Adjuvant Endocrine Therapy for Hormone Receptor-Positive Breast Cancer
What is hormone receptor-positive breast cancer?
Breast cancer subtypes can be characterised by the expression of oestrogen, progesterone and human epidermal growth factor (HER2) receptors on the surface of tumour cells. The identification of these subtypes plays a crucial role in selection of the optimal treatment plan for a patient with breast cancer. The most common subtype of breast cancer is hormone-receptor-positive (HR+), HER2-negative breast cancer accounting for approximately 70% of female breast cancer cases world-wide. HR+/ HER2- breast cancer also carries the best prognosis with a 5-year relative survival rate of approximately 95.1%. Treatments that target hormone receptors in both the early and advanced settings can provide excellent clinical outcomes for patients and are associated with less toxicity than chemotherapy.1, 2
Surgery is the primary treatment for early breast cancer (i.e. to remove completely disease confined to the breast and/or local lymph nodes). Hormone-blocking treatment (sometimes termed ‘endocrine therapy’), chemotherapy or a combination of both, are recommended after surgery to reduce the risk of recurrence. Radiation may also be provided to the chest wall and draining lymph node regions. This is termed ‘adjuvant therapy’. Choice of treatment/s offered are increasingly tailored based on tumour- and patient-specific factors including tumour size, receptor status, grade, nodal status, patient co-morbidities and genomic signature. In this article we will focus on adjuvant anti-hormonal treatment of HR+/HER2- breast cancer, including selection criteria, duration of treatment and common adverse effects of treatment.2,3
In mammary gland development oestrogen receptors (ER) have a critical role in controlling cell division in coordination with other hormones such as progesterone. In tumour cells that express an increased level of ER’s, oestrogen-mediated cell division becomes upregulated leading to tumorigenesis, growth and proliferation of malignant cells. As a result these tumours are sensitive to therapies that block ER activity, such as endocrine therapy.3 The degree of immunohistochemical (IHC) expression of oestrogen and progesterone receptors by tumour cells help predict who will respond best to hormone-blocking endocrine therapy. (hereafter referred to as ET). A breast cancer is classified as ER positive when ≥1% of tumour nuclei stain positive for ER. Tumours with very low (1-10%) ER staining on IHC behave and may be treated like triple negative breast cancers but have been shown to benefit from the addition of adjuvant ET.4, 5
Current standard of care adjuvant ET is with either an aromatase inhibitor (AI) such as anastrozole, letrozole or exemestane or a selective oestrogen receptor modulator (SERM), such as Tamoxifen. SERMs exert their effect by directly blocking oestrogen receptors and can be used safely and independently in both pre- and post-menopausal women. AI’s act upstream in the oestrogen pathway preventing the conversion of androgens to oestrogen, this form of oestrogen blockade is optimal in post-menopausal women. In premenopausal women a compensatory response is produced when an AI is used via increased ovarian oestrogen production. Therefore, when using an AI in pre-menopausal women it is imperative to administer adequate ovarian function suppression (OFS), such as an gonadotropin-releasing hormone agonist (GnRH), to eliminate this compensation and adequately suppress oestrogen levels.3
Choice of adjuvant endocrine therapy
To determine the appropriate endocrine treatment for patients’ several prognostic factors are considered including receptor status, proliferation index, tumour grade, anatomical stage (size/ nodal burden) and genomic assay with the latter three being the most significant indictors of recurrence risk. For example, a small, node-negative, low-grade tumour with high ER/PR expression tends to have a better overall prognosis and lower recurrence rate than a larger, high grade, node-positive tumour with lower ER/PR expression.2, 6 Both increasing tumour diameter and larger nodal burden amount to higher rates of recurrence, i.e. a T1N0 tumour would have an expected 5 to 20-year recurrence rate of 13% in contrast to larger and node-positive tumours which have a recurrence risk of higher than 40%.6 Uniquely, the risk of recurrence continues for many years after diagnosis in ER-positive breast cancer.6
A pivotal meta-analysis from the Early Breast Cancer Trials Collaborative Group (EBCTG) demonstrated that more than 50% of HR+ breast cancer recurrences occur after completion of 5 years of endocrine therapy. In this analysis the introduction of adjuvant tamoxifen for five years demonstrated a reduction in both distant and loco-regional recurrence by up to 50%, with its effect lasting long after drug discontinuation, as well as a significant reduction in mortality of 25% compared with placebo. This led to the introduction of tamoxifen as the first standard of care adjuvant ET for HR+ breast cancer regardless of menopausal status for a duration of 5 years.7 Tumours with stronger ER expression benefit more from ET than those with low expression.6
Tamoxifen remained standard of care for all patients until the introduction of third generation AIs, which have been found to further improve disease-free survival (DFS) in post-menopausal women when used either alone or sequentially after 2-3 years of tamoxifen. They also avoid the tamoxifen-related adverse events of venous thromboembolism or endometrial carcinoma.8
In premenopausal women with high-risk HR+ early breast cancer OFS in combination with tamoxifen or an AI reduces recurrence risk compared to tamoxifen alone.9-11 Long term follow-up identified a sustained reduction in recurrence risk with exemestane/ OFS versus tamoxifen/OFS, but this has not translated to an overall survival (OS) benefit at 12 years (HR 0.93, p=0.43). However, an OS benefit was observed in a small cohort of trial patients deemed ‘high-risk’ (age younger than 35, high tumour grade 3 or tumour larger than 2cm in size, leading Pagani et al to conclude that it is important to select out the appropriate cohort of premenopausal women who benefit from OFS given the effect on quality-of-life observed with treatment intensification.12
Determining menopausal status is paramount to selecting appropriate endocrine therapy. If uncertainty arises potential consideration for treatment should include using tamoxifen treatment alone or medical/ surgical induction of menopause with GnRH agonists or oophorectomy.10
Duration of adjuvant endocrine therapy
Current standard duration of treatment for a patient with low risk, node negative HR+ disease is five years of adjuvant therapy, with newer evidence supporting an extension of 7 to 10 years in those with higher risk disease.6, 8
The ATLAS and ATTOM trials randomised patients with early HR+ breast cancer regardless of menopausal status to either 5 or 10 years of tamoxifen treatment. Both trials demonstrated that extended therapy of 10 years reduced breast cancer recurrence and mortality compared to 5 years of treatment, by 3.7% and 2.8% respectively as per the ATLAS trial. However, an extended course of tamoxifen was associated with an increase in adverse events observed, most concerningly the risk of developing an endometrial cancer or a thromboembolic event.13, 14
Guidelines changed with the introduction of the better tolerated third generation aromatase inhibitors (AIs: anastrozole, letrozole and exemestane).15 AIs provided a further small improvement in disease-free survival after breast cancer diagnosis when compared with tamoxifen in post-menopausal women and offer an improved side-effect profile.16 Further work has assessed the impact of ovarian function suppression in pre-menopausal women which can then allow an AI to be used. A study assessing AI and OFS versus tamoxifen and OFS in premenopausal woman with early HR+ breast cancer demonstrated a greater reduction in recurrence rate with an AI/OFS (absolute 5-year recurrence risk of 6.9% versus 10.1% with Tamoxifen/OFS) but no difference in mortality between groups was observed(p=0.94), longer follow up is required.17
Multiple studies were designed to assess the benefit of an extended duration of AI therapy early HR+ breast cancer in the postmenopausal setting, as outlined in table 1.18-26 Clinical trials extending therapy from 7-8 years to 10 years (IDEAL and ABCSG 16) failed to show better clinical outcomes with the longer duration of treatment.22, 23 The breast cancer risk profile of study participants in those trials may be one of the reasons for negative results, such as in the ABCSG 16 trial where 65% of patients with early breast cancer were node-negative and where 73% had T1 disease.23 On balance we consider that for the majority of patients with intermediate risk disease, 7 years appears to be the optimal duration, and in those with high-risk features, endocrine therapy up to 10 years may be considered.
When interpreting these trials into clinical practice an individualised patient approach is required, especially amongst women with low-risk cancers in whom the possible toxicities of treatment must be weighed against minimal potential improvements in clinical outcome.
Management of adjuvant endocrine therapy toxicity
Unfortunately, adherence to adjuvant ET is often poor with rates of adherence at five years reported to be as low as 66.2% in multiple different populations. Factors such as presence of co-morbidities, depression and experience of adverse events are associated with lower adherence with ET whereas use of AIs and prior chemotherapy are associated with better adherence.27-29
The most common side effects of ET are hot flushes, night sweats, vaginal dryness, decreased libido and mood disturbances which contribute to poor treatment adherence. Premenopausal patients, especially when receiving OFS, often experience more side effects of ET due to the sudden drop in oestrogen levels.
Tolerance and adherence are important issues to address in survivorship breast clinics particularly when extended adjuvant ET is being considered.
Non-pharmacological interventions such as regular exercise, a healthy diet, minimal alcohol intake, smoking cessation, weight management and cognitive behavioural therapy should be recommended as part of patients’ survivorship care and may also help to ameliorate adverse effects associated with ET.30 Proactive symptom management such as symptom assessment, education and appropriate interventions (pharmacological or behavioural), improve symptom control.31 Symptoms occurring due to oestrogen deficiency are best treated with oestrogen replacement, however this is contra-indicated in a woman with any history of HR+ breast cancer as it increases the risk of breast cancer recurrence.32
Oncologists may use some medications ‘off-label’ such as anti-depressants and anti-convulsants which have demonstrated significant reductions in hot flush frequency and intensity in clinical trials[33-36]. In one randomised controlled trial venlafaxine reduced hot flushes by 61% within 4 weeks of treatment.37 Gabapentin and the acetylcholine inhibitor oxybutynin have also been shown to reduce hot flushes more than placebo in clinical trials.35, 38 Fezolinetant is the most recently approved medication for hot flush management, this neurokinin (NK) 3 receptor antagonist demonstrated successful initial and prolonged management of vasomotor symptoms with an acceptable safety profile among menopausal women without cancer however, close monitoring of liver function tests is required.39, 40 This year it has been announced that a Phase III study of the NK3 antagonist elinzanetant has met all primary endpoints demonstrating a statistically significant reduction in frequency of moderate to severe vasomotor symptoms (VMS) caused by adjuvant endocrine therapy compared to placebo in women with or at high risk of developing HR-positive breast cancer.41
Another common ET-associated symptom is vaginal dryness/ genito-urinary symptoms which can result in severe discomfort for patients. There are several non-oestrogen and oestrogen-containing vaginal tablets or lubricants which can provide significant relief to patients and have demonstrated to be safe to use in the context of a previously diagnosed HR+ breast cancer.42 Women on tamoxifen who present with abnormal gynaecological symptoms, such as vaginal bleeding or discharge, should be investigated promptly with a gynaecological review +/- ultrasound pelvis/endometrial biopsy. Tamoxifen has tumour-promoting activity in the uterus and has been associated with an increased risk of endometrial hyperplasia, polyp formation and more rarely invasive carcinoma and uterine sarcoma.43
There is approximately a 2-3-fold increase in the risk of thromboembolic events in healthy women treated with tamoxifen, factors increasing this risk are personal or family history of VTE, severe obesity, smoking and increasing age. Prophylactic anti-coagulation is not routinely recommended but can be considered in certain cases such as women with multiple VTE risk factors unable to use an AI. Following development of a VTE on tamoxifen patients require therapeutic anticoagulation and consideration of alternative ET.44
Thromboembolic events and gynaecological malignancies are not associated with AIs. However, AIs can be associated with aromatase-associated arthralgia which presents as joint pain and swelling and is treated with analgesia and gentle exercise but in some cases drug discontinuation is required. AIs are also associated with decreasing bone mineral density; therefore, women commencing an AI should undergo a baseline DEXA scan and be treated with a bisphosphonate if required alongside calcium and vitamin D supplementation. A pre-existing diagnosis of osteoporosis is not a contra-indication for AI use but appropriate treatment should be commenced.45
In younger patients’ commencing chemotherapy or ET, fertility goals should be addressed. High-risk premenopausal patients benefit from OFS for several years to improve OS and recurrence risk.
Women of childbearing age must be educated that tamoxifen is a teratogenic agent and a wash out period of 3 months is recommended before attempting to conceive.
The POSITIVE trial investigated temporary interruption of adjuvant ET after at least 18 months of treatment in young women (42 years or younger) with stage I-III disease to attempt pregnancy. The 3-year incidence rate of breast cancer events was 8.9% compared to 9.2% in the no interruption cohort indicating a temporary interruption of therapy for pregnancy did not demonstrate a negative short-term effect in lower-risk groups but longer follow up is required.46
Adjuvant bisphosphonates
AI use can lead to a reduction in bone mineral density and subsequent bone fractures. In post-menopausal women receiving AI treatment or pre-menopausal women receiving OFS, bisphosphonates are felt to not only have a role in the prevention and/or treatment of bone loss but may also improve breast cancer survival. The EBCTCG meta-analysis found statistically significant benefit for bisphosphonates in all postmenopausal patients with breast cancer for bone recurrence, fracture rates, breast cancer mortality and OS.47 These differences did not vary as a function of treatment features (bisphosphonate class, treatment schedule, and dose). As with all treatments, the balance of potential clinical benefit versus potential toxicities should be weighed carefully with patients.47-49 The most well-studied adjuvant bisphosphonate is intravenous zoledronic acid however oral agents are often prescribed to avoid the need for IV infusions.50-52
CDK4/6 inhibitors
The management of HR-positive, HER2 negative metastatic breast cancer has recently changed to incorporate CDK4/6 inhibitors (Abemaciclib, Ribociclib and Palbociclib). The combination of CDK4/6 inhibitors and ET when compared to ET alone improves both progression free survival and OS in advanced breast cancer.53, 54 More recently, their role and benefit in early-stage HR-positive, HER2 negative breast cancer has been published in both the Monarche (Abemaciclib)55 and Natalee (Ribociclib)56 studies as shown in table 2.
Monarche randomised women with high-risk early breast cancer (node positive) to endocrine therapy with or without Abemaciclib 150mg orally twice a day for 2 years followed by continued ET. At four years follow up the absolute difference in IDFS with Abemaciclib was 6.4%. A continued benefit was seen post completion of 2 years of Abemaciclib.55 At 5-years a sustained benefit of Abemaciclib versus placebo in IDFS is seen however, despite fewer deaths observed in the Abemaciclib arm (208 vs 234), overall survival data did not reach statistical significance.57
The NATALEE trial investigated 3 years of adjuvant Ribociclib with a non-steroidal aromatase inhibitor (NSAI) compared to NSAI alone, both followed by continued ET in patients with stage II or III breast cancer. Like Monarche, a significant improvement was seen in IDFS but not overall survival with the addition of Ribociclib.
No benefit was observed with the addition of adjuvant palbociclib to standard ET as per the PALLAS trial.58
It remains to be seen whether the addition of abemaciclib or ribociclib to adjuvant ET will ultimately improve overall survival compared with standard ET alone and with the initiation of CDK4/6 inhibitors at time of metastatic relapse. CDK4/6 inhibitors are associated with significant toxicity and require relatively intensive monitoring and surveillance in dedicated clinics. Additional treatment is associated with an increase in financial, time and drug toxicity which should be borne in mind when prescribing for healthy breast cancer survivors. Abemaciclib and ribociclib are both approved by the FDA and EMA but only abemaciclib is available for public patients in Ireland for use in adjuvant high-risk HR+ breast cancer patients.
What treatments do we recommend in our practice for patients with HR+ early breast cancer?
All suitable patients should be offered adjuvant endocrine therapy with several evidence-based and reasonable options available as outlined in Figure 1.8, 25
Conclusion
Adjuvant anti-hormonal therapy is an effective intervention to reduce recurrence rates and improve overall survival among patients with hormone-receptor-positive early breast cancer. Almost all patients will benefit from at least 5 years of anti-hormonal therapy with additional combinations of bisphosphonates, ovarian function suppression, CDK 4/6 inhibitors and/or extended adjuvant endocrine therapy appropriate for some patient subgroups. Oncologists play an important role in explaining the rationale for adjuvant endocrine therapy to breast cancer survivors, the potential incremental benefits of additional treatments as well as their associated potential toxicities. A flexible and responsive oncology clinic for the management of patients on adjuvant endocrine therapy is best positioned to support patients and maximise adherence to treatment.
References available on request
Written by Jemma Buchalter, Michaela J. Higgins
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