Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women, accounting for 25 % of the total cancer cases (1.68 million) and 15 % of the cancer deaths (520,000) worldwide [
1,
2]. In the United States, it is estimated that there will be 231,840 new cases of invasive breast cancer and 40,290 deaths from the disease in 2015, and that one in eight women will develop breast cancer during their lifetime [
3]. The disease is localized to the breast at presentation in 61 % of cases, regionally advanced in 32 %, and metastatic in 7 % [
4]. When localized or regionally advanced, the disease is potentially curable with local and systemic therapy. Adjuvant systemic therapies reduce the risk of distant recurrence, presumably by treating micro-metastatic disease that may not be clinically evident at the time of local therapy. Prognostic factors for distant recurrence irrespective of treatment include classical clinicopathologic features such as tumor size, tumor grade, and number of axillary lymph nodes with metastasis. Predictive factors that identify benefit from specific therapies include expression of the estrogen receptor (ER) and progesterone receptor (PR), which identify patients who benefit from adjuvant endocrine therapy [
5], and overexpression of human epidermal growth factor receptor 2 (HER2) protein (or HER2 gene amplification) [
6], which identifies patients who benefit from adjuvant HER2-directed therapy. Multiparameter gene expression assays may also provide both prognostic information and prediction of benefit from adjuvant chemotherapy in patients with ER-positive disease [
7,
8].
An abbreviated history of adjuvant systemic therapy
The initial approach to therapy for breast cancer was based on the premise that the disease metastasized via locoregional spread in an orderly fashion, and thus could be cured with aggressive surgery. The radical mastectomy was thus the standard surgical procedure for breast cancer in the early 20
th century [
9]. Randomized trials subsequently showed no benefit from radical mastectomy compared with less aggressive surgical procedures, and demonstrated that distant recurrence remained a major clinical problem irrespective of the primary surgical therapy [
10,
11].
As the approach to local therapy evolved from more aggressive to less aggressive, the types of adjuvant systemic therapies and their indications expanded. A series of seminal clinical trials demonstrated that adjuvant systemic chemotherapy, endocrine therapy, and anti-HER2 directed therapy substantially reduced the risk of recurrence and improved overall survival when added to local therapy. In addition to the milestones achieved by individual trials summarized in Box 1, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has periodically reported meta-analyses of all clinical trials with available data that have added to our knowledge about the benefits of adjuvant systemic therapy [
12‐
16]. Based upon the improvements in outcomes associated with systemic therapies described below, current adjuvant therapy options summarized in Table
1 are commonly tailored to four phenotypic subtypes that are defined in a practical manner by utilizing information on ER, PR, and HER2 expression. This practical phenotypic classification roughly corresponds to “intrinsic subtypes” identified by gene expression profiling [
17], although the latter classification may provide more accurate prognostic and predictive information [
18,
19].
Table 1
Systemic adjuvant therapy options for operable breast cancer
Hormone receptors | HER2 overexpression | | | | |
+
|
–
| Luminal A or B | Yes | No | Yes (if high risk) |
+
|
+
| Luminal B or HER2 enriched | Yes | Yes | Yes |
–
|
–
| Basal | No | No | Yes |
–
|
+
| HER2 enriched | No | Yes | Yes |
The first randomized trial evaluating adjuvant chemotherapy in breast cancer was the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-01 trial initiated in 1958, which reported in 1968 that an adjuvant alkylating agent (thiotepa) given after radical mastectomy significantly decreased recurrence rate in pre-menopausal women with four or more positive axillary lymph nodes [
20]. A subsequent randomized study reported in 1975 showed benefit from another alkylating agent (L-phenylalinine mustard) [
21]. Other reports from the Istituto Nazionale Tumori in Milan, Italy, showed that combination chemotherapy regimen called “CMF” including an alkylating agent (cyclophosphamide) and antimetabolites (methotrexate and 5-fluorouracil) significantly reduced the risk of recurrence [
22], thus ushering in the modern age of adjuvant polychemotherapy regimens that are now commonly used in clinical practice. These trials were among the first to establish a role for adjuvant chemotherapy, initially in premenopausal women with axillary node-positive disease at highest risk for recurrence [
22], with subsequent trials also showing benefit in lower risk post-menopausal women [
23] and women with axillary node-negative disease [
24‐
26]. In 2001, a National Institute of Health consensus panel in the US concluded: “
Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status.” [
27] Although the widespread adoption of more effective systemic therapies contributed to declining breast cancer mortality rates in the US and globally [
1,
28], it also resulted in many patients being unintentionally “overtreated” with chemotherapy who might otherwise may been cured without it. Several multiparameter gene expression assays have recently been shown to provide prognostic information in patients with ER-positive breast cancer [
7,
8] and also identify which patients derive greatest benefit from adjuvant chemotherapy [
29,
30]. Some of these assays are endorsed by evidence-based guidelines for making clinical decisions regarding the use of adjuvant chemotherapy in specific settings [
31].
Approximately 75 % of all breast cancers express hormone receptors [
5]. Endocrine therapy reduces the risk of recurrence in hormone receptor-expressing disease, whether used alone or in addition to chemotherapy. In 1982, adjuvant tamoxifen given for 2 years was shown to reduce the risk of recurrence [
32] and improve survival [
33]. Subsequent studies and a meta-analyses of these studies confirmed a survival benefit [
12], and also showed that 5 years of therapy was more effective than shorter durations, the proportional benefits were similar irrespective of nodal metastasis, and that the benefits were seen only in patients with ER-positive tumors [
13,
15]. Aromatase inhibitors were subsequently shown to be more effective than tamoxifen in postmenopausal women [
34,
35]. In addition, extended adjuvant therapy for up to 10 years was shown to be more effective than 5 years of therapy, including sequential tamoxifen followed by an aromatase inhibitor [
36], or tamoxifen for up to 10 years [
37]. Finally, in premenopausal women at high risk for recurrence, ovarian suppression plus an aromatase inhibitor was shown to be more effective than tamoxifen [
38,
39].
Approximately 25 % of all breast cancers overexpress the HER2 oncogene [
6]. In 2005, several randomized trials demonstrated that addition of the anti-HER2 antibody trastuzumab to adjuvant chemotherapy, either concurrently or sequentially, substantially decreased the risk of recurrence in patients with HER2 overexpressing node-positive or high-risk node-negative breast cancer [
40‐
43]. Addition of trastuzumab to sequential anthracycline/cyclophosphamide-taxane was associated with about a 3 % risk of cardiac toxicity [
40‐
42], while the combination of trastuzumab with non-anthracycline regimens (e.g. carboplatin/docetaxel) was associated with lower rates of cardiac toxicity [
43]. Non-randomized single arm studies have also shown excellent outcomes in patients with lower risk node-negative disease not included in other studies who would have been expected to have higher recurrence rates without adjuvant trastuzumab [
44,
45]. Subsequent studies demonstrated that 1 year of trastuzumab was more effective than 6 months [
46], but 2 years of therapy was no more effective than 1 year [
47]. The addition of the HER2 tyrosine kinase inhibitor lapatinib did not improve outcomes when added to trastuzumab [
48].
Adjuvant chemotherapy: first, second, and third generation regimens
Adjuvant! is a web-based decision aid commonly used in clinical practice that allows clinicians and patients to better understand the potential benefits of adjuvant therapy, especially chemotherapy [
49]. Estimates provided by Adjuvant! have been shown to correlate closely with actual clinical outcomes in population- and hospital-based cohorts [
50,
51]. Adjuvant! classifies adjuvant chemotherapy regimens as first, second, and third-generation, as exemplified in Table
2. A modification of this classification will be used here to categorize the numerous chemotherapy regimens discussed in this review, and to describe the clinical trials summarized in Table
3. The regimens used in these studies generally included anthracyclines (doxorubicin, epirubicin) and/or taxanes (paclitaxel, docetaxel), which are the two most active classes of cytotoxic agents for both early and advanced stage breast cancer.
Table 2
Classification of adjuvant chemotherapy regimens
First | 35 % reduction in breast cancer mortality compared with no adjuvant chemotherapy | CMFx6, ACx4, FEC50x6 |
Second | 20 % reduction in breast cancer mortality compared with first generation regimen | FEC100x6, CAFx6, FACx6 |
ACx4-Tx4 (q3wks) |
DCx4, Ex4-CMFx4 |
Third | 20 % reduction in breast cancer mortality compared with second generation regimen | FECx4-Dx3, FECx4-weekly Tx8 |
Concurrent DAC |
Dose-dense ACx4-Tx4 |
ACx4-weekly paclitaxel |
ACx4-docetaxel (q 3 weeks) |
Table 3
Select phase III trials of first, second, and third generation trials
First | | Positive | 386 | 28.5 | 0.71 (P = 0.005) | 0.79 (P = 0.04) |
| CMF + Tam vs Tam (B20) [ 26] | Negative | 2306 | 5 | 0.65 (P = 0.001) | 0.64 (P = 0.03) |
| | Positive | 2194 | 3 | P = 0.5* | P = 0.8* |
| | Negative | 2008 | 5 | P = 0.9* | P = 0.4* |
| | Positive | 457 | 9.4 | 0.46 (P = 0.0008) | 0.65 (P = 0.07) |
Second | | Positive | 546 | 5.6 | 0.63 (P = 0.02) | 0.45 (P = 0.005) |
| ACx4-Tx4 vs ACx4 (C9344) [ 82] | Positive | 3121 | 5.8 | 0.83 (P = 0.002) | 0.82 (P = 0.006) |
| ACx4-Tx4 vs ACx4 (B28) [ 83] | Positive | 3060 | 5.4 | 0.83 (P = 0.006) | 0.93 (P = 0.46) |
| | 0–3 Positive | 1016 | 7 | 0.74 (P = 0.033) | 0.69 (P = 0.032) |
| Ex4-CMFx4 vs CMFx6/CMFx8 [ 84] | Positive Negative | 2391 | 4 | 0.69 (P <0.001) | 0.67 (P <0.001) |
Third | | Positive | 1491 | 10.3 | 0.80 (P = 0.004) | 0.74 (P = 0.002) |
| | Negative | 1060 | 6.4 | 0.68 (P = 0.01) | 0.76 (P = 0.29) |
| | Positive | 1099 | 7.8 | 0.85 (P = 0.036) | 0.75 (P = 0.007) |
| | Positive | 1246 | 5.5 | 0.77 (P = 0.022) | 0.78 (P = 0.11) |
| FAC-weekly T vs FAC [ 113] | Negative | 1925 | 5.3 | 0.73 (P = 0.04) | 0.79 (P = 0.31) |
| | Positive | 2005 | 5.8 | 0.80 (P = 0.01) | 0.85 (P = 0.04) |
| AC-T vs AC-weekly T [ 100, 101] | Positive | 4954 | 12.1 | 0.84 (P = 0.011) | 0.87 (P = 0.09) |
AC-T vs AC-D | 0.79 (P = 0.001 | 0.86 (P = 0.054) |
| | Positive | 5351 | 6.1 | 0.83 (P = 0.01) | 0.86 (P = 0.09) |
AC-D vs AD | 0.80 (P = 0.001) | 0.83 (P = 0.03) |
Anthracyclines
Anthracyclines, derivatives of the antibiotic rhodomycin B, were initially isolated in the 1950s from gram-positive Streptomyces present in an Indian soil sample [
52]. Doxorubicin was isolated from
Streptomyces peucetius [
53], a mutant of the original Streptomyces strain found near the Adriatic sea, and was therefore named Adriamycin. Doxorubicin was found to be one of the most active single cytotoxic agents in metastatic breast cancer [
54,
55], although congestive cardiomyopathy emerged as a toxicity that required limiting the cumulative lifetime dose in order to minimize the risk of this toxicity [
56]. Epirubicin, an epimer of doxorubicin differing in the orientation of the C4 hydroxyl group on the sugar, is a less cardiotoxic anthracycline than doxorubicin [
57,
58].
Taxanes
Paclitaxel was originally isolated from the bark of the Pacific yew tree
taxus brevifolia, and its antitumor activity was initially described in 1971 [
59]. Paclitaxel binds to microtubules and induces their stabilization by inhibiting their depolymerization, thereby leading to mitotic arrest [
60,
61] and chromosome missegregation on abnormal multipolar spindles [
62,
63]. Despite its unique mechanism of action, paclitaxel’s initial development was slow due to its scarcity and poor solubility. A formulation of paclitaxel solubilized in Cremophor EL was eventually developed but was associated with hypersensitivity reactions to the Cremophor EL vehicle [
64], requiring premedication with corticosteroids and histamine blockers, which nearly thwarted paclitaxel’s clinical development. In 1994, Cremophor-EL-paclitaxel was approved by the United States Food and Drug Administration (FDA) for treatment of metastatic breast cancer in patients who had progressed after anthracycline-based combination chemotherapy or who relapsed less than 6 months after adjuvant therapy [
64]. In order to address the initial scarcity of paclitaxel, docetaxel, a semi-synthetic agent derived from the needles of the European yew tree
taxus baccata, was developed [
65]. Docetaxel has a similar mechanism of action to paclitaxel, but is a more potent microtubule inhibitor
in vitro [
65]. Docetaxel is also slightly more water-soluble than paclitaxel, and is dissolved in polysorbate-80. Despite the different solvent, premedication is also required to reduce the risk of acute hypersensitivity reactions and cumulative fluid retention associated with docetaxel infusions [
66]. A direct comparison of docetaxel with paclitaxel in metastatic breast cancer showed greater efficacy for docetaxel but more toxicity [
67], whereas a direct comparison of paclitaxel with doxorubicin as first line therapy showed comparable efficacy [
68]. Both of these agents have been extensively tested in adjuvant trials based upon substantial single agent activity for each agent in metastatic breast cancer [
69].
Tailoring the optimal regimen for individual patients
Factors considered in selecting patients for adjuvant therapy include tumor-specific factors, such as tumor size, axillary node metastasis, and tumor biology (i.e. ER/PR and HER2 expression, multiparameter gene expression assays), and patient specific factors such as age, comorbidities, and patient preference. A risk classification and potential therapeutic options for each risk category is proposed in Table
4. Patients with T1a tumors (1–5 mm) and negative nodes are at very low-risk of recurrence and generally do not require systemic chemotherapy. Patients with intermediate or high-risk disease should receive chemotherapy, whereas those with low-risk disease may be considered for chemotherapy if younger (<50–60 years). Patients with high-risk disease requiring chemotherapy are usually advised to receive an anthracycline and taxane containing regimen (i.e. third generation regimen), whereas those with low or moderate-risk disease may be treated with a taxane-containing regimen without an anthracycline (i.e. second generation regimen). All patients with ER- and/or PR-positive disease should always receive at least a 5-year course of endocrine therapy, usually initiated after chemotherapy is completed if given. Patients with HER2-positive disease should also always receive trastuzumab in combination with chemotherapy. Although data for adjuvant pertuzumab is currently lacking, it is recommended by National Comprehensive Cancer Center Network guidelines as a component of adjuvant therapy [
107] for high-risk HER2-positive breast cancer based on improved survival when used in metastatic HER2-postive breast cancer [
108], and improved pathologic complete response when used in locally advanced breast cancer [
109]. On the other hand, other expert panels do not recommend use of adjuvant pertuzumab until results of the APHINITY trial (NCT01358877) become available [
110], an adjuvant trial designed to determine whether adding pertuzumab to adjuvant trastuzumab-chemotherapy regimen improves clinical outcomes.
Table 4
Commonly recommended adjuvant chemotherapy regimens
Very low risk |
• Node-Neg, T1a | No chemotherapy | No chemotherapy | No chemotherapy |
Low risk |
• Node-Neg, T1b | Consider second generation chemotherapy regimen if RS is high | Consider second generation chemotherapy regimen | Consider weekly paclitaxel + H |
• Node-Neg, T1c, | Second generation chemotherapy regimen if RS is high (or consider if intermediate) | Second generation chemotherapy regimen | Weekly paclitaxel + H or TCH |
Moderate risk |
• Node-Neg, T2 | Second or third generation chemotherapy regimen if RS intermediate-high | Third generation chemotherapy regimen | AC-T + H or TCH +/− P |
High risk |
• 1+ Pos Nodes or T3 | Third generation chemotherapy regimen if RS intermediate-high (or 4+ positive nodes irrespective of RS) | Third generation chemotherapy regimen | AC-T + H or TCH+/−P |