Adjuvant therapy for breast cancer is designed to treat micrometastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but have not yet had an established, identifiable metastasis.
The image below depicts the anatomy of the breast.
Chemotherapy in early-stage breast cancer
Agents used in adjuvant breast cancer chemotherapy include the following:
Taxanes: Among the most active and commonly used chemotherapeutic agents for the treatment of early stage breast cancer
Anthracyclines: Used in the treatment of early stage breast cancer for decades, although concerns regarding anthracycline-associated cardiotoxicity or leukemogenic potential remain
Tamoxifen: Used in the treatment of estrogen receptor (ER) ̶ positive breast cancer; decreases estrogen's ability to stimulate existing micrometastases or dormant cancer cells
Aromatase inhibitors (AIs): Inhibit aromatase, the enzyme responsible for converting other steroid hormones into estrogen
Combination chemotherapy regimens are standard recommendations in the adjuvant setting. Major Cancer and Leukemia Group B (CALGB) chemotherapy clinical trials have consistently shown that chemotherapy produces significantly better disease-free and overall survival in patients with ER-negative disease.
The best candidates for neoadjuvant chemotherapy are patients with ER-negative or HER2-positive expressing tumors whose pathologically complete response (pCR) rates are generally above 20% and predict long-term survival. Patients with ER-positive, HER2-negative locally advanced breast cancer (LABC) are unlikely to achieve a pCR from currently available chemotherapy.
Research has been performed on targeted chemotherapy agents, including the following:
Small-molecule vascular endothelial cell growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs)
Dual blockade by antiangiogenic/HER2 agents
Insulinlike growth factor–1 receptor inhibitors
PI3K/Akt/mammalian target of rapamycin (mTor) inhibitors
Heat shock protein 90 inhibitors
Poly(adenosine diphosphate [ADP] ̶ ribose) polymerase (PARP) inhibitors
Farnesyltransferase inhibitors (FTIs)
Src kinase inhibitors
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but have not yet had an established identifiable metastasis. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality rate.
A study by King et al found that low rates of occult contralateral breast cancer do not support the use of contralateral prophylactic mastectomy in average-risk women with newly diagnosed breast cancer. 
Combination Regimens for Breast Cancer
Combination chemotherapy regimens are standard recommendations in the adjuvant setting. The most commonly used regimens are shown in Table 1 below.
Table 1. Adjuvant Chemotherapy Regimens for Breast Cancer (Open Table in a new window)
|Regimen||Dose and Schedule||Frequency||Cycles|
|T - Docetaxel (Taxotere)||75 mg/m² IV day 1||Every 21 days||6|
|A – Doxorubicin (Adriamycin)||50 mg/m² IV day 1|
|C - Cyclophosphamide||500 mg/m² IV day 1|
|AC ⇒Taxol (T) (conventional regimen)|
|Adriamycin||60 mg/m² IV day 1||Every 21 days||4|
|Cyclophosphamide||600 mg/m² IV day 1|
|Paclitaxel (Taxol)||175 mg/m² IV day 1||Every 21 days||4|
|Adriamycin||60 mg/m² IV day 1||Every 14 days||4|
|Cyclophosphamide||600 mg/m² IV day 1|
|Paclitaxel||175 mg/m² IV day 1||Every 14 days||4|
|Adriamycin||20 mg/m² IV day 1||Every week||12|
|Cyclophosphamide||50 mg/m² PO||Every day|
|Paclitaxel||80 mg/m² IV day 1||Every week||12|
|AC ⇒T + H (trastuzumab [Herceptin])|
Trastuzumab dosage: 4 mg/kg IV load, then 2 mg/kg weekly with paclitaxel, then give 6 mg/kg IV every 3 weeks for 40 weeks
NOTE: Trastuzumab to be added to a weekly paclitaxel regimen in HER2-positive breast cancer patients
|5-Fluorouracil (5-FU)||500 mg/m² IV day 1||Every 21 days||6|
|Epirubicin||100 mg/m² IV day 1|
|Cyclophosphamide||500 mg/m² IV day 1|
|5-FU||600 mg/m² IV day 1||Every 21 days||4|
|Adriamycin||60 mg/m² IV day 1|
|Cyclophosphamide||600 mg/m² IV day 1|
|5-FU||500 mg/m² IV days 1 and 8||Every 28 days||6|
|Adriamycin||30 mg/m² IV days 1 and 8|
|Cyclophosphamide||100 mg/m² PO days 1-14|
|CMF (Bonadonna regimen)|
|Cyclophosphamide||100 mg/m² PO days 1-14||Every 28 days||6|
|Methotrexate||40 mg/m² IV days 1 and 8|
|5-FU||600 mg/m² IV days 1 and 8|
|Cyclophosphamide||50 mg/m² PO days 1-7||Weekly||24|
|Methotrexate||15 mg/m² IV|
|5-FU||300 mg/m² IV|
|Taxotere (Docetaxel)||75 mg/m² IV day 1||Every 21 days||4|
|Cyclophosphamide||600 mg/m² IV day 1|
|Taxotere||75 mg/m² IV day 1||Every 21 days||6|
|Carboplatin||AUC* 6 IV day 1|
4 mg/kg loading dose IV followed by
2 mg/kg/wk X 18 then q3wk X 12
*AUC = systemic exposure.
References for chemotherapy regimens: TAC, [2, 3] AC => Taxol (T) (conventional regimen),  AC ⇒T + H (trastuzumab [Herceptin]),  FEC-100,  FAC, [7, 8] CMF (Bonadonna regimen),  Metronomic regimen,  TC,  TCH 
Major chemotherapy clinical trials by the Cancer and Leukemia Group B (CALGB) from the last few decades have consistently shown that chemotherapy produces significantly better disease-free and overall survival in patients with estrogen receptor (ER)–negative disease. These trials included the following:
C8541 - Comparison of various doses of CAF (cyclophosphamide, doxorubicin [Adriamycin], and fluorouracil) 
C9344 - Addition of paclitaxel to standard-dose Adriamycin-cyclophosphamide [AC]) 
C9741 - Comparison of 3- and 2-week dosing in patients with ER-positive and ER-negative disease 
A comparison of the inferior-dose arm of C8541 with the dose-dense arm of C9741 demonstrated a remarkable 63% improvement in disease-free survival and a 59% improvement in overall survival in patients with ER-negative disease, compared with 32% improvement in disease-free survival and 18% improvement in overall survival in patients with ER-positive disease. Overall, the advantages of chemotherapy, particularly in ER-negative disease, were observed across all three trials, irrespective of the chemotherapy regimen used.
The AZURE trial is an ongoing phase III trial that is evaluating the role of zoledronic acid in the adjuvant therapy of women with stage II/III breast cancer.  Thus far, the study has determined that zoledronic acid is well tolerated and can be safely administered in addition to adjuvant therapy, including chemotherapy.
However, a separate study by Coleman et al found no significant benefits and an increased incidence of osteonecrosis of the jaw associated with zoledronic acid use. Those findings do not support the routine use of zoledronic acid in adjuvant management. 
Taxanes are among the most active and commonly used chemotherapeutic agents for the treatment of early-stage breast cancer. However, questions have lingered as to whether taxanes are the most effective chemotherapeutic agent to use in this setting and, if so, which is the best dosing schedule.
A Cochrane meta-analysis showed a statistically significant overall survival and disease-free survival for the taxane-containing regimens compared with the nontaxane regimens. The meta-analysis included 12 studies and more than 21,000 patients in evaluating the role of taxanes in the adjuvant treatment of operable breast cancer (stages I-III). However, this meta-analysis did not identify any subgroups of patients within the evaluated studies in which a taxane-containing regimen would be more effective. 
The Cancer and Leukemia Group B (CALGB) 9344 study demonstrated a survival benefit for the sequential use of paclitaxel following Adriamycin (doxorubicin) and cyclophosphamide (AC) chemotherapy. This investigation was one of the largest trials to evaluate taxanes in the adjuvant setting for early-stage breast cancer, with more than 3000 women with node-positive breast cancer. 
In a retrospective analysis of CALGB 9344 testing for HER2 status using 1322 original participant tumor blocks, HER2 positivity irrespective of estrogen receptor status predicted a significant benefit from paclitaxel in terms of reduced disease recurrence. Patients with ER-positive, HER2-negative, node-positive breast cancer did not seem to benefit from the addition of a taxane. 
However, the National Cancer Institute of Canada MA.21  and UK TACT trials,  which used taxane- and nontaxane-based chemotherapeutic regimens in early-stage breast cancer patients, did not demonstrate a benefit in using taxanes. Although the precise role of adjuvant taxane therapy remains controversial, the optimal scheduling of taxane administration has been determined.
The Eastern Coast Oncology Group (ECOG) 1199 study demonstrated that paclitaxel weekly and docetaxel every 3 weeks were superior to two other regimens in terms of disease-free survival after a median follow-up of 64 months. This trial randomized 4950 women with lymph node-positive or high-risk lymph node–negative early-stage breast cancer to four cycles of AC followed by four different taxane regimens: paclitaxel at 175 mg/m2 q3wk; paclitaxel at 80 mg/m2 weekly; docetaxel (Taxotere) at 100 mg/m2 q3wk; and docetaxel at 35 mg/m2 weekly. 
Similarly, the TAX 311 trial, performed by the US Oncology Group in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen, showed that every-3-week docetaxel at 100 mg/m2 improved time to progression (TTP) and overall survival when compared with paclitaxel at 175 mg/m2 given every 3 weeks. 
Thus, taxane-based regimens still have use in the treatment of early-stage breast cancer and should be considered in treating women, especially those with HER2-positive disease, using either the weekly paclitaxel or every-3-week docetaxel dosing schedules.
Anthracycline-containing adjuvant chemotherapy regimens have been used in the treatment of early-stage breast cancer for decades, although concerns regarding anthracycline-associated cardiotoxicity or leukemogenic potential remain. In the 2000 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview, anthracycline-based regimens were associated with an annual risk of cardiac mortality of 0.08% per year, as compared with 0.06% per year in patients treated with nonanthracycline-based regimens. However, the question of long-term cardiac safety remains, particularly for older women with early-stage breast cancer.
The US Oncology 9735 trial established TC (docetaxel/cyclophosphamide) as a viable option for treating women with early-stage breast cancer, especially those at high risk of cardiotoxicity or requiring only 12 weeks of therapy.  This study randomized 1016 women with operable breast cancer (stages I-III) to 4 cycles of TC versus 4 cycles of standard dose AC (Adriamycin/cyclophosphamide).
After a median of 7 years’ follow-up, both disease-free survival (81% vs 75%) and overall survival (87% vs 82%) were superior in the TC arm. Grade 5 cardiotoxicity (resulting in death) was seen in 6 patients treated with AC (4 from myocardial infarction; 2 from congestive heart failure) versus 2 patients (myocardial infarction) in the TC group. 
Additionally, a meta-analysis of 8 trials, comprising 6564 women with early-stage breast cancer, of anthracycline-based versus nonanthracycline-based regimens, suggested a benefit with anthracycline administration only in patients with HER2-positive disease. 
Biologically, anthracyclines inhibit topoisomerase IIa, whose gene (TOP2A) lies adjacent to the HER2 gene on chromosome 17. TOP2A is co-amplified in approximately 35% of HER2-overexpressing breast cancers.
The original trials demonstrating superiority of anthracycline-based regimens over CMF (cyclophosphamide, methotrexate, fluorouracil) did not include TOP2A or HER2 testing. The BCIRG 006 trial, which randomized women with HER2-positive disease to AC followed by T, AC followed by TH (docetaxel/trastuzumab [Herceptin]), or TCH (docetaxel and carboplatin plus trastuzumab), did test for TOP2A and HER2 co-amplification. 
This group comprises only approximately 8% of the total breast cancer population and may be the only subgroup to benefit from anthracycline administration. The role of TOP2A as a predictive marker of response to anthracyclines needs further validation. Until then, patients should not be deprived of anthracycline-based adjuvant chemotherapy if their risk assessment so determines it.
A study that compared the effectiveness of oral uracil-tegafur (UFT) with that of CMF given as a postoperative adjuvant to women with node-negative, high-risk breast cancer demonstrated that risk-free survival and overall survival were similar in the 2 groups, but the quality of life scores were higher for patients given UFT than for those given CMF. The study concluded that for women with node-negative, high-risk breast cancer, UFT is a promising alternative to CMF. 
An anthracycline followed by or concurrent with a taxane is the optimal therapy for "triple-negative" breast cancer patients with no medical contraindications. However, it remains unclear what the optimal combination chemotherapy regimen is for ER-positive, HER2-negative tumors. Currently, CMF, TC, or an anthracycline-based regimen may all be reasonable options.
Adjuvant Hormone Therapy
In ER-positive early-stage breast cancer, hormone therapy plays a main role in adjuvant treatment, either alone or in combination with chemotherapy. Hormone treatments function to decrease estrogen's ability to stimulate existing micrometastases or dormant cancer cells.
Adjuvant hormone therapy can reduce the relative risk of distant, ipsilateral, and contralateral breast cancer recurrence by up to 50% in tumors with high ER expression. FDA-approved endocrine therapies for adjuvant treatment of breast cancer include tamoxifen and the aromatase inhibitors (anastrozole, letrozole [Estroblock], exemestane [Aromasin]  ).
Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to and inhibits estrogen receptor signaling in the breast. As a receptor antagonist, it is effective in both premenopausal and postmenopausal women. Tamoxifen has ER-stimulating effects in other tissues, including bone (resulting in preservation of bone density) and endometrium (leading to a 2- to 4-fold increased risk of endometrial cancer).
A pilot study by Nielsen et al found that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen among patients with ER-positive early breast cancer.  However, the prognostic and predictive impact of ESR1 copy number changes requires further study.
Tamoxifen has been approved for breast cancer treatment since the early 1980s and has been shown in multiple studies to decrease breast cancer–associated mortality and recurrence. In an analysis of 55 trials evaluating tamoxifen versus placebo in the adjuvant treatment of breast cancer, 5 years of tamoxifen therapy resulted in a 47% reduction in recurrence and a 22% reduction in mortality.
In 2014, the American Society of Clinical Oncology (ASCO) issued an updated clinical practice guideline on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer. The guideline includes the recommendation that women with stage I to III disease consider taking tamoxifen for 10 years. [28, 29]
For pre- or perimenopausal patients, ASCO recommends offering adjuvant endocrine therapy with tamoxifen for 5 years, after which the patient should receive additional therapy based on her menopausal status. If the patient is premenopausal, she should be offered continued tamoxifen for a total duration of 10 years. If the patient is postmenopausal, she should be offered continued tamoxifen for a total duration of 10 years or an aromatase inhibitor for a total duration of up to 10 years of adjuvant endocrine therapy. [28, 29]
Tamoxifen for 10 years
An aromatase inhibitor for 5 years
Tamoxifen for 5 years, then switching to an aromatase inhibitor for up to 5 years
Tamoxifen for 2-3 years, then switching to an aromatase inhibitor for up to 5 years
Postmenopausal patients who are intolerant of either tamoxifen or an aromatase inhibitor should be offered an alternative adjuvant endocrine therapy. Patients who have received an aromatase inhibitor but discontinued treatment at less than 5 years may be offered tamoxifen for a total of 5 years. Patients who have received tamoxifen for 2-3 years should be offered an aromatase inhibitor for up to 5 years, for a total duration of up to 7-8 years of adjuvant endocrine therapy. [28, 29]
The 2000 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis demonstrated that the risk reduction from adjuvant tamoxifen is similar in older and younger women (or even superior in older women). 
Relative risk of recurrence by patient age was as follows:
Older than 70 years - 0.49
60-69 years - 0.55
50-59 years - 0.66
40-49 years - 0.71
Common adverse effects associated with tamoxifen included the following:
Hot flashes (up to 80%)
Vaginal bleeding (2-23%)
Vaginal discharge (13-55%)
Vaginal dryness (< 1%)
Urinary frequency or urgency (10%)
Mood changes (12-18%)
Although many patients attribute postdiagnosis weight gain to tamoxifen, the literature suggests only a 5% increase in weight is associated with tamoxifen use.
Tamoxifen is a prodrug that is metabolized primarily by the cytochrome P450 (CYP2D6) system to its active metabolite, endoxifen. More than 80 different alleles of the CYP2D6 gene have been identified with varying activity levels. Consequently, patients can be categorized by their level of CYP2D6 activity into high/extensive or low/poor metabolizers.
Up to 7% of the white and black populations are poor metabolizers of tamoxifen. Poor metabolizers have been shown in several retrospective studies to have lower disease-free survival and higher recurrence rates than extensive metabolizers. Poor metabolizers also seem to tolerate tamoxifen better, with less severe hot flashes and endocrine-related toxicities.
A study by Varga et al found that concomitant tamoxifen therapy demonstrated an independent role in the development of radiogenic lung fibrosis. 
A study by Tang et al compared the Oncotype DX Recurrence Score (RS) with the Adjuvant! scoring system in terms of genomic prediction of outcome and response to adjuvant chemotherapy in patients with ER-positive breast cancer. Both scoring systems provided strong independent prognostic information in tamoxifen-treated patients.  Combining RS and individual clinicopathologic characteristics was superior to prognostic discrimination using RS and the Adjuvant! system. The study’s authors suggest that RS should still be used for estimating relative chemotherapy benefit. 
Several laboratories now offer CYP2D6 testing for patients treated with tamoxifen. Recommendation for this testing is still controversial, but it is reasonable in women who have alternative treatment options.
Considerable interest has arisen in inhibitors of CYP2D6 activity. Many agents, of which the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac) and paroxetine (Paxil) are most prominent, are potent CYP2D6 inhibitors that can also decrease conversion of tamoxifen to endoxifen.  Thus, the use of potent CYP2D6 inhibitors should be avoided if possible in patients on tamoxifen. Other drugs that are strong inhibitors of CYP2D6 include quinidine, risperidone, and tenofovir.
At the 2009 American Society of Clinical Oncology (ASCO) 45th annual meeting, experts presented contradictory results on the risk of recurrence with the use of SSRIs in women taking tamoxifen to reduce their risk of breast cancer recurrence. However, they concurred that until more data are available, these patients should avoid concomitant use of SSRIs. [33, 34, 35]
A study by the Early Breast Cancer Trialists’ Collaborative Group found that 5 years of adjuvant tamoxifen therapy safely reduces the 15-year risks of breast cancer recurrence and death. 
For more information on tamoxifen metabolism, see Tamoxifen Metabolism and CYP2D6.
Aromatase inhibitors (AIs) function by inhibiting aromatase, the enzyme (found in body fat, adrenal glands, and breast tissue, as well as tumor cells) responsible for converting other steroid hormones into estrogen. Aromatase is the sole source of estrogen in postmenopausal women and likely the underlying reason that obesity (larger volume of body fat produces more estrogen) has been associated with a higher risk of breast cancer in postmenopausal patients.
As the AIs have no effect on ovarian estrogen production, these agents are effective only in postmenopausal women. Common side effects of AIs include hot flashes (12-36%), arthralgia/arthritis (17%), headache (9-13%), vaginal dryness (2%), and mood changes (19%).
Several large randomized trials, including the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, have shown AIs to be superior to tamoxifen with regard to disease-free survival in postmenopausal women with early-stage breast cancer.  The ATAC trial results are most mature at more than 100 months of follow-up and show anastrozole [Arimidex] to be superior to tamoxifen in improving disease-free survival. 
Significant benefit was also seen in time-to-recurrence of contralateral breast cancer. However, none of the head-to-head comparison trials has yielded an improvement in overall survival compared with tamoxifen. Early switching trials in which AIs are initiated after 2-3 years of tamoxifen have also shown improved disease-free survival. However, in contrast to the upfront trials, an improved overall survival is observed when ER-negative patients are excluded and randomization occurs at the time of switching.
The Canadian-led MA.17 trial randomized patients to an additional 5 years of AI therapy with letrozole after completion of 5 years of tamoxifen therapy and resulted in improved disease-free survival in all patients randomized, as well as improved overall survival in the higher-risk lymph node–positive subset of patients.  This study was the first to suggest that prolonged hormone therapy may be more effective than 5 years of therapy.
The optimal duration and sequence for the use of AIs has not been defined clearly, but their benefits in terms of breast cancer recurrence and survival clearly support their use in all postmenopausal women. Ongoing trials are now comparing 5 and 10 years of AI therapy, including a continuation of the MA.17 trial, which will include patients receiving hormone therapies for up to 15 years, and evaluation of whether the sequence of hormone agent (ie, tamoxifen followed by AI vs AI followed by tamoxifen) affects efficacy.
The BIG 1-98 Collaborative Group found that disease-free survival was not significantly better between 2 sequential treatment groups with letrozole and letrozole monotherapy and that overall survival was not statistically different between monotherapy with letrozole and monotherapy with tamoxifen (when combined with previous trial data comparing efficacy in 4922 postmenopausal patients with endocrine-responsive breast cancer for letrozole).  In this randomized, double-blind, phase III trial to evaluate the optimal treatment strategy, 6182 patients were randomly assigned to the following treatment groups: 5 years of tamoxifen; 5 years of letrozole; letrozole for 2 years followed by tamoxifen for 3 years; and tamoxifen for 2 years followed by letrozole for 3 years.
Most programs of neoadjuvant therapy used in the United States have been anthracycline-based, with FAC (doxorubicin in combination with fluorouracil and cyclophosphamide) as the best historical reference. In inflammatory breast cancer (IBC), the early program of 4 cycles of FAC, then surgery followed by an additional 4 cycles of FAC, then irradiation, led to a median survival of about 2 years and 5-year survival of about 30% of patients, which are dramatic improvements over historical outcome with local therapy alone (5-year survival of < 5%).
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial proved that preoperative chemotherapy with 4 cycles of standard-dose AC was equivalent to 4 cycles of postoperative standard-dose AC. This trial also found that pathologically complete response (pCR) in the primary tumor predicts excellent overall survival and is an excellent surrogate for long-term disease-free survival and overall survival. 
In the NSABP B-27 trial, the addition of 4 cycles of docetaxel to standard AC increased pCR from 14% to 26%; in addition, sandwiching surgery in between the chemotherapy regimens was less effective than administering all chemotherapy up front. This trial consisted of 3 arms: 4 cycles of standard-dose AC; 4 cycles of standard-dose AC combined with non–cross-resistant docetaxel at 100 mg/m2; and primary surgery sandwiched between the neoadjuvant 4 cycles of AC and the adjuvant 4 cycles of docetaxel. 
About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Patients who have no residual disease in both the primary site (pCR) and lymph nodes (N0) have the best overall prognosis, with a markedly prolonged disease-free survival.
To date, no cooperative group trial has attempted to improve upon the results of neoadjuvant chemotherapy, given as induction, with administration of alternative treatment after surgery when the surgical result was suboptimal. A final important observation made by the MD Anderson group, from a randomized design, was that 12 cycles of weekly docetaxel followed by FAC was superior to paclitaxel given every 3 weeks for 4 cycles, followed by the same FAC program, resulting in a doubling of the pCR rate for locally advanced breast cancer from 14% to 28%.
The pCR in this trial was defined as disappearance of microscopic evidence of all invasive disease at both the primary site and the axilla, whereas much of the other literature (including trials done by the NSABP) reports on pCR at the primary site only. About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Both criteria, however, predict for markedly superior long-term disease-free survival, with the pCR N0 criterion having the best outcome.
The Southwest Oncology Group (SWOG) confirmed the results of several other neoadjuvant trials in that ER-negative tumors have a higher pCR compared with ER-positive tumors and that infiltrating ductal histologies have a higher pCR rate compared with infiltrating lobular histologies. The investigators reported the preliminary results of their prospective, randomized trial in which "standard" AC, given every 3 weeks at standard doses, was compared with a schedule of continuous chemotherapy with the same agents (weekly Adriamycin [A], daily oral cyclophosphamide [C] [Cytoxan]) in patients with locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC).
The continuous or "metronomic" schedule required administration of granulocyte colony-stimulating factor (GCSF) as growth factor support. All patients on the trial, after completing AC, went on to receive weekly paclitaxel. The pCR rate was higher on the "continuous" arm, and this effect was most marked in patients with IBC, as well as triple negative (ER-negative, PR-negative, HER2-negative) patients with LABC.
For patients with HER2 overexpression, the value of adding trastuzumab in the adjuvant setting led to its incorporation into neoadjuvant therapies for patients with the HER2-positive phenotype. This results in higher rates of pCR for operable patients—as high as 65% initially reported by the MD Anderson group—when trastuzumab was given concurrently with an epirubicin (Ellence)-containing program. One preliminary report from a randomized trial in Europe indicates an improvement in pCR rate from 13% to 48% when trastuzumab was added to standard neoadjuvant chemotherapy.
A study by Slamon et al found that adding 1 year of adjuvant trastuzumab therapy significantly improved both disease-free and overall survival among women who had HER2-positive breast cancer. The TCH regimen was preferred over the doxorubicin and cyclophosphamide followed by docetaxel (AC-T) regimen due to fewer toxic effects and lower risks of cardiotoxicity and leukemia. 
Pertuzumab (Perjeta), a humanized monoclonal antibody that blocks the activation of the HER2 receptor by hindering dimerization, was approved by the FDA in June 2012 in combination with trastuzumab and docetaxel for adjuvant treatment of metastatic HER2-positive breast cancer. Approval was based on results from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. 
Pertuzumab elicits action at a different ligand binding site from trastuzumab to prevent HER2 dimerization. The combination of both HER2 receptor antibodies (pertuzumab plus trastuzumab) is superior to either agent alone. 
The CLEOPATRA trial compared first-line trastuzumab plus docetaxel (plus placebo) to trastuzumab plus docetaxel plus pertuzumab in HER2-postive metastatic breast cancer. Results from the study showed an average increase in progression-free survival of 6.1 months in patients receiving pertuzumab in addition to trastuzumab and docetaxel with minimal to no increase in cardiac toxic effects. 
In September 2013, pertuzumab became the first medicine approved by the FDA for the neoadjuvant treatment of breast cancer. The FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive). 
Approval was based on a randomized trial that compared a number of regimens with and without pertuzumab in women with HER2-positive breast cancer. In the trial, 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel (n = 107) achieved a pathologic complete response (pCR) compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery.  A confirmatory trial will provide long-term outcomes and is expected to be completed in 2016.
Although not yet tested on a large scale, it appears likely that the addition of agents with antiangiogenesis activity may also be of value as targeted therapy in IBC, given its profile of excessive blood vessel formation. Preclinical data suggest that metronomic chemotherapy works through an antiangiogenic mechanism, which may explain the apparent benefits seen from the SWOG trial for that regimen in patients with IBC.
Neoadjuvant hormone therapy
The best candidates for neoadjuvant chemotherapy are ER-negative or HER2-positive expressing tumors in which pCR rates are generally above 20% and predict long-term survival. Patients with ER-positive, HER2-negative LABC are unlikely to achieve a pCR from currently available chemotherapy, and the best approach for these patients is likely to involve building on a backbone of hormone therapy, either alone or in combination with targeted agents.
There has been little experience in the United States with neoadjuvant hormone therapy, although this approach has been tested in several clinical trials in Europe. Neoadjuvant hormone therapies appear to be very effective in shrinking tumor size to enable breast-conserving surgery, but pCR is rare.
A study by Fitzal et al determined that breast conserving therapy is oncologically safe after tumor downsizing via neoadjuvant chemotherapy in patients primarily scheduled for mastectomy.  However, the authors of that study advise that patients should not receive breast conserving therapy without a demonstrated response after neoadjuvant therapy.
A study by Jacobs et al determined that using multimodality proton, (23)Na MRI, and positron emission tomography (PET)/CT scanning metrics as radiological biomarkers is to monitor response to neoadjuvant chemotherapy is feasible. 
The NSABP B-18 trial found no significant difference in overall survival or disease-free survival between patients with operable breast cancer randomized to neoadjuvant chemotherapy and patients treated with surgery first and then followed by chemotherapy. However, survival advantage was significant for the 36% of patients who experienced a pCR.
Given the notorious propensity of IBC for locoregional as well as systemic recurrence, patients with this disease are nearly always best served by having mastectomy as their definitive surgery.
Advances in Targeted Therapy
The molecular era in cancer therapy has flourished and our knowledge of cancer biology has expanded. As increased numbers of targeted therapies show promise for the treatment of breast cancer, the goal is to optimize these expensive and toxic therapies with existing anticancer approaches.
Novel antiangiogenic agents
Small-molecule vascular endothelial cell growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) offer several potential advantages over antibody therapies, including oral administration, a shorter half-life, and multitargeted effects.
An open-label, multicenter, phase II study evaluated sunitinib (Sutent), an oral multi-targeted kinase inhibitor of VEGFR and platelet-derived growth factor (PDGF)receptor, as monotherapy in 64 metastatic breast cancer patients previously treated with an anthracycline and a taxane. Median time to progression (TTP) was 10 weeks, and overall survival was 38 weeks, with the best responses observed in triple-negative and HER2-positive disease. Most adverse events were grade 1/2 fatigue, nausea, and diarrhea, but 56% of patients required dose reductions. 
Sunitinib has also demonstrated activity in combination with paclitaxel (ORR = 33%) and sequentially with docetaxel (ORR = 72%) as first-line therapy in metastatic breast cancer.
Axitinib, another oral TKI of VEGFR, showed promising antitumor activity in combination with docetaxel in a randomized phase II trial of first-line chemotherapy in 168 patients with locally recurrent/metastatic breast cancer. The ORR was 40% in the axitinib/docetaxel arm, versus 23% in the docetaxel-alone arm, similar to the results from E2100. The most common adverse events included diarrhea (60%), nausea (53%), fatigue (49%), and stomatitis (44%), with an increase in febrile neutropenia with the combination arm (16%).
Other VEGFR TKIs such as pazopanib, vatalanib, cediranib, and motesanib are under investigation.
Dual blockade by antiangiogenic/HER2 agents
HER2-targeted therapies have been investigated in combination with angiogenesis inhibitors, with promising results. HER2 overexpression is associated with an increase in VEGF levels in primary breast cancers. Combination therapy targeting HER2, EGFR, and VEGF pathways produces greater inhibition of human breast cancer cell lines than inhibition of any single or dual pathway.
The angiogenesis inhibitor, pazopanib, showed promise in a randomized phase II study in combination with lapatinib versus lapatinib alone in chemotherapy-naive, HER2-positive metastatic breast cancer.  A 45% response rate was observed in the combination arm, compared with 28% in the lapatinib-alone arm at 12 weeks. Adverse events included diarrhea, rash, nausea, and elevated liver function tests, with only 5% experiencing cardiac toxicity in the combination arm.
Additional trials of lapatinib in combination with endocrine therapy or other targeted agents are ongoing.
Insulinlike growth factor–1 receptor inhibitors
Insulinlike growth factor–1 receptor (IGF-1R) overexpression is associated with the development of breast cancer and correlates with disease-free survival in patients with primary breast cancer. IGF-1R-mediated growth and antiapoptotic signaling occurs through the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways.
To date, drug development targeting the IGF pathway has focused on IGF-1R monoclonal antibodies (mAbs). Studies have shown that these compounds yield antitumor activity in several breast cancer models in vitro and in vivo.
Breast cancer cell lines with IGF-1R overexpression appear to be more resistant to trastuzumab and ER-targeted therapies; thus, clinical trials are focusing on hormone-refractory and/or HER2-positive disease. This strategy of dual targeting is being employed in an ongoing phase II trial of CP-751,871, an mAb targeting IGF-1R, in combination with the AI exemestane, compared with exemestane alone in postmenopausal patients with hormone receptor–positive advanced breast cancer.
PI3K/AKT/mammalian target of rapamycin (mTor) inhibitors
Among signaling pathways, the PI3K/Akt/mTor pathway is thought to be highly active in human breast cancer development and progression. In breast cancer, this pathway can be activated through PI3K by membrane protein receptors, including the HER family of growth factor receptors, IGF-1R and ER. PI3K activates downstream Akt, leading to mTor phosphorylation and promotion of breast cancer cell survival, as well as resistance to chemotherapy and targeted agents such as trastuzumab and tamoxifen.
Constitutively active mutations of PI3K have been described in up to 40% of primary breast cancer tumors, implicating a role for PI3K in breast cancer tumorigenesis. SF1126 is a chemical conjugate of LY294002, the most studied of the PI3K inhibitors. This compound has a broad spectrum of inhibition via Akt and mTor resulting in antitumor and antiangiogenic activity. The water-soluble SF1126 has a good pharmacokinetic profile and is well tolerated in murine systems. Phase I trials are ongoing with this compound and other novel PI3K inhibitors.
In preclinical breast cancer models, mTor inhibitors substantially inhibit tumor growth. In 109 heavily pretreated LABC or metastatic breast cancer patients, single-agent activity of the mTor inhibitor, temsirolimus (Torisel), yielded an overall response rate of 9%, consisting of 10 partial responses.
Based on preclinical data showing a synergistic effect between mTor inhibitors and endocrine therapy, clinical trials have focused on combination therapy. Initial randomized trials investigating letrozole alone or in combination with temsirolimus showed no significant clinical benefit in LABC/metastatic breast cancer.
However, a phase I study of letrozole in combination with daily everolimus (RAD001, Afinitor), another selective mTor inhibitor with a good safety profile, proved promising, with 1 complete response and 1 partial response in 18 patients with advanced breast cancer. The most common adverse events included stomatitis (50%), fatigue (44.4%), and diarrhea (38.9%).
In a recent study by Baselga et al, the addition of everolimus (10 mg/d) significantly increased letrozole (2.5 mg/d) efficacy (antiproliferative response defined by reduction of Ki67 expression) as compared with letrozole and placebo.  The study included 270 postmenopausal women with operable ER-positive breast cancer. Biopsies were obtained at baseline and after 2 weeks of treatment.
In July 2010, the US Food and Drug Administration approved everolimus (Afinitor) in combination with exemestane to treat postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer. The drug combination is intended to be used in women with recurrent or progressive breast cancer after failure of treatment with either letrozole (Femara) or anastrozole (Arimidex). Approval was based on another trial by Baselga of everolimus 10 mg/d plus exemestane 25 mg/d (n=485) vs placebo plus exemestane (n=239). Median progression-free survival was 11.0 months in the everolimus plus exemestane group compared with 4.1 months in the placebo plus exemestane group (P < 0.0001). 
Heat shock protein 90 inhibitors
Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of several expressed and/or activated signaling proteins. Direct inhibition of HSP90 inactivates, destabilizes, and degrades numerous chaperone-dependent client proteins, resulting in antitumor activity, antiangiogenesis, and apoptosis in cancer cells. A preclinical study reported that HER2 is particularly susceptible to degradation when exposed to the HSP90 inhibitor tanespimycin (KOS-953).
A phase I study of trastuzumab/tanespimycin in 25 patients with advanced solid tumors yielded a response in 5 patients with HER2-positive metastatic breast cancer. Furthermore, phase II results of trastuzumab/tanespimycin in trastuzumab-refractory metastatic breast cancer patients showed an ORR of 26%, with a clinical benefit rate of 63%. Drug-related toxicities included fatigue, diarrhea, dizziness, and headache. Grade 3/4 fatigue, elevated AST, and headache were observed in 2 patients each.
Poly(adenosine diphosphate [ADP] – ribose) polymerase (PARP) inhibitors were initially developed to investigate the role of PARP-1, a nuclear enzyme involved in DNA repair. However, these agents have also proven to have antitumor activity in breast cancer cells. BRCA1- and BRCA2-deficient cell lines are defective in homologous recombination, thus relying on PARP-1 for DNA repair. BRCA-deficient cells treated with PARP inhibitors demonstrate an increase in DNA fragmentation and cell death.
A phase IB study showed that BS-201, a PARP inhibitor, was well tolerated in combination with several chemotherapeutic agents in patients with advanced solid tumors. Thus, PARP inhibitors may have the potential to improve the efficacy of commonly used chemotherapeutics without adding significant toxicity.
Trials of PARP inhibitors in breast cancer patients are ongoing, including a phase II study of chemotherapy with or without BSI-201 in patients with triple-negative metastatic breast cancer. The PARP inhibitors AGO14699 and AZD2281 are also under investigation in phase I and II trials in patients with advanced breast cancer.
Results with BSI-201 were presented at the 2009 ASCO 45th annual meeting. In combination with conventional chemotherapy, a phase II study found that with BSI-201, women with metastatic triple-negative breast cancer had significant improvement in overall and progression-free survival compared with chemotherapy alone. [52, 53]
The Ras oncogene family is a key component of the MAPK signaling pathway, which promotes mitogenic activity. Aberrant Ras expression resulting in downstream signaling has been reported in breast cancer, although Ras mutations are rare in this malignancy.
Farnesyltransferase inhibitors (FTIs) such as tipifarnib and lonafarnib were developed to block farnesylation and subsequent membrane localization of Ras. Early clinical data suggested that FTIs may modulate endocrine response. However, a phase II randomized clinical trial of letrozole with or without tipifarnib in advanced breast cancer failed to meet its primary endpoint.
In contrast, a phase II trial showed an overall clinical benefit of 24% in ER-negative or hormone-refractory breast cancer patients treated with tipifarnib, sparking renewed interest in these agents. HER2-positive tumors derived the most clinical benefit from the addition of FTIs, suggesting that HER2 is upstream of Ras.
Src kinase inhibitors
Dasatinib (Sprycel) is a novel oral kinase inhibitor that targets the Src family kinases and BCR-abl. Dasatinib is approved by the FDA for the treatment of chronic myelogenous leukemia (CML).
A preclinical study revealed a dasatinib-sensitive signature in the basal breast cancer subtype. Additionally, preliminary results from a phase I study of gemcitabine/dasatinib demonstrated antitumor activity in a patient with IBC. Phase I and II clinical studies of dasatinib as a single agent or in combination with capecitabine in various breast cancer subtypes are under way. Studies of the combination of dasatinib and AIs are also under way in hormone receptor–positive metastatic breast cancer.