Endocrine Therapy in Breast Cancer: The Neoadjuvant, Adjuvant, and Metastatic Approach

Accepted Manuscript Endocrine Therapy in Breast Cancer: the Neoadjuvant, Adjuvant, and Metastatic Approach Raquel E. Reinbolt, MD, Neha Mangini, PharmD, Jordan L. Hill, PharmD, Lauren B. Levine, PharmD, Jessica L. Dempsey, PharmD, Janani Singaravelu, Kevin Koehler, MD, Allison Talley, CNP, Maryam B. Lustberg, MD MPH PII:

S0749-2081(15)00018-2

DOI:

10.1016/j.soncn.2015.02.002

Reference:

YSONU 50682

To appear in:

Seminars in Oncology Nursing

Please cite this article as: Reinbolt RE, Mangini N, Hill JL, Levine LB, Dempsey JL, Singaravelu J, Koehler K, Talley A, Lustberg MB, Endocrine Therapy in Breast Cancer: the Neoadjuvant, Adjuvant, and Metastatic Approach, Seminars in Oncology Nursing (2015), doi: 10.1016/j.soncn.2015.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Endocrine Therapy in Breast Cancer: the Neoadjuvant, Adjuvant, and Metastatic Approach Authors: Reinbolt RE, Mangini N, Hill JL, Levine LB, Dempsey JL, Singaravelu J, Koehler KA, Talley A, Lustberg MB

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Affiliations:

Raquel E. Reinbolt MD: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, Columbus, OH Neha Mangini PharmD: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH

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Jordan L. Hill PharmD: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH

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Lauren B. Levine PharmD: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH Jessica L. Dempsey PharmD: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH Janani Singaravelu: The Ohio State University College of Medicine, Columbus, OH Kevin Koehler MD: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH

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Allison Talley CNP: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, Columbus, OH

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Maryam B. Lustberg MD MPH: The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, Columbus, OH

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Abstract

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Objectives: To review the rationale for endocrine therapy in the neoadjuvant, adjuvant, and metastatic breast cancer setting and to highlight clinical considerations unique to this treatment. Data source: Contemporary literature, clinical guidelines, and national statistics.

Conclusion: Endocrine therapy represents an important strategy in the management of both early and advanced hormone positive breast cancer. Additional research is required to better define the role of neoadjuvant therapy and the optimal duration of treatment.

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Implications for Nursing Practice: Nurses play a pivotal role in the identification and management of endocrine therapy-associated symptoms. Prompt symptom intervention may improve therapy adherence and ultimately, may improve long-term disease outcomes.

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Breast cancer is the second most common cancer overall and the most common cancer among women in the United States with an estimated 232,670 new cases in 2014 [1]. The overall 5-year survival rate is high at approximately 89%, but this rate is reduced to 25% in the presence of metastatic disease

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[1]. Breast cancers may arise from the milk ducts, known as ductal breast cancer, or from the milkproducing lobules of the breast, known as lobular breast cancer. Ductal and lobular carcinomas can be further classified as in situ or invasive (Figure 1). In situ tumors are those that do not spread from their

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origin and represent only 20% of all breast cancers. Ductal carcinoma in situ (DCIS) is both the earliest stage of breast cancer and the most common type of non-invasive breast cancer, representing 83% of all

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in situ carcinomas [2]. Lobular carcinoma in situ (LCIS), also known as lobular neoplasia, is not considered malignant, but patients with LCIS are at risk for the future development of a separate invasive breast cancer. In contrast, invasive breast cancers occur much more frequently, spread to the surrounding tissue, and have the potential to metastasize to other areas of the body.

Breast cancer can be further defined by its growth response in the presence or absence of the

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hormone receptors (HR), estrogen and/or progesterone. These receptors can be targeted by anti-endocrine therapies, which represent the mainstay of treatment for estrogen receptor (ER)/progesterone receptor (PR) positive (+) breast cancer. In addition to endocrine receptor status, breast cancer is also

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differentiated by the presence or absence of a mutation in the human epidermal growth factor receptor 2

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(HER2) gene, which encodes for proteins that promote the growth of cells, including malignant cells [3]. Endocrine Therapy

In HR+ breast cancer, exposure to endogenous estrogen, which includes estrone, estradiol, and

estriol, results in dimerization of the ER and promotes estrogen regulated gene transcription. In premenopausal women, the ovaries are the main source of estrogen production. In postmenopausal women, androgens released by the adrenal glands are converted into estrogen by aromatase primarily in the adipose tissue and the muscle. Endocrine therapy functions by blocking the effect of estrogen at the receptor level or by inhibiting estrogen production. Several classes of endocrine therapy have been 3

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developed to date and these include selective estrogen receptor modulators (SERM), selective estrogen receptor downregulators (SERD), aromatase inhibitors (AIs), luteinizing hormone releasing hormone agonists (LHRH), high dose estrogens, and targeted therapies (Table 1) [4].

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Tamoxifen (TAM) is a SERM due to its tissue specific activity and is indicated in pre- and postmenopausal women. TAM exerts anti-estrogenic activity in the breast and vaginal mucosa through partial inhibition of ER dimerization. However, TAM also exerts an estrogenic effect on the endometrium

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(promoting endometrial hyperplasia), the coagulation system (promoting thromboembolic events), bones (preventing osteoporosis), lipids (preventing hyperlipidemia), and the liver (promoting hepatotoxicity). In

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contrast, fulvestrant completely inhibits ER dimerization and ultimately results in downregulation of ER expression. Fulvestrant is anti-estrogenic in all tissue; it is categorized as a SERD [4–8]. Aromatase inhibitors block the synthesis of estrogen through inhibition of aromatase. Anastrozole and letrozole are non-steroidal AIs with reversible inhibition of aromatase, whereas exemestane is a

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steroidal AI with irreversible inhibition of aromatase requiring production of new aromatase to overcome inhibition. AIs are indicated in postmenopausal women; in premenopausal women, the decrease in peripheral estrogen production stimulates increased ovarian production of estrogen through a negative

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feedback pathway [4, 9–11].

Luteinizing hormone releasing hormone agonists suppress steroidogenesis in premenopausal

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women by binding to LHRH receptors on the pituitary gland leading to an initial stimulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH) production during the first few days. Over time, the ligand-receptor complexes cluster and become sequestered intracellularly leading to a reduction in the number of receptors on the surface. As a result, FSH and LH fall into postmenopausal states within 21 days. High dose estrogens (ethinyl estradiol and diethylstilbestrol) and progresterones (megestrol acetate and medroxyprogesterone) also serve as therapeutic options; however, their mechanism of action is not understood and these agents are associated with an adverse event profile. Finally, targeted therapies

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have recently been combined with endocrine therapy with the goal of overcoming resistance. Everolimus is a mammalian target of rapamycin (mTor) inhibitor and new agents like palbociclib and LEE011 are Cyclin D kinase inhibitors [4].

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Nursing Considerations

The toxicities associated with these different classes of endocrine therapy can lead to significant physical symptoms and diminished quality of life. Musculoskeletal symptoms, the most common being arthralgias,

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bone pain, and joint stiffness, associated with AIs can be particularly debilitating. Symptoms typically manifest 1-3 month after AI initiation; early screening for symptom distress and intervention is essential

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[12, 13]. Potential management strategies include the prescription of nonsteroidal anti-inflammatory drugs or acetaminophen, physical therapy/activity, acupuncture, or consideration of an alternative AI [12]. Hot flashes are also a common side effect of endocrine therapies and can be associated with sleep disturbances, distress and disruption of patients’ lives [13]. A variety of pharmacologic and nonpharmacologic interventions have been investigated; the greatest body of evidence supports the use of the

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serotonin and norepinephrine reuptake inhibitor, venlafaxine, or the neuropathic agent, gabapentin [14]. Neoadjuvant endocrine therapy in early breast cancer There is a clear proven benefit to adjuvant therapy, both hormonal and chemotherapy, for HR+

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breast cancers in most settings. However, the role of neoadjuvant endocrine therapy for HR+ breast cancer is less well defined. The rationale for neoadjuvant therapy in HR+ breast cancer is similar to other

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clinical subtypes of breast cancer: 1) the ability to downgrade tumor size in Stage II or III disease, thus making breast conserving therapy (BCT) possible; 2) to impact progression-free survival (PFS) or overall survival (OS); and 3) to use therapy response as a prognostic marker. Pathological complete response (pCR) to a given therapy is often used as a surrogate of long-term survival and cure from breast cancer [15]. To date, only 2% to 10% of ER+ tumors will achieve a pCR after neoadjuvant hormonal therapy or chemotherapy, regardless of regimen [16]. Furthermore, at the present time, there is no evidence that

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neoadjuvant endocrine therapy improves PFS or OS. Thus, we will now review the evolving role of neoadjuvant hormonal therapy in early stage HR+ breast cancer. Neoadjuvant endocrine therapy in breast cancer patients has historically been reserved for

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patients, typically elderly, who are deemed not suitable for chemotherapy and/or surgery. Early studies with neoadjuvant single agent TAM reported response rates of 49% to 68% in patients with unknown ER status [17]. AIs were later compared to TAM in the neoadjuvant setting. In a randomized, double-blind,

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multicenter study, the P024 trial demonstrated the superiority of neoadjuvant letrozole over TAM in downgrading tumor size and increasing the rate of BCT. Comparing the effect of four months of

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neoadjuvant letrozole versus TAM in women with early stage ER+ breast cancer, letrozole was associated with both an improved clinical response (55% vs 36%, P<0.001) and improved rate of BCT (45% vs 35%, P=0.02) compared to TAM [18]. These findings were again confirmed in the IMPACT (Immediate Preoperative Anastrozole, TAM, or Combined with TAM) trial, which was a randomized study of 124 post-menopausal women with ER+, operable or locally-advanced breast cancer to three months of

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neoadjuvant TAM, anastrozole or combination of TAM and anastrozole. While no difference in objective response rate (ORR) was observed, patients on anastrozole had significantly improved mastectomy to BCT conversion rates compared to TAM (46% vs 22%) [19]. The PROACT trial (Preoperative Arimidex

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Compared to Tamoxifen) similarly noted an advantage to surgical down-staging in 451 post-menopausal women randomized to neoadjuvant TAM versus anastrozole [20]. In sum, these studies suggest that

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neoadjuvant aromatase inhibitors may serve as a means to improve conversion rates from mastectomy to BCT in select patients with ER+ early stage breast cancer. Multiple additional studies are presently underway to better define the impact of neoadjuvant

endocrine therapy on early stage breast cancer. For example, the Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in Postmenopausal Women: A Phase III Study, is an ongoing trial that seeks to define the rate of endocrine resistant disease, recurrence-free survival, and rates of pCR in this population after treatment with 6

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fulvestrant, anastrozole, or the combination of the two agents [21]. The role of neoadjuvant endocrine therapy will need to be re-evaluated as additional data becomes available Nursing Considerations

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The recommendation to pursue a neoadjuvant approach may sometimes be met with resistance. In our experience, delaying definitive surgery may be anxiety provoking to some patients. Furthermore, if objective tumor response is not appreciated during neoadjuvant treatment, patients may experience

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additional distress regarding the lack of therapy efficacy and potential need to consider alternative therapy choices. Reassurance and close monitoring for distress during this period of treatment may be beneficial

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to the patient. Adjuvant Agents

Adjuvant therapy has been shown to reduce the odds of recurrence and death in all age groups; it is indicated in the treatment of breast cancer based on individual risk of relapse, predicted sensitivity to a particular treatment, and is individualized on a patient-specific basis [22]. Several adjuvant endocrine

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therapies are approved for the treatment of HR+ breast cancer. In premenopausal women, treatment with TAM for five years has become the gold standard for adjuvant endocrine treatment. The 2011 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis examined data from over 20 trials

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that included both pre- and post-menopausal women. This study compared five years of TAM to no adjuvant therapy and showed that TAM significantly reduced recurrence rates by 39% for patients with

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ER+ disease (n=10,645, P < 0.00001). Recurrence rates were significantly decreased during years 0-9 of treatment; no further benefit was seen during years 10-14 of therapy. Treatment with TAM proved to be beneficial even in patients with low levels of ER positivity, with an overall decrease in breast cancer mortality of one-third throughout the first 15 years [23]. Similarly, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial examined 2,892 women with ER+, node-negative breast cancer who received either TAM or placebo for five years. Five years of TAM was associated with significantly longer relapse-free survival (RFS) (HR 0.58, 95% CI 0.5-0.67, P<0.0001) and improved OS (HR 0.80, 7

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95% CI, 0.71-0.91, P=0.0008), a finding that ultimately led to TAM’s 5-year duration treatment recommendation. The NSABP B-14 trial also postulated that there is no benefit to continuing TAM therapy beyond five years. At the 7-year follow-up, women who did not have additional TAM therapy

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had improved disease-free survival (DFS) (82% vs 78%, P=0.03), RFS (94% vs 92%, P=0.13), and OS (94% vs 91%, P=0.07) [24]. However, this conclusion was later challenged by the results of several other large trials. The Adjuvant Tamoxifen Long Against Short (ATLAS) trial examined the effects of TAM

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continuation for up to 10 years in 12,894 disease-free women (59% ER+, 41% ER-untested) who had previously received five years of TAM. Ten years of TAM therapy was associated with a decreased

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recurrence risk (RR 0.84, 95% CI 0.76-0.94), significant decreases in breast cancer mortality after year 10 (RR 0.71, 95% CI 0.58-0.88), and a significant reduction in the incidence of contralateral breast cancer [25]. The Adjuvant Tamoxifen- To Offer More (aTTom) trial also investigated TAM therapy for a total duration of 5 or 10 years in 6,934 women who were currently on TAM therapy. Similar to the ATLAS findings, a significant reduction in recurrence risk (RR 0.85, 95% CI 0.76-0.95) and a trend toward

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reduced mortality (RR 0.88, 95% CI 0.77-1.01) was noted in the 10-year treatment group [26]. More recently, additional anti-estrogen strategies have been introduced for pre-menopausal women. The Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) on

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preliminary review demonstrated that the combination of ovarian suppression with an AI is associated with higher rates of DFS (91 vs 87%, HR 0.72, 95% CI 0.60-0.85) than the combination of TAM with

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ovarian suppression in pre-menopausal women with HR+ breast cancer [27]. Upon final analysis to TAM alone, it was noted that adding ovarian suppression to TAM only provided improved disease free outcomes for those women at sufficient risk for recurrence to warrant adjuvant chemotherapy and whom remained premenopausal. Using exemestane with ovarian suppression in this specific population further improved outcomes. However, the addition of ovarian suppression to TAM did not provide a significant benefit aside from in this select patient group [28].

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AI therapy has also been compared to TAM for the treatment of post-menopausal early stage breast cancer patients. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial demonstrated greater effectiveness of anastrozole over TAM in the treatment of 9,366 postmenopausal women with

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HR+ early breast cancer. Patients received anastrozole, TAM, or the combination of both for five years. After a median follow-up of 68 months, patients who received anastrozole had a significantly prolonged DFS (575 events with anastrozole versus 651 with TAM, hazard ratio 0.87, 95% CI 0.78-0.97, P=0.01),

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prolonged time to recurrence, and reduced incidence of distant metastases and contralateral breast

cancers. Anastrozole therapy was also associated with a more favorable side effect profile [29]. The

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Breast International Group 1-98 (BIG 1-98) trial examined the effectiveness of TAM or letrozole alone for five years, TAM for two years followed by letrozole for three years, or letrozole for two years followed by TAM for three years in 8,010 postmenopausal women with HR+ breast cancer. At a preliminary analysis, letrozole monotherapy demonstrated a significantly improved DFS at five years compared to TAM monotherapy (84.0% and 81.1%, p=0.007), as well as a greater time to distant

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recurrence. Following the results of the primary core analysis in 2005, 619 (25.2%) patients initially randomized to TAM monotherapy were selectively crossed over to letrozole [30]. Similarly, the International Exemestane Study (IES) investigated the utility of TAM therapy for 2 to 3 years followed by

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exemestane, as compared to TAM monotherapy for a total duration of five years in 4,742 women with ER+ or ER-unknown tumors who were rendered disease-free after 2 to 3 years of TAM therapy. DFS was

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prolonged in the exemestane treatment arm at 55.7 months follow-up and a significant improvement in OS was observed (hazard ratio 0.83, 95% CI 0.69-1.00, P=0.05) in those patients with ER+ tumors who switched to exemestane [31]. To date, no differences in efficacy or toxicity have been observed amongst the available AI therapies. The optimal duration of AI treatment in postmenopausal women remains unknown and continues to be investigated in clinical trials. Nursing Considerations

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Non-adherence is a significant problem in women taking endocrine therapy. A variety of factors may contribute to non-adherence, including demographic and social considerations, experience of side effects and lack of understanding that missed therapy may impact treatment efficacy [32-33]. The presence of

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negative mood prior to the initiation of therapy may also predict for non-adherence [34]. Some studies have reported that women do not perceive that their healthcare team is routinely assessing treatment adherence [33]. Nursing staff can play a pivotal role in the screening process for symptom experience and

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adherence to endocrine therapy.

Endocrine Therapy in Metastatic Hormone Receptor Positive Breast Cancer

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Endocrine therapies play an important role in the treatment of HR+ metastatic breast cancer (MBC) due to their favorable adverse effect profile. While the optimal sequence of therapy is yet to be determined, guidelines suggest that those who responded to endocrine therapy will benefit from additional endocrine therapy at the time of disease progression (Table 2) [22,35].

Prior to the discovery of the ER, George Thomas Beatson, in 1896, published on the regression of

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disease in three cases of advanced breast cancer following bilateral oophorectomies [36]. As a result, ovarian ablation or suppression evolved as a treatment strategy in premenopausal women with MBC. In the 1980s, TAM became the standard of care in HR+ MBC after it was found to have a superior safety

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profile compared to diethylstilbestrol and megestrol acetate [37,38]. In the first-line setting, multiple clinical trials have compared the use of an AI against megestrol acetate and against TAM. A Cochrane

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review has suggested a survival benefit with AI therapy compared to other endocrine therapies, but the overall reported benefit is small [39]. In comparison to TAM, AIs have demonstrated benefit in improving PFS or time to progression (TTP) [40–43]. In a 2006 meta-analysis of 23 randomized trials with over 8,500 post-menopausal patients, treatment with an AI also resulted in improved OS compared with TAM (HR 0.89, 95% CI 0.80-0.99) [44]. Following AIs, fulvestrant was the next endocrine therapy to reach the market. In the first-line setting, fulvestrant has been evaluated alone and in combination with TAM and AIs. Howell and 10

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colleagues compared fulvestrant to TAM and did not meet endpoints for non-inferiority. However, fulvestrant was dosed at 250 mg every 28 days and approximately 20% of patients in each arm had unknown HR status [45]. The open-label phase II FIRST (Fulvestrant First-Line Study Comparing

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Endocrine Treatments) trial compared fulvestrant 500 mg to anastrozole and demonstrated a statistically significant improvement in TTP of 23.4 months versus 13.1 months with similar ORR, clinical benefit rate (CBR), and toxicity [46,47]. Two phase II trials have explored the combination of fulvestrant with an

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AI. The open-label FACT (Fulvestrant and Anastrozole Combination Therapy) trial showed no benefit of fulvestrant 500 mg loading dose followed by 250 mg every 28 days compared to anastrozole [48].

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However, the Southwestern Oncology Group (SWOG) 0226 trial using the same dosing schedule as FACT demonstrated a statistically significant improvement in median PFS (15 vs 13.5 months) and OS (47.7 vs 42.3 months). A subset analysis of the S0226 trial suggested patients without prior TAM experienced the greatest benefit. Furthermore, the S0226 trial enrolled a higher proportion of previously untreated patients than the FACT trial, which may help explain the conflicting results [49].

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In the second-line setting, two studies compared fulvestrant 250 mg to anastrozole in patients who progressed on TAM; similar efficacy and safety profiles were demonstrated [50,51]. The phase III EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial) trial compared fulvestrant 500 mg

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loading dose followed by 250 mg on day 14 and every 28 days to daily exemestane in postmenopausal women who had progressed on a non-steroidal AI therapy. The study demonstrated comparable TTP of

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3.7 months in both groups (P=0.65) and comparable CBR of 32.2% versus 31.5% (P=0.853) [52]. The phase III double-blind, placebo-controlled CONFIRM (Comparison of Fulvestrant in Recurrent or MBC) trial compared second-line therapy with high dose fulvestrant (500 mg) to low dose (250 mg). Superior PFS and OS were seen with the higher dose, which ultimately resulted in an FDA labeling change [53]. The Phase III SoFEA (Study of Faslodex with or without concomitant Arimidex vs Exemestane following progression on non-steroidal AIs) trial compared fulvestrant in combination with anastrozole versus fulvestrant alone versus exemestane alone in patients who had progressed on non-steroidal AI therapy.

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The median PFS was 4.4 months versus 4.8 months versus 3.4 months, respectively. No difference was observed in ORR, CBR, and OS [54]. Most recently, treatment for HR+ MBC has focused on the use of targeted therapies in

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combination with endocrine therapies to overcome acquired resistance. The phase III BOLERO-2 study compared exemestane plus everolimus to exemestane alone following progression on a non-steroidal AI. The median PFS by central review was 10.6 months versus 4.1 months (P<0.001) [55]. The addition of

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everolimus to TAM has also been investigated. Compared to TAM monotherapy, the combination of everolimus with TAM resulted in an improved TTP (median 9 vs 5 months; HR 0.54, 95% CI 0.36-0.81)

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and decreased risk of death (HR 0.45, 95% CI 0.24-0.81); no difference in ORR was appreciated (14 vs 13%) [56]. The PALOMA-1 trial compared first line treatment with letrozole plus palbociclib to letrozole alone in newly diagnosed HR+ MBC and found a PFS of 20.2 months versus 10.2 months (P=0.0004) [57]. Further studies with various targeted agents and endocrine therapies are presently underway. Nursing Considerations

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Patients’ preference regarding tablet versus injection forms of therapy vary. One study reported that 63% of patients preferred tables, whereas 24.5% preferred the injection and 12.5% had no preference [58]. Fulvestrant, an injected endocrine therapy, should be given using a Z-track injection technique to prevent

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leakage into the subcutaneous tissue and to decrease the risk of local irritation [59-61]. Pressure should be

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applied to obtain a slow injection speed, which will take 1–2 minutes.

Conclusion

Endocrine therapy plays a pivotal role in the treatment of HR+ breast cancer patients. The use of

these agents has been well defined in the adjuvant and metastatic setting; however, the role of endocrine therapy in the neoadjuvant setting must be further characterized. Furthermore, additional work to describe the optimal duration and combination of endocrine agents that will provide the greatest benefit to patients is warranted.

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A hard pill to swallow: a qualitative study of women's experiences of adjuvant endocrine therapy for breast cancer. BMJ Open. 2014;4: e005285. 34. Bender CM, Gentry AL, Brufsky AM et al. Influence of patient and treatment factors on adherence to adjuvant endocrine therapy in breast cancer. Oncol Nurs Forum. 2014; 41:274-285. 35. Burstein HJ, Temin S, Anderson H, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 2014. 36. Beatson G. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet. 1896;2:104-107. 37. Ingle JN, Ahmann DL, Green SJ, et al. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981;304(1):16-21.

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38. Mouridsen HB, Wells HB, Paschold EH, et al. Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1988;6(7):1098-1106. 39. Gibson L, Lawrence D, Dawson C, Bliss J. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane database Syst Rev. 2009;(4):CD003370. 40. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18(22):37583767. 41. Bonneterre J, Thürlimann B, Robertson JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000;18(22):3748-3757. 42. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21(11):2101-2109. 43. Paridaens RJ, Dirix LY, Beex L V, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008;26(30):4883-4890. 44. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JPA. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cance r Inst. 2006;98(18):1285-1291. 45. Howell A, Robertson JFR, Abram P, et al. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004;22(9):1605-1613. 46. Robertson JFR, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009;27(27):4530-4535. 47. Robertson JFR, Lindemann JPO, Llombart-Cussac A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized “FIRST” study. Breast Cancer Res Treat. 2012;136(2):503-511. 48. Bergh J, Jönsson P-E, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30(16):1919-1925. 49. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367(5):435-444. 50. Howell A, Robertson JFR, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002;20(16):3396-3403. 51. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002;20(16):3386-3395. 52. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26(10):1664-1670. 53. DiLeo A, Jersusalem G, Petruzelka L et al. Final analysis of overall survival for the Phase III CONFIRM Trial: fulvestrant 500 mg versus 250 mg [abstract]. Cancer Res 2012;72 (Suppl_24): Abstract S1-4. 54. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentr. Lancet Oncol. 2013;14(10):989-998. 55. Pritchard KI, Lebrun F, Beck JT, et al. Everolimus in Postmenopausal Hormone- Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2012;366:520-529. 56. Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718-2724. 57. Finn RS, Crown JP, Lang I, et al. Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract nr CT101. 58. Fallowfield L, Atkins L, Catt S et al. Patients' preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol. 2006;17:205-210. 59. Owers R. Clinical experience with fulvestrant ('Faslodex'): a nurse's perspective. Eur J Oncol Nurs .2004;8 Suppl 2:S89-94. 60. Versea L, Rosenzweig M. Hormonal therapy for breast cancer: focus on fulvestrant. Clin J Oncol Nurs. 2003;7:307-311. 61. Litsas G. Nursing perspectives on fulvestrant for the treatment of postmenopausal women with metastatic breast cancer. Clin J Oncol Nurs. 2011;15:674-681.

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In Situ or Invasive

ER+ PR+

ER+ PR-

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Lobular or Ductal ER- PR-

HER2+ or HER2-

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Figure 1. Breast Cancer Classification

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Table 1. Summary of Endocrine Therapies Comments

Thromboembolic events, CVA, endometrial hyperplasia and cancer, cataracts, hot flashes, mild nausea, vaginal discharge Similar profile to TAM

- Estrogenic in endometrium, coagulation system, bones, liver - Antiestrogenic in breast, vaginal mucosa

- Used in metastatic setting

- Approved in postmenopausal women only

- Nonsteroidal AI - Reversible Inhibitor

LEE011

NA

125 mg PO daily

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Palbociclib

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M AN U

Toremifene 1997 60 mg PO daily (Fareston®) Selective Estrogen Receptor Downregulator (SERD) Fulvestrant 2002 500 mg IM Injection site pain, bone pain, (Faslodex®) every 28 days arthralgia, headache, back pain, fatigue, pain in extremity, hot flashes, nausea, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation Aromatase Inhibitors (AI) Anastrozole 1995 2.5 mg PO daily Asthenia, myalgias/arthralgias, (Arimidex®) headaches, diarrhea, hot flashes, mild nausea, vaginal dryness, possible bone loss with long-term use. Letrozole 1997 1 mg PO daily Hot flashes, mild nausea, (Femara®) headache, fatigue, arthralgias, possible bone-loss with longterm use. Exemestane 1999 25 mg PO daily Fatigue, hot flashes, nausea, (Aromasin®) dyspnea, anxiety, insomnia, pain at tumor sites, asthenia. Luteinizing Hormone Releasing Hormone Agonists (LHRH Agonists) Goserelin 1989 3.6 mg SQ every Hot flashes, injection site (Zoladex®) 28 days reactions, bone loss with longterm use Leuprolide 1998 3.75 mg IM (Lupron®) every 28 days Triptorelin 2000 3.75 mg IM (Trelstar®) every 28 days Tyrosine Kinase Inhibitors (TKIs) Everolimus 2012 10 mg PO daily Stomatitis, pneumonitis, (Afinitor®) metabolic effects (hyperlipidemia, hypertriglyceridemia, and hyperglycemia), increase infection risk

RI PT

Toxicities

SC

Agent FDA Dose (Trade Name) Approval Selective Estrogen Receptor Modulators (SERM) Tamoxifen 1977 20 mg PO daily (Nolvadex®)

NA

Neutropenia, leukopenia, fatigue, and anemia

- Nonsteroidal AI - Reversible inhibitor

- Steroidal AI - Irreversible inhibitor

- FDA approved for breast cancer - Not FDA approved for breast cancer - Not FDA approved for breast cancer

- mTor inhibitor - In combination with exemestane or TAM

- CDK 4/6 inhibitor - In combination with letrozole - CDK 4/6 inhibitor

Abbreviations: CVA: cardiovascular accident; TAM: tamoxifen; AI: aromatase inhibitor; FDA: Federal Drug Administration; mTor: mammalian target of rapamycin; CDK: cyclin-dependent kinase.

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Table 2. Summary of First-Line Treatments for Hormone-Receptor Positive Metastatic Breast Cancer Study Treatment Arms First-Line Tamoxifen Therapy Ingle et al. [37] Tamoxifen vs Diethylstilbestrol (DES)

N

Outcome

143

ORR: 33 vs 41% (P = 0.37)

Muss et al. [38]

138

RI PT

TTP or PFS: 171 days vs 142 days (P= 0.95) Tamoxifen 10 mg BID vs DES 5 mg TID Tamoxifen vs Megesterol Acetate

ORR: 31 vs 28% (95% CI= 3±17%)

TTP or PFS: 7.7 vs 7.7 mos (P=0.007)

First-Line Aromatase Inhibitor Therapy Nabholtz et al. [40] Anastrozole vs Tamoxifen

353

ORR: 21 vs 17% CBR: 59 vs 46%

Anastrozole vs Tamoxifen

668

TTP or PFS: 11.1 vs 5.6* mos (P=0.005) ORR: 32.9 vs 32.6%

M AN U

Bonneterre et al. [42]

SC

Tamoxifen 10 mg BID vs Megestrol acetate 40 mg QID

CBR: 56.2 vs 55.5%

Mouridsen et al. [42]

Letrozole vs Tamoxifen

916

TTP or PFS: 8.2 vs 8.3 mos ORR: 32 vs 21%* CBR: 50 vs 38%

Paidaens et al. [43]

Exemestane vs Tamoxifen

371

TTP or PFS: 9.4 vs 6.0* mos ORR: 46 vs 31%*

TTP or PFS: 9.9 vs 5.8* mos (P = 0.0282)

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First-Line Fulvestrant Therapy Howell et al. [45]) Fulvestrant vs Tamoxifen

587

Fulvestrant 250 mg every 28 days Robertson et al. [46] Robertson et al. [47] FIRST Trial

Fulvestrant vs Anastrozole

Bergh et al. [48] FACT Trial

Fulvestrant + Anastrozole vs Anastrozole Alone

EP

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Mehta et al. [49] SWOG S0226

CBR: 54.3 vs 62% (P=0.026)

206

Fulvestrant 500mg Days 1, 14, 28 then every 28 days

Fulvestrant 250 mg every 28 days Fulvestrants + Anastrozole vs Anastrozole alone Fulvestrant 250 mg every 28 days

ORR: 31.6 vs 33.9% (P=0.45)

TTP or PFS: 6.8 vs 8.3 mos ORR: 36 vs 35.5% CBR: 72.5 vs 67%

514

TTP or PFS: 23.4 vs 13.1 mos ORR: 31.8 vs 33.6% (P=0.76) CBR: 55 vs 55.1% (P=0.99)

707

TTP or PFS: 10.8 vs 10.2 mos (P=0.91) ORR: 27 vs 22 % (P=0.26) CBR: 73 vs 70% (P=0.39) TTP or PFS: 15.5 vs 13.5 mos (P=0.007)

Abbreviations: ORR: objective response rate; TTP: time to progression; PFS: progression free survival; CI: confidence interval; CBR: clinical benefit rate.

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