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SOFT trial can be very hard on young women
The Breast 24 (2015) 767e768
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Correspondence
SOFT trial can be very hard on young women
Keywords: SOFT trial Risks of ovarian suppression Long-term impact
The results of the Suppression of Ovarian Function Trial (SOFT) by Francis et al. are reported as “practice changing” for treatment of ER positive premenopausal breast cancer [1]. The authors concluded that for women who are at sufficient risk for recurrence to warrant adjuvant chemotherapy [2] and who remained premenopausal, the addition of ovarian suppression (OS) improved disease outcomes. Chemotherapy was used at physician discretion [3,4]. The added absolute benefit of OS versus Tamoxifen alone for prevention of recurrence was 4.5% in favor of Tamoxifen þ OS and 7.7% in favor of Exemestane þ OS [1]. This benefit has to be reconciled with the risks of OS. First, we know that compliance with endocrine treatment is difficult in ER positive breast cancer patient. In the SOFT trial, the rate of non-adherence to OS rose to 22% by the median follow up of 67 months [1]. Targeted adverse events including menopausal symptoms, depression, hypertension, osteoporosis and sexual dysfunction of grade 3 or higher were reported in 31.3% in the OS arm. Second, long-term impact of OS has been reported from studies conducted on oophorectomy associated with hysterectomy for benign disease. A prospective observational study that followed over 30,000 women for 28 years revealed that 16.8% women with bilateral oophorectomy died from all-cause mortality versus 13.3% women who had ovarian conservation [5,6]. Even though mortality from breast and ovarian cancer was lower, at no age was all-cause (ischemic heart disease, lung cancer, and stroke) mortality lower in women with oophorectomy. Specifically in women undergoing oophorectomy under the age of 50, the hazard ratio for all-cause mortality was 1.141 (95% CI 1.04e1.92); this translates into one additional death for every 8 women undergoing oophorectomy [5]. In the SOFT trial, the number needed to be treated with Tamoxifen þ OS compared to Tamoxifen alone to prevent one breast cancer relapse (local or systemic) is 49. OS decreases mortality from ovarian and breast cancer but it increases mortality from coronary heart disease, lung cancer, and osteoporosis [6]. Every year approximately 40,000 women die from breast cancer [7], and 14,000 from ovarian cancer [6]. These figures need to be balanced against 267,000 deaths from heart http://dx.doi.org/10.1016/j.breast.2015.08.010 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
attacks e six times as many women as breast cancer [8]. Additionally 48,000 women die within a year of hip fracture [9,10]. Since the overall survival is not yet reported from SOFT trial, how do we interpret this trial in terms of overall mortality, today? This concept can be explored in terms of local relapse versus distant relapse. A metaanalysis of published trials (including SOFT and TEXT trials) on Tamoxifen alone versus Tamoxifen plus OS reported 382 distant relapses in 2099 women treated with Tamoxifen alone compared to 367 distant relapses in 2078 women treated with Tamoxifen plus OS; the absolute risk reduction probability for a distant relapse with addition of OS is 0.0054 and the number needed to treat is 186 [11]. The number of local relapses in Tamoxifen alone group is 84 in 2099 women versus 62 in 2078 women in Tamoxifen plus OS group. The number needed to treat with OS to prevent one local relapse is 98. In the absence of any other causes of death, avoiding 4 local breast cancer recurrences at 5 years results in one life saved at 15 years [12]. From the meta-analysis numbers [11], to avoid 4 recurrences in short-term, 392 women will have to undergo OS to add one overall survivor. Reconciling one additional all-cause mortality for every 8 OS's, this would mean 49 additional deaths from other causes for every one life saved from breast cancer. These figures along with quality of life issues do not suggest that the results of SOFT trial should be “practice-changing” without accounting for long-term impact. Conflict of interest statement The authors have no conflict of interest. Acknowledgment No grants or funds supported this work.
References [1] Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N. Engl J Med Jan 29, 2015;372(5):436e46. [2] Regan MM, Pagani O, Walley B, Torrisi R, Perez EA, Francis P, et al. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol: Official Journal of the European Society for Medical Oncology/ESMO Jul, 2008;19(7):1231e41. [3] Francis PA, Regan MM, Fleming GF. Adjuvant ovarian suppression in premenopausal breast cancer. N. Engl J Med Apr 23, 2015;372(17):1673. [4] Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA: the Journal of the American Medical Association Apr 12, 2006;295(14):1658e67. [5] Parker WH, Feskanich D, Broder MS, Chang E, Shoupe D, Farquhar CM, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses' health study. Obstet Gynecol Apr, 2013;121(4): 709e16.
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Correspondence / The Breast 24 (2015) 767e768
[6] Parker WH. Ovarian conservation versus bilateral oophorectomy at the time of hysterectomy for benign disease. Menopause (New York, N.Y.) Feb, 2014;21(2):192e4. [7] U.S. breast cancer statistics. 2015. http://www.breastcancer.org/symptoms/ understand_bc/statistics. [8] Women and heart disease facts. http://www.womensheart.org/content/ heartdisease/heart_disease_facts.asp, [accessed 19.05.15]. [9] CDC-hip fractures among older adults. http://www.cdc.gov/ HomeandRecreationalSafety/Falls/adulthipfx.html, [accessed 19.05.15]. [10] Farahmand BY, Michaelsson K, Ahlbom A, Ljunghall S, Baron JA. Swedish Hip Fracture Study G. Survival after hip fracture. Osteoporosis Int: a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA Dec, 2005;16(12):1583e90. [11] Yan S, Li K, Jiao X, Zou H. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials. Onco Targets Ther 2015;8:1433e41. [12] Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. 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 randomised trials. Lancet Dec 17, 2005;366(9503):2087e106.
Rakhshanda Layeequr Rahman* Texas Tech University Health Sciences Center, Breast Center of Excellence, 1400 Coulter, 3rd Floor, Amarillo, TX 79106, USA Teresa Baker Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, USA Sybil Crawford Department of Internal Medicine, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, USA Robert Kauffman Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, USA *
Corresponding author. Tel.: þ1 806 414 9420. E-mail address: [email protected] (R. Layeequr Rahman). 24 May 2015 Available online 19 September 2015
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Correspondence
SOFT trial can be very hard on young women
Keywords: SOFT trial Risks of ovarian suppression Long-term impact
The results of the Suppression of Ovarian Function Trial (SOFT) by Francis et al. are reported as “practice changing” for treatment of ER positive premenopausal breast cancer [1]. The authors concluded that for women who are at sufficient risk for recurrence to warrant adjuvant chemotherapy [2] and who remained premenopausal, the addition of ovarian suppression (OS) improved disease outcomes. Chemotherapy was used at physician discretion [3,4]. The added absolute benefit of OS versus Tamoxifen alone for prevention of recurrence was 4.5% in favor of Tamoxifen þ OS and 7.7% in favor of Exemestane þ OS [1]. This benefit has to be reconciled with the risks of OS. First, we know that compliance with endocrine treatment is difficult in ER positive breast cancer patient. In the SOFT trial, the rate of non-adherence to OS rose to 22% by the median follow up of 67 months [1]. Targeted adverse events including menopausal symptoms, depression, hypertension, osteoporosis and sexual dysfunction of grade 3 or higher were reported in 31.3% in the OS arm. Second, long-term impact of OS has been reported from studies conducted on oophorectomy associated with hysterectomy for benign disease. A prospective observational study that followed over 30,000 women for 28 years revealed that 16.8% women with bilateral oophorectomy died from all-cause mortality versus 13.3% women who had ovarian conservation [5,6]. Even though mortality from breast and ovarian cancer was lower, at no age was all-cause (ischemic heart disease, lung cancer, and stroke) mortality lower in women with oophorectomy. Specifically in women undergoing oophorectomy under the age of 50, the hazard ratio for all-cause mortality was 1.141 (95% CI 1.04e1.92); this translates into one additional death for every 8 women undergoing oophorectomy [5]. In the SOFT trial, the number needed to be treated with Tamoxifen þ OS compared to Tamoxifen alone to prevent one breast cancer relapse (local or systemic) is 49. OS decreases mortality from ovarian and breast cancer but it increases mortality from coronary heart disease, lung cancer, and osteoporosis [6]. Every year approximately 40,000 women die from breast cancer [7], and 14,000 from ovarian cancer [6]. These figures need to be balanced against 267,000 deaths from heart http://dx.doi.org/10.1016/j.breast.2015.08.010 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
attacks e six times as many women as breast cancer [8]. Additionally 48,000 women die within a year of hip fracture [9,10]. Since the overall survival is not yet reported from SOFT trial, how do we interpret this trial in terms of overall mortality, today? This concept can be explored in terms of local relapse versus distant relapse. A metaanalysis of published trials (including SOFT and TEXT trials) on Tamoxifen alone versus Tamoxifen plus OS reported 382 distant relapses in 2099 women treated with Tamoxifen alone compared to 367 distant relapses in 2078 women treated with Tamoxifen plus OS; the absolute risk reduction probability for a distant relapse with addition of OS is 0.0054 and the number needed to treat is 186 [11]. The number of local relapses in Tamoxifen alone group is 84 in 2099 women versus 62 in 2078 women in Tamoxifen plus OS group. The number needed to treat with OS to prevent one local relapse is 98. In the absence of any other causes of death, avoiding 4 local breast cancer recurrences at 5 years results in one life saved at 15 years [12]. From the meta-analysis numbers [11], to avoid 4 recurrences in short-term, 392 women will have to undergo OS to add one overall survivor. Reconciling one additional all-cause mortality for every 8 OS's, this would mean 49 additional deaths from other causes for every one life saved from breast cancer. These figures along with quality of life issues do not suggest that the results of SOFT trial should be “practice-changing” without accounting for long-term impact. Conflict of interest statement The authors have no conflict of interest. Acknowledgment No grants or funds supported this work.
References [1] Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N. Engl J Med Jan 29, 2015;372(5):436e46. [2] Regan MM, Pagani O, Walley B, Torrisi R, Perez EA, Francis P, et al. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol: Official Journal of the European Society for Medical Oncology/ESMO Jul, 2008;19(7):1231e41. [3] Francis PA, Regan MM, Fleming GF. Adjuvant ovarian suppression in premenopausal breast cancer. N. Engl J Med Apr 23, 2015;372(17):1673. [4] Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA: the Journal of the American Medical Association Apr 12, 2006;295(14):1658e67. [5] Parker WH, Feskanich D, Broder MS, Chang E, Shoupe D, Farquhar CM, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses' health study. Obstet Gynecol Apr, 2013;121(4): 709e16.
768
Correspondence / The Breast 24 (2015) 767e768
[6] Parker WH. Ovarian conservation versus bilateral oophorectomy at the time of hysterectomy for benign disease. Menopause (New York, N.Y.) Feb, 2014;21(2):192e4. [7] U.S. breast cancer statistics. 2015. http://www.breastcancer.org/symptoms/ understand_bc/statistics. [8] Women and heart disease facts. http://www.womensheart.org/content/ heartdisease/heart_disease_facts.asp, [accessed 19.05.15]. [9] CDC-hip fractures among older adults. http://www.cdc.gov/ HomeandRecreationalSafety/Falls/adulthipfx.html, [accessed 19.05.15]. [10] Farahmand BY, Michaelsson K, Ahlbom A, Ljunghall S, Baron JA. Swedish Hip Fracture Study G. Survival after hip fracture. Osteoporosis Int: a Journal Established as Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA Dec, 2005;16(12):1583e90. [11] Yan S, Li K, Jiao X, Zou H. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials. Onco Targets Ther 2015;8:1433e41. [12] Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. 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 randomised trials. Lancet Dec 17, 2005;366(9503):2087e106.
Rakhshanda Layeequr Rahman* Texas Tech University Health Sciences Center, Breast Center of Excellence, 1400 Coulter, 3rd Floor, Amarillo, TX 79106, USA Teresa Baker Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, USA Sybil Crawford Department of Internal Medicine, Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, USA Robert Kauffman Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, USA *
Corresponding author. Tel.: þ1 806 414 9420. E-mail address: [email protected] (R. Layeequr Rahman). 24 May 2015 Available online 19 September 2015