Hormonal Therapy in Nonmetastatic Breast Cancer

(1)

Chennai Breast Centre, Chennai, India

Adjuvant Hormonal Therapy

Introduction

Breast cancer is one of the few cancers which are under hormonal regulation, and the manipulation of hormonal control has shown marvelous results. Role of hormones in breast cancer was first highlighted when it was observed that in certain patients, the diseased regressed with the onset of menopause. This was further consolidated when similar regression was observed by Beaston, that in many premenopausal women the disease regresses after surgical oophorectomy. Hormone-positive breast cancers account for nearly two third of total breast cancer patients. Hormonal therapy has proven its effectiveness in both adjuvant and advanced settings and also known to be devoid of major toxicities.

Certain supporting hormones are vital for maintaining the life of malignant cells in hormone-dependent cancers. Therefore a hormone-dependent tumor cannot sustain when supporting hormones are blocked or their source is removed. This hormone dependence of receptor-positive breast cancers forms the basis of hormonal therapy. Hormonal treatment works by targeting the pathway that is critical for the tumor growth, leading to hormone deprivation or hormone interference. A major caveat to the use of hormonal therapy in any form is that the hormonal treatment can be given only to patients with receptor-positive tumors.

Modalities of Hormonal Therapy in Adjuvant Setting

Selective Estrogenic Receptor Modulators (SERM)

SERMs are compounds that modulate the action of estrogen via their effects on the ER. The action of a given selective estrogenic receptor modulator depends on activation of a different hormone-binding domain, which determines an agonist, antagonist, or mixed response. Since estrogen receptors are present on bones and uterine tissue also and modulate different action there, an ideal SERM is a compound that has an antiestrogenic effect in breast and uterine cancer, but has an agonist action on the bones and cardiovascular system. This is the basis of their protective effect on bone mineralization and heart.

Tamoxifen

Tamoxifen is the most used antiestrogen for hormone-positive breast cancer. It has antagonistic action on breast tissue, with partial agonistic action on bone and uterine tissue. It also blocks the receptors at hypothalamic-pituitary axis, thus causing a reflex rise in gonadotrophins [1]. Since tamoxifen acts directly on the breast tissue, the impact of receptor blockade is there, despite increase in circulating estrogen caused by interruption of the hypothalamic-pituitary axis feedback system. Tamoxifen is a prodrug and has active metabolites 4-hydroxytamoxifen and endoxifen. Endoxifen is the most abundant metabolite and needs CYP2D6-mediated oxidation reactions for its production. Tamoxifen is indicated in premenopausal and postmenopausal women with hormone receptor-positive breast cancers [2, 3].

In adjuvant setting, the duration of use is 5–10 years [2, 4, 5].The dose of tamoxifen is 20 mg once daily [2]. There is no benefit of higher doses [2, 3, 6]. The other benefit of tamoxifen is decreased bone loss because of partial agonistic action on bone tissue. This is major benefit as compared to AIs, which cause significant bone loss and increased risk of fractures.

Side Effects of Tamoxifen

The most common side effects are hot flashes affecting around 50 % of treated women. Hot flashes increase in first few months and then plateau. Many medications like Megestrol, antidepressants, and anticonvulsant like Gabapentin have been shown to decrease hot flashes but drugs like fluoxetine that inhibit CYP2D6 should be avoided.

It also has partial agonist action on uterine tissue, thus its use may lead to endometrial hyperplasia and increased chances of endometrial cancer. Although the incidence of uterine cancer increases significantly, still it is very low because of the overall low incidence of endometrial cancer in general population. Secondly, the endometrial cancers due to tamoxifen use are usually low grade and do not cause much problem. The major issue is the onset of endometrial hyperplasia and the fear of development of endometrial cancer leading to significant increase in the number of hysterectomies [3]. Tamoxifen predisposes patients to thromboembolic episodes and is thus contraindicated in patients with significant risk of thromboembolism.

Aromatase Inhibitors: Letrozole, Anastrazole, Exemestane

AIs are of two types; Letrozole and anastrazole are reversible nonsteroidal AIs, exemestane is irreversible and steroidal AI. They block the peripheral production of estrogens in postmenopausal women by blocking the aromatase enzyme. AIs are not used in premenopausal women because gonadotrophins can reverse the ovarian aromatase blockade [7]. The use of AIs in premenopausal women will be ineffective, unless combined with other modalities to overcoming the gonadotrophin surge. Such treatments include surgical oophorectomy, radiotherapy ablation of ovaries, high-dose progestins, or long-acting GnRH agonists or antagonists. The benefit of “total estrogen blockade” in premenopausal women with ER + breast cancers using GnRH agonist and AIs can also be used. This leads to medical oophorectomy and artificial menopause. There are no outcome differences between the different types of AIs, although a letrozole has better patient acceptance as compared to anastrazole [8]. But this was a small study and the results should be interpreted with care. The dose of anastrazole is 1 mg once daily, letrozole is 2.5 mg once daily, and exemestane is 25 mg once daily. They are used in neoadjuvant, adjuvant, as well as advanced breast cancers [9].

Side Effects of Aromatase Inhibitors

They cause severe estrogen deficiency leading to symptoms like hot flushes, vaginal dryness, and loss of libido. Due to estrogen deficiency, they cause significant bone loss and use of AIs has been associated with significant increase in vertebral fractures. Thus AIs use need regular supplementation with calcium and vitamin D and regular monitoring of bone densitometry [9].

Because AI therapy in women who are clinically menopausal effectively suppresses E2 and eliminates most negative feedback on the gonadotropes, Luteinizing hormone hormone (LH) and Follicular Stimulating hormone (FSH) might rise even further. In some postmenopausal women, this gonadotropin surge, which mimics the mid-cycle surge, induces ovulation and/or menses. Often only one cycle is experienced, but this phenomenon, which is rather distressing to patient and doctor alike, also brings into question whether the menopausal status has been correctly assigned. Will such patients still benefit from AI therapy? In general, patients with a single episode of menses on an AI can be considered postmenopausal, although serum estradiol measurements before and during AI therapy are required in this setting. As long as serum estradiol remains low, AI therapy continues to be an option [7, 9–11].

Ovarian Ablation

Ovarian ablation (OA) is done for suppression of hormonal function of ovaries, thus reducing the production of estrogens in premenopausal ladies, in whom ovary is the main site of estrogen production [12]. It does not have any effect in postmenopausal women, as the ovaries have already stopped functioning and the postmenopausal estrogen is derived from adrenal glands and peripheral tissues.

Methods of OA

Surgical removal of the ovaries. It can be collaborated with the primary surgery of breast cancer. Surgical oophrectomy leads to rapid onset of menopause, but is irreversible in nature.

Radiotherapy OA – The radiations can also be used for ovarian ablation. This process takes 6 weeks for the full destruction of ovarian function. Also, in some patients it may not be fully effective, thus necessitating the measurement of hormone levels in blood for confirmation of postmenopausal status. Radiation-induced OA can be performed with a total dose of 16 Gy to the pelvis delivered by a megavoltage photon beam in four daily fractions [12]. As with surgical oophrectomy, this method is also permanent in nature.

Medical Oophorectomy – With the use of long-acting gonadotrophin-releasing hormones (GnRH), it is possible to shut the ovarian function. This also leads to postmenopausal state, although medical oophorectomy also takes full month for complete action [13]. Secondly, it is the only reversible method of OA. Thirdly, the initial stimulation provided by GnRHs may sometimes cause tumor flare and aggravate the symptoms related to tumor. After initial stimulation, their persistent presence renders the pituitary gland unresponsive. This happens because of loss of pulsatile exposure of pituitary to the GnRH analogues. This results in reduced secretion of luteinizing hormone, which in turn reduces the level of circulating estradiol, leading to a postmenopausal state in 21 days. While using GnRH analogues, there are chances of flare reaction and worsening of symptoms. It should be explained to patient before using them. They are usually given once monthly subcutaneous injection, although long-acting formulations, which can be used once in 3 months, are also available.

Treatment Decision Making

Menopause is defined as permanent cessation of menopause and for breast cancer it implies cessation of estrogen synthesis from ovaries. NCCN guidelines defines menopause as age more than 60 years, history of bilateral oophorectomy, less than 60 years of age and amenorreic for more than 12 months in absence of tamoxifen, GnRH analogues, chemotherapy, and FSH and estradiol within postmenopausal range [14].

Indication of Endocrinal Therapy in Adjuvant Setting

Endocrinal therapy is indicated in all patients with detectable estrogen receptor expression, defined as ≥1 % of invasive cancer cells and does not depend on chemotherapy or other targeted therapies.

Endocrinal Therapy in Premenopausal Women

In adjuvant setting in premenopausal women, Tamoxifen remains the only approved endocrinal agent till date. Tamoxifen enhances the survival of women with ER-positive tumors and also prevents the development of new ER-positive breast cancers. Tamoxifen for 5 years causes 41 % reduction in rate of annual breast cancer recurrence and 34 % reduction in annual death rate according to EBCTCG 2005 analysis [15]. The benefit in terms of absolute risk reduction is greater in women with node-positive disease.

Endocrinal Therapy in Postmenopausal Women

Multiple clinical trials have addressed question whether incorporation of AI improves the outcomes compared to that seen with 5 years of tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. Table below shows major trials in which AI have been used in primary therapy, as switch therapy after 2–3 years of tamoxifen, or as sequential therapy after 5 years of tamoxifen. Disease-free survival (DFS) improved modestly in all these trials with increased overall survival (OS) in some trials due to decreased distant metastasis, ipsilateral and contralateral recurrences (Table 42.1). Looking at the improved outcomes with use of AIs compared to tamoxifen alone, both American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommend the incorporation of AIs at some point in the treatment of postmenopausal women with hormone-positive breast cancer [14, 23].

Table 42.1

Randomized trials of aromatase inhibitor vs 5 years of tamoxifen