Adjuvant Endocrine Therapy for Premenopausal Breast Cancer

Humans

To the Editor

The results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) reported by Francis et al. (July 12 issue)1 prompt one to consider their global relevance. The annual global case burden of hormone-receptor–positive breast cancer in premenopausal women is approximately 350,000 to 420,000 cases in low- and middle-income countries and 125,000 cases in high-income countries. Most patients in low- and middle-income countries have to pay out of pocket for pharmaceuticals, commonly less than $10 per month for tamoxifen but more than $100 per month each for aromatase inhibitors and gonadotropin-releasing hormone (GnRH) agonists. Such costs are the major reason that women in these countries do not seek and do not receive these treatments.2 In addition, the rate of adherence to hormonal treatment for 5 years was reported to be less than 50% in a population-based study,3 in contrast to the 80% rate reported in the article by Francis and colleagues.

Oophorectomy, which is widely available in hospitals, plus tamoxifen is the practical treatment of choice for women with human epidermal growth factor receptor 2 (HER2)–positive disease worldwide. Findings regarding the benefit to such patients and the greater preservation of bone density than that found in studies of tamoxifen alone or tamoxifen plus GnRH agonists in premenopausal women further support this approach.4 In addition, the timing of oophorectomy in the menstrual cycle may further improve outcomes.5,6

Richard R. Love, M.D.
Marquette University, Milwaukee, WI

No potential conflict of interest relevant to this letter was reported.

  1. 1. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 2018;379:122137.

  2. 2. Pisani P, Parkin DM, Ngelangel C, et al. Outcome of screening by clinical examination of the breast in a trial in the Philippines. Int J Cancer 2006;118:149154.

  3. 3. van Herk-Sukel MP, van de Poll-Franse LV, Voogd AC, Nieuwenhuijzen GA, Coebergh JW, Herings RM. Half of breast cancer patients discontinue tamoxifen and any endocrine treatment before the end of the recommended treatment period of 5 years: a population-based analysis. Breast Cancer Res Treat 2010;122:843851.

  4. 4. Love RR, Young GS, Laudico AV, et al. Bone mineral density changes following surgical oophorectomy and tamoxifen adjuvant therapy for operable breast cancer in pre-menopausal Filipino and Vietnamese women. Cancer 2013;119:37463752.

  5. 5. Love RR, Laudico AV, Van Dinh N, et al. Timing of adjuvant surgical oophorectomy in the menstrual cycle and disease-free and overall survival in premenopausal women with operable breast cancer. J Natl Cancer Inst 2015;107:djv064djv064.

  6. 6. Love RR, Hossain SM, Hussain MM, et al. Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer. Eur J Cancer 2016;60:107116.

To the Editor

In the recently published updated analysis of the results of SOFT and TEXT, HER2-positive patients had a much greater benefit from the addition of ovarian suppression to tamoxifen (as compared with tamoxifen alone) than HER2-negative patients (Fig. 3 of the article). In fact, although the majority of the patients had HER2-negative disease, there was no significant benefit with respect to disease-free survival among patients in this subgroup. In addition, patients with HER2-positive tumors derived no significant benefit from ovarian suppression with exemestane, as compared with ovarian suppression with tamoxifen (Fig. S6 in the Supplementary Appendix, available with the full text of the article at NEJM.org).

A similar trend was previously seen in the initial publication of the SOFT data1 (Fig. S2 in the Supplementary Appendix of the 2015 article, available with the full text of the article at NEJM.org); these findings have been reinforced with longer follow-up. There is a strong possibility that the disease-free survival benefit seen in the overall population may simply be a reflection of the strong signal in the smaller HER2-positive subgroup, whereas the larger HER2-negative subgroup received no significant benefit other than in smaller subgroups of patients who received chemotherapy.

This finding has important implications for practice. Women with HER2-positive disease derive a benefit from ovarian suppression with tamoxifen and may not need to be treated with ovarian suppression with exemestane. Women with HER2-negative disease may preferably receive ovarian suppression with exemestane.

Amol Patel, M.D., D.M.
Army Hospital Research and Referral, New Delhi, India

Vineet G. Gupta, M.D., D.M.
Max Super Speciality Hospital, New Delhi, India

No potential conflict of interest relevant to this letter was reported.

  1. 1. Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:436446.

To the Editor

The investigators in SOFT found that tamoxifen plus ovarian suppression increased rates of disease-free and overall survival among premenopausal women with hormone-receptor–positive, HER2-negative breast cancer. However, we have questioned the endorsement of the aromatase inhibitor exemestane plus ovarian suppression in these patients, on the basis of our review of findings from SOFT and TEXT1 and from the Austrian Breast and Colorectal Cancer Study Group Trial 12.2

In the prespecified updated analysis of SOFT, although the rate of freedom from distant recurrence was somewhat higher in the exemestane–ovarian suppression group than in the tamoxifen–ovarian suppression group, only in the tamoxifen–ovarian suppression group was the rate of survival significantly higher than the rate among women who received tamoxifen alone (hazard ratio for death, 0.67; 95% confidence interval [CI], 0.48 to 0.92). Death after distant recurrence was more frequent in the exemestane–ovarian suppression group than in the tamoxifen–ovarian suppression group (76 of 87 patients [87%] vs. 61 of 104 patients [59%]). Since consistent suppression of estrogen levels may not be achieved with current pharmacologic approaches,3 would not a recommendation for the use of tamoxifen–ovarian suppression be prudent pending longer-term results in patients who have received the exemestane–ovarian suppression intervention?

Rowan T. Chlebowski, M.D., Ph.D.
City of Hope National Medical Center, Duarte, CA

Kathy Pan, M.D.
Los Angeles Biomedical Research Institute, Torrance, CA

Dr. Chlebowski reports receiving consulting fees from Novartis, AstraZeneca, and Genentech and honoraria from Novartis and AstraZeneca. No other potential conflict of interest relevant to this letter was reported.

  1. 1. Chlebowski RT, Pan K, Col NF. Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer. Breast Cancer Res Treat 2017;161:185190.

  2. 2. Gnant M, Mlineritsch B, Stoeger H, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 2015;26:313320.

  3. 3. Bellet M, Gray KP, Francis PA, et al. Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): the SOFT-EST substudy. J Clin Oncol 2016;34:15841593.

Response

The authors reply: We agree with Love that for premenopausal women with hormone-receptor–positive tumors and a clinically significant risk of recurrence, bilateral oophorectomy can provide a cost-effective alternative to four weekly injections of an adjuvant GnRH agonist for 5 years after the initiation of injections, as in SOFT and TEXT. Laparoscopic surgery, if available, allows fast postoperative recovery. Among the minority of patients with a germline BRCA mutation, bilateral salpingo-oophorectomy also reduces the risk of subsequent ovarian or fallopian tube cancer.

In SOFT, the absolute benefit from ovarian suppression was greatest in women younger than 35 years of age. In SOFT and TEXT, ovarian ablation was less frequently chosen as the method of ovarian suppression in women in this age group,1 in whom the childbearing years may not be complete. In addition, long-term adverse health consequences of premature menopause,2 also resulting in costs, need to be considered when discussing permanent surgical versus reversible medical ovarian suppression. Aromatase inhibitors have been expensive in the past, but with the availability of cheaper generic formulations, the costs of aromatase inhibitors may no longer be prohibitive. The Breast Health Global Initiative aims to develop evidence-based, economically feasible, culturally appropriate guidelines for low- and middle-income nations to improve breast-health outcomes.3 However, we do not recommend routine substitution of ovarian ablation with medical ovarian suppression in young premenopausal women in high-income countries.

In interpreting the results of SOFT and TEXT regarding oral endocrine therapy in women with HER2-positive tumors, we urge Patel and Gupta not to overinterpret the excellent results in SOFT with tamoxifen plus ovarian suppression. These results are complicated by the varying timing of HER2-targeted therapy in relation to the year of accrual and the use of chemotherapy and endocrine therapy in women enrolled in SOFT and TEXT.

We agree with Chlebowski and Pan that observing longer-term survival results in SOFT and TEXT remains vital. In the meantime, in both trials, there were absolute improvements in distant recurrence rates at 8 years among patients with HER2-negative tumors who received chemotherapy, and there was a hazard ratio for death of 0.86 (95% CI, 0.68 to 1.10) in the overall HER2-negative population slightly favoring exemestane plus ovarian suppression over tamoxifen plus ovarian suppression. Overall, the SOFT Estrogen Suppression substudy results4 show significantly lower estrogen levels with exemestane plus triptorelin than with tamoxifen plus triptorelin during the first year of therapy. In patients with advanced disease, medical ovarian suppression plus aromatase inhibitors or fulvestrant, with or without inhibition of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is considered to be a valid option.5 Recent randomized trials of inhibitors of CDK4 and CDK6 included premenopausal women receiving ovarian suppression, and efficacy was independent of natural or medical menopause.

Prudence A. Francis, M.D.
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Olivia Pagani, M.D.
Institute of Oncology of Southern Switzerland, Bellinzona, Switzerland

Meredith M. Regan, Sc.D.
Dana–Farber Cancer Institute, Boston, MA

Since publication of their article, the authors report no further potential conflict of interest.

  1. 1. Saha P, Regan MM, Pagani O, et al. Treatment efficacy, adherence, and quality of life among women younger than 35 years in the International Breast Cancer Study Group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol 2017;35:31133122.

  2. 2. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ III. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821828.

  3. 3. Birnbaum JK, Duggan C, Anderson BO, Etzioni R. Early detection and treatment strategies for breast cancer in low-income and upper middle-income countries: a modelling study. Lancet Glob Health 2018;6(8):e885e893.

  4. 4. Bellet M, Gray KP, Francis PA, et al. Twelve-month estrogen levels in premenopausal women with hormone receptor-positive breast cancer receiving adjuvant triptorelin plus exemestane or tamoxifen in the Suppression of Ovarian Function Trial (SOFT): the SOFT-EST Substudy. J Clin Oncol 2016;34:15841593.

  5. 5. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol 2018;29:16341657.

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