Adjuvant Tamoxifen : Longer Against Shorter Research Articles

P-317 Risk of endometrial polyps and hyperplasia after tamoxifen treatment in women with breast cancer: a population-based study in Taiwan

Abstract Study question This study aimed to examine the association between tamoxifen treatment and incident risks of uterine disease among breast cancer patients in Taiwan. Summary answer We found tamoxifen treatment group may have greater risk of endometrial polyps and hyperplasia than unexposured group after adjusting for age and body mass index. What is known already In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) breast cancer treatment trail reported that the women continue tamoxifen up to 10 years, compared with 5 years may reduce breast cancer recurrence and mortality rate. However, tamoxifen use has been reported to be associated with the cumulative risk of subsequently endometrial cancer during 5–14 years was 3.1%. Specifically, several Western studies have showed that the high incidence of endometrial cancer in breast cancer survivors with tamoxifen treatment. Study design, size, duration We conducted a retrospective cohort study using population-based data from Taiwan Cancer Registry and the National Health Insurance Research Database (NHIRD), and the National Population Registry Data set from 2011 to 2020. Participants/materials, setting, methods A total 138,934 newly diagnosed breast cancer female patients with age greater than 18 years old were included. We further used a 1-to-1 propensity score matching to generate comparable exposure and un-exposure groups. Cox proportional hazard regression models were used to examine the research question. All statistical analysis was performed using SAS version 9.4, and p-values < 0.05 were considered statistically significant Main results and the role of chance Incidence rate ratio (IRR) to compare incidence rate of uterine disease between tamoxifen treatment groups and unexposed group, adjusting for age and BMI. Our results showed that IRR were 1.36, 0.33, 3.73, 0.63, endometrial polyps, endometrial carcinoma, endometrial hyperplasia and uterine carcinosarcoma, respectively. This study found possible correlations between tamoxifen exposure with endometrial polyps and hyperplasia among breast cancer. During the 10-year study period, tamoxifen group did not significantly increase the risk of endometrial cancer in breast cancer survivors at aged 40 and over. Limitations, reasons for caution Our cohort study with 10-year period is its short study period, Tamoxifen group did not significantly increase the risk of endometrial cancer. Wider implications of the findings This cohort study found higher endometrial polyps and hyperplasia incidence rates among women with breast cancer who received tamoxifen women than those not treated with tamoxifen. Results of this study suggest that clinicians should consider the risk of uterine disease among tamoxifen use and counsel patients accordingly. Trial registration number KMUHIRB-G(II)20200217

Adjuvant Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer in Premenopausal Patient: Understanding the Data

Breast cancer diagnosed at a young age is associated with a poor prognosis. It is possible that inadequate endocrine therapy for the youngest women contributes to their poorer prognosis. Data on optimal endocrine therapy selection as well as duration for premenopausal women are crucial. Recently published clinical trials including Australian Breast and Colorectal Cancer Study Group-12 (ABCSG-12), E-3193, and Suppression of Ovarian Function Trial (SOFT)/Tamoxifen and Exemestane Trial (TEXT) have shed light on the role of ovarian function suppression and aromatase inhibitors in premenopausal women. Additionally, optimal duration of endocrine therapy has been addressed in the recent Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and Adjuvant Tamoxifen—To Offer More? (aTTom) trials.

Should We Embrace or Ablate Our Urge to (Ovarian) Suppress?

The quest to define optimal endocrine therapy for premenopausal women with early-stage breast cancer began more than 50 years ago but is still unfulfilled. Multiple strategies have emerged, including tamoxifen, ovarian function suppression (OFS) by surgery, luteinizing hormone–releasing hormone agonist or radiation, and combination strategies such as tamoxifen plus OFS or aromatase inhibitor plus OFS. An added confounder is that these strategies have frequently been assessed in the context of adjuvant chemotherapy, which is commonly used in premenopausal women and may have indirect endocrine effects because of chemotherapy-induced menopause. This complex landscape was reviewed in a 2011 American Society of Clinical Oncology (ASCO) endorsement of the 2010 Cancer Care Ontario guideline recommending against the routine use of OFS in addition to tamoxifen or chemotherapy and a 2014 ASCO guideline endorsing consideration of 10 years of tamoxifen for these young women with hormone-responsive disease. Against this backdrop, in the article that accompanies this editorial, Tevaarwerk et al report the final results of a phase III Eastern Cooperative Oncology Group trial (E-3193, INT-0142) in which 345 premenopausal women with lymph node–negative, hormone receptor–positive breast cancer measuring 3 cm were randomly assigned from 1994-1997 to receive 5 years of tamoxifen alone or 5 years of tamoxifen plus OFS; no chemotherapy was permitted. With a median follow-up of almost 10 years, there were no significant differences in the primary end points of disease-free survival (DFS; 87.9% v 89.7% P .62) or overall survival (95.2% v 97.6%; P .67). Secondary end points included toxicity and several patient-reported outcomes (PROs) including menopausal symptoms, sexual function, and health-related quality of life. These results suggest that tamoxifen plus OFS leads to increased toxicity, more menopausal symptoms, and reduced sexual function, peaking around year 3 and then diminishing over time. The strengths of this study include the importance of the question, the clean design that enabled the testing of hormone therapies in the absence of chemotherapy, the focus on hormone-responsive tumors, the balance between the arms, the long follow-up, and the assessment of PROs. The major limitation is, of course, that the study’s early closure as a result of poor accrual left it vastly underpowered for its primary end points; this trial fell victim to the 1997 report of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, which recommended the use of chemotherapy in addition to tamoxifen for women with axillary lymph node–negative, hormoneresponsive breast cancer, especially women younger than 50 years of age. However, E-3193 was a success in its collection of detailed PROs, and it is noteworthy that it met the prespecified target accrual for these secondary end points. Given the exceptional outcomes for patients enrolled onto this trial, which had greater than 95% overall survival in the absence of chemotherapy, such patient-reported data are valuable contributions to the discussion between physicians and patients about the risks and benefits of individual therapies. Several crucial questions remain. Given the statistical limitations of this trial, might the combination of OFS plus tamoxifen actually be better than tamoxifen? What about the combination of OFS plus an aromatase inhibitor, given the efficacy of aromatase inhibitors in postmenopausal hormone receptor–positive breast cancer? Three large trials are helping to address these two questions: ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12), SOFT (Suppression of Ovarian Function Trial), and TEXT (Tamoxifen and Exemestane Trial). A lingering concern is how we can integrate the results of all of these trials that use 3 to 5 years of adjuvant endocrine therapy with the findings of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (Adjuvant Tamoxifen—To Offer More?) trials, which support the use of 10 years of tamoxifen. In the SOFT trial, 3,066 premenopausal women with hormoneresponsive breast cancer were randomly assigned to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS; (neo)adjuvant chemotherapy was permitted as long as patients remained premenopausal at its completion. In the TEXT trial, 2,672 premenopausal patients with hormone-responsive breast cancer were randomly assigned to receive 5 years of tamoxifen plus OFS or exemestane plus OFS; endocrine therapy was started concurrently with chemotherapy if chemotherapy was planned. Because of lower than expected event rates, the statistical plans for these two trials were revised some years ago to enable a joint analysis of 4,690 women receiving tamoxifen plus OFS versus exemestane plus OFS. In contrast to E-3193, 42% of these women were lymph node positive, and 57% received some type of chemotherapy. At a median follow-up of 68 months, a significantly improved DFS was seen with exemestane plus OFS (91.1% v 87.3%; HR, 0.72; 95% CI, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1

Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy.

The impressive first results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and the adjuvant Tamoxifen To offer more (aTTom) trials both demonstrate that 10 years of tamoxifen is superior to five years of treatment. Tamoxifen is a nonsteroidal antiestrogen that blocks estrogen-stimulated tumor growth. Paradoxically, mortality decreases dramatically only in the decade after long-term tamoxifen is stopped. It is proposed that the evolution and clonal selection of micrometastases that acquire tamoxifen resistance now become increasingly vulnerable to endogenous estrogen-induced apoptosis. Laboratory and clinical studies confirm the concept, and supporting clinical evidence from the estrogen-alone trial in the Women's Health Initiative (WHI), demonstrate that long-term estrogen-deprived women given exogenous physiologic estrogen have a decreased incidence of breast cancer and decreased mortality. It is proposed that a natural process of apoptosis is recruited to execute the long-term survival benefit of stopping ten years of adjuvant tamoxifen, but only after clonal selection of vulnerable breast cancer cells in an estrogen-deprived environment.

Our Takeaways from the San Antonio Breast Cancer Symposium

Our Takeaways from the San Antonio Breast Cancer Symposium

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

SummaryBackgroundFor women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years.MethodsIn the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633.FindingsAmong women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%).InterpretationFor women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.FundingCancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Extended adjuvant tamoxifen for breast cancer—a new era?

Tamoxifen has been shown to reduce the risk of relapse and mortality in randomised trials of women with operable oestrogen receptor (ER)-positive breast cancer, with treatment for 5 years showing greater effectiveness than treatment for 2 years.1 However, results of trials assessing tamoxifen treatment for more than 5 years have been inconclusive.2–5 To address this uncertainty, Christina Davies and colleagues started the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, which included substantially more participants than any previous trials, and preliminary results are reported in The Lancet.

A Question of Duration: Do Patients with Early-Stage Breast Cancer Need More Than Five Years of Adjuvant Endocrine Therapy?

Women with hormone receptor—positive breast cancer continue to be at risk for recurrence and mortality for many years after diagnosis. Previous clinical trials established 5 years of endocrine therapy as a standard of care for both premenopausal and postmenopausal women, resulting in long-lasting benefit over shorter durations of treatment. Until recently, trials testing durations of tamoxifen longer than 5 years have not shown additional benefit, but the ATLAS (Adjuvant Tamoxifen, Longer Against Shorter) trial, reported in 2007, showed a small but significant reduction in risk of recurrence with 10 compared with 5 years of tamoxifen therapy. Aromatase inhibitors (AIs) improve relapse-free survival (RFS) in postmenopausal women when they are used sequentially with, or replace, tamoxifen for a total of 5 years of therapy. Extension of endocrine therapy to 10 years in the National Cancer Institute of Canada Clinical Trials Group MA.17 trial demonstrated that 5 years of letrozole therapy following 5 years of tamoxifen therapy results in an improvement in RFS, but not overall survival, in postmenopausal women. Trials testing durations of AI therapy for longer than 5 years are ongoing. Selection of candidates for extended endocrine therapy should balance recurrence risk, toxicity of treatment, and comorbidities that might impact life expectancy and risk of side effects.

The evolution of treatment for early breast cancer: what's next?

The evolution of treatment for early breast cancer: what's next?

Adjuvant Tamoxifen – Longer Against Shorter (ATLAS)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Adjuvant tamoxifen – longer against shorter (ATLAS). Clinical trials include: Phase III ATLAS adjuvant tamoxifen – longer against shorter: an international trial of adjuvant hormonal treatment duration (www.ctsu.ox.ac.uk/~atlas/index.html).

Author reply

The low percentage of patients receiving adjuvant therapies in our study1 reflects the guidelines in place at the time the women were enrolled (1989-1996). The indications of the National Cancer Institute Consensus Conference of 19852 suggested that chemotherapy was possible (not mandatory) for postmenopausal, N+, estrogen receptor-negative patients, but was not recommended for patients with lymph node-positive, estrogen receptor-positive disease. The Italian guidelines confirmed these indications and did not recommend radiotherapy after mastectomy.3 Dr. Alliot suggests that this low percentage could represent a confounder for the association between longer tamoxifen administration and better outcomes. However, the 1998 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) metaanalysis demonstrated (from the indirect comparison of longer vs. shorter tamoxifen administration) that longer tamoxifen use was of benefit in delaying the development of disease recurrence (the same appeared to be true for mortality) regardless of whether chemotherapy was to be used.4 These results were confirmed by the 2005 EBCTCG overview; the proportional risk reductions produced by tamoxifen appeared to be approximately the same as chemoendocrine therapy versus the same chemotherapy alone.5 With regard to radiotherapy, the last EBCTCG overview demonstrated that better local treatment adds to the effects of systemic therapy (chemotherapy and/or tamoxifen) on the development of local recurrence as well as mortality.6 These data suggest that tamoxifen reduces the risk of events irrespective of adjuvant therapies; it is unlikely that other adjuvant treatments could confound the benefits of longer tamoxifen administration. The ongoing Adjuvant Tamoxifen-Longer Against Shorter (ATLAS) and Adjuvant Tamoxifen Treatment-Offer More (ATTOM) trials will help to clarify the role of longer tamoxifen use in women already receiving adjuvant therapies. Existing evidence has demonstrated that the gains noted in both disease-free and overall survival as a result of the longer administration of tamoxifen outweigh the side effects and costs of the drug, which are relatively low. Any consideration of other hormonal therapies will be clarified by ad hoc studies and future EBCTCG metaanalyses.

Duration of adjuvant tamoxifen therapy.

The benefit of using adjuvant tamoxifen to treat breast cancer has been firmly established for patients with estrogen receptor (ER)-positive tumors, regardless of age, lymph node status, or menopausal status. Uncertainty remains, however, regarding the optimal duration of tamoxifen therapy. We reviewed the findings of randomized clinical trials that directly compared alternative treatment durations. Trials comparing short-term adjuvant treatment with tamoxifen (i.e., 1-3 years) with treatments having durations of about 5 years consistently have demonstrated additional benefits stemming from the longer therapy. Trials testing 5 years of treatment with longer durations have, in the aggregate, suggested no additional benefit for the patient. Nevertheless, the number of recurrences reported to date in these trials is not large, and the results of the individual trials are heterogeneous. Furthermore, as a result of tamoxifen's "carryover" effect, duration trials require considerable follow-up before definitive results can be established. Until more definitive data become available, adjuvant treatment with tamoxifen should be limited to 5 years outside the clinical trials setting. Continued accrual of ER-positive patients to ongoing tamoxifen duration trials, including the Adjuvant Tamoxifen Treatment Offer More (aTTom) and Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trials, is appropriate. Alternatively, patients who remain disease free after 5 years of tamoxifen therapy should be encouraged to participate in trials testing crossover to other hormonal interventions, including selective ER modulators or aromatase inhibitors.