Hormone-Responsive Cancers

Breast Cancer

Breast cancer is the most common cancer in women.
Breast cancers are molecularly classified into luminal A, luminal B, basal-like, and HER2-enriched breast cancers. Clinically, breast cancers are classified as hormone receptor-positive, HER2 positive, or triple negative. The majority of breast cancers are hormone receptor-positive (express the estrogen receptor or progesterone receptor).
Despite effective endocrine treatments that target the estrogen receptor, resistance to these treatments is a major clinical challenge. There are multiple mechanisms for endocrine resistance.
CDK4/6 inhibitors in combination with endocrine treatment are widely used for the treatment of hormone receptor-positive breast cancer.

Introduction

In the United States, breast cancer is the most common cancer diagnosed in women, with the exception of skin cancers, and the second leading cause of cancer mortality after lung cancer. It is estimated that in 2021 there will be about 281,550 new cases of invasive breast cancer, and about 43,600 women will die from breast cancer in the United States. The average lifetime risk of a woman developing breast cancer in the United States is 13%, meaning that there is a 1 in 8 chance that a woman will develop breast cancer. Much progress has been made in the care of breast cancer over the past 30 years. Since 2007 death rates from breast cancer have been steady in women younger than 50 years but have continued to decrease in older women. From 2013 to 2018, the annual death rate dropped by 1%. These decreases are likely due to improved screening for earlier detection of breast cancer and better treatments.

Risk Factors for Breast Cancer

Gender and Age

Breast cancer occurs 100 times more frequently in women than men. Breast cancer in men accounts for only 1% of all breast cancers. Additionally, the risk of breast cancer increases with age. In the United States from 2015 to 2017, the probability of developing breast cancer from birth to age 49 years in women was 2.1%, whereas in women 70 years and older the probability was 7% .

Dietary and Lifestyle Factors

Epidemiological observations suggest a role of obesity, high fat diet, exercise, and alcohol consumption in the development of breast cancer. ^, The association between obesity, defined as body mass index (BMI) $\geq$ $\geq$ 30 kg/m ² , and the risk of breast cancer differs based on menopausal status. For postmenopausal women, a higher BMI and perimenopausal weight gain is associated with an increased risk of breast cancer. In the Million Women cohort study increasing BMI was associated with an increased risk of postmenopausal breast cancer with a relative risk of 1.4. A meta-analysis of 89 published reports showed that a BMI of $\geq$ $\geq$ 30 kg/m ² compared to <25 kg/m ² was associated with a summary risk ratio of 1.4 for hormone receptor (HR) positive breast cancer in postmenopausal women and 0.78 for premenopausal women. The increased risk in postmenopausal women was particularly significant for women who did not take estrogen-progestin therapy. In premenopausal women, the inverse association between BMI and risk of breast cancer was the strongest association for BMI at young ages. ^, The biological mechanisms underlying this association are unclear.

Multiple studies have shown a link between alcohol consumption and the risk of breast cancer. Levels of alcohol as low as 5 to 9.9 grams per day, equivalent to 3 to 6 drinks per week, were associated with an increased risk of breast cancer with a relative risk of 1.15. Alcohol consumption between menarche and first pregnancy and after first pregnancy is also associated with an increased risk of breast cancer. In addition to increasing estrogen levels, alcohol can increase DNA damage through reactive oxygen species and its metabolite acetaldehyde.

Hormonal Factors

Hormonal factors and particularly estrogens contribute to the development of breast cancer. Administration of exogenous estrogens to various animal species results in breast neoplasms. Spontaneous development of breast cancer in aging rats can be prevented by oophorectomy or administration of aromatase inhibitors to block estrogen production. As outlined in Fig. 30.1 , epidemiological studies implicate several hormonal factors that are associated with an increased incidence of breast cancer.

Fig. 30.1, Relative risk of breast cancer as a function of several factors which relate to the long-term exposure to estradiol (E 2 ).

Intensity of Estrogen Exposure

Many of the risk factors for breast cancer relate to the duration or intensity of a woman’s exposure to endogenous or exogenous estrogens ( Fig. 30.1 ). Early menarche and/or late menopause increase breast cancer risk and these effects are stronger for estrogen receptor-positive breast cancer than estrogen receptor-negative breast cancer. ^, Elevations in circulating estradiol levels predict the risk of developing breast cancer over the ensuing years in postmenopausal women. In premenopausal women, there is evidence that high levels of circulating estrogens are associated with an increased risk of breast cancer. Estrogen levels provide information independent of other known risk factors such as family history and history of breast cancer. An estradiol in the top quintile may increase the relative risk of breast cancer by 2–2.5-fold ^, ^, An index weighing several circulating estrogens (E1, E2, E3, E1-S, E2-S) provides a higher estimate of risk than estradiol alone. Estrogen metabolites, which do not act through the estrogen receptor, are also associated with an increased risk of breast cancer. For example, weighted averages of several estradiol metabolites involving the 4-hydroxylation pathway predict a greater risk of breast cancer than levels of E2 alone. Increased exposure to estradiol in utero can increase the risk of breast cancer as demonstrated by the nearly twofold increase in breast cancer with exposure to diethylstilbestrol in utero. Early pregnancy and prolonged duration of breastfeeding diminish the risk. ^, More dramatic is the 75% reduction in risk caused by bilateral oophorectomy before age 35 or use of antiestrogens by premenopausal and postmenopausal women.

Sources of Estrogen

The estradiol present in breast tissue is synthesized in three sites: the ovary, extraglandular tissues, and the breast itself. Direct glandular secretion by the ovary results in the delivery of estradiol to the breast through an endocrine mechanism in premenopausal women. After menopause, extraglandular production of estrogen from ovarian and adrenal androgens in fat and muscle provides the second source of estradiol. The breast itself can synthesize estradiol via aromatization of androgens to estrogens, cleavage of estrone-sulfate to free estrone via the enzyme sulfatase, and conversion of estrone to estradiol via 17βOH-HSD. Classic studies involving the infusion of radiolabeled androgens and estrogens into women provide direct evidence of both in situ production in the breast and uptake from plasma. Studies relating plasma estrogen levels to expression of estrogen-responsive genes in breast tumor tissue suggest that ER-mediated uptake might predominate over in situ synthesis. Several factors regulate in situ estradiol synthesis but the most important is the degree of obesity which increases the amount of aromatase in the breast and, consequently, estradiol production. The mechanism for obesity-related induction of aromatase involves leptin, adiponectin, and AMP-kinase, which allow CRTC2 to become detached from a 14-3-3 protein and enter the nucleus to increase aromatase transcription.

Mammographic Density

Breast density represents a strong risk factor for breast cancer risk ( Fig. 30.2 ). The increase in breast cancer risk from lowest to highest breast density category is on the order of fivefold depending upon the age of the patient with greater relative risk in older women. Mammographic density, when added to the factors used in the Gail predictive model, increases the power of prediction and thus is independent of several other risk factors. Radiographic mammographic density corresponds to a higher fraction of stroma and epithelium relative to adipose tissue and areas of increased breast density contain higher levels of aromatase than nondense areas suggesting a role for increased in situ estrogen production. The causes of increased breast density are poorly understood but are partly related to genetic factors, as shown by twin studies, and estrogen levels since exogenous estrogens increase and antiestrogens reduce breast density. Only those individuals with a reduction in breast density of greater than 10% on tamoxifen experienced prevention of breast cancer, further supporting the biological significance of breast density.

Exogenous Hormones and Breast Cancer Risk

In premenopausal women, the use of oral hormonal contraceptives for 10 or more years increases the relative risk of breast cancer by approximately 10% to 20%. This increase affects very few women since the age-related absolute incidence of breast cancer is minimal in women taking oral contraceptives. The median age in the largest study of oral contraceptive use was 26 years old. In contrast, a study of women ages 35 to 64 years showed no increased risk of breast cancer in current or former users of oral contraceptives. A more recent study looked at the association between the risk of breast cancer and contemporary hormonal contraception and showed that the relative risk of breast cancer among ongoing users and recent users of hormonal contraception compared to women who had never used oral contraception was 1.2. The risk increases with a longer duration and continues to exist after discontinuation of the hormonal contraception. However, the overall absolute increased risk is small and translates to an approximate 1 extra breast cancer for every 7690 women using a year of contraception.

The concept that menopausal hormonal replacement treatment (MHT) increased the risk of breast cancer was initially controversial as it was based on conflicting observational studies. ^, The large Collaborative Group on Hormonal Factors in Breast Cancer Study (CGHFBC study), which was a meta-analysis of 51 studies published in 1997, helped to clarify some of the factors responsible for the differing conclusions among the various observational reports, as outlined below :

1.
The relative risk of breast cancer from MHT is small and large studies with a long duration of follow-up are required to minimize type I and type II statistical errors.
2.
The risk of breast cancer increases linearly with the duration of MHT use. Accordingly, comparisons of “ever users” with “never users” are invalid since the duration of estrogen use is not considered.
3.
The increased risk of breast cancer imparted by MHT dissipates within 4 years of cessation of therapy. Therefore, only women using MHT within 4 years of study might be found to be at increased risk.
4.
Breast cancer risk also diminishes over a 4-year period following menopause, presumably as a reflection of decreased estrogen and progesterone levels. As a result, analyses of observational studies need to match users versus nonusers as to the time following menopause.
5.
The increased risk of breast cancer from MHT is higher in women with lower weight or BMI. Inclusion of a large proportion of women with high BMIs in a single study might then obscure associations between MHT use and breast cancer risk.

When the CGHFBC took these confounding factors into account, the pooled observational data were relatively consistent and suggested an increased risk of breast cancer in women using estrogen plus a progestogen over 5 years or taking estrogen alone long-term for 10 or more years. The large, prospective, randomized, placebo-controlled Women’s Health Initiative (WHI) trial in postmenopausal women first published in 2002 supported the observational data on estrogen plus a progestogen. Nearly 16,000 postmenopausal women with an average age of 63 enrolled in the estrogen plus progestin arm of the WHI study and received either placebo or conjugated equine estrogens plus medroxyprogesterone acetate for 5 years. An increased risk of breast cancer was first seen after 3 years of estrogen plus a progestogen in women who had previously used MHT and in year 4 in women who had no prior use. At study termination after 5.2 years, the relative risk was reported as 1.26. The absolute increase in risk was relatively small with 4 cases per 1000 women treated for 5 years.

In the original WHI report, it was noted that 74% of the participants were never users of MHT, 19.7% were past users, and 6.4% were current users. Among the never users, breast cancer risk was not increased (RR 1.09, CI 0.86–1.40), a statistic confirmed in a subsequent publication in 2006. Long-term follow-up data after more than 20 years of follow-up showed that estrogen plus a progestogen is associated with a significant increase in the incidence of breast cancer compared to placebo (annual rate of 0.45% versus 0.36%) but there was no significant increase in breast cancer mortality.

Effect of Specific Progestogens and Progesterone

The WHI estrogen plus a progestogen study utilized only one progestogen (synthetic progesterone), medroxyprogesterone acetate (MPA), and did not address whether different progestogens might have lesser effects on breast cancer risk. Several observational studies examined the effects of various types of progestogen as well as differences between combined continuous and sequential regimens. The Million Women Study suggested that all types of progestogen (medroxyprogesterone acetate, norgestrel, and norethisterone) are associated with an increased risk of breast cancer, and the combination of an estrogen and progestogen was associated with an about fourfold greater increase in breast cancer incidence than estrogen alone. However, there is evidence that progesterone itself may be associated with a lower risk or no risk of breast cancer as opposed to synthetic progestogens. Studies examining the levels of circulating progesterone and risk of breast cancer showed either no association or a decreased risk. ^, In addition, the French component of the European Prospective Investigation into Cancer and Nutrition (EPIC) study reported on 2354 cases of invasive breast cancer among 59,216 French postmenopausal women followed for an average of 8.1 years. This study reported a relative risk of 1.08 (CI 0.89–1.31) for estradiol in combination with micronized progesterone. In contrast, the relative risk (RR) for estradiol combined with synthetic progestogens in that study was 1.69 (1.50–1.91), similar to risks reported in other epidemiological studies. Micronized progesterone, which is associated with a lower risk of breast cancer, is the typical progesterone in current MHT regimens.

An understanding of the physiological basis for the association of progestogens with breast cancer rests on data indicating that progestogens are mitogenic on breast tissue in contrast to their antimitogenic effects on the uterus. While data from cell cultures or animal studies are conflicting, the weight of evidence from patients suggests that progestogens are mitogenic in the breast. Mammographic studies demonstrate that estrogen/progestogen combinations increase breast density to a greater extent than estrogen alone or placebo. Histological examination demonstrates enhanced cell proliferation and percent of the breast containing glandular tissue as a function of the duration of progestogen usage. Increased proliferation would be expected to increase both initiation and promotion of breast cancer in a manner similar to that thought to occur with estrogens. However, preclinical studies in breast cancer cell lines have shown that there is a crosstalk between the progesterone receptor and estrogen receptor, and in the presence of estrogen, a progestogen may have antimitogenic activities. Furthermore, the MPA analog megestrol acetate has been used as a treatment for breast cancer, suggesting that progestogen may have disparate effects in normal breast tissue and breast cancer.

Confounding Factors

Several commentators have pointed out factors confounding the interpretation of the WHI studies: (1) the frequency of dropouts (30%) and drop-ins (7%) (i.e., patients randomized to placebo and then deciding to take MHT during the study), (2) the exclusive use of MPA as the progestogen, (3) the average age of participants was 63 years old, (4) the fact that 26.5% of women had used prior hormone therapy and then underwent washout before starting MHT, (5) the paucity of women with menopausal symptoms, (6) the fact that only 3.5% of the subjects were in the 50- to 54-year-old age group which represents women who usually consider initiation of MHT use and, (7) limitation of an increase in breast cancer to women who had previously used MHT and then stopped before randomization. Despite these issues, the WHI remains the only large-randomized trial and the data on MHT and breast cancer risk appear valid. Further, the conclusions are congruent with the findings of the majority of the observational studies.

Estrogen Alone.

Another arm of the WHI compared placebo with conjugated equine estrogen alone in women who had previously undergone a total abdominal hysterectomy. This study showed that the use of estrogen alone was associated with a lower incidence of invasive breast cancer. ^, In the 11.8-year follow-up of the WHI alone trial (i.e., 7 years of conjugated equine estrogen alone and 4.8 years of subsequent observation), the reduction in breast cancer risk did reach statistical significance in the total group (RR 0.77, CI 0.62–0.95) and to an even greater extent in compliant patients (sensitivity analysis RR 0.69, CI 0.49–0.95). The protective effect was confined to those without a family history of breast cancer or benign breast disease.

Benign Breast Disease and Risk of Breast Cancer

Benign breast lesions with an enhanced rate of proliferation predict an increased incidence of breast cancer over time. A major consideration for women who present with breast problems is whether they have a higher than normal risk of developing breast cancer. Certain breast lesions such as fibrocystic changes are associated with no increased risk of subsequent breast cancer unless a strong family history is present. Other lesions, characterized by the presence of increased cellular proliferation such as usual ductal hyperplasia, hyperplastic elongated lobular units, and solitary or multiple papillomas impart a small (i.e., less than twofold) relative increase in risk. ^, With atypical ductal hyperplasia (ADH), the relative risk (RR) is 3.88 overall and 10.35 in those with multifocal (i.e., 3 or more) lesions with calcifications. In younger women, ADH imparts a 6.75 RR (i.e., women younger than 45 years old). The relative risk of development of invasive cancer is increased tenfold to twelvefold when ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are present.

Estimating Breast Cancer Risk

The Gail model and the more recent modified Gail model were developed to aid in assessing breast cancer risk. This model utilizes answers to seven questions to calculate the 5-year and lifetime risk of developing breast cancer and is used for women ≥35 years old that do not harbor a BRCA1/2, P53, or PTEN mutation, have a strong family history of breast cancer, a history of thoracic radiation before the age of 30 or a history of LCIS. ^, This model has recognized deficiencies in that it does not consider breast density, plasma estradiol levels, bone density, body mass index, weight gain in adulthood, second degree relatives with breast cancer, proliferative lesions of breast other than ADH, alcohol intake, or birth control pill and MHT use. Nonetheless, several prospective studies validated the Gail model in high risk (National Surgical Adjuvant Breast Project [NSABP] prevention study) and in average risk women (the Nurses’ Health Study). The National Comprehensive Cancer Network (NCCN) has adopted the 1.7% or greater 5-year actuarial breast cancer risk based on the Gail model as the value to identify women eligible for risk-reducing agents such as tamoxifen, raloxifene, anastrozole, and exemestane. This was the threshold that was used in the NSABP Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) trial. This risk tool is available on the National Cancer Institute website.

Biological Subtypes of Breast Cancer

For many years the WHO classified breast cancers into 17 histological subtypes. However, this classification was limited since the majority of breast cancers were classified as Invasive Ductal Carcinoma (IDC) not otherwise specified and tumors within this class did not have distinct clinical behavior and response to treatments. The use of the microarray technology led to major advances in the understanding of the molecular heterogeneity of breast cancers and in seminal studies breast cancers were classified into four intrinsic subtypes. ^, These subtypes include luminal A, luminal B, HER2 enriched, and basal-like breast cancer. Luminal A subtype breast cancers are usually positive for estrogen receptor (ER) and progesterone receptor (PR), have a low pathological grade and low proliferation; luminal B subtype cancer are ER-positive, usually PR negative or PR low, have a higher grade and higher proliferation index and are less responsive to endocrine treatment; HER2-enriched tumors have HER2 (ERBB2 ) amplifications and high pathological grade. Basal-like cancers typically do not express hormone receptors or HER2, are characterized by the expression of basal markers, such as CK5 and CK6, and have a high pathological grade and proliferation index. The intrinsic subgroup of basal-like cancers is a heterogeneous class of cancers by itself and can be further classified into six subtypes, including two basal-like subtypes, an immunomodulatory subtype, a mesenchymal subtype, a mesenchymal stem-like subtype, and a luminal androgen-receptor subtype. Subsequent studies showed that the intrinsic subgroups can be simplified and a set of 50 genes called PAM50 can be used to classify tumors to the four intrinsic subgroups and can be applied to predict the risk of recurrence in early-stage disease.

The Cancer Genome Atlas Network (TCGA) performed whole exome sequencing (WES) of over 800 primary tumors and additional high throughput analyses of subsets of these tumors. Integration of the WES and mRNA expression revealed intrinsic subtype-specific mutational patterns. Overall the mutation rate was highest in basal-like and HER2-enriched tumors and lowest in luminal tumors but significantly mutated genes were more diverse and recurrent within luminal-type tumors compared to basal-like and HER2 enriched. The most common mutation in luminal A tumors is PIK3CA mutations (found in up to 45% of luminal A tumors) followed by mutations in MAP3K1 , GATA3, TP53, and CDH1 and MAP2K4. TP53 and PIK3CA mutations are the most common mutations in luminal B cancers (29% each). In basal-like tumors, the most frequent mutation was TP53 , which was found in 80% of the cases and PIK3CA mutations were less common. In addition, loss of RB1 was found to be characteristic of basal-like tumors. Overall, the basal-like cancers exhibited many molecular commonalities with high-grade serous ovarian cancers. The HER2-enriched subtype had a high rate of HER2 amplifications and the most common mutated genes within this subgroup were TP53 and PIK3CA .

The genomic landscape in breast cancer has unveiled multiple opportunities for precision medicine and numerous research studies are currently underway testing targeted agents based on this information. However, clinically, off a research study, breast cancers are approached as either ER and/or PR positive (hormone receptor positive), HER2 positive, or triple negative (negative for ER/PR and HER2). The most prevalent type of breast cancer is hormone receptor (HR) positive breast cancer (expressing ER and/or PR), which is also the leading cause of breast cancer mortality.

The Estrogen Receptor

1.
ER is a transcription factor and a member of the nuclear receptor superfamily. ER regulates the transcription of hundreds of genes ultimately leading to cell division. ER has an important role in mammary gland development and growth that occurs in pregnancy. In ER-positive (ER+) breast cancers, ER is a driving transcription factor leading to uncontrolled cell division resulting in tumor initiation and progression. Details of the structure and function of ER are described in Chapter 5 . Endocrine treatments that target ER are the first class of targeted treatments in cancer and are the mainstay treatment in ER+ breast cancers.
2.
ER is composed of several conserved functional domains. These include an N-terminal transcriptional activation function (AF-1) domain; within AF-1 is a DNA-binding domain (DBD) that includes a zinc-finger domain responsible for recognizing the estrogen-responsive element (ERE) and a second zinc finger that stabilizes protein-DNA interactions. The zinc finger domains likely have a role in tethering ER to noncanonical or imperfect ERE DNA motifs. ER has a hinge region between AF1 and the ligand binding domain (LBD), which forms the second activation domain (AF-2). The ER LBD structure is similar to those of the nuclear receptor superfamily and includes an α helical pocket, which is the site of estrogen binding as well as antagonists, such as tamoxifen. After estrogen binds to ER helices 3,4,5 and 12, it forms a groove to enable interaction with coactivators. The p160 coactivator family are the most well-characterized ER coactivators and include SRC1, GRIP1, and A1B1. In breast cancers, AIB1 is amplified in about 10% of tumors and overexpressed in more than 50%; studies in engineered mouse models demonstrated the oncogenic activity of AIB1, indicating a role in breast cancer development. In addition, there are also corepressors, such as NCOR1 and SMRT, which inhibit ER activity. ER chromatin binding is further regulated by chromatin accessibility and many predicted EREs do not correspond to observable ER binding. The forkhead box protein FOXA1 is a pioneer factor and was found to be required for chromatin accessibility and ER binding. Furthermore, FOXA1 dictates the distribution of ER binding in a cell-dependent manner. Additionally, there is also evidence of ligand-independent activation of ER by receptor tyrosine kinases, such as IGF1R, EGFR, and HER2, which leads to distinct ER recruitment.

Endocrine Treatments

Tamoxifen

In premenopausal women, tamoxifen exerts antiestrogenic effects on the breast that are similar to those induced by surgical removal of the ovaries with resultant estrogen deprivation. The estrogen agonistic properties of tamoxifen in premenopausal women are minimal. In postmenopausal women, tamoxifen acts as an antiestrogen on breast tissue but exerts estrogen agonistic effects on the uterus, vagina, bone, pituitary, and liver. For this reason, tamoxifen is classified as a selective estrogen receptor modulator or SERM as is its close relative, toremifene. Attempts to determine the mechanistic reasons for the divergent actions of tamoxifen on various tissues in premenopausal and postmenopausal women have led to a better understanding of the complexity of ER-mediated transcriptional regulation. Tamoxifen binds to ERα in the LBD and leads to conformational changes in the ER binding pocket at helix 12 that hinder the binding of coactivators to the ER and facilitate the binding of corepressors. The continued presence of corepressors in the complex is thought to explain the antiestrogenic properties of tamoxifen. The relative amounts of corepressor and coactivator in certain tissues and the presence of other factors regulate whether tamoxifen acts as an agonist or antagonist.

Inhibitors of Estradiol Synthesis

The aromatase enzyme catalyzes the rate-limiting step in the conversion of androgens to estrogens. One steroidal aromatase inhibitor, exemestane, and two nonsteroidal, anastrozole and letrozole, are highly potent and specific. Both subclasses of inhibitor reduce aromatase to 1% to 2.5% of baseline activity in postmenopausal women, substantially reduce plasma estradiol levels, suppress tissue concentrations of this steroid in breast tumors, and are devoid of estrogen agonistic properties. Only postmenopausal patients benefit from aromatase inhibitors as a single modality since interruption of estradiol negative feedback with a reflex increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) results in an override of aromatase blockade in premenopausal women.

The efficacy of these agents in the adjuvant setting has been examined by trials comparing aromatase inhibitors (AIs) with tamoxifen. Two similar large trials, the ATAC (Anastrazole and Tamoxifen Alone and in Combination; ATAC trial) and the Breast International Group (BIG)-98 trials, compared the effects of nonsteroidal AIs (letrozole or anastrozole) with those of tamoxifen with endpoints of time to progression of the disease, time to treatment failure, and overall survival ( Fig. 30.3 ). At 5 years of follow-up, all three trials demonstrated an absolute superiority of the AI of approximately 3%. The BIG-98 study reported an 18% (HR 0.82 95%, CI 0.70–0.95) significant increase in overall survival with letrozole, but only after correcting for selective crossover of tamoxifen patients. Albeit, improved overall survival was not seen in the ATAC trial.

Fig. 30.3, Results of the Breast International Group 98 (BIG 98) trial with four arms; tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years with switching to letrozole and letrozole for 2 years with switching to tamoxifen.

Sequential Use

Several studies compared the sequential use of AIs or tamoxifen during adjuvant therapy. The IES study (International Exemestane Study) compared the effect of continuing tamoxifen for 5 years or switching to exemestane for 2 to 3 years after completing 2 to 3 years of tamoxifen. This study showed an increase in reduction in new cancer events in the AI compared to the tamoxifen group with a moderate improvement in overall survival. Likewise, a combined analysis of the ABCSG and ARNO trials—which had similar designs but used anastrozole rather than exemestane—showed that a switch to the AI after 2 years of tamoxifen versus continued tamoxifen resulted in a 3% improvement in event-free survival and in overall survival. The Italian Tamoxifen Anastrozole (ITA) trial also investigated 5 years of tamoxifen versus 2 to 3 years of tamoxifen followed by anastrozole for a total of 5 years of adjuvant endocrine treatment. The results from this study were consistent with the other studies and showed that switching to anastrozole resulted in improvement in disease-free survival. The TEAM (Tamoxifen Exemestane Adjuvant Multinational study) investigated 5 years of exemestane versus exemestane following tamoxifen and showed that the side effect profiles of the two arms were different but disease-free survival rates were comparable.

A large Early Breast Cancer Trialists’ Collaborative Group meta-analysis included over 30,000 patients treated with either tamoxifen alone, an aromatase inhibitor alone, or a sequence of these agents. This meta-analysis showed that, in comparison to tamoxifen alone, aromatase inhibitor-based therapy in the first five years reduces the risk of recurrence and improves overall survival to 10 years. Sequential therapy with tamoxifen followed by an aromatase inhibitor versus upfront aromatase inhibitors during the first five years yielded recurrence rates that were nearly the same. In general, given the increased benefit of reducing the risk of recurrence compared to tamoxifen, postmenopausal women should consider 5 years of adjuvant treatment with an aromatase inhibitor either as initial therapy or after 2 to 3 years of tamoxifen. However, in general, aromatase inhibitors are of more value compared to tamoxifen in high-risk breast cancer (based on stage and grade) and possibly in invasive lobular breast cancers according to retrospective data.

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