Long-Term Raloxifene in a Woman at High Risk for Breast Cancer
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《新英格兰医药杂志》
To the Editor: The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 trial recently demonstrated that raloxifene, a selective estrogen-receptor modulator, was as effective as tamoxifen in reducing the risk of invasive breast cancer in postmenopausal women.1 However, fewer noninvasive breast cancers were detected in women who received tamoxifen than in women who received raloxifene (1.51 cases per 1000 women vs. 2.11 cases per 1000 women),1 suggesting that raloxifene may not prevent noninvasive breast cancer. Here, we present evidence that mammary atypia developed during raloxifene therapy in a woman at high risk for breast cancer.
In March 2001, a 39-year-old perimenopausal white woman with a clinically significant family history of breast cancer was prescribed raloxifene (60 mg per day) by an outside physician. Mammographic density initially decreased (Figure 1A) and menstrual periods stopped. In August 2003, the patient enrolled in a clinical trial involving random periareolar fine-needle aspiration (RPFNA), a research procedure developed to assess early cytologic changes in women at high risk for breast cancer.2 RPFNA showed a score of 10 on the Masood Cytology Index (MCI),2,4 which was consistent with nonproliferative (normal) cytologic findings (Figure 1B). Methylation testing (sensitivity, 1 methylated cell per 1000 cells) showed an absence of promoter hypermethylation in the genes for retinoic acid receptor (RAR),4 estrogen receptor (367 to 494 bp) (ER), p16 (167 to 317 bp), and BRCA1 (–150 to 32 bp).
Figure 1. Serial Assessments of Mammographic Density (Panel A) and Findings on RPFNA (Panel B) and Magnetic Resonance Imaging (Panels C and D).
The percentage of breast area with increased density on mammographic examinations was assessed with the use of Cumulus software by an investigator who did not know when the imaging took place and whether the patient was taking raloxifene (Panel A). RPFNA (Panel B) and 3.0-tesla (3T) MRI (Panels C and D) were performed according to previously published methods.2,3 Serial RPFNA samples were tested for cytologic abnormality as defined by the Masood Cytology Index (MCI)2,3 and for promoter hypermethylation in the genes for retinoic acid receptor (RAR), 4 estrogen receptor (367 to 494 bp) (ER), p16 (167 to 317 bp), and BRCA1 (150 to 32 bp) with the use of methylation-specific polymerase chain reaction according to previously published methods.3 Panel B shows methylated alleles (M) and unmethylated alleles (U). Bilateral dynamic imaging of the breast was performed with 3T MRI before and after the intravenous administration of gadolinium. No rapidly enhancing or suspicious-appearing irregular masses, which would suggest the presence of cancer, were observed. In the image obtained on September 7, 2004 (Panel C), heterogeneously dense fibroglandular tissue is present, as well as multiple round and oval, moderately enhancing masses and foci (arrow). In the image obtained on June 9, 2005 (Panel D), the number of round and oval, moderately enhancing masses and foci is decreased.
Surprisingly, when repeated in September 2004, RPFNA demonstrated extensive atypia (MCI score, 15) and new hypermethylation of RAR, ER, and p16 (Figure 1B). Magnetic resonance imaging (MRI) on September 7, 2004, did not show evidence of neoplasia but did show numerous small, moderately enhancing foci (Figure 1C, arrow).
Prolonged treatment of breast cancer with tamoxifen can result in the conversion of tamoxifen from an antagonist to an agonist.5 We considered the possibility that prolonged administration of raloxifene in a woman at high risk for breast cancer might similarly convert raloxifene to an agonist. Raloxifene was stopped on November 10, 2004; the patient's menses did not resume. RPFNA was repeated in March 2005 and showed an absence of atypia, with a reduced MCI score (12, indicating hyperplasia), but hypermethylation of RAR and ER persisted (Figure 1B). MRI on June 9, 2005, showed a considerable reduction in the number of moderately enhancing foci (Figure 1D).
RPFNA was repeated in October 2005 and showed an increased MCI score (16, indicating atypia). Owing to her family history and the presence of persistent atypia, the patient underwent prophylactic mastectomy. Analysis revealed extensive atypia but no evidence of cancer.
This case raises questions about the long-term use of raloxifene as chemoprevention in women who are at high risk for breast cancer and who potentially have genetically unstable cells. Can raloxifene be converted to an agonist? Does raloxifene promote DNA hypermethylation?
Gregory R. Bean, B.S.
Duke University Medical Center
Durham, NC 27710
Bruce F. Kimler, Ph.D.
University of Kansas Medical Center
Kansas City, KS 66160
Victoria L. Seewaldt, M.D.
Duke University Medical Center
Durham, NC 27710
seewa001@mc.duke.edu
References
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-2741.
Fabian CJ, Kimler BF, Zalles CM, et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 2000;92:1217-1227.
Bean GR, Scott V, Yee L, et al. Retinoic acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration. Cancer Epidemiol Biomarkers Prev 2005;14:790-798.
Masood S, Frykberg ER, McLellan GL, Scalapino MC, Mitchum DG, Bullard JB. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990;66:1480-1487.
Jordan VC, Lewis JS, Osipo C, Cheng D. The apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy. Breast 2005;14:624-630.
In March 2001, a 39-year-old perimenopausal white woman with a clinically significant family history of breast cancer was prescribed raloxifene (60 mg per day) by an outside physician. Mammographic density initially decreased (Figure 1A) and menstrual periods stopped. In August 2003, the patient enrolled in a clinical trial involving random periareolar fine-needle aspiration (RPFNA), a research procedure developed to assess early cytologic changes in women at high risk for breast cancer.2 RPFNA showed a score of 10 on the Masood Cytology Index (MCI),2,4 which was consistent with nonproliferative (normal) cytologic findings (Figure 1B). Methylation testing (sensitivity, 1 methylated cell per 1000 cells) showed an absence of promoter hypermethylation in the genes for retinoic acid receptor (RAR),4 estrogen receptor (367 to 494 bp) (ER), p16 (167 to 317 bp), and BRCA1 (–150 to 32 bp).
Figure 1. Serial Assessments of Mammographic Density (Panel A) and Findings on RPFNA (Panel B) and Magnetic Resonance Imaging (Panels C and D).
The percentage of breast area with increased density on mammographic examinations was assessed with the use of Cumulus software by an investigator who did not know when the imaging took place and whether the patient was taking raloxifene (Panel A). RPFNA (Panel B) and 3.0-tesla (3T) MRI (Panels C and D) were performed according to previously published methods.2,3 Serial RPFNA samples were tested for cytologic abnormality as defined by the Masood Cytology Index (MCI)2,3 and for promoter hypermethylation in the genes for retinoic acid receptor (RAR), 4 estrogen receptor (367 to 494 bp) (ER), p16 (167 to 317 bp), and BRCA1 (150 to 32 bp) with the use of methylation-specific polymerase chain reaction according to previously published methods.3 Panel B shows methylated alleles (M) and unmethylated alleles (U). Bilateral dynamic imaging of the breast was performed with 3T MRI before and after the intravenous administration of gadolinium. No rapidly enhancing or suspicious-appearing irregular masses, which would suggest the presence of cancer, were observed. In the image obtained on September 7, 2004 (Panel C), heterogeneously dense fibroglandular tissue is present, as well as multiple round and oval, moderately enhancing masses and foci (arrow). In the image obtained on June 9, 2005 (Panel D), the number of round and oval, moderately enhancing masses and foci is decreased.
Surprisingly, when repeated in September 2004, RPFNA demonstrated extensive atypia (MCI score, 15) and new hypermethylation of RAR, ER, and p16 (Figure 1B). Magnetic resonance imaging (MRI) on September 7, 2004, did not show evidence of neoplasia but did show numerous small, moderately enhancing foci (Figure 1C, arrow).
Prolonged treatment of breast cancer with tamoxifen can result in the conversion of tamoxifen from an antagonist to an agonist.5 We considered the possibility that prolonged administration of raloxifene in a woman at high risk for breast cancer might similarly convert raloxifene to an agonist. Raloxifene was stopped on November 10, 2004; the patient's menses did not resume. RPFNA was repeated in March 2005 and showed an absence of atypia, with a reduced MCI score (12, indicating hyperplasia), but hypermethylation of RAR and ER persisted (Figure 1B). MRI on June 9, 2005, showed a considerable reduction in the number of moderately enhancing foci (Figure 1D).
RPFNA was repeated in October 2005 and showed an increased MCI score (16, indicating atypia). Owing to her family history and the presence of persistent atypia, the patient underwent prophylactic mastectomy. Analysis revealed extensive atypia but no evidence of cancer.
This case raises questions about the long-term use of raloxifene as chemoprevention in women who are at high risk for breast cancer and who potentially have genetically unstable cells. Can raloxifene be converted to an agonist? Does raloxifene promote DNA hypermethylation?
Gregory R. Bean, B.S.
Duke University Medical Center
Durham, NC 27710
Bruce F. Kimler, Ph.D.
University of Kansas Medical Center
Kansas City, KS 66160
Victoria L. Seewaldt, M.D.
Duke University Medical Center
Durham, NC 27710
seewa001@mc.duke.edu
References
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-2741.
Fabian CJ, Kimler BF, Zalles CM, et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 2000;92:1217-1227.
Bean GR, Scott V, Yee L, et al. Retinoic acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration. Cancer Epidemiol Biomarkers Prev 2005;14:790-798.
Masood S, Frykberg ER, McLellan GL, Scalapino MC, Mitchum DG, Bullard JB. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990;66:1480-1487.
Jordan VC, Lewis JS, Osipo C, Cheng D. The apoptotic action of estrogen following exhaustive antihormonal therapy: a new clinical treatment strategy. Breast 2005;14:624-630.