Adjuvant Endocrine Therapy Breast Cancer

Baseline Predictors Of Treatment Restarting

Information on age at diagnosis, tumor size, lymph node status, progesterone receptor status, human epidermal growth factor receptor 2 status, and type of surgery was retrieved from the Stockholm-Gotland Breast Cancer Register. Information on comorbidities used to calculate the Charlson Comorbidity Score was retrieved from Swedish Patient Register and Swedish Cancer Register . Information on parity, heredity, cigarette smoking, and body mass index was retrieved from the self-reported questionnaire. Family history of breast cancer was defined as a self-reported positive BRCA mutation or a diagnosis of breast cancer in a first-degree relative . The use of hormone therapy was defined as filling at least one prescription of estrogen/progesterone for systematic use during one year before breast cancer diagnosis, excluding local use such as the patch and vaginal cream .

Best Use Of Adjuvant Endocrine Therapy Inhr

M. Alexander Otto, PA, MMS

The study covered in this summary was and has not yet been peer reviewed.

Key Takeaway

• For breast cancers with low expression of hormone receptors , the survival benefit associated with adjuvant endocrine therapy is limited to patients who do not have adjuvant radiation.

Why This Matters

• As a result of limited data, debate about the role of adjuvant endocrine therapy in breast cancers with low expression of hormone receptors continues.

• These findings, which suggest that adjuvant endocrine therapy may be best when limited to low-expression patients who do not plan to have adjuvant radiotherapy, may help clarify the issue.

Study Design

• Investigators compared disease free survival and overall survival between 320 women who had endocrine therapy following surgery with 128 who did not.

• Overall, 133 received tamoxifen, 155 received an aromatase inhibitor, and 32 had tamoxifen followed by an aromatase inhibitor.

Key Results

• Tumors recurred in 84 women , and 51 died during a median follow-up of 7.9 years.

• Overall, DFS and OS for women who received and did not receive adjuvant endocrine therapy were not significantly different in a propensity score-weighted log-rank test and a Cox proportional regression analysis.

• But women who received adjuvant endocrine therapy but not adjuvant radiation therapy did have a survival benefit .

Limitations

Hormone Therapy After Surgery For Breast Cancer

After surgery, hormone therapy can be given to reduce the risk of the cancer coming back. Taking an AI, either alone or after tamoxifen, has been shown to work better than taking just tamoxifen for 5 years.

These hormone therapy schedules are known to be helpful for women who are post-menopausal when diagnosed:

• Tamoxifen for 2 to 3 years, followed by an AI for 2 to 3 years
• Tamoxifen for 2 to 3 years, followed by an AI for 5 years
• Tamoxifen for 4½ to 6 years, followed by an AI for 5 years
• Tamoxifen for 5 to 10 years
• An AI for 5 to 10 years
• An AI for 2 to 3 years, followed by tamoxifen for 2 to 3 years
• For women who are unable to take an AI, tamoxifen for 5 to 10 years is an option

For most post-menopausal women whose cancers are hormone receptor-positive, most doctors recommend taking an AI at some point during adjuvant therapy. Standard treatment is to take these drugs for about 5 years, or to take in sequence with tamoxifen for 5 to 10 years. For women at a higher risk of recurrence, hormone treatment for longer than 5 years may be recommended. Tamoxifen is an option for some women who cannot take an AI. Taking tamoxifen for 10 years is considered more effective than taking it for 5 years, but you and your doctor will decide the best schedule of treatment for you.

These therapy schedules are known to be helpful forwomen who are pre-menopausal when diagnosed:

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Clinical Effective Of Ais Compared With Tam

The third-generation AIs are currently considered standard of care for adjuvant treatment of postmenopausal women with HR positive breast cancer, and several strategies has been investigated, including upfront AIs for five years, switch to TAM after 23 years up front AIs, or switch to AIs after 23 years of TAM .

For the upfront strategy, the ATAC trial enrolled HR positive patients randomized to Anastrozole and TAM , the results were significantly in favor of Anastrozole for DFS , time to recurrence , and time to distant recurrence after a median of 120 months follow-up . Similar, in the BIG 198 trial, 2,459 patients were randomly assigned to five years monotherapy with TAM and 2,463 to monotherapy with Letrozole. With a median follow-up of 8·7 years, Letrozole was significantly better, whether by IPCW or intention-to-treat analysis Although, there was no significant improvement in overall survival observed in these trials, which might be due to crossover in considerable numbers of patients, AIs appeared to be better tolerated with less treatment-related serious adverse events. Of note, concurrent administration of Anastrozole and TAM in the ATAC trial showed detrimental effects in DFS compared to Anastrozole single agent .

Possible Side Effects Of Ais

The most common side effects of AIs are:

• Bone and joint pain

AIs tend to have side effects different from tamoxifen. They don’t cause uterine cancers and very rarely cause blood clots. They can, however, cause muscle pain and joint stiffness and/or pain. The joint pain may be similar to a feeling of having arthritis in many different joints at one time. Options for treating this side effect include, stopping the AI and then switching to a different AI, taking a medicine called duloxetine , or routine exercise with nonsteroidal anti-inflammatory drugs . But the muscle and joint pain has led some women to stop treatment. If this happens, most doctors recommend using tamoxifen to complete 5 to 10 years of hormone treatment.

Because AIs drastically lower the estrogen level in women after menopause, they can also cause bone thinning, sometimes leading to osteoporosis and even fractures. If you are taking an AI, your bone density may be tested regularly and you may also be given bisphosphonates or denosumab , to strengthen your bones.

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Ovarian Function Suppression For Premenopausal Patients

To optimize the endocrine treatment for premenopausal patients, ovarian function suppression was tested in the SOFT and TEXT trials . Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS in SOFT and to receive tamoxifen plus OFS or exemestane plus OFS in TEXT after chemotherapy. In SOFT, the 8-year DFS rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus OFS, and 85.9% with exemestane plus OFS . The 8-year rate of OS was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus OFS, and 92.1% with exemestane plus OFS .

OFS can be initiated concurrently with or after chemotherapy . Starting before chemotherapy supports fertility preservation .

Even if there are no data the AGO-Mamma recommends an extended treatment with another 5 years of tamoxifen after 5 years of tamoxifen plus OFS for premenopausal women at risk .

Adjuvant Aromatase Inhibitor Trials

The development of inhibitors of aromatase, the enzyme that synthesizes estrogens from androgens, has provided an alternative strategy to deprive breast tumors of stimulation by endogenous estrogens in post-menopausal women whose ovaries are no longer active and in pre-menopausal women in whom ovarian function has been suppressed or the ovaries have been removed . It is important to note that AIs are ineffective in pre-menopausal women with functioning ovaries .

Aminoglutethimide was the first AI to be developed for clinical use and showed benefit initially in advanced disease and then as adjuvant therapy , but it also suppressed aldosterone and had toxicities, including rash and somnolence. A randomized clinical trial involving 2,021 post-menopausal women receiving tamoxifen alone for 5 years or in combination with AG for the first 2 years of treatment showed no significant difference in 5-year DFS and OS . Moreover, more patients failed to complete combination treatment because of side effects compared with tamoxifen alone .

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Endocrine Therapy As Adjuvant Or Neoadjuvant Therapy For Breast Cancer: Selecting The Best Agents The Timing And Duration Of Treatment

Department of Breast Surgery, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

Contributions: Conception and design: ZM Shao Administrative support: All authors Provision of study materials or patients: JJ Li Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors.

Correspondence to:

Keywords: Breast cancer endocrine therapy adjuvant neoadjuvant

Submitted Mar 22, 2016. Accepted for publication Mar 28, 2016.

doi: 10.21037/cco.2016.03.24

Adjuvant Endocrine Therapy For Breast Cancer

Melody A. Cobleigh, MDOncology

In this article, we review the current guidelines for adjuvant endocrine therapy in both premenopausal and postmenopausal women, and we discuss the clinical trials that were used to develop these guidelines.

Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptorpositive breast cancer, and has been shown to reduce the risk of recurrence and death from breast cancer. For decades, 5 years of tamoxifen has been the standard treatment. For premenopausal women, it remains so, and we await the results of ongoing trials to define the role of ovarian suppression or ablation with endocrine therapy. If a woman becomes postmenopausal during treatment, consideration should be given to extended adjuvant therapy with an aromatase inhibitor for another 5 years. In postmenopausal women, trials have shown that AIs are more beneficial than tamoxifen in preventing disease recurrence. They have been compared as upfront treatment for 5 years, as sequential therapy after 2 to 3 years of tamoxifen, and as extended treatment for 5 years after 5 years of tamoxifen. Among the questions still being studied are the optimal duration of extended adjuvant therapy with AIs, how one AI performs compared to another, and whether there is a benefit to intermittent extended adjuvant treatment.

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What Is Hormone Therapy

Hormone therapy slows or stops the growth of hormone-sensitive tumors by blocking the bodys ability to produce hormones or by interfering with effects of hormones on breast cancer cells. Tumors that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy.

Hormone therapy for breast cancer should not be confused with menopausal hormone therapy treatment with estrogen alone or in combination with progesterone to help relieve symptoms of menopause. These two types of therapy produce opposite effects: hormone therapy for breast cancer blocks the growth of HR-positive breast cancer, whereas MHT can stimulate the growth of HR-positive breast cancer. For this reason, when a woman taking MHT is diagnosed with HR-positive breast cancer she is usually asked to stop that therapy.

Breast International Group 1

The BIG 1-98 study involved the other third-generation non-steroidal AI, letrozole, and compared 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one of these agents followed by 3 years of the other. The primary core analysis included all 8,010 patients but did not include any events after the first 2 years for patients in the two sequential arms . These results showed that letrozole improved DFS and TTDR versus tamoxifen alone. After a median follow-up of 25.8 months, 5-year DFS estimates were 84.0% and 81.4%, respectively. Compared with tamoxifen, letrozole significantly reduced the risk of a DFS event and the risk of distant recurrence .

The OS analysis of this trial was problematic as patients on the tamoxifen-alone arm were given the option to cross over to letrozole once initial results became available. Different analytical tools were developed to overcome this, including inverse probability of censoring weighted analysis, which achieves better estimates of relative treatment effects in the presence of selective crossover . At a median follow-up of 8.7 years from random assignment, letrozole monotherapy was confirmed to be significantly better than tamoxifen, not just for DFS but for OS by both intention to treat and IPCW analysis .

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Trial Sequential Analysis Results

In trial sequential analysis of DFS, OS, RFS, DMFS and NBCCI, we estimated a required sample size of 1990 , and the cumulative Z-curve significantly crossed the conventional monitoring boundary and RIS boundary, further suggesting that no additional studies were needed for a stable conclusion . For adverse events, trial sequential analysis estimated a required information size of 28854, 10890 and 13025 respectively for hot flashes, osteoporosis and arthralgia, which greatly exceeded the accumulated sample size in our study. Furthermore, although accumulative Z-curve crossed conventional monitoring boundary, it did not cross the trial sequential monitoring boundary. Therefore, we cannot draw a definitive conclusion about hot flashes, osteoporosis and arthralgia due to the presence of false positive. However, a relatively definite conclusion of bone fracture can be obtained from this meta-analysis, as the the cumulative Z-curve crossed both the conventional monitoring boundary and RIS boundary .

Guidelines For Premenopausal Women

The 2010 American Society of Clinical Oncology guidelines recommend tamoxifen for premenopausal women, since AIs are contraindicated in women with residual ovarian function. These guidelines state that, currently, the benefit of ovarian suppression in this population is not known, and that the results of the Suppression of Ovarian Function trial are awaited to further define its role. The National Comprehensive Cancer Network guidelines recommend tamoxifen for 5 years with or without ovarian suppression or ablation if a woman is premenopausal at diagnosis. At the end of the 5 years, if the patient is postmenopausal, another 5 years of treatment with an AI should be considered. The St. Gallen Expert Panel recommended tamoxifen alone, but stated that ovarian suppression plus tamoxifen was an acceptable alternative for premenopausal women. For patients with a contraindication to tamoxifen, the St. Gallen Panel recommended ovarian function suppression plus an AI. The most recently published meta-analysis from the EBCTCG confirmed the benefits of tamoxifen in women younger than 45 years for reducing the risk of recurrence and breast cancer mortality .

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Adverse Events Of Extended Endocrine Treatment Versus The Control

Four studies reported hot flashes, with no statistical heterogeneity between the included studies . A fixed-effect model was used for statistical analysis. Our meta-analysis revealed that extended adjuvant endocrine therapy group was without a significant risk of hot flashes compared with routine group .

Figure 5 Forest plot of meta-analysis of extended adjuvant endocrine therapy for adverse events. Hot flashes, bone fracture, osteoporosis, arthralgia.

Seven studies reported bone fracture, revealing that extended treatment group was associated with a significantly higher risk of bone fracture compared with control group . There was no statistical heterogeneity between the included studies .

Four studies reported osteoporosis, revealing that extended adjuvant endocrine treatment was associated with a significantly higher risk of osteoporosis compared with the control . There was significant heterogeneity between the included studies .

Four studies reported arthralgia, revealing that no risk difference between extended and routinely endocrine treatment . There was significant heterogeneity between the included studies .

Extended Adjuvant Endocrine Therapy For Women With Hormone Receptor

• 1Department of Science and Education, The Third Hospital of Changsha, Changsha, China
• 2Department of Preventive Medicine, School of Medicine, Hunan Normal University, Changsha, China
• 3Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
• 4Department of Geriatrics, The Third Hospital of Changsha, Changsha, China

Objectives: The aim of the current study is to explore the association between extended adjuvant endocrine treatment and prognosis of women with hormone receptor-positive early breast cancer.

Methods: Databases including PubMed, Web of Science, Embase and the Cochrane Library databases were electronically searched to identify randomized controlled trials that reported extended endocrine therapy for women with HR+ early breast cancer. The retrieval time was limited from inception to September 2022. Two reviewers independently screened literature, extracted data, and assessed risk bias of included studies. Meta-analysis was performed by using R software Version 4.1.2 and STATA Version 12.0.

Our study showed that extended adjuvant endocrine therapy increased DFS, OS, RFS, DMFS, the incidence of bone fracture and osteoporosis, and reduced NBCCI.

Systematic Review Registration:, identifier

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Side Effects Of Tamoxifen And Toremifene

The most common side effects of tamoxifen and toremifene are:

• Vaginal dryness or discharge
• Changes in the menstrual cycle

When tamoxifen treatment starts, a small number of women with cancer that has spread to the bones might have a tumor flare which can cause bone pain. This usually decreases quickly, but in some rare cases a woman may also develop a high calcium level in the blood that is hard to control. If this happens, the treatment may need to be stopped for a time.

Rare, but more serious side effects are also possible:

Hormone Therapy For Breast Cancer

Some types of breast cancer are affected by hormones, like estrogen and progesterone. The breast cancer cells have receptors that attach to estrogen and progesterone, which helps them grow. Treatments that stop these hormones from attaching to these receptors are called hormone or endocrine therapy.

Hormone therapy can reach cancer cells almost anywhere in the body and not just in the breast. It’s recommended for women with tumors that are hormone receptor-positive. It does not help women whose tumors don’t have hormone receptors .

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Choice Of Adjuvant Endocrine Therapy Duration

• TAM or AIs for five years
• TAM for ten years, premenopausal or postmenopausal /
• TAM for five years, if postmenopausal, followed by letrozole for five years.

Patients with HR positive breast cancer initially have lower rates of recurrence compared with HR negative disease, however, they have a constant and unrelenting risk of relapse that extends up to 15 years despite the use of five years adjuvant TAM . Clinical investigation has focused on the optimal duration of adjuvant endocrine therapy , potential strategies differ depending on a womans menopausal status.

Table 1