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Abstract

Several advances in the adjuvant systemic therapy of primary breast cancer have occurred in the last decade and contributed to a decline in disease-related mortality. These include the introduction of aromatase inhibitors, new chemotherapy agents, and the novel antibody trastuzumab. New supportive treatments, such as growth factors, have contributed to the optimization of chemotherapy dose and schedule, and have improved the efficacy and safety of the treatment. In this review we will outline some of the recent advances in the adjuvant and neoadjuvant treatment of breast cancer. We will also discuss ongoing and proposed clinical trials.

Keywords

adjuvant treatment aromatase inhibitors breast cancer chemotherapy hormonal therapy neoadjuvant treatment trastuzumab

Breast cancer is the most commonly diagnosed malignancy among women worldwide and the second leading cause of cancer death. The American Cancer Society estimates that in 2006, over 210,000 women in the USA were diagnosed with breast cancer and approximately 41,000 died of the disease [101]. In addition, approximately 62,000 women were diagnosed with ductal carcinoma in situ (DCIS), the precursor of the invasive disease. While the incidence of breast cancer has been rising in the last two decades, disease-related mortality has declined. The decline in mortality is attributed to early screening, and optimal local and adjuvant systemic therapy [1]. Systemic therapy for breast cancer can be largely divided into hormonal manipulation, chemotherapy and novel therapy. In this review we will discuss some of the advances in the systemic therapy of breast cancer that have occurred in recent years.

Hormonal manipulation

The strong relationship between estrogen and the development and progression of breast cancer was recognized over a century ago. In 1895, Thomas Beatson, a surgeon from Scotland, described a clinical remission in two premenopausal women with advanced breast cancer following the removal of the ovaries [2]. Indeed, approximately 75% of newly diagnosed breast cancers are hormone-dependent as evident by the presence of estrogen receptors (ERs) and/or progesterone receptors (PRs) on tumor cells [3]. Once the ER was recognized as a target, treatments other than surgical castration or radiation of the ovaries became the goal [4].

Tamoxifen

Tamoxifen is a first-generation selective estrogen receptor modulator (SERM) and the most commonly used hormone therapy in the world. The drug acts as a selective antagonist of the ER, competitively blocking the binding of estrogen to its receptor [5]. Tamoxifen is metabolized to several compounds, mostly through the hepatic cytochrome P450 (CYP) enzymes. Metabolites such as 4-hydroxy tamoxifen and endoxifen are potent antiestrogens, while others are associated with estrogen-like activity. Tamoxifen was introduced as a systemic treatment for metastatic breast cancer and approved by the US FDA in 1977 for this indication [6]. Several clinical trials conducted worldwide have subsequently demonstrated that tamoxifen administered in the adjuvant setting is associated with a significant improvement in the risk of breast cancer recurrence and death.

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has met every 5 years since the mid-1980's to perform an overview of breast cancer-related, adjuvant, randomized clinical trials (designated the Oxford Overview). The most recent published analysis, which includes data presented at the 2000 meeting, reported that adjuvant tamoxifen reduces breast cancer recurrence in women whose tumors are ER positive by more than 40%, and the annual breast cancer death rate by 31% [7]. The benefits from tamoxifen were independent of the use of chemotherapy, age, PR status or other tumor characteristics. The results support the use of 5 years of tamoxifen. When used for 10 years, tamoxifen did not improve outcomes and led to an increased risk of adverse events [8]. When used for more than 5 years, the estrogen-like properties of tamoxifen increase the risk for adverse events such as endometrial cancer, thromboembolic disease and stroke, and outweigh potential additional benefits.

Importantly, not all patients with ER- or PR-expressing tumors benefit from tamoxifen. Several hypotheses have been proposed to explain potential mechanisms of resistance, including overexpression or amplification of other genes such as the human epidermal growth factor receptor (HER)2/neu proto-oncogene, other single genes, or gene signatures [9]. Whether HER2/neu, also designated epidermal growth factor receptor 2 (EGFR2 or c-erbB-2), overexpression or amplification predicts a relative resistance to tamoxifen is not known due to the lack of prospective trials that specifically addressed this question. One multigene assay, designated Oncotype Dx, has recently been introduced into practice and includes a series of five reference genes and 16 cancer-related genes that can be profiled using a reverse-transcriptase polymerase chain reaction (RT-PCR) method on slides obtained from paraffin-embedded tissues. The genes include housekeeping genes, genes that are associated with hormone responsiveness and genes associated with cell growth. The test results are translated into one score, designated recurrence score. Using the recurrence score, a woman can receive an estimate of her own risk of recurrence with tamoxifen, as well as a more individualized prediction of absolute benefit from chemotherapy [10]. Host factors, such as the presence of wild-type or variant alleles of CYP2D6, encoding for the most important enzyme in the tamoxifen to endoxifen metabolic pathway, may also predict the efficacy of tamoxifen's [11,12]. Both Oncotype Dx and CYP2D6 genotype are under additional evaluation in validation studies and should not be used routinely in clinical practice.

While investigations of the mechanisms of tamoxifen resistance and the methods of individualizing therapies continue, other agents that may block estrogen activity on the target cells have been proposed. Since the growth of ER-expressing cells is stimulated by estrogen, estrogen deprivation can reverse these effects. There are two main approaches to block the effects of estrogen on its target. The first, as outlined above, is the modulation of the receptor by an antagonist. A second approach involves manipulation of estrogen synthesis. Estrogen in premenopausal women is produced predominately in the ovaries. By contrast, circulating estrogens in postmenopausal women derive from the aromatization of circulating androgens into estrogens in peripheral tissues.

Aromatase inhibitors

Aromatase (CYP19 enzyme complex) plays an essential role in the biosynthesis of estrogen, catalyzing the last steps in the aromatization of androstendione and testosterone into estrone and estradiol [13]. Aromatase can be found in a variety of tissues including the ovaries, fat, muscle, liver and breast. In postmenopausal women, androstendione is present at higher plasma concentrations compared with testosterone. Androstendione is also associated with a high affinity with the aromatase enzyme and it is presumed that 85–90% of the circulating estrogen originates from the aromatization of androstendione [14,15]. It has also been suggested that estrogen production within the breast of postmenopausal women increases, and contributes to comparable concentrations of estrogen in the breast of both pre- and post-menopausal women, despite lower peripheral plasma concentrations seen in the latter group [16]. Aromatase inhibitors (AIs) can be divided into different classes. The steroidal AIs (type I inhibitors) are derivatives of androstendione that bind to the substrate-binding site of aromatase and lead, depending on the availability of the substrate, to a reversible or irreversible inhibition of the enzyme. The nonsteroidal agents (type II inhibitors) interact competitively with the heme group of the CYP component of aromatase [13]. The third-generation AIs include the nonsteroidal agents anastrozole and letrozole, and the steroidal AI exemestane. Preclinical and small clinical investigations suggest minor differences among the agents [17,18]; however, the clinical implications are unknown. Others suggested that the three third-generation AIs may be associated with a differential anticancer activity or effects on other target organs of estrogen, such as bone [19].

During the last 5 years, data from eight large, prospective, randomized clinical trials that incorporated an AI in the adjuvant treatment of breast cancer have been reported and have influenced the adjuvant treatment of breast cancer ( Table 1 ) [19 –31]. Three general approaches to incorporate adjuvant AI have been studied. The first approach compares 5 years of an AI versus tamoxifen up-front. The three trials included in this category are the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial [20], the Breast International Group trial 1–98 (BIG 1–98) [21] and the Tamoxifen and Exemestane Adjuvant Multicenter (TEAM) trial. Both the ATAC and BIG 1–98 trials demonstrated small improvements in disease-free survival favoring the AI. The main results from the TEAM trial have not been reported. A second approach included a comparison of 5 years of tamoxifenalone with tamoxifen followed by an AI in a ‘switching mode’ for a total of 5 years of hormonal therapy, as studied in the Intergroup Exemestane Study (IES) [30], the Italian Tamoxifen Anastrozole (ITA) trial [23] and the Arimidex/Novaldex and Austrian Breast and Colorectal Study Group trials designated ARNO95/ABCSG8 [24]. Disease-free survival improved for women in the sequential arms. In addition, IES suggests an improvement in overall survival for women with tumors that are ER positive or of unknown ER status. Recent publications of a pooled analysis of two consecutive Italian trials as well as a meta-analysis of the ABCSG8, the ARNO95 and the ITA trials reported a survival benefit for women who received tamoxifen followed by an AI compared with tamoxifen alone [25,26]. Finally, the National Cancer Institute of Canada Clinical Trials Group (NCIC) trial MA.17, ABCSG trial 6a and the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-33 evaluated the role of AIs in the extended adjuvant setting after the completion of 5 years of tamoxifen treatment [28,29,31]. Tamoxifen followed by an AI (total of 10 years of hormonal therapy) was associated with superior outcomes compared with 5 years of tamoxifen. The NCIC study has also suggested that women with node-positive disease are more likely to benefit from the extended adjuvant treatment compared with node-negative women [31].

Table 1.

Summary of the experience with third-generation aromatase inhibitors in the adjuvant treatment of postmenopausal women with breast cancer.

Trial	Author (year)	Number of patients (% node +)	Agent (duration in years)	DFS	TTR	TTDR	Ref.
Aromatase inhibitor upfront
ATAC	Howell (2005)	9366 (39)	Anastrozole (5) vs tamoxifen (5)	HR: 0.87; p = 0.01	HR: 0.79; p = 0.0005	HR: 0.86; p = 0.04	[20]
BIG 1–98	Thurlimann (2005)	8010 (41)	Letrozole (5) vs tamoxifen (5)	HR: 0.81; p = 0.003	HR: 0.72; p = 0.0002	HR: 0.73; p = 0.0012	[21]
TEAM	Not yet reported		Exemestane (5) vs tamoxifen (5)
Aromatase inhibitor in the sequential setting
IES	Coombes (2007)	4724 (44)	Tamoxifen → exemestane (total 5) vs tamoxifen (5)	HR: 0.75; p = 0.0001	Time to contralateral breast cancerHR 0.55; p = 0.03	HR 0.82; p = 0.03	[30]
ITA	Boccardo (2005)	448 (100)	Tamoxifen → anastrozole (total 5) vs tamoxifen (5)	RFS;HR: 0.35; p = 0.001	Local RFS;HR: 0.15; p = 0.003	Distant metastases-free survival; HR: 0.49; p = 0.06	[23]
ARNO95/ABCSG 8	Jakesz (2005)	3224 (27)	Tamoxifen → anastrozole (total 5) vs tamoxifen (5)	Event-free survivalHR: 0.59; p = 0.0008	HR: 0.61; p = 0.0067	Distant metastasis as first event; HR: 0.54; p = 0.0016	[24]
BIG 1–98	Not yet reported		Tamoxifen → letrozole vs letrozole → tamoxifen (total 5) vs tamoxifen (5) or letrozole (5)
Aromatase inhibitor in the extended setting
NCIC CTG MA. 17	Ingle (2006)	5187 (46)	Tamoxifen → letrozole (5 each) vs tamoxifen (5)	HR: 0.19; p < 0.0001	Not described	DDFSHR: 0.21; p = 0.0013	[27]
NSABP B-33	Mamounas (2006)	1598 (48)	Tamoxifen → exemestane (5 each) vs exemestane (5)	RR: 0.68; p = 0.07	RFS;RR: 0.44; p = 0.004	DDFSRR: 0.69; p = 0.13	[29]
ABCSG 6a	Jakesz (2005)	856 (42)	Tamoxifen → AG (total 5) vs tamoxifen (5) → anastrozole (3) vs nil	Disease recurrenceHR: 0.64; p = 0.047	Not described	Not described	[28]

ABCSG: Austrian Breast and Colorectal Study Group; AG: Aminoglutethimide; ARNO: Arimidex/Novaldex; ATAC: Arimidex, Tamoxifen Alone or in Combination; BIG: Breast International Group; DDFS: Distant disease-free survival; DFS: Disease-free survival; HR: Hazard Ratio; IES: Intergroup Exemestane Study; ITA Italian Tamoxifen Anastrozole trial; RFS: Recurrence free survival; NCIC CTG: National Cancer Institute of Canada Clinical Trials Group; NSABP: National Surgical Adjuvant Breast and Bowel Project; RFS: Recurrence free survival; TEAM: Tamoxifen and Exemestane Adjuvant Multicenter; TTDR: Time to distant recurrence; TTR: Time to recurrence.

In summary, the cumulative data suggest that AI therapy in each of the three settings (upfront, sequential or extended) is superior to 5 years of tamoxifen alone ( Table 1 ). Given the data, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have concluded that adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an AI to reduce the risk of tumor recurrence [32,33]. However, it is important to note that, despite the large amount of data, the full spectrum of benefits and adverse effects of AI therapy is not fully known due to the short-term follow-up. In addition, the optimal timing and duration of AI therapy has not been established. Results from ongoing trials will help determine the optimal use of AI.

Estrogen deprivation in premenopausal women

Tamoxifen remains the gold-standard hormonal treatment for premenopausal women. The tamoxifen-associated reduction in breast cancer recurrence and death is equivalent in pre- and post-menopausal women. Since major estrogen production in premenopausal women is concentrated in the ovary, adjuvant ovarian suppression has been investigated and is indeed associated with improved outcomes. Several studies have evaluated the role of luteinizing hormone-releasing hormone (LHRH) agonists in the adjuvant setting. However, most studies were conducted in the 1980s and early 1990s when tamoxifen was not considered a standard of care for premenopausal women. Therefore, most studies evaluated the role of LHRH agonists in addition to or instead of chemotherapy. The cumulative data suggest that LHRH agonists may improve outcomes of women with hormone receptor-positive breast cancer [7]. A major concern regarding prolonged ovarian suppression is quality of life. Recently, the International Breast Cancer Study Group (IBCSG) trial VIII compared quality of life and menopausal symptoms among 874 pre- and peri-menopausal women treated with goserelin alone, six treatments of combination chemotherapy with the cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimen, or CMF followed by goserelin. Compared with CMF-treated women, women receiving goserelin alone reported less impact on their quality of life in the first 6 months. At 3 years, quality of life was similar among the three groups, except for higher scores for hot flashes in the CMF-treated patients [34]. Retrospective analysis has also suggested that very young women with hormone-sensitive disease who resume menstruation following adjuvant chemotherapy may benefit from the addition of ovarian suppression to chemotherapy [35]. Several trials have been designed to address this question ( Table 2 ).

Table 2.

Ongoing trials incorporating aromatase inhibitors in premenopausal women.

Trial	Treatment arms (all arms include a 5-year treatment duration)
Chemotherapy at the discretion of treating physician
SOFT	Tamoxifen
	OFS* plus tamoxifen
	OFS* plus exemestane
TEXT	Triptorelin plus tamoxifen
	Triptorelin plus exemestane
ABCSG trial 12	Goserelin plus anastrozole
	Goserelin plus anastrozole plus zoledronic acid
	Goserelin plus tamoxifen
	Goserelin plus tamoxifen plus zoledronic acid
With chemotherapy
PERCHE	OFS‡ plus tamoxifen
	OFS‡ plus exemestane Chemotherapy plus
	OFS‡ plus tamoxifen Chemotherapy plus
	OFS‡ plus exemestane
PROMISE trial	Goserelin plus anastrozole ± radiotherapy
	Goserelin plus anastrozole ± radiotherapy plus FEC

The OFS might be reached by administration of triptorelin, surgical oophorectomy or ovarian irradiation.

‡

OFS by application of 5 years triptorelin or ovarectomy.

ABCSG: Austrian Breast and Colorectal Study Group; FEC: 5-Fluorouracil, Epirubicin and Cyclophosphamide; OFS: Ovarian function suppression; PERCHE: Premenopausal Endocrine Responsive Chemotherapy; PROMISE: PRemenopausal Optimal Management IS Endocrine therapy (BOOG1: The Promise Study); SOFT: Suppression of Ovarian Function Trial; TEXT: Tamoxifen and Exemestane Trial.

AIs should not be administered to premenopausal women as a monotherapy. AIs may reduce estrogen concentrations in premenopausal women and may be associated with an increase in gonadotropin secretion, promoting ovarian cysts. Furthermore, first- and second-generation AIs may not suppress plasma estrogen concentrations efficiently [36]. Small studies of the combination of LHRH agonists and AIs in premenopausal women with advanced breast cancer have demonstrated efficacy [37,38]. Several ongoing trials address the question whether a combination of an AI and ovarian suppression is associated with improved outcomes in the adjuvant treatment of hormone receptor-positive premenopausal patients ( Table 2 ).

Estrogen deprivation is clearly associated with bone mineral density loss. A significantly higher loss was demonstrated in premenopausal women treated with a combination of an AI and goserelin [39]. While estrogen deprivation-induced bone loss can be counteracted by concurrent therapy with zoledronic acid, it is not clear whether bisphosphonate therapy should be initiated prior to evidence of significant bone loss. Until results from ongoing trials are available, AIs should not be used in premenopausal women outside of clinical trials [40].

Neoadjuvant hormonal therapy

The idea of preoperative treatment was first introduced many decades ago to avoid surgery in elderly women [41]. Three Phase III trials compared 3–4 months of AI treatment with tamoxifen therapy in this setting ( Table 3 ). The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial was designed to mirror the large, adjuvant ATAC trial. The investigators hypothesized that studies in the preoperative setting may provide similar conclusions to trials in the adjuvant setting but with a smaller number of patients and a short-term follow-up. The authors did not observe significant differences in the objective response between the three treatment groups. A trend favoring anastrozole was observed in the HER2-positive cancers (odds ratio [OR] 58% in anastrozole- compared with 22% in tamoxifen-treated women, p = 0.18), but the number of patients in this subgroup was very small (n = 34) [42]. More recently, a retrospective analysis of the tumor blocks obtained from patients treated in the ATAC trial with either anastrozole or tamoxifen alone could not confirm differences between the two agents in women with HER2-positive or negative disease [43].

Table 3.

Overview of trials incorporating aromatase inhibitors in the preoperative setting in postmenopausal women with hormone receptor-positive breast cancer.

Trial	Author (year)	Treatment arms	Number of patients	Duration of treatment	Objective response	Ref.
IMPACT	Smith (2005)	Tamoxifen vs anastrozole vs combination	330	12 weeks	No significant difference	[42]
PROACT	Cataliotti (2006)	Anastrozole vs tamoxifen ± chemotherapy	451	12 weeks	Numerically higher for anastrozole without reaching significance	[44]
	Eiermann (2001)	Letrozole vs tamoxifen	337	16 weeks	55 vs 36% p < 0.001	[45]
	Semiglazov (2005)	Exemestane vs tamoxifen	151	12 weeks	76.3 vs 40% p = 0.05	[73]
ACOSOG Z1031	Ongoing	Anastrozole vs letrozole vs exemestane	Expected 375	16 weeks

ACOSOG: American College of Surgeons Oncology Group; IMPACT: Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen; PROACT: PReOperative Arimidex® Compared with Tamoxifen.

In contrast to the IMPACT trial, the Preoperative ‘Arimidex’ Compared with Tamoxifen (PROACT) trial compared objective responses to anastrozole or tamoxifen in the neoadjuvant setting with or without chemotherapy. The authors demonstrated that preoperative treatment with anastrozole was at least as effective as tamoxifen in all patients and was perhaps more effective than tamoxifen in certain subgroups [44]. In a third trial that compared letrozole and tamoxifen, the overall objective response was statistically significantly higher in the letrozole group (55 vs 36%, p < 0.001) [45]. A subsequent hypothesis-generating analysis revealed that 60% of the patients with centrally confirmed ER-and/or PR-positive tumors treated with letrozole responded to the treatment compared with 41% of the tamoxifen-treated patients (p = 0.004). Tumors that overexpressed EGFR or ErbB 1 or 2, were associated with response rates of 88 versus 21% (p = 0.0004) in the letrozole- and tamoxifen-treated patients, respectively [46].

The American College of Surgeons Oncology Group (ACOSOG) is currently comparing response and biomarker modulation to anastrozole, letrozole and exemestane administered for 16 weeks in a neoadjuvant setting. This immediate comparison will provide valuable information regarding the responsiveness, different side-effects and efficacy in relation to the expression of ER, PR and HER2. Until further information is available, preoperative hormone therapy should be used only in postmenopausal patients with endocrine-responsive disease to enhance breast conservation or to improve surgical options. Since response rates and breast conservation rates were higher in women treated with AIs compared with tamoxifen, AIs should be favored in this setting [47].

Adjuvant chemotherapy

The EBCTCG overview has also evaluated prospective clinical trials of adjuvant chemotherapy. Compared with no chemotherapy, chemotherapy of any type reduced the risk of breast cancer recurrence and mortality by 22 and 15%, respectively, and all-cause mortality by 13%. Anthracycline-based regimens provided additional benefit compared with the traditional CMF-containing regimens. Women who received anthracycline-based regimens showed greater reduction in annual odds of breast cancer recurrence of 11% and any death by 15% compared with those who received CMF-like regimens. Chemotherapy is associated with a larger benefit in younger women. In patients aged under 50 years, polychemotherapy was associated with a 12% reduction in absolute risk of breast cancer recurrence at 15 years and a 10% decrease in disease-related mortality compared with no chemotherapy. The results were more modest in women aged 50–59 years (4.1 and 3.0%) [7]. The magnitude of benefit was inversely correlated with age. Indeed, women aged 65 years or older had substantially less gain. Since age under 50 years has often been used as an indicator for premenopausal status, it is not possible to determine whether young age or premenopausal status is associated with an improved benefit from chemotherapy in the younger age group. Premenopausal women with ER-positive disease may gain additional benefit from chemotherapy-induced ovarian failure. In addition, cancer in younger women is more likely to lack hormone receptors and display high grade, factors that may predict relative chemosensitivity [48]. Older women may also gain less benefit from chemotherapy due to competing comorbidities, which may lead to lower life expectancy and poor performance status.

Recently, researchers compared differences in benefits from adjuvant chemotherapy in patients with ER-negative and -positive tumors. Data from three major adjuvant studies conducted by the Cancer and Acute Leukemia Group B (CALGB) and the US Breast Cancer Intergroup, designated CALGB 9741, CALGB 9344 and CALGB 8541, were included [49 –51]. The addition of chemotherapy was associated with a statistically significantly higher benefit in patients with ER-negative tumors, compared with the benefits observed with the same therapy in patients with ER-positive disease who have also received tamoxifen. In patients with ER-negative and -positive tumors, chemotherapy overall reduced mortality by 55 and 23%, respectively [52]. The most beneficial regimen in this analysis was the biweekly, or dose-dense, regimen of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with growth-factor support.

Whether there is an optimal adjuvant chemotherapy regimen for the treatment of breast cancer is not known. A large number of studies have compared different adjuvant chemotherapy regimens over the past 30 years. The choice of specific agents or combinations, dose, schedule, sequence and duration are under debate [48]. Based on data from 59 trials included in the Oxford Overview, which enrolled 183,514 patients, polychemotherapy was associated with a statistically significant reduction in both risk of breast cancer recurrence and mortality. Polychemotherapy, sequential or in combination, is better than single-agent therapy [7]. Other questions include the role of individual anthracycline, whether to add a taxane, and, if so, which. The choice and the dose of the anthracycline have been mostly dictated by geographical preferences (doxorubicin in the USA and epirubicin in Europe and Canada). Head-to-head comparisons of the different regimens are not available. It is therefore reasonable to utilize doxorubicin or epirubicin-based regimens.

Taxanes in the adjuvant setting

Based on encouraging experiences in metastatic breast cancer, several prospective trials evaluated the role of taxanes in addition to or instead of anthracycline therapy ( Table 4 ). The first study, designated CALBG 9344, reported that the addition of four cycles of paclitaxel to four cycles of standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²) improved disease-free survival and resulted in the US FDA approval of taxanes in the adjuvant setting [50]. The NSABP B-28 study has also investigated the use of paclitaxel following four cycles of standard AC, and supported the results from the CALBG 9344 [53]. However, a confounding factor in both the CALGB and NSABP studies was the number of cycles: four in the standard AC arm compared with eight in the AC followed by paclitaxel investigational arm. Others compared combination anthracycline-based therapy with or without taxanes. The Breast Cancer International Research Group (BCIRG) 001 study compared docetaxel, doxorubicin and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). With a median follow-up of 55 months, TAC compared with FAC was associated with a reduction in the risk of relapse by 28% (p = 0.001) and of death by 30% (p = 0.008) [54]. Other investigators have recently reported a comparison of four cycles of AC versus four cycles of docetaxel and cyclophosphamide combination. Superior disease-free survival was seen in the docetaxel- and cyclophosphamide-treated patients (hazard ratio [HR]: 0.67, p = 0.015). The differences in the overall survival were not significant (HR: 0.76, p = 0.13), but the study was not powered to detect such differences [55]. By contrast, the Eastern Cooperative Oncology Group (ECOG)/Intergroup 2197 study compared four cycles of AC with four cycles of combination doxorubicin and paclitaxel. Disease-free survival and overall survival were equivalent in the treatment groups [56]. The recently published 5-year follow-up of the French PACS 01 study demonstrated that outcomes were improved for node-positive patients who received three cycles of 5-fluorouracil, epirubicin (100 mg/m²) and cyclophosphamide (FEC100) followed by three cycles of docetaxel, compared with six cycles of FEC100 (disease-free survival: 73.2 vs 78.4%, p = 0.012 and overall survival: 86.7 vs 90.7%, p = 0.017) [57]. Finally, preliminary results of a head-to-head comparison of the two taxanes following adjuvant AC were reported. In ECOG 1193, women received four cycles of AC followed by paclitaxel or docetaxel administered every 3 weeks or weekly for a total of 12 weeks. With a median follow-up of 46.5 months, disease-free and overall survival did not differ among the groups; however, a trend favoring weekly paclitaxel was seen in ER-negative women [58].

Table 4.

Prospective randomized clinical trials of adjuvant taxane-containing chemotherapy regimens.

Trial	Author (year)	Number of patients (% node +)	Treatment arms (concentration in mg/m²)	Disease-free survival	Overall survival	Ref.
Taxane in addition to AC
CALGB 9344	Henderson (2003)	3121 (100)	4 × AC (60,75,90/600) every 3 weeks vs4 × AC (60,75,90/600) → 4 × P (175) every 3 weeks	65 vs 70%*	77 vs 80%*	[50]
NSABP B-28	Mamounas (2005)	3060 (100)	4 × AC (60/600) every 3 weeks vs4 × AC (60/600) → 4 × P (225) every 3 weeks	72 vs 76%HR: 0.83p = 0.006	No difference	[53]
Taxane instead of another chemotherapeutic agent
BCIRG 001	Martin (2005)	1491 (100)	6 × FAC (500/50/500) every 3 weeks vs6 × DAC (75/50/500) every 3 weeks	HR: 0.72p = 0.001	HR: 0.70p = 0.008	[54]
	Jones (2006)	1016 (52)	4 × AC (60/600) every 3 weeks vs4 × DC (75/600) every 3 weeks	80 vs 86%HR: 0.67p = 0.015	87 vs 90%HR: 0.76p = 0.13	[55]
ECOG/Intergroup 2197	Goldstein (2005)	2778 (35)	4 × AP (60/60) every 3 weeks vs4 × AC (60/600) every 3 weeks	No difference	No difference	[56]
Studies in which all arms included taxane
CALGB 9741	Citron (2003)	2005 (100)	4 × A (60) → 4 × P (175) → 4 × C (600) every 3 weeks vs4 × A (60) → 4 × P (175) → 4 × C (600) every 2 weeks vs4 × AC (60/600) → 4 × P (175) every 3 weeks vs4 × AC (60/600) → 4 × P (175) every 2 weeks	HR: 0.74p = 0.010‡	HR: 0.69 p = 0.013‡	[49]
ECOG/Intergroup 1199	Sparano et al. (2006)	4988 (unknown)	4 × AC → 4 × P (175) every 3 weeks vs4 × AC → 12 × P (80) every week vs4 × AC → 4 × D (100) every 3 weeks vs4 × AC → 12 × D (35) every week	No difference	No difference	[58]

Data shown for the comparison of AC alone versus AC → P, no evidence of a doxorubicin effect.

‡

Data shown for every 2 weeks arm vs every 3 weeks arm.

A: Doxorubicin; BCIRG: Breast Cancer International Research Group; C: Cyclophosphamide; CALGB: Cancer and Acute Leukemia Group B; D: Docetaxel; ECOG: Eastern Cooperative Oncology Group; F: Fluorouracil; HR: Hazard ratio; NSABP: National Surgical Adjuvant Breast and Bowel Project; P: Paclitaxel.

The Intergroup Trial 40101, in which women with 0–3 positive lymph nodes primary breast cancer are randomized to AC or paclitaxel given every 2 weeks for four or six cycles, was designed to address whether AC and paclitaxel are associated with similar benefits and to assess optimal duration. Over half of the expected patients have already been recruited to the study. Results from the NSABP B-30, in which 4000 node-positive patients were randomly assigned to AC followed by docetaxel, versus a combination of doxorubicin and docetaxel, or TAC, are also pending. In addition, accrual is ongoing to NSABP B-38, comparing TAC versus dose-dense AC followed by paclitaxel with or without gemcitabine. An adjuvant study conducted by the Southwest Oncology Group (SWOG) is comparing a continuous schedule of AC, versus AC every 2 weeks, followed by four cycles of paclitaxel administered either every 2 weeks or weekly in patients with node-positive or high-risk node-negative breast cancer. Another study is evaluating the addition of one of three bisphosphonates as adjuvant therapy for primary breast cancer.

Adjuvant chemotherapy & trastuzumab

The importance of HER2/neu as a prognostic and predictive factor in breast cancer has been established over the last two decades. Predictive factors such as the presence of hormone receptors or HER2/neu status play a clear role in the selection of optimal treatment of breast cancer. In 2005, all four trials that compared the addition of trastuzumab to adjuvant chemotherapy with chemotherapy alone have favored the trastuzumab-containing regimens ( Table 5 ). While all trials revealed improvement in disease- or recurrence-free survival, an improvement in the overall survival was seen only in the North American trial (which combined data from the NSABP trial and the North Central Cancer Treatment Group [NCCTG]/Intergroup trials) [59] and in the HERceptin Adjuvant (HERA) trial [60]. The BCIRG 006 trial was the only one containing an anthracycline-free regimen, attempting to reduce the cardiac toxicity for high-risk patients [61]. Additional follow-up is required to assess whether trastuzumab benefit is equal in women who received the agent in combination with chemotherapy or following the completion of all chemotherapy.

Table 5.

Prospective, randomized trials incorporating adjuvant trastuzumab.

Trial	Author (year)	Number of patients (% node +)	Treatment arms (concentration mg/m²)	Duration of trastuzumab	Disease-free survival	Overall survival	Ref.
HERA	Piccart-Gebhart (2005) Smith (2007)	3388 (67)	Any chemotherapy regimen → T (loading 8 mg → 6 mg every 3 weeks)	1 year*	HR: 0.63 p < 0.0001	HR: 0.63 p = 0.0051	[60]
NSABP B-31‡	Romond (2005)	1736 (100)	4 × AC (60/600) → 4 × P (175) every 3 weeks or 12 × P (80) every week ± T (loading 4 mg → 2 mg every week)	1 year	After 4 years 67.1 vs 85.3% HR: 0.48 p = 3 × 10⁻¹²	After 4 years 86.6 vs 91.4% HR: 0.67 p = 0.015	[59]
NCCTG 9831‡	Romond (2005)	1615 (88)	4 × AC (60/600) → 12 × P (80) every week ± T (loading 4 mg → 2 mg every week, starting after T or concurrent with T)	1 year	After 4 years 67.1 vs 85.3% HR: 0.48 p = 3 × 10⁻¹²	After 4 years 86.6 vs 91.4% HR: 0.67 p = 0.015	[59]
BCIRG 006	Slamon (2005)	3222 (72)	4 × AC (60/600) → 4 × D (100) every 3 weeks vs 4 × AC (60/600) → 4 × D (100) + T (every week during chemotherapy then every 3 weeks) vs 6 × DCarbo (100/AUC6) every 3 weeks + T (every week during chemotherapy then every 3 weeks)	1 year	73 vs 84 vs 80% HR: 0.49 (AC→TH vs AC→T) p < 0.0001 HR: 0.61 (TCH vs AC→T), p = 0.0002	Data not mature	[61]
FinHer	Joensuu (2006)	232 (84)	3 × D (100) every 3 weeks → 3 × FEC (600/60/600) every 3 weeks ± T (loading 4 mg → 2 mg every week) vs 3 × V (25) days 1,8,1 5 → 3 × FEC (600/60/600) every 3 weeks ± T (loading 4 mg → 2 mg every week)	9 weeks	89 vs 78% HR: 0.42 p = 0.01	HR for death 0.41 p = 0.07	[63]

2-year data not reported.

‡

The NSABP B-31 and NCCTG 9831 were analyzed together.

A: Doxorubicinl; AUC: Area under the curve; C: Cyclophosphamide; Carbo: Carboplatin; BCIRG: Breast Cancer International Research Group; D: Docetaxel; E: Epirubicin; F: 5-Fluorouracil; FinHer: Finland Herceptin; HERA: HERceptin Adjuvant; HR: Hazard ratio; NCCTG: North Central Cancer Treatment Group; n.s.: Not significant; NSABP: National Surgical Adjuvant Breast and Bowel Project; P: Paclitaxel; T: Trastuzumab; V: Vinorelbine.

The optimal duration of trastuzumab therapy has not yet been determined. Recently, the 2-year follow-up data of the HERA study were released, showing that 1 year of treatment with trastuzumab is associated with a significant overall survival benefit with a short–median follow-up of 23.5 months. The unadjusted HR for the risk of death with trastuzumab compared with observation alone was 0.66 (p = 0.0115) [62]. Results from the 1- versus 2-year trastuzumab therapy comparison are not yet published. Interestingly, the Finland Herceptin (FinHer) trial has demonstrated improved outcomes for the addition of 9 weeks of trastuzumab to chemotherapy [63]. Planned studies will address the optimal duration of trastuzumab and the addition of new agents such as the dual EGFR1 and 2 inhibitor lapatinib.

Neoadjuvant chemotherapy and/or trastuzumab

Neoadjuvant, also known as preoperative or primary, systemic chemotherapy has become widely accepted in the treatment of patients with locally advanced disease. The main goals of neoadjuvant chemotherapy in women with primary operable disease are to enhance breast conservation and improve surgical options. Another important goal is to utilize neoadjuvant therapy as an in vivo sensitivity marker of the tumor response. It has been suggested that the primary tumor can be used as a monitor for the treatment of micrometastasis. Indeed, women whose disease disappears completely after neoadjuvant therapy have improved disease-free and overall survival. Others hypothesized that drug resistance could be minimized with early exposure to systemic therapy [64]. The neoadjuvant approach has also become an important vehicle for the evaluation of new agents and the introduction and testing of surrogate markers for the prediction of tumor response and clinical outcome.

Over a dozen studies compared chemotherapy in the neoadjuvant setting versus the same regimen in the adjuvant setting. Although a difference in survival could not be found, the trials established that neoadjuvant chemotherapy is equivalent to postoperative therapy in terms of efficacy [47,65]. Newer studies evaluated the addition of taxanes. The first trial comparing the efficacy of docetaxel with an anthracycline-based regimen in the neoadjuvant setting was the Aberdeen trial [66]. An impressive survival benefit was demonstrated in this study after 65 months follow-up in women who received a taxane in addition to an anthracycline-based regimen [67]. However, the survival data are limited due to the small size of the study, which was not originally powered to detect survival differences. The largest neoadjuvant trial that incorporated a taxane was the NSABP B-27, demonstrating an increase in pathological complete response (pCR) for the addition of four cycles of docetaxel to AC in comparison with AC alone [68]. While large differences in survival could not be demonstrated among the treatment arms, women with a PCR had clearly enjoyed improved outcomes [69].

Trastuzumab was evaluated in small studies in the neoadjuvant setting. MD Anderson Cancer Center investigators conducted a study that compared paclitaxel followed by FEC with or without trastuzumab. The authors noted a high proportion of pCR in study participants, which led to an early closure of the trial. Indeed, 66.7% of women who received combination trastuzumab and chemotherapy had a pCR compared with 25% of women who received chemotherapy alone [70]. In a recent update the investigators revealed that the pCR rate among a larger cohort treated with chemotherapy plus trastuzumab was 60% [71].

Conclusion

A substantial amount of data have been compiled in the last three decades from large, prospective, randomized trials, which indicate a marked reduction in breast cancer-related mortality. The hormonal treatment for women with endocrine-responsive disease is the therapy of first choice and the benefits from additional chemotherapy are small. Additional tools are needed to determine with better accuracy who will benefit from endocrine interventions alone and who may require additional or alternative therapies. Compared with tamoxifen, AI therapy is associated with improved efficacy in several schedules in the adjuvant setting; however, the optimal sequence or duration of AI is not known. Ongoing studies in premenopausal women will help determine the benefits and risks from the addition of ovarian suppression to tamoxifen, or from ovarian suppression and AI. It is also hoped that additional information will be available regarding the long-term and individual susceptibility to AI-associated adverse events. Other studies may combine hormone therapies and chemotherapy.

The available data to date suggest that polychemotherapy regimens of 3–6 months are acceptable adjuvant systemic options for women with high-risk primary breast cancer. Node-negative women with moderate risk can be treated with 2–4 months of chemotherapy, while node-positive patients may derive additional benefit from longer treatment duration [48]. Consensus statements suggest that standard regimens include AC, CMF, doxorubicin followed by CMF, the Canadian cyclophosphamide, epirubicin, and 5-fluorouracil, cyclophosphamide, doxorubicin, and 5-fluorouracil dose-dense AC followed by paclitaxel, FEC 100 alone or followed by docetaxel, tailored-FEC and TAC [72]. The addition of taxanes to anthracycline-based therapy has been utilized primarily in node-positive women, but may be appropriate in women with high-risk node-negative disease.

The neoadjuvant approach is equally as effective as adjuvant therapy. Neoadjuvant chemotherapy may be offered to women who are expected to be candidates for adjuvant systemic therapy [47]. Compared with adjuvant therapy, neoadjuvant chemotherapy does not affect disease-free survival or overall survival, but may enhance breast conservation [47]. Women with cancers that overexpress or amplify HER2/neu should also receive trastuzumab, in the adjuvant or neoadjuvant setting. Trastuzumab may be administered with or following chemotherapy. Neoadjuvant therapy with an AI may be used in hormone receptor-positive postmenopausal women for whom chemotherapy is not recommended but who may benefit from reduction in tumor size to allow for breast conservation or to improve surgical outcomes.

Future perspective

Despite the reduction in breast cancer-related recurrence and death, many women suffer a relapse or present with a new metastatic disease. Metastatic breast cancer may be controlled or treated for many years, but remains largely incurable. Therefore, the optimization of adjuvant treatment for individual women remains a major goal. It is hoped that with our growing knowledge of the different features of breast tumors and host factors, the treatment will become much more individualized and targeted.

Ongoing investigations may help answer several questions. Several hormonal interventions are currently available for patients with a hormone receptor-expressing tumor. Evaluations of tumor and host characteristics will enable selection of the therapy with the best therapeutic profile for an individual. The role of AI needs to be further defined and the indication for premenopausal women further examined. Other questions include the appropriate schedule of AI, the choice of the agent in different biological settings (e.g., HER2-positive tumors, ER-negative and PR-positive tumors, or premenopausal patients), the overall duration of treatment and the probability of side effects. The optimal use of adjuvant LHRH agonist in combination with tamoxifen or an AI in premenopausal women with hormone receptor-positive disease is also under investigation. Ongoing research will also help determine the benefits of chemotherapy when added to hormone therapy in hormone receptor-positive individuals. For example, over 10,000 women will be recruited to the Trial Assigning IndividuaLized Options for Treatment Rx (TAILORx), a study that was recently launched to examine whether genes that are frequently associated with risk of recurrence for women with early-stage breast cancer can be used to assign patients to the most appropriate treatment. The study will also provide a large tissue and blood database for future assessments.

Executive summary

Hormonal manipulation

Tamoxifen

Adjuvant tamoxifen for 5 years reduces breast cancer recurrence in women whose tumors are estrogen receptor (ER)-positive by more than 40%, and the annual breast cancer death rate by 31 %.

The benefits from tamoxifen are independent of the use of chemotherapy, age, progesterone receptor status or other tumor characteristics.

Aromatase inhibitors:

During the last 5 years, data from seven large, prospective, randomized clinical trials that incorporated aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer have been reported and have influenced the adjuvant treatment of breast cancer.

Cumulative data suggest that an AI in each of the three settings (upfront, sequential or extended) is superior to 5 years of tamoxifen alone.

The American Society of Clinical Oncology and the National Comprehensive Cancer Network have concluded that adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an AI.

Estrogen deprivation in premenopausal women:

Tamoxifen remains the gold standard in the hormonal treatment of premenopausal women.

Cumulative data suggest that lutenizing hormone-releasing hormone agonists may improve outcomes in women with hormone receptor-positive breast cancer. Retrospective analysis has also suggested that very young women with hormone-sensitive disease who resume menstruation following adjuvant chemotherapy may benefit from the addition of ovarian suppression to chemotherapy.

AIs should not be administered to premenopausal women as a monotherapy.

Neoadjuvant hormonal therapy:

Three Phase III trials compared 3–4 months treatment with an AI or tamoxifen in this setting.

Preoperative hormone therapy should be used only in postmenopausal patients with endocrine-responsive disease to enhance breast conservation or improve surgical options.

Adjuvant chemotherapy

Compared with no chemotherapy, chemotherapy of any type reduces the risk of breast cancer recurrence and mortality.

Anthracycline-based regimens provide additional benefit compared with the traditional cyclophosphamide, methotrexate and 5-fluorouracil-containing regimens.

The choice and dose of the anthracycline have been mostly dictated by geographical preferences. It is reasonable to utilize doxorubicin- or epirubicin-based regimens.

The addition of chemotherapy was associated with a statistically significantly higher benefit in patients with ER-negative tumors, compared with the benefits observed with the same therapy in patients with ER-positive disease who have also received tamoxifen.

Choice of specific agents or combinations, dose, schedule, sequence and duration are still debated.

Taxanes in the adjuvant setting:

Prospective trials suggest small benefits from the addition of taxane to anthracycline-based therapy in women with ER-positive or -negative high-risk primary breast cancer.

Adjuvant chemotherapy and trastuzumab:

In 2005, all four trials that compared combination of chemotherapy and trastuzumab to chemotherapy alone have favored trastuzumab-containing regimens.

An improvement in the overall survival was only seen in the North American trial and in the HERceptin Adjuvant trial.

The Breast Cancer International Research Group (BCIRG) 006 Trial was the only one containing an anthracycline-free regimen, thus demonstrating new possibilities to reduce the cardiac toxicity for high-risk patients.

Neoadjuvant chemotherapy and/or trastuzumab:

In women with primary operable disease, treatment with the same chemotherapy in the adjuvant or neoadjuvant setting is associated with a similar disease-free and overall survival.

The main goals of neoadjuvant chemotherapy in women with primary operable breast cancer are to enhance breast conservation and improve surgical options. Another important goal is to utilize the neoadjuvant therapy as an in vivo sensitivity marker of the tumor response.

An increase in pathological complete response for the addition of four cycles of docetaxel to doxorubicin and cyclophosphamide (AC) compared with AC alone was demonstrated in the National Surgical Adjuvant Breast and Bowel Project B-27. While a large difference in survival was not seen in the docetaxel-containing group, women with a complete pathological response had improved outcome. In a smaller study, the addition of taxanes to an anthracycline-based regimen was associated with a survival benefit.

The addition of trastuzumab to a preoperative anthracycline and taxane-containing regimen was related to an impressive improvement of the pathological complete response.

While it is expected that most women will gain benefit from adjuvant chemotherapy, many will recur despite the treatment, emphasizing the need for studies of resistance and mechanism of action. An exciting area of investigation is the implementation of new agents, antibodies and small molecules into the treatment of breast cancer. With the fast-growing number of these possibilities for treatment, a significant challenge is to determine how to effectively test these new agents or approaches either alone or in combination with standard or other novel therapies. Neoadjuvant chemotherapy may be an important tool to test drug sensitivity and incorporate novel agents, while minimizing the risks for patients not responding to the initial therapy.

Footnotes

Dr Stearns received investigator-initiated grants from Novartis Pharmaceuticals and Pfizer, Inc.

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American Cancer Society www.cancer.org

Advances in the Adjuvant and Neoadjuvant Treatment of Breast Cancer

Abstract

Keywords

Hormonal manipulation

Tamoxifen

Aromatase inhibitors

Estrogen deprivation in premenopausal women

Neoadjuvant hormonal therapy

Adjuvant chemotherapy

Taxanes in the adjuvant setting

Adjuvant chemotherapy & trastuzumab

Neoadjuvant chemotherapy and/or trastuzumab

Conclusion

Future perspective

Footnotes

References