Adjuvant endocrine therapy is the backbone of systemic treatment for early-stage steroid hormone receptor–positive (HR+) invasive breast cancer. For many years, the selective estrogen receptor modulator tamoxifen was the agent of choice for women of all ages, and randomized clinical trials have shown that a treatment duration of 10 years of tamoxifen is superior to five years (1,2). More recently, individual trials and a meta-analyses have established that most postmenopausal women should receive an aromatase inhibitor (AI) instead of or in addition to tamoxifen as part of their endocrine therapy because of improved outcomes (3–11); however, the optimal duration of AI therapy remains unknown. In this issue, Blok et al. report the results of the Investigation on the Duration of Extended Adjuvant Letrozole treatment (IDEAL) trial (12). From 2007 to 2011, this open-label Dutch multicenter trial randomized 1824 postmenopausal women with early HR+ breast cancer to either 2.5 or five years of adjuvant letrozole after completion of five years of any endocrine therapy. The arms were well balanced, and the trial evaluated a moderately high-risk population (68% received chemotherapy, 61% had pN1-pN3 nodal involvement, and 88% had received AI of some duration). The primary outcome was disease-free survival (DFS). With a median follow-up of 6.6 years, the hazard ratio (HR) for DFS was 0.92 (95% confidence interval [CI] = 0.74 to 1.16). There was also no difference in hazard ratio for overall survival (1.04, 95% = CI = 0.78 to 1.38) or distant recurrences (1.06, 95% CI = 0.78 to 1.45) though a statistically significant reduction in second primary breast cancers (HR = 0.39, 95% CI = 0.19 to 0.81) was observed with five years of letrozole. A preplanned subgroup analysis did not identify a subgroup with statistically significant benefit with five years vs 2.5 years; however, there are plans to complete an exploratory analysis evaluating 10 years of follow-up and investigating possible predictive biomarkers. Safety analysis during the time of active treatment showed a numerical increase in osteoporosis and fractures for longer- vs shorter-duration letrozole (12.7% vs 7.5% and 5.0% vs 2.8%, respectively). The authors are to be congratulated on the completion of this large trial addressing the important question of duration of endocrine therapy in a moderately high-risk postmenopausal population. A strength of the study is that 88% of women had received some years of adjuvant AI, mirroring contemporary practice; also, compliance was carefully monitored. A limitation is that the trial was not powered to be a noninferiority trial. Nonetheless it is an important contribution to the body of reported studies investigating extended (more than five years) AI therapy, including Letrozole in Treating Women With Primary Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy (MA17.R), Different Durations of Adjuvant Anastrozole Therapy After 2 to 3 Years Tamoxifen Therapy in Breast Cancer (DATA), and Letrozole in Treating Postmenopausal Women Who Have Received Hormone Therapy for Hormone Receptor-Positive Breast Cancer (NSABP 42) (Table 1) (12–15). Final reports from NSABP B-42 and DATA are not yet published, but thus far only MA17.R has demonstrated a statistically significant benefit in the primary end point of DFS (95%, 95% CI = 93% to 96%, vs 91%, 95% CI = 89% to 93%; HR = 0.66, 95% CI = 0.48 to 0.91; P = .01), which was driven primarily by reduction in second primary breast cancers (13). A reduction in second breast cancers was also observed in IDEAL and NSABP B-42. None of the four trials of extended AI therapy has demonstrated a survival benefit, in contrast to the benefit reported with extended tamoxifen (1,2). Most of the extended AI trials showed an increase in osteoporosis and fracture rates with longer AI use. Table 1. Clinical trials evaluating extended adjuvant AI therapy Trial No. of patients Design Population Primary end point Secondary end points 5-y DFS (95% CI) HR (95% CI) P Definition HR (95% CI) P MA.17 R Goss et al. 2016 (13) 1918 5 y of letrozole vs placebo after 5 to 10 y of prior therapy including 5 y of AI 51% N+ Prior: 21% AI only 79% tam followed by 5 y of AI 95% (93% to 96%) vs 91% (89% to 93%) 0.66 (0.48 to 0.91) .01 Contralateral breast primary 0.42 (0.22 to 0.81) .007 IDEAL Blok et al. 2017 (12) 1824 5 vs 2.5 y of letrozole after 5 y of any therapy 60% N+ Prior: 12% tam 29% AI 59% tam-AI 85.4% vs 82.0% (CIs not given in the Blok paper) 0.92 (0.74 to 1.16) .49 Second breast primary 0.39 (0.19 to 0.81) .01 NSABP-B42 Mamounas et al. 2016 (14) 3966 5 y of letrozole vs placebo after 5 y of prior endocrine therapy 42% N+ Prior: 39% tam-AI 61% AI 7-y DFS 84.7% vs 81.3% (CIs not given in the abstract) 0.85 (0.73 to 0.999) .048* BCFI Distant recurrence 0.71 (0.56 to 0.89) 0.72 (0.53 to 0.97) .003 .03 DATA Tjan- Heijnen et al. 2016 (15) 1912 6 vs 3 y of anastrozole after 2 to 3 y of tam 67% N+ Prior: 100% tam 83% vs 79% (CIs not given in the abstract) 0.78 (0.61 to 1.00) .0528 DFS for the N + 0.71 (0.53 to 0.96) .02 Trial No. of patients Design Population Primary end point Secondary end points 5-y DFS (95% CI) HR (95% CI) P Definition HR (95% CI) P MA.17 R Goss et al. 2016 (13) 1918 5 y of letrozole vs placebo after 5 to 10 y of prior therapy including 5 y of AI 51% N+ Prior: 21% AI only 79% tam followed by 5 y of AI 95% (93% to 96%) vs 91% (89% to 93%) 0.66 (0.48 to 0.91) .01 Contralateral breast primary 0.42 (0.22 to 0.81) .007 IDEAL Blok et al. 2017 (12) 1824 5 vs 2.5 y of letrozole after 5 y of any therapy 60% N+ Prior: 12% tam 29% AI 59% tam-AI 85.4% vs 82.0% (CIs not given in the Blok paper) 0.92 (0.74 to 1.16) .49 Second breast primary 0.39 (0.19 to 0.81) .01 NSABP-B42 Mamounas et al. 2016 (14) 3966 5 y of letrozole vs placebo after 5 y of prior endocrine therapy 42% N+ Prior: 39% tam-AI 61% AI 7-y DFS 84.7% vs 81.3% (CIs not given in the abstract) 0.85 (0.73 to 0.999) .048* BCFI Distant recurrence 0.71 (0.56 to 0.89) 0.72 (0.53 to 0.97) .003 .03 DATA Tjan- Heijnen et al. 2016 (15) 1912 6 vs 3 y of anastrozole after 2 to 3 y of tam 67% N+ Prior: 100% tam 83% vs 79% (CIs not given in the abstract) 0.78 (0.61 to 1.00) .0528 DFS for the N + 0.71 (0.53 to 0.96) .02 * Not statistically significant, cutoff of .0418. BCFI = breast cancer–free interval; CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; N + = node-positive disease; tam = tamoxifen. Given the excellent prognosis that our patients enjoy, extended endocrine trials require thousands of women and substantial time in order to show even a small statistical advantage. As these trials mature, a patient-level meta-analysis could help elucidate the magnitude and type of benefit that women may receive from extended AI therapy. Of course, cross-trial comparisons are fraught with difficulty as the length of extended therapy and type of previous endocrine therapies differ (some participants having never received AI, which is the current standard of care). But at this time, the available data suggest that the majority of the benefit conferred with extended AI is prevention of second primary breast cancers, and improvements in the arguably more important outcomes of improved survival and decreased distant metastasis are not convincingly established. Because there are currently 3.3 million breast cancer survivors in the United States, another critical goal is to minimize overtreatment and improve cancer survivorship. Late side effects of treatment, such as late osteoporotic fractures, are not captured in the time frame of these trials and may lead to an increase in morbidity, mortality, expense, and inability to live independently. It is important to recognize these risks when discussing the risk-benefit ratio for any given woman who is deciding whether to pursue extended AI therapy. To our collective dismay, most adjuvant endocrine therapy trials have failed to define subgroups of HR+ patients that preferentially benefit from a particular type or duration of endocrine therapy; rather, the benefits are assumed to be proportional to the absolute risk of recurrence. In the pursuit of precision therapy, there are ongoing investigations to identify better prognostic or predictive biomarkers that may help further stratify risk over standard clinical factors like stage and grade. Although the Breast Cancer Index is prognostic for late distant recurrence, it remains to be seen if this assay (or others like it) predicts benefit from extended AI therapy (16,17). In the interim, we are reliant on baseline prognostic factors, comorbidities, and patient preference when counseling patients for or against extended adjuvant therapy. In our own practice, we generally recommend against extended AI therapy for women with smaller node-negative cancers and consider a discussion of the risks and benefits for women at higher baseline absolute risk (eg, T3 or node positive) to be appropriate. Because the IDEAL trial was not powered as a noninferiority trial, it is not possible to conclude that 2.5 additional years of AI is as good as five additional years, but the trial does suggest that there is unlikely to be substantial clinical benefit gained from extending total AI treatment from 7.5 to 10 years. Finally, although we may have reached a plateau for risk reduction effects of extended AI therapy, other promising avenues are under investigation. Currently, evidence supports consideration of adjuvant bisphosphonate for postmenopausal women (18). Several trials are evaluating the combination of endocrine therapy with drugs such as CDK4/6 inhibitors (19) or MTOR inhibitors (20) for high-risk disease. Still other trials are investigating novel concepts like lifestyle changes/weight loss (21) or aspirin (22) as well as efforts to increase compliance to endocrine therapy (23) to decrease cancer mortality. We are optimistic that one or more of these approaches will also contribute to our continuing quest to identify the ideal adjuvant therapy. Note The authors have no conflicts of interest to disclose. References 1 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( 9869): 805– 816. Google Scholar CrossRef Search ADS PubMed 2 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(18_suppl): 5- 5. Google Scholar CrossRef Search ADS 3 Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: Analyses adjusting for treatment crossover. J Clin Oncol . 2012; 30( 7): 718– 721. Google Scholar CrossRef Search ADS PubMed 4 Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005; 97( 17): 1262– 1271. Google Scholar CrossRef Search ADS PubMed 5 Mamounas EP, Jeong JH, Wickerham DL, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: Intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol . 2008; 26( 12): 1965– 1971. Google Scholar CrossRef Search ADS PubMed 6 Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med . 2003; 349( 19): 1793– 1802. Google Scholar CrossRef Search ADS PubMed 7 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): 2255– 2269. Google Scholar CrossRef Search ADS PubMed 8 Early Breast Cancer Trialists' Collaborative G, Dowsett M, Forbes JF, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet . 2015; 386( 10001): 1341– 1352. Google Scholar CrossRef Search ADS PubMed 9 Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005; 366( 9484): 455– 462. Google Scholar CrossRef Search ADS PubMed 10 Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005; 365( 9453): 60– 62. Google Scholar CrossRef Search ADS PubMed 11 Regan MM, Neven P, Giobbie-Hurder A, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: The BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol . 2011; 12( 12): 1101– 1108. Google Scholar CrossRef Search ADS PubMed 12 Blok E, Kroep J, Meershoek‐Klein Kranenbarg E, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL‐trial (BOOG 2006‐05). J Natl Cancer Inst . 2018: 110( 1): 40– 48. 13 Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med . 2016; 375( 3): 209– 219. Google Scholar CrossRef Search ADS PubMed 14 Mamounas EP P, Bandos H, Lembersky BC C, et al. A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): Results from NRG Oncology/NSABP B-42. In: San Antonio Breast Cancer Symposium. San Antonio, TX; 2016. Abstract S1-05. 15 Tjan-Heijnen VC, Van Hellemond IE, Peer PG G, et al. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. In: San Antonio Breast Cancer Symposium. San Antonio, TX; 2016. Abstract S1-03. 16 Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: A prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol . 2013; 14( 11): 1067– 1076. Google Scholar CrossRef Search ADS PubMed 17 Zhang Y, Schnabel CA, Schroeder BE, et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin Cancer Res . 2013; 19( 15): 4196– 4205. Google Scholar CrossRef Search ADS PubMed 18 Early Breast Cancer Trialists' Collaborative G, Coleman R, Powles T, et al. Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials. Lancet . 2015; 386( 10001): 1353– 1361. Google Scholar CrossRef Search ADS PubMed 19 Bertagnolli M, Mayer E, DeMichele A, Gnant M. PALbociclib CoLlaborative Adjuvant Study: A randomized phase III trial of palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (PALLAS). 2015. https://clinicaltrials.gov/ct2/show/NCT02513394?term=PALLAS&rank=1. Accessed May 31, 2017. 20 Chavez-MacGregor M. S1207 hormone therapy with or without everolimus in treating patients with breast cancer (e3) NCT01674140. 2012. https://clinicaltrials.gov/ct2/show/NCT01674140?term=SWOG+everolimus&rank=2. Accessed May 31, 2017. 21 Ligibel J. Breast Cancer WEight Loss Study (BWEL Study) NCT02750826. 2016. https://clinicaltrials.gov/ct2/show/NCT02750826. Accessed May 31, 2017. 22 Chen W. Aspirin in preventing recurrence of cancer in patients with node positive HER2 negative stage II-III breast cancer after chemotherapy, surgery, and/or radiation therapy. NCT02927249. 2016. https://clinicaltrials.gov/ct2/show/NCT02927249. Accessed May 31, 2017. 23 Accordino MK, Hershman DL. Disparities and challenges in adherence to oral antineoplastic agents. Am Soc Clin Oncol Educ Book . 2013: 271– 276. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: email@example.com.
JNCI: Journal of the National Cancer Institute – Oxford University Press
Published: Jan 1, 2018
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