- Email: [email protected]
Are SOFT and TEXT results practice changing and how?
The Breast 27 (2016) 122e125
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Are SOFT and TEXT results practice changing and how? Olivia Pagani a, b, *, Meredith M. Regan b, c, Prudence A. Francis b, d, e a
Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona, Switzerland International Breast Cancer Study Group, Bern, Switzerland c Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA d Peter MacCallum Cancer Centre, St Vincent's Hospital Melbourne, University of Melbourne, Melbourne, Australia e Australia and New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 August 2015 Received in revised form 8 February 2016 Accepted 22 February 2016
Optimal adjuvant endocrine therapy for premenopausal women with hormone-receptor positive breast cancer has long been debated. In particular, the role of ovarian function suppression in addition to standard tamoxifen divided oncologists worldwide, and more recently, the role of aromatase inhibitors as an alternative to tamoxifen in the setting of ovarian suppression became a key question. In 2014, the long awaited results of the International Breast Cancer Study Group (IBCSG) led randomized, phase 3 trials, Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT), provided additional evidence to inform the discussion. The interpretation of the SOFT and TEXT trial data can facilitate better selection of appropriate endocrine therapy according to individual disease characteristics, recognizing the complexity of the puzzle, which is still not complete. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Premenopausal Breast cancer Endocrine therapy Exemestane Ovarian suppression Tamoxifen
Adjuvant endocrine therapy (ET) for premenopausal women with hormone-receptor positive (HRþ) breast cancer (BC) has been extensively debated. The major controversial topics were, and still are: 1. 2. 3. 4.
Is tamoxifen alone an optimal treatment? What is the role of ovarian function suppression (OFS)? Is there a place for aromatase inhibitors (AIs)? What is the optimal treatment duration?
The results of the complementary TEXT and SOFT trials (Fig. 1), specifically designed to answer the first 3 questions, may help clinicians in better tailoring adjuvant ET in different clinical scenarios. 1. Is tamoxifen alone an optimal treatment? The available guidelines [1e5] considered tamoxifen for 5e10 years as the standard adjuvant ET. In the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 2011 meta-analysis, 5 years of
* Corresponding author. Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona, Switzerland. E-mail address: [email protected] (O. Pagani). http://dx.doi.org/10.1016/j.breast.2016.02.008 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
tamoxifen compared to no ET was associated with a 15-year risk reduction of 39% in BC recurrence and of 30% in BC mortality, regardless of age, the use of chemotherapy and nodal status [6]. Overall, the 5-year disease-free survival (DFS) rate in SOFT was not significantly different in patients treated with tamoxifen-OFS or with tamoxifen alone (86.6% versus 84.7%, hazard ratio [HR] 0.83; 95% Confidence Interval [CI] 0.66e1.04; P ¼ 0.10) [7]. Overall survival (OS) at 5 years was also similar in the two groups (96.7% versus 95.1%, HR 0.74; 95% CI, 0.51e1.09; P ¼ 0.13) but longer follow-up is required in HRþ patients who can develop late relapses. In the lowrisk subpopulation of patients who did not receive chemotherapy (predominantly women >40 years, with small, node-negative [N-] tumors of low to intermediate grade), >95% remained free from BC and without distant recurrences at 5 years with tamoxifen alone. In this cohort of patients tamoxifen alone is very effective and can still be considered the standard of care. 2. What is the role of OFS? Several studies [8e10] and two meta-analyses [11,12] did not provide definitive evidence for routine use of OFS. In particular: few women were enrolled in trials testing the addition of a gonadotropinreleasing-hormone agonist (GnRHa) to tamoxifen ± chemotherapy [13]; some studies, closed due to poor accrual, were underpowered
O. Pagani et al. / The Breast 27 (2016) 122e125
123
Fig. 1. TEXT and SOFT design.
[14]; no trials assessed a GnRHa versus chemotherapy with tamoxifen in both arms [15] and in women receiving current standard adjuvant chemotherapy. The addition of OFS was considered questionable, to be discussed on an individual basis. In the pre-planned analysis of the cohort of patients in SOFT who received prior modern adjuvant chemotherapy and remained premenopausal, freedom from BC at 5 years was improved in patients receiving tamoxifen-OFS as compared with those receiving tamoxifen alone (82.5% versus 78.0%, HR 0.78; 95% CI, 0.60e1.02) and further improved to 85.7% in patients receiving exemestaneOFS. OS at 5 years was 94.5% among patients under tamoxifenOFS and 90.9% among those under tamoxifen alone (HR 0.64; 95% CI, 0.42e0.96). This chemotherapy cohort comprised higher risk patients than the no chemotherapy cohort (median age 40 years, with larger tumors, that were more frequently lymph node positive and of intermediate to high grade). The impact of adding OFS to tamoxifen was particularly striking in patients <35 years (11.5% of the population, 94% pretreated with chemotherapy): the 5-year BCfree rate was 67.7% for patients receiving tamoxifen alone, 78.9% for those assigned tamoxifen-OFS and 83.4% for those assigned
exemestane-OFS. These cohorts of patients can clearly benefit from the addition of OFS to oral ET and this approach should be routinely considered and for the very young patients, usually retaining menses after chemotherapy, could be recommended. SOFT does not provide any information for the small population of patients <35 years with luminal-A-like BC who do not receive adjuvant chemotherapy. Side effects and adherence are relevant when considering OFS in premenopausal patients, especially if very young. Grade 3 adverse events were more frequent in patients receiving OFS than tamoxifen alone (31.3% versus 23.7%) and were consistent with the treatments assigned. Tamoxifen was discontinued early in 16.7% of the tamoxifen-OFS group and in 21.7% of the tamoxifen group, the rate of non-adherence with OFS reached 21.9% at 4 years, in agreement with the available literature [16e18]. 3. Is there a place for Aromatase Inhibitors (AIs)? In postmenopausal women, the available evidence shows a modest but significant reduction in the risk of recurrence (<5%
124
O. Pagani et al. / The Breast 27 (2016) 122e125
absolute difference at long-term follow-up) with AIs over tamoxifen [19e21]. In the TEXT-SOFT combined analysis, the 5-year DFS was 91.1% in the exemestane-OFS group versus 87.3% in the tamoxifeneOFS group (HR 0.72; 95% CI, 0.60e0.85; P < 0.001) with no striking heterogeneity of treatment effect [22]. The 5 year BC-free interval was 92.8% in patients assigned exemestane-OFS and 88.8% in those assigned tamoxifen-OFS (HR 0.66; 95% CI, 0.55e0.80; P < 0.001). Five-years OS was >95% in both groups, not significantly different according to treatment assignment, but not considered mature. In patients who received chemotherapy, SOFT and TEXT differed relative to the timing of chemotherapy and ET initiation: in TEXT patients received OFS concurrently with chemotherapy, commencing an average of 1.2 months after surgery, with the oral ET commenced after chemotherapy; in SOFT patients completed all chemotherapy before enrollment and started OFS, if assigned, an average of 8 months after surgery, but were allowed to have received oral ET (typically tamoxifen) prior to randomization, while premenopausal status was being ascertained. Among patients who received chemotherapy, the absolute improvement in the 5-year BC-free rate with exemestane-OFS as compared with tamoxifenOFS was 5.5% in TEXT and 3.9% in SOFT. We are currently exploring if the longer time from diagnosis to initiation of OFS might explain any differential treatment benefit achieved in SOFT compared with TEXT. For the comparison of exemestane-OFS versus tamoxifen-OFS, the frequency of Grade 3e4 targeted adverse events was similar in the two treatment groups (~30%), as was the proportion of women stopping all treatments early (13.7%): specific drug-related symptoms were reported, but the overall quality-of-life (QoL) assessment did not favor either treatment [23]. Overall, SOFT and TEXT provide new evidence that exemestaneOFS improves short-term outcomes as compared with tamoxifenOFS in premenopausal women with HRþ early BC. Longer followup is needed to ascertain the ultimate impact of this strategy. In patients deserving OFS according to their individual risk, exemestane-OFS should in our opinion be proposed and balanced against potential side effects. In very young and/or higher risk patients who do not tolerate exemestane, assessing tolerability of tamoxifen-OFS should also be considered, as a more effective option than tamoxifen alone. The ABCSG-12 trial, after 94.4 months of median follow-up, showed no DFS benefit and a higher risk of death (HR ¼ 1.63; 95% CI, 1.05e1.45; P ¼ 0.030) in the anastrozole-OFS randomized group as compared with the tamoxifen-OFS group [24]. ABCSG-12 and SOFT-TEXT have several potentially relevant differences: in the Austrian trial, only 5% of the patients received chemotherapy; the statistical power was lower (half the number of events); treatment duration was only 3 years; zoledronic acid was an additional randomization, and obesity might have abrogated the effect of the AI anastrozole in this young population undergoing OFS. 4. What is the optimal treatment duration? OFS in SOFT and TEXT was given for 5 years to allow for exemestane administration, the suppression of peripheral aromatase otherwise resulting in ovarian stimulation consequent to the hypothalamic loop. No direct comparison between different durations of GnRHa is and will be available in the future: the good outcome of lowrisk patients treated for 3 years [24] suggests this can be a reasonable approach, especially in women reporting severe side effects. Based on the most recent data from the ATLAS and aTTom trials in almost 20.000 women [25,26], tamoxifen for 10 years should be considered in premenopausal women at higher risk for late relapse. To date, no data are available on extended oral ET (AIs/TAM) plus OFS beyond 5
years in premenopausal patients. A Phase II single-arm trial evaluating 2 years of OFS in women who remained premenopausal after 5 years of tamoxifen was prematurely closed due to insufficient accrual, suggesting young women may not be motivated to late introduction of extended combined ET [27].
Conclusions Based on the available evidence, can we claim SOFT and TEXT should and did change clinical practice? SOFT and TEXT confirm the need to definitively overcome the “one size fits all” strategy when treating premenopausal patients with HRþ early BC. Evidence is now available to better select ET according to the individual risk: tamoxifen alone is still the gold standard in low-risk patients, OFS should be considered in patients at sufficient risk to deserve adjuvant chemotherapy and particularly when very young. When OFS is indicated, exemestane further improves short-term outcomes, as highlighted by the last St Gallen recommendations [2830]. Nonetheless, several features still need to be clarified before a definitive picture can be drawn. In the joint analysis of TEXT and SOFT thus far, the 5-year median follow-up and the low event rate are insufficient to assess whether the significant improvement in DFS with exemestane-OFS will translate into an overall survival benefit. Chemotherapy-induced OFS is common in older premenopausal women and is associated with improved BC outcomes [31]. In SOFT, only women who were premenopausal after chemotherapy could be enrolled. In TEXT, early initiation of OFS together with chemotherapy seems an effective approach and outcomes to date support the safety of concomitant OFS and chemotherapy [32,33]. An in-depth analysis of these variants will help in better understanding the interactions between treatment timing and patients' characteristics. SOFT and TEXT also demonstrate that premenopausal women with HRþ early BC may have excellent prognoses with modern ET. Overall, <5% of the patients in the two trials have died with 5 years follow-up, contrasting with previous observations of a poor prognosis in premenopausal patients with HRþ BC treated with chemotherapy alone. In particular, when looking at patients who did not receive chemotherapy in the combined TEXT-SOFT analysis (21% in TEXT and 9% in SOFT with Nþ disease), the 5-year BC-free rate was >97% in women who received exemestane-OFS, arguing against the universal need for adjuvant chemotherapy in Nþ premenopausal patients. In SOFT and TEXT 12% of patients had HER2þ tumors, 60% and 55% received HER2-targeted therapy. The addition of OFS to tamoxifen in SOFT appeared to be beneficial in this subgroup and this combination has previously been found to be effective in HER2þ tumors [34]. Timing of chemotherapy and HER2-targeted therapy differed relative to endocrine therapy initiation in the two trials (median start of OFS after surgery was 1.2 and 8 months in TEXT and SOFT, respectively); HER2 central assessment and further analysis are needed before HER2 status is used for oral ET selection. The role of body-mass index (BMI) is under investigation and suboptimal OFS in patients receiving exemestane has been reported in at least 17% of patients in the prospective SOFT-EST Substudy [35]. Baseline factors significantly related to suboptimal estrogen suppression were no prior chemotherapy, high BMI, low FSH & LH, but not age. It should be emphasized that in young women with chemotherapy-induced amenorrhea cessation of menses alone is insufficient to confirm sustained OFS: AIs should not be given without OFS due to the significant risk of recovery of ovarian function resulting in ineffective adjuvant ET.
O. Pagani et al. / The Breast 27 (2016) 122e125
The specific toxicity profiles, costs and country availability play also an important role when discussing the treatment plan with individual patients. In conclusion, clinicians now have several proven premenopausal BC adjuvant endocrine therapies. We need to learn how to better interpret and apply the risk-benefit balance in our routine clinical practice and best convey this information to our patients when discussing their individual options. Conflict of interest statement The authors declare no potential conflict of interest relevant to this article. The trials were supported by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute. References [1] Partridge AH, Pagani O, Abulkhair O, et al. First international consensus guidelines for breast cancer in young women (BCY1). Breast 2014;23(3): 209e20. [2] Senkus E, Kyriakides S, Penault-Llorca F, et al., ESMO guidelines working group. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl. 6):vi7e23. [3] Version 2.2015 NCCN clinical practice guidelines in oncology. Breast cancer Available at: www.nccn.com. [4] Cardoso F, Loibl S, Pagani O, et al. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012;48(18):3355e77. [5] Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 2014;32(21):2255e69. [6] Davies C, Godwin J, Gray R, et al., Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378:771e84. [7] Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015;372:436e46. [8] Jakesz R, Hausmaninger H, Kubista E, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancerdAustrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20:4621e7. [9] The Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 2007;99(7):516e25. [10] Hackshaw A, Baum M, Fornander T, et al. Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer. J Natl Cancer Inst 2009;101(5):341e9. [11] Cuzick J, Ambroisine L, Davidson N, et al., LHRH-Agonists in Early Breast Cancer Overview Group. Use of luteinizing-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormonereceptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007;369:1711e23. [12] 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. [13] Thürlimann B, Price KN, Gelber RD, et al. Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. Breast Cancer Res Treat 2009;113:137e44. [14] Tevaarwerk AJ, Wang M, Zhao F, et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative hormone receptorepositive breast cancer (E3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2014 Dec 10;32(35):3948e58.
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[15] Davidson NE, O'Neill AM, Vukov AM, et al. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol 2005;23(25):5973e82. [16] Ruddy KJ, Partridge AH. Adherence with adjuvant hormonal therapy for breast cancer. Ann Oncol 2009;20(3):401e2. [17] Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010;28(27):4120e8. [18] Brito C, Portela MC, de Vasconcellos MT. Adherence to hormone therapy among women with breast cancer. BMC Cancer 2014;14:397e405. [19] Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 2010;28(23):3784e96. [20] Freedman OC, Fletcher GG, Gandhi S, et al. Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline. Curr Oncol 2015;22(Suppl. 1): S95e113. [21] Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015. http://dx.doi.org/10.1016/S01406736(15)61074-1. [22] Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371(2): 107e18. [23] Bernhard J, Luo W, Ribi K, et al. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 2015;16(7):848e58. [24] 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(2):313e20. [25] Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381: 805e16. [26] Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(suppl). abstr 5. [27] Ruddy KJ, DeSantis SD, Barry W, et al. Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen. Clin Breast Cancer 2014;14(6):413e6. [28] Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 2015;26(8): 1533e46. [29] Paluch-Shimon S, Pagani O, Partridge AH, et al. Second international consensus guidelines for breast cancer in young women (BCY2). The Breast 2016;26:87e99. [30] Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American society of clinical oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016 pii: JCO659573. [31] Swain SM, Jeong J-H, Wolmark N. Amenorrhea from breast cancer therapy d not a matter of dose. N Engl J Med 2010;363:2268e70. [32] International Breast Cancer Study Group. Late effects of adjuvant oophorectomy and chemotherapy upon premenopausal breast cancer patients. Ann Oncol 1990;1:30e5. ^ MG, Spielmann M, et al. Randomized trial of adjuvant ovarian [33] Arriagada R, Le suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol 2005;16:389e96. [34] Love RR, Duc NB, Havighurst TC, et al. Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptorpositive premenopausal women with operable breast cancer. J Clin Oncol 2003;21:453e7. [35] 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. pii: JCO612259.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Are SOFT and TEXT results practice changing and how? Olivia Pagani a, b, *, Meredith M. Regan b, c, Prudence A. Francis b, d, e a
Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona, Switzerland International Breast Cancer Study Group, Bern, Switzerland c Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA d Peter MacCallum Cancer Centre, St Vincent's Hospital Melbourne, University of Melbourne, Melbourne, Australia e Australia and New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 August 2015 Received in revised form 8 February 2016 Accepted 22 February 2016
Optimal adjuvant endocrine therapy for premenopausal women with hormone-receptor positive breast cancer has long been debated. In particular, the role of ovarian function suppression in addition to standard tamoxifen divided oncologists worldwide, and more recently, the role of aromatase inhibitors as an alternative to tamoxifen in the setting of ovarian suppression became a key question. In 2014, the long awaited results of the International Breast Cancer Study Group (IBCSG) led randomized, phase 3 trials, Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT), provided additional evidence to inform the discussion. The interpretation of the SOFT and TEXT trial data can facilitate better selection of appropriate endocrine therapy according to individual disease characteristics, recognizing the complexity of the puzzle, which is still not complete. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Premenopausal Breast cancer Endocrine therapy Exemestane Ovarian suppression Tamoxifen
Adjuvant endocrine therapy (ET) for premenopausal women with hormone-receptor positive (HRþ) breast cancer (BC) has been extensively debated. The major controversial topics were, and still are: 1. 2. 3. 4.
Is tamoxifen alone an optimal treatment? What is the role of ovarian function suppression (OFS)? Is there a place for aromatase inhibitors (AIs)? What is the optimal treatment duration?
The results of the complementary TEXT and SOFT trials (Fig. 1), specifically designed to answer the first 3 questions, may help clinicians in better tailoring adjuvant ET in different clinical scenarios. 1. Is tamoxifen alone an optimal treatment? The available guidelines [1e5] considered tamoxifen for 5e10 years as the standard adjuvant ET. In the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) 2011 meta-analysis, 5 years of
* Corresponding author. Institute of Oncology and Breast Unit of Southern Switzerland, Bellinzona, Switzerland. E-mail address: [email protected] (O. Pagani). http://dx.doi.org/10.1016/j.breast.2016.02.008 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
tamoxifen compared to no ET was associated with a 15-year risk reduction of 39% in BC recurrence and of 30% in BC mortality, regardless of age, the use of chemotherapy and nodal status [6]. Overall, the 5-year disease-free survival (DFS) rate in SOFT was not significantly different in patients treated with tamoxifen-OFS or with tamoxifen alone (86.6% versus 84.7%, hazard ratio [HR] 0.83; 95% Confidence Interval [CI] 0.66e1.04; P ¼ 0.10) [7]. Overall survival (OS) at 5 years was also similar in the two groups (96.7% versus 95.1%, HR 0.74; 95% CI, 0.51e1.09; P ¼ 0.13) but longer follow-up is required in HRþ patients who can develop late relapses. In the lowrisk subpopulation of patients who did not receive chemotherapy (predominantly women >40 years, with small, node-negative [N-] tumors of low to intermediate grade), >95% remained free from BC and without distant recurrences at 5 years with tamoxifen alone. In this cohort of patients tamoxifen alone is very effective and can still be considered the standard of care. 2. What is the role of OFS? Several studies [8e10] and two meta-analyses [11,12] did not provide definitive evidence for routine use of OFS. In particular: few women were enrolled in trials testing the addition of a gonadotropinreleasing-hormone agonist (GnRHa) to tamoxifen ± chemotherapy [13]; some studies, closed due to poor accrual, were underpowered
O. Pagani et al. / The Breast 27 (2016) 122e125
123
Fig. 1. TEXT and SOFT design.
[14]; no trials assessed a GnRHa versus chemotherapy with tamoxifen in both arms [15] and in women receiving current standard adjuvant chemotherapy. The addition of OFS was considered questionable, to be discussed on an individual basis. In the pre-planned analysis of the cohort of patients in SOFT who received prior modern adjuvant chemotherapy and remained premenopausal, freedom from BC at 5 years was improved in patients receiving tamoxifen-OFS as compared with those receiving tamoxifen alone (82.5% versus 78.0%, HR 0.78; 95% CI, 0.60e1.02) and further improved to 85.7% in patients receiving exemestaneOFS. OS at 5 years was 94.5% among patients under tamoxifenOFS and 90.9% among those under tamoxifen alone (HR 0.64; 95% CI, 0.42e0.96). This chemotherapy cohort comprised higher risk patients than the no chemotherapy cohort (median age 40 years, with larger tumors, that were more frequently lymph node positive and of intermediate to high grade). The impact of adding OFS to tamoxifen was particularly striking in patients <35 years (11.5% of the population, 94% pretreated with chemotherapy): the 5-year BCfree rate was 67.7% for patients receiving tamoxifen alone, 78.9% for those assigned tamoxifen-OFS and 83.4% for those assigned
exemestane-OFS. These cohorts of patients can clearly benefit from the addition of OFS to oral ET and this approach should be routinely considered and for the very young patients, usually retaining menses after chemotherapy, could be recommended. SOFT does not provide any information for the small population of patients <35 years with luminal-A-like BC who do not receive adjuvant chemotherapy. Side effects and adherence are relevant when considering OFS in premenopausal patients, especially if very young. Grade 3 adverse events were more frequent in patients receiving OFS than tamoxifen alone (31.3% versus 23.7%) and were consistent with the treatments assigned. Tamoxifen was discontinued early in 16.7% of the tamoxifen-OFS group and in 21.7% of the tamoxifen group, the rate of non-adherence with OFS reached 21.9% at 4 years, in agreement with the available literature [16e18]. 3. Is there a place for Aromatase Inhibitors (AIs)? In postmenopausal women, the available evidence shows a modest but significant reduction in the risk of recurrence (<5%
124
O. Pagani et al. / The Breast 27 (2016) 122e125
absolute difference at long-term follow-up) with AIs over tamoxifen [19e21]. In the TEXT-SOFT combined analysis, the 5-year DFS was 91.1% in the exemestane-OFS group versus 87.3% in the tamoxifeneOFS group (HR 0.72; 95% CI, 0.60e0.85; P < 0.001) with no striking heterogeneity of treatment effect [22]. The 5 year BC-free interval was 92.8% in patients assigned exemestane-OFS and 88.8% in those assigned tamoxifen-OFS (HR 0.66; 95% CI, 0.55e0.80; P < 0.001). Five-years OS was >95% in both groups, not significantly different according to treatment assignment, but not considered mature. In patients who received chemotherapy, SOFT and TEXT differed relative to the timing of chemotherapy and ET initiation: in TEXT patients received OFS concurrently with chemotherapy, commencing an average of 1.2 months after surgery, with the oral ET commenced after chemotherapy; in SOFT patients completed all chemotherapy before enrollment and started OFS, if assigned, an average of 8 months after surgery, but were allowed to have received oral ET (typically tamoxifen) prior to randomization, while premenopausal status was being ascertained. Among patients who received chemotherapy, the absolute improvement in the 5-year BC-free rate with exemestane-OFS as compared with tamoxifenOFS was 5.5% in TEXT and 3.9% in SOFT. We are currently exploring if the longer time from diagnosis to initiation of OFS might explain any differential treatment benefit achieved in SOFT compared with TEXT. For the comparison of exemestane-OFS versus tamoxifen-OFS, the frequency of Grade 3e4 targeted adverse events was similar in the two treatment groups (~30%), as was the proportion of women stopping all treatments early (13.7%): specific drug-related symptoms were reported, but the overall quality-of-life (QoL) assessment did not favor either treatment [23]. Overall, SOFT and TEXT provide new evidence that exemestaneOFS improves short-term outcomes as compared with tamoxifenOFS in premenopausal women with HRþ early BC. Longer followup is needed to ascertain the ultimate impact of this strategy. In patients deserving OFS according to their individual risk, exemestane-OFS should in our opinion be proposed and balanced against potential side effects. In very young and/or higher risk patients who do not tolerate exemestane, assessing tolerability of tamoxifen-OFS should also be considered, as a more effective option than tamoxifen alone. The ABCSG-12 trial, after 94.4 months of median follow-up, showed no DFS benefit and a higher risk of death (HR ¼ 1.63; 95% CI, 1.05e1.45; P ¼ 0.030) in the anastrozole-OFS randomized group as compared with the tamoxifen-OFS group [24]. ABCSG-12 and SOFT-TEXT have several potentially relevant differences: in the Austrian trial, only 5% of the patients received chemotherapy; the statistical power was lower (half the number of events); treatment duration was only 3 years; zoledronic acid was an additional randomization, and obesity might have abrogated the effect of the AI anastrozole in this young population undergoing OFS. 4. What is the optimal treatment duration? OFS in SOFT and TEXT was given for 5 years to allow for exemestane administration, the suppression of peripheral aromatase otherwise resulting in ovarian stimulation consequent to the hypothalamic loop. No direct comparison between different durations of GnRHa is and will be available in the future: the good outcome of lowrisk patients treated for 3 years [24] suggests this can be a reasonable approach, especially in women reporting severe side effects. Based on the most recent data from the ATLAS and aTTom trials in almost 20.000 women [25,26], tamoxifen for 10 years should be considered in premenopausal women at higher risk for late relapse. To date, no data are available on extended oral ET (AIs/TAM) plus OFS beyond 5
years in premenopausal patients. A Phase II single-arm trial evaluating 2 years of OFS in women who remained premenopausal after 5 years of tamoxifen was prematurely closed due to insufficient accrual, suggesting young women may not be motivated to late introduction of extended combined ET [27].
Conclusions Based on the available evidence, can we claim SOFT and TEXT should and did change clinical practice? SOFT and TEXT confirm the need to definitively overcome the “one size fits all” strategy when treating premenopausal patients with HRþ early BC. Evidence is now available to better select ET according to the individual risk: tamoxifen alone is still the gold standard in low-risk patients, OFS should be considered in patients at sufficient risk to deserve adjuvant chemotherapy and particularly when very young. When OFS is indicated, exemestane further improves short-term outcomes, as highlighted by the last St Gallen recommendations [2830]. Nonetheless, several features still need to be clarified before a definitive picture can be drawn. In the joint analysis of TEXT and SOFT thus far, the 5-year median follow-up and the low event rate are insufficient to assess whether the significant improvement in DFS with exemestane-OFS will translate into an overall survival benefit. Chemotherapy-induced OFS is common in older premenopausal women and is associated with improved BC outcomes [31]. In SOFT, only women who were premenopausal after chemotherapy could be enrolled. In TEXT, early initiation of OFS together with chemotherapy seems an effective approach and outcomes to date support the safety of concomitant OFS and chemotherapy [32,33]. An in-depth analysis of these variants will help in better understanding the interactions between treatment timing and patients' characteristics. SOFT and TEXT also demonstrate that premenopausal women with HRþ early BC may have excellent prognoses with modern ET. Overall, <5% of the patients in the two trials have died with 5 years follow-up, contrasting with previous observations of a poor prognosis in premenopausal patients with HRþ BC treated with chemotherapy alone. In particular, when looking at patients who did not receive chemotherapy in the combined TEXT-SOFT analysis (21% in TEXT and 9% in SOFT with Nþ disease), the 5-year BC-free rate was >97% in women who received exemestane-OFS, arguing against the universal need for adjuvant chemotherapy in Nþ premenopausal patients. In SOFT and TEXT 12% of patients had HER2þ tumors, 60% and 55% received HER2-targeted therapy. The addition of OFS to tamoxifen in SOFT appeared to be beneficial in this subgroup and this combination has previously been found to be effective in HER2þ tumors [34]. Timing of chemotherapy and HER2-targeted therapy differed relative to endocrine therapy initiation in the two trials (median start of OFS after surgery was 1.2 and 8 months in TEXT and SOFT, respectively); HER2 central assessment and further analysis are needed before HER2 status is used for oral ET selection. The role of body-mass index (BMI) is under investigation and suboptimal OFS in patients receiving exemestane has been reported in at least 17% of patients in the prospective SOFT-EST Substudy [35]. Baseline factors significantly related to suboptimal estrogen suppression were no prior chemotherapy, high BMI, low FSH & LH, but not age. It should be emphasized that in young women with chemotherapy-induced amenorrhea cessation of menses alone is insufficient to confirm sustained OFS: AIs should not be given without OFS due to the significant risk of recovery of ovarian function resulting in ineffective adjuvant ET.
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