Adjuvant Therapy for Breast Cancer

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 established an identifiable metastasis.

The image below depicts the anatomy of the breast.

Anatomy of the breast.

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Adjuvant systemic therapy in early-stage breast cancer

Agents used in adjuvant breast cancer systemic therapy include the following ^[1] :

• 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

• Pertuzumab: Used in combination with trastuzumab and chemotherapy as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence

• Ado-trastuzumab emtansine: Used in adjuvant treatment of patient with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment

• Trastuzumab: Used in the adjuvant treatment in patients with HER2-positive breast cancer

• 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; anastrozole, exemestane, letrozole): Inhibit aromatase, the enzyme responsible for converting other steroid hormones into estrogen

• Neratinib: A tyrosine kinase inhibitor approved for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer, following adjuvant trastuzumab-based therapy. 

​Combination regimens

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, particularly in patients with ER-negative disease.

Neoadjuvant chemotherapy

The best candidates for neoadjuvant chemotherapy are patients with ER-negative and/or HER2-positive expressing tumors, whose pathologically complete response (pCR) rates can approach 65% 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.

Targeted chemotherapy in early-stage breast cancer

Research has been performed on targeted chemotherapy agents, including the following:

• Cyclin-dependent kinase (CDK) inhibitors
• Small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)
• Blockade by antiangiogenic agents
• PI3K/Akt/mammalian target of rapamycin (mTor) inhibitors
• Poly(adenosine diphosphate [ADP] ̶ ribose) polymerase (PARP) inhibitors]

The CDK4/6 inhibitor abemaciclib (Verzenio) has been approved for use in early breast cancer for use in hormone receptor positve, HER2-negative early breast cancer, for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of ≥20%, as determined by a US Food and Drug Administration (FDA)–approved test. ^[2]

For more information, see Breast Cancer, HER2 Breast Cancer, and Breast Cancer Treatment Protocols.

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 established an 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.

However, genomic analysis may identify patients whose risk of metastasis is low even if they do not receive adjuvant treatment. In the MINDACT study, which used a 70-gene signature test (MammaPrint) to identify1550 women with early-stage breast cancer who were at high clinical risk but low genomic risk for recurrence, those patients who did not receive chemotherapy had a 5-year rate of survival without distant metastasis of 94.7% (95% confidence interval, 92.5% to 96.2%). That rate was 1.5 percentage points lower than the rate in woment who did receive chemotherapy.  The MINDACT investigators concluded that approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. ^[3]

A study by King et al found that the 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. ^[4]

Guidelines

In 2016 the American Society for Clinical Oncology (ASCO) published guidelines, based on the Cancer Care Ontario Clinical Practice Guideline, for the selection of optimal adjuvant chemotherapy regimens for HER2-negative and HER2-positive breast cancers. ^[5]  The guidelines advised that treatment recommendations be guided by the following:

• Risk of recurrence
• Potential toxicities
• Comorbidities
• Overall likelihood of benefit  

Guideline recommendations included the following:

• For patients at high risk of recurrence, treatment with an anthracycline and a taxane is preferred
• For patients not felt to be candidates for anthracyclines, docetaxel/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil are acceptable alternative regimens 
• On the basis of recent negative trials, gemcitabine and capecitabine are not recommended in the adjuvant setttings
• For patients with node-negative Her2Neu-positive cancer (defined as 3+ on immunohistochemistry a ratio of ≥ 2.0 on fluorescent in situ hybridization [FISH] testing, or a Her2 copy number ≥ 6) with tumors > 1 cm, trastuzumab should be offered for 12 months. It can also be considered in patients with tumors ≤ 1 cm. When given in this setting, trastuzumab should be given concurrently with non-anthracycline chemotherapy.

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)

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) ^[17]
• C9344 - Addition of paclitaxel to standard-dose Adriamycin-cyclophosphamide [AC]) ^[18]
• C9741 - Comparison of 3- and 2-week dosing in patients with ER-positive and ER-negative disease ^[8]

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 randomized, prospective phase III CALGB 9741 study assigned 2005 subjects to one of 4 arms:

• Conventional AC x 4 cycles → T x 4 cycles (all q 3 weeks)
• AC × 4 cycles → T x 4 cycles  (all q 2 weeks)
• A × 4 cycles  →  T x 4 cycles → C x 4 cycles (all q 3 weeks)
• A × 4 cycles →  T x 4 cycles → C x 4 cycles (all q 2 weeks) 

Dosing was the same in all arms, and the dose-dense groups received peg-filgrastim support on day 2 of each 14-day cycle. The 4-year disease-free survival for the dose-dense groups was 82%, versus 75% for the other two. Subsequent trials have failed to replicate the results of this pivotal trial, so the dose-dense schedule has not emerged as the standard of the care.

In the phase III AZURE trial, the addition of zoledronic acid to standard adjuvant therapy in women with stage II/III breast cancer did not affect disease-free survival. However, zoledronic acid did reduce the development of bone metastases (hazard ratio [HR], 0.78). In women who had entered menopause more than 5 years before trial entry, zoledronic acid improved invasive disease–free survival (HR, 0.77). ^[19]

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.  Although they are gernally better tolerated than the anthracyclines, they can have considerable toxicity:  peripheral neuropathy, myelosuppression, myalgias, and the risk of infusions reactions.

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. ^[20]

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. ^[18]

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. ^[21]

However, the National Cancer Institute of Canada MA.21 ^[22] and UK TACT trials, ^[23] 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. ^[24]

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. ^[25]

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. ^[26] 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. ^[26]

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. ^[27]

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. ^[16]

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.

However, final analysis of the BCIRG-006 trial confirmed the increased toxicity of anthracyclines and called their therapeutic value into question. The 10-year disease-free survival was 74.6% with AC-TH versus 73.0% with TCH, and overall survival at 10 years was 85.9% and 83.3%, respectively, but neither difference reached statistical significance.

Safety differences in BCIRG-006 proved significant. Grades 3/4 congestive heart failure occurred in 21 AC-TH patients but in only 4 TCH patients (P = 0.0005) and a sustained  ≥10% relative decline in left ventricular ejection fraction was seen in 200 AC-TH patients, compared with 97 in TCH patients (P< 0.0001). Seven treatment-related cases of acute leukemia occurred in patients receiving anthracyclines, compared with one case in a TCH patient. ^[16]

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.

The drug combination uracil-tegafur (UFT) is not approved in the United States, but is used in many other countries worldwide. A study that compared the effectiveness of oral 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. ^[28]

Trastuzumab

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 pathologic complete response (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.

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. ^[29]

Pertuzumab

Pertuzumab (Perjeta), a humanized monoclonal antibody that blocks the activation of the HER2 receptor by hindering dimerization, was approved by the US Food and Drug Administration (FDA) in June 2012 in combination with trastuzumab and docetaxel for adjuvant treatment of metastatic HER2-positive cancer. Approval was based on results from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. ^[30]

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. ^[30]

The CLEOPATRA trial compared first-line trastuzumab plus docetaxel (plus placebo) with 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. ^[30]

The phase II TRYPHAENA cardiac safety trial found low rates of symptomatic left ventricular systolic dysfunction (LVSD) in 225 patients with locally advanced, operable, or inflammatory HER2-positive breast cancer. who received pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens. ^[31]  

On long-term efficacy analysis of TRYPHAENA, 3-year Kaplan-Meier survival estimates for disease-free survival (DFS) were 87-90%, depending on the specific regimen used; progression-free survival (PFS) rates were 87-89%. During post-treatment follow-up, LVSD of any grade occurred in 2.8-5.4% of patients, and declines in left ventricular ejection fraction of 10% to < 50% occurred in 11.1-16% of patients. ^[32]

In 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). ^[33]

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 pCR compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery. ^[34]  

Results on 5-year follow-up supported the primary endpoint of improved pCR when neoadjuvant therapy combines pertuzumab with trastuzumab and docetaxel, although confidence indices are large and overlapping. Additionally, the study results suggested that total pCR could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer. ^[35]

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine (Kadcyla)—trastuzumab covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative)—undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death. ^[36]

In 2019, the FDA approved ado-trastuzumab emtansine for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment.

Approval was based on KATHERINE, a randomized, multicenter, open-label clinical trial in which ado-trastuzumab emtansine reduced the risk of an invasive recurrence or death by 50% compared with trastuzumab, in 1486 patients with HER2-positive early-stage breast cancer with residual invasive disease after receiving neoadjuvant chemotherapy and trastuzumab. At the interim analysis, invasive disease or death had occurred in 12.2% of patients in the ado-trastuzumab emtansine arm, versus 22.2% in the trastuzumab arm. Secondary efficacy endpoints of disease-free survival and distant recurrence–free survival interval also showed clinically meaningful improvements with ado-trastuzumab emtansine relative to trastuzumab. ^[37]

Pertuzumab/trastuzumab/hyaluronidase (Phesgo)

In 2020, the FDA granted accelerated approval to a new fixed-dose combination, Phesgo (pertuzumab/trastuzumab/hyaluronidase), in combination with IV chemotherapy, for the treatment of early and metastatic HER2-positive breast cancer. Phesgo is administered subcutaneously, which allows patients to receive treatment either at a treatment center or at home by a healthcare professional.

Approval was based on FeDeriCa, an open-label, multicenter trial that randomized 500 patients to receive neoadjuvant chemotherapy with concurrent administration of either Phesgo or IV pertuzumab and trastuzumab during neoadjuvant and adjuvant therapies. Serum trough concentrations of Phesgo proved noninferior to those of IV pertuzumab/trastuzumab. The pathological complete response was 59.7% in the Phesgo arm and 59.5%% in the IV pertuzumab/trastuzumab arm. ^[38]

Pembrolizumab

Pwmbrolizumab is a monoclonal antibody to programmed cell death–1 protein (PD-1) and its ligands, PD-L1 and PD-L2. In 2021, the FDA approved pembrolizumab for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery. Approval was based on results of the KEYNOTE-522 trial. ^[39]

The FDA also approved use of pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an FDA-approved test Approval was based on results of the phase III KEYNOTE-522 trial. ^[40]  

In estrogen receptor (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] ^[41] ).

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, which has both beneficial and adverse consequences: in bone, the stimulation results in preservation of bone density; in endometrium, it leads 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. ^[42] However, the prognostic and predictive impact of ESR1 copy number changes requires further study, and such testing is not considered standard of care.

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. ^{[43, 44]}

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. ^{[43, 44]}

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. ^[45]

Postmenopausal patients should be offered adjuvant endocrine therapy with one of the following regimens ^{[43, 44]} :

• 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. ^{[43, 44]}

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). ^[46]

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%)
• Dyspareunia (3-5%)
• Urinary frequency or urgency (10%)
• Mood changes (12-18%)
• Depression (2-12%)

Although many patients attribute postdiagnosis weight gain to tamoxifen, the literature suggests only a 5% increase in weight is associated with tamoxifen use.

A study by Varga et al found that concomitant tamoxifen therapy demonstrated an independent role in the development of radiogenic lung fibrosis. ^[47]

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. ^[48] 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. ^[48]

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.  Some laboratories now offer CYP2D6 testing for patients treated with tamoxifen, but this testing is still controversial. For more information on tamoxifen metabolism, see Tamoxifen Metabolism and CYP2D6.

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.

Considerable interest has arisen regarding tamoxifen and 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. ^[49]  

At the 2009 American Society of Clinical Oncology (ASCO) 45th annual meeting, experts presented contradictory results on the risk of breast cancer recurrence with the use of SSRIs in women taking tamoxifen to reduce their risk of recurrence. However, they concurred that until more data are available, these patients should avoid concomitant use of SSRIs. ^{[49, 50, 51]}

More recently, Donneyong et al found no increase in all-cause mortality in patients taking tamoxifen and potent CYP2D6-inhibiting SSRIs compared with patients taking tamoxifen and other SSRIs. ^[52]  These authors reviewed data from five US databases on 14,532 women who were prescribed an SSRI either before or during their tamoxifen treatment; of those, 5,799 were prescribed paroxetine or fluoxetine, while the remainder received the weak CYP2D6 inhibitors citalopram, escitalopram, fluvoxamine, or sertraline.

Although the study sample was large, the study period was only 2 years, which many experts feel is too short to permit definitive conclusions. Consequently, until longer-term followup data become available, the use of potent CYP2D6 inhibitors should be avoided if possible in patients on tamoxifen. Other strong inhibitors of CYP2D6 include quinidine, risperidone, and tenofovir.

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. ^[53] 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. ^[54]

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. ^[55] 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 results of a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for 10 years were significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. ^[56]

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). ^[57] 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.

A meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) of randomized trials in early breast cancer  found that early recurrence rates favored AIs over tamoxifen in a variety of regimens; for example, with 5 years of AIs versus 5 years of tamoxifen, the rate ratio (RR) for recurrence with 5 years of aromatase inhibitor versus 5 years of tamoxifen was 0.64 in years 0-1 and 0.80 in years 2-3, but was not significantly different thereafter. The 10-year breast cancer mortality rates were approximately 15% lower in patients who received 5 years of an aromatase inhibitor than in those treated with 5 years of tamoxifen. ^[58]

Most programs of neoadjuvant therapy used in the United States have been anthracycline-based, with FAC (doxorubicin [Adriamycin] 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. ^[59]

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. ^[59]

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.

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. ^[60] 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. ^[61]

Locoregional therapy

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.