanisms of AI resistance and the development of strategies to overcome AI resistance will be instrumental in improving the outcomes of patients with HR-positive breast cancer.
genic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. Methods.—We performed a casecontrol study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer
between July 1999 and June 2002. Controls were identified through random-digit dialing. Results.—We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] ¼ 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR ¼ 3.0; 95% CI, 1.3 to 6.9).
Y. H. Chia, MD C. X. Ma, MD, PhD
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 1 2009
95
multivariate analysis, significantly increased risks of local recurrence were associated with (1) medial tumor location (compared with lateral/ central location) and (2) an interval greater than 2 months between surgery and the start of radiation therapy. Of borderline statistical significance on multivariate analysis were negative hormone receptor status (compared with positive status) and an external-beam boost technique (compared with an interstitial highdose rate technique). The radiation boost to the primary tumor bed was delivered by using 1 of 3 techniques: (a) electron boost, (b) interstitial boost, or (c) photon boost. Similar to
other studies, an interval to the start of radiation therapy greater than 2 months was associated with an increased risk of local recurrence when compared to a longer interval (adjusted hazard ratio ¼ 2.485; P ¼ 0.037). The results from this study confirm that the long-term results of breast-conserving surgery followed by radiation therapy achieve high rates of local control and that attention to technical radiation treatment is important to optimize local control.
many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods.—Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results.—A total of 693 women were randomly assigned to fulvestrant (n ¼ 351) or exemestane (n ¼342).
Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio ¼ 0.963; 95% CI, 0.819 to 1.133; P ¼ .6531). The overall response rate (7.4% v 6.7%; P ¼ .736) and clinical benefit rate (32.2% v 31.5%; P ¼ .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion.—Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced
L. J. Solin, MD
CHEMOTHERAPY Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer: Results From EFECT Chia S, Gradishar W, Mauriac L, et al (Univ of British Columbia, Vancouver, Canada) J Clin Oncol 26:1664-1670, 2008
Purpose.—The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor– positive (HR+) breast cancer. Because
94
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 1 2009
progression or recurrence during treatment with a nonsteroidal AI. As third-generation AIs are increasingly being prescribed for adjuvant therapy and first-line therapy for metastatic disease in postmenopausal women with HRpositive breast cancer, one of the major challenges faced by oncologists today is the selection of an optimum therapeutic strategy after disease progression on an AI. There are currently multiple options for continuing endocrine therapy, including receiving an alternative AI, such as switching from a nonsteroidal AI to a steroidal AI or vice versa, receiving a selective estrogen receptor modulator (eg, tamoxifen), receiving a pure estrogen antagonist (eg, fulvestrant), or receiving steroid hormones (eg, progestins, androgens, or estrogens). Among these choices, fulvestrant and AIs are frequently chosen, as they are generally well tolerated. Until the publication of the EFECT trial, there had been no head-
Impact of Raloxifene or Tamoxifen Use on Endometrial Cancer Risk: A PopulationBased Case-Control Study DeMichele A, Troxel AB, Berlin JA, et al (Univ of Pennsylvania; Abramson Cancer Ctr, PA; Children's Hosp of Philadelphia, PA; et al) J Clin Oncol 26:4151-4159, 2008
Purpose.—Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estro-
to-head comparisons between the different agents in the setting of AI treatment failure. The EFECT trial is a double-blind, placebo-controlled phase III trial comparing fulvestrant to exemestane, a steroidal AI, in postmenopausal women with HRpositive breast cancer that had progressed on nonsteroidal AIs. The trial demonstrated equivalent efficacy for fulvestrant and exemestane, with an overall response rate of 7.4% versus 6.7% and a clinical benefit rate of 32.2% versus 31.5% for fulvestrant and exemestane, respectively. However, the median TTP of 3.7 months in both groups was short. Though the study supports the current practice of using 1 of these 2 agents in postmenopausal women with HR-positive breast cancer that progresses while on a nonsteroidal AI, many questions remain. Close to 70% of the patients in EFECT, including some who were thought to have endocrine-sensitive tumors based on the duration of response to previous AI therapy, did not benefit from either
agent. Strategies to better predict whether an HR-positive tumor would still be responsive to additional endocrine therapy, as well as strategies to overcome endocrine therapy resistance, are desperately needed. It has been increasingly recognized that the mechanisms of AI resistance involve other signaling pathways, providing the rationale for combining endocrine therapy with targeted agents. In this regard, ongoing clinical trials are evaluating the combination of endocrine therapy with inhibitors of growth factor receptor signaling pathways or tumor angiogenesis. A deeper understanding of the mechanisms of AI resistance and the development of strategies to overcome AI resistance will be instrumental in improving the outcomes of patients with HR-positive breast cancer.
genic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. Methods.—We performed a casecontrol study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer
between July 1999 and June 2002. Controls were identified through random-digit dialing. Results.—We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] ¼ 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR ¼ 3.0; 95% CI, 1.3 to 6.9).
Y. H. Chia, MD C. X. Ma, MD, PhD
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 1 2009
95