Breast Cancer Treatment (PDQ®) 3/4 —Health Professional Version - National Cancer Institute

Breast Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Breast Cancer Treatment (PDQ®)–Health Professional Version

Early/Localized/Operable Breast Cancer

In This Section

• Treatment Option Overview for Early/Localized/Operable Breast Cancer
• Surgery
  • Locoregional treatment
  • Axillary lymph node management
  • Breast reconstruction
• Postoperative Radiation Therapy
  • Post–breast-conserving surgery
  • Regional nodal irradiation
  • Postmastectomy
  • Timing of postoperative radiation therapy
  • Late toxic effects of radiation
• Postoperative Systemic Therapy
  • Chemotherapy
  • HER2/neu–negative breast cancer
  • HER2/neu–positive breast cancer
  • Hormone receptor–positive breast cancer
  • Bisphosphonates
• Preoperative Systemic Therapy
  • Patient selection, staging, treatment, and follow-up
  • HER2/neu–negative breast cancer
  • HER2/neu-positive breast cancer
  • Cardiac toxic effects with pertuzumab and lapatinib
  • Preoperative endocrine therapy
  • Postoperative therapy
• Posttherapy Surveillance
• Current Clinical Trials

Treatment Option Overview for Early/Localized/Operable Breast Cancer

Standard treatment options for early, localized, or operable breast cancer may include the following:

Surgery:

1. Breast-conserving surgery (lumpectomy) and sentinel lymph node (SLN) biopsy with or without axillary lymph node dissection for positive SLNs.
2. Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Postoperative radiation therapy:

1. Axillary node–negative breast cancer (postmastectomy):
   • No additional therapy.
   • Radiation therapy.
2. Axillary node–positive breast cancer (postmastectomy):
   • For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.
   • For four or more nodes or extranodal involvement, regional radiation therapy is advised.
3. Axillary node–negative or positive breast cancer (post–breast-conserving therapy):
   • Whole-breast radiation therapy.

Postoperative systemic therapy:

1. Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu–negative] status). Adjuvant treatment options may include the following:
   • Tamoxifen.
   • Aromatase inhibitor (AI) therapy.
   • Ovarian function suppression.
   • Chemotherapy.

Preoperative systemic therapy:

1. Chemotherapy.
2. HER2 targeted therapy.
3. Endocrine therapy.

Surgery

Stages I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:

• Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.
• Surgical procedure. After the presence of a malignancy is confirmed by biopsy, the following surgical treatment options can be discussed with the patient before a therapeutic procedure is selected:
  • Breast-conserving surgery.
  • Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.[1-5]

Locoregional treatment

Selection of a local therapeutic approach depends on the following:[6]

• Location and size of the lesion.
• Analysis of the mammogram.
• Breast size.
• Patient’s desire to preserve the breast.

Options for surgical management of the primary tumor include the following:

• Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.[7] However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.
• Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is equivalent with any of these options, as documented in the trial of the European Organization for Research and Treatment of Cancer (EORTC) (EORTC-10801) [8] and other prospective randomized trials.[9-15] Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER positive or PR positive; ER negative and PR negative but HER2/neu positive; and triple negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.[16]

The rate of local recurrence in the breast after conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated.[17-19] However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:[20]

• Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.
• More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.
• There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re-excision. A clinical trial of 235 patients with stage 0 to III breast cancer who underwent partial mastectomy, with or without resection of selective margins, randomly assigned patients to have additional cavity shave margins resected (shave group) or not (no-shave group).[21] Patients in the shave group had a significantly lower rate of positive margins than those in the no-shave group (19% vs. 34%, P = .01) and a lower rate of second surgery for clearing margins (10% vs. 21%, P = .02).[21][Level of evidence: 1iiDiv]

Axillary lymph node management

Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[22,23] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[24][Level of evidence: 3iiiA]

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[25,26] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.[27-30]

Because of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

Evidence (SLN biopsy):

1. A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.[31][Level of evidence: 1iiC]
   • Quality of life (QOL) at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% deteriorating in the SLN biopsy group vs. 35% in the ALND group; P = .001). Arm function was also better in the SLN group.
2. The National Surgical Adjuvant Breast and Bowel Project’s (NSABP-B-32[NCT00003830]) multicenter, phase III trial randomly assigned women (N = 5,611) to undergo either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.[32][Level of evidence: 1iiA]
   • The study showed no detectable difference in overall survival (OS), disease-free survival (DFS), and regional control. OS was 91.8% for SLN plus ALND versus 90.3% for SLN resection alone (P = .12).

Because of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.

Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):

1. A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.[33][Level of evidence: 1iiA]
   • At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone.
   • The secondary endpoint of 5-year DFS was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.
2. In a similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to ALND or no ALND.[34][Level of evidence: 1iiA]
   • Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11).
   • No difference in OS was observed.
3. The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node.[35][Level of evidence: 1iiA]
   • ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.
   • The use of axillary radiation therapy was also associated with significantly less morbidity.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).[36-39] Breast contour can be restored by the following:

• Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA] website for more information on breast implants.)
• Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.

After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.[40]

Postoperative Radiation Therapy

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[41]

Post–breast-conserving surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women.[42] Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death.[43] Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Evidence (breast-conserving surgery followed by radiation therapy):

1. A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[43][Level of evidence: 1iiA]
   • Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% for whole-breast radiation therapy vs. 35% for breast-conserving surgery alone; relative risk (RR) = 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% for whole-breast radiation therapy vs. 25% for breast-conserving surgery alone; RR, 0.82; 95% CI, 0.75–0.90).

Regarding radiation dosing and schedule, the following has been noted:

• Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.
• Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[44][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).[45][Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[46][Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.[47]
• Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.
  • A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule.[48] The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).[48][Level of evidence: 1iiDii
  • Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to receive conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.[49][Level of evidence: 1iiDii]
  • A meta-analysis that included the three trials mentioned above plus six others confirmed that differences with respect to local recurrence or cosmesis between shorter and conventional fractionation schedules were neither statistically nor clinically significant.[50]
  Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.[49]

Regional nodal irradiation

Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes; however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear. A randomized trial (NCT00005957) of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence (10-year DFS, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS, 82.8% vs. 81.8%; HR, 0.91; 95% CI, 0.72–1.13; P = .38).[51][Level of evidence: 1iiA]

Similar findings were reported from the EORTC trial (NCT00002851). Women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to receive whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Breast-conserving surgery was performed for 76.1% of the study population, and the remaining study population underwent mastectomy. No improvement in OS was seen at 10 years among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal radiation (82.3% vs. 80.7%, P = .06). Distant DFS was improved among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal irradiation (78% vs. 75%, P = .02).[52][Level of evidence: 1iiA]

A meta-analysis that combined the results of the two trials mentioned above found a marginally statistically significant difference in OS (HR, 0.88; 95% CI, 0.78–0.99; P = .034; absolute difference, 1.6% at 5 years).[53]

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for locoregional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:[54-56]

• Four or more positive axillary nodes.
• Grossly evident extracapsular nodal extension.
• Large primary tumors.
• Very close or positive deep margins of resection of the primary tumor.

In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.[57]

Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.

Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):

1. The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[41][Level of evidence: 1iiA]
   • For women with node-positive disease postmastectomy and axillary clearance (removal of axillary lymph nodes and surrounding fat), radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95% CI, 15.2%–18.8%). This translated into a significant reduction (P = .002) in breast cancer mortality, 54.7% versus 60.1%, with an absolute gain of 5.4% (95% CI, 2.9%–7.9%).
   • In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P [2-sided significance level] < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).[58][Level of evidence: 1iiA]
   • In contrast, for women at low risk of local recurrence with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality (absolute gain, 1.0%; P > .1; 95% CI, -0.8%–2.8%).

Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.[59]

Timing of postoperative radiation therapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.

Evidence (timing of postoperative radiation therapy):

1. In a randomized trial, patients received one of the following regimens:[60][Level of evidence: 1iiA]
   1. Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation.
   2. Breast radiation first (n = 122), followed by the same chemotherapy.
   The following results were observed:
   • With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).
   • The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and 14% in the chemotherapy-first group for local recurrence and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07).
   • Further analyses revealed that differences in recurrence patterns persisted for most subgroups except for those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses was low.
   • Potential explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages because of increased myelosuppression.
2. Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.
   1. In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of cyclophosphamide, methotrexate, and 5-FU (CMF) (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.[61][Level of evidence: 1iiA]
      • No differences in DFS, distant DFS, and OS were observed between these two arms.
   2. The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.[62]

These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[63][Level of evidence: 1iiA]

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu–positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[64] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Late toxic effects of radiation

Late toxic effects of radiation therapy are uncommon and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:

• Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.[65] The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[65][Level of evidence: 3iii]
• Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.[57,66-68] This was probably caused by the radiation received by the left myocardium.
  Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.[69,70]
  An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) data from 1973 to 1989 that reviewed deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[71,72][Level of evidence: 3iB]
• Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy.[73-75] (Refer to the PDQ summary on Lymphedema for more information.)
• Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were monitored for 5.5 years to assess the rate of brachial plexus injury.[76] The diagnosis of such injury was made clinically with computerized tomography (CT) to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.
• Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy.[77] No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy.[78] Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.[79]
• Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years.[80] In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.[81]

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.

An international consensus panel proposed a risk classification system and systemic therapy treatment options.[82] This classification, with some modification, is described below:

Table 11. Systemic Treatment for Early Breast Cancer by Subtypea

Subtype	Treatment Options	Comments
HER2 = human epidermal growth factor receptor 2; LN = lymph node; PR = progesterone receptor.
aModified from Senkus et al.[82]
Luminal A–like
– Hormone receptor–positive	Endocrine therapy alone in most cases	Consider chemotherapy if:
– HER2-negative		– High tumor burden (≥4 LNs, T3 or higher)
– PR >20%
– Ki67 low		– Grade 3
Luminal B–like
– Hormone receptor–positive	Endocrine therapy plus chemotherapy in most cases
– HER2-negative
– Either Ki67 high or PR low
HER2-positive	Chemotherapy plus anti-HER2 therapy	Use endocrine therapy if also hormone receptor–positive
		May consider omitting chemotherapy plus anti-HER2 for small node-negative tumors
Triple-negative	Chemotherapy	May consider omitting chemotherapy for small node-negative tumors

The selection of therapy is most appropriately based on knowledge of an individual’s risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their situation. The treatment options described below should be modified based on both patient and tumor characteristics.

Table 12. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast Cancer

Patient Group	Treatment Options
ER = estrogen receptor; PR = progesterone receptor.
Premenopausal, hormone receptor–positive (ER or PR)	No additional therapy
	Tamoxifen
	Tamoxifen plus chemotherapy
	Ovarian function suppression plus tamoxifen
	Ovarian function suppression plus aromatase inhibitor
Premenopausal, hormone receptor–negative (ER or PR)	No additional therapy
	Chemotherapy
Postmenopausal, hormone receptor–positive (ER or PR)	No additional therapy
	Upfront aromatase inhibitor therapy or tamoxifen followed by aromatase inhibitor with or without chemotherapy
Postmenopausal, hormone receptor–negative (ER or PR)	No additional therapy
	Chemotherapy

Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (CMF)

The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and 5-FU). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.[83]

Evidence (anthracycline-based regimens):

1. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of 5-FU, epirubicin, and cyclophosphamide [FEC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]) with CMF (either PO or intravenous [IV]) in approximately 14,000 women, 64% of whom were younger than 50 years.[83]
   • Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[84][Level of evidence: 1iiA]
   • Of note, few women older than 70 years were studied, and specific conclusions could not be reached for this age group.
   • Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to hormone-receptor status, and the trials were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[83] As a result, the data may not reflect treatment outcomes based on evolving treatment patterns.

Study results suggest that tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.

Evidence (anthracycline-based regimen in women with HER2/neu amplification):

1. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and 5-FU (CAF),[2] or the addition of doxorubicin to the adjuvant regimen,[3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]
2. A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and 5-FU(CEF).[85][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods.
   • The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in relapse-free survival (RFS) and OS.
   • In patients with HER2/neu amplification, the RFS and OS were increased by CEF.
   • In the absence of HER2/neu amplification, CEF and CMF were similar with regard to RFS (HR for relapse, 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HRdeath, 1.06; 95% CI, 0.83–1.44; P = .68).
3. Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with nonanthracycline-containing regimens.[86]

Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy

Several trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.

Evidence (adding a taxane to an anthracycline-based regimen):

1. A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).[87][Level of evidence: 1iiA]
   • Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens.
   • There were no differences in benefit observed in patient subsets defined by nodal status, hormone-receptor status, or age and menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies that were reviewed involved a direct comparison between paclitaxel and docetaxel.
2. A U.S. intergroup study (CLB-9344 [NT00897026]) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to receive paclitaxel (175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with hormone receptor-positive tumors also received tamoxifen for 5 years.[88][Level of evidence: 1iiA]
   • Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).
3. The NSABP-B-28 (NCT01420185) trial randomly assigned 3,060 women with node-positive breast cancer to receive four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.[89][Level of evidence: 1iiA]
   • DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%).
   • The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).
4. In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.[90,91][Level of evidence: 1iiA]
   • There was a 75% DFS rate at 5 years in the TAC group compared with a 68% DFS rate in the FAC group (P = .001).
   • TAC was associated with a 30% overall lower risk of death (5% absolute difference) than was FAC (HR, 0.70; 98% CI, 0.53–0.91; P < .008).
   • Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group. (Refer to the PDQ summary on Fatigue for information on anemia.)

An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[92][Level of evidence: 1iiA] Study findings include the following:

• There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).
• There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).
• Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).
• Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.

Chemotherapy schedule: Dose-density

Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.

Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):

1. A U.S. intergroup trial (CLB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[93][Level of evidence: 1iiA]
   • At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P = .018), but not OS (HR, 0.85; P = .12).[94][Level of evidence: 1iiA]
   • There was no interaction between density and sequence.
   • Severe neutropenia was less frequent in patients who received the dose-dense regimens.[95][Level of evidence: 1iiA]
2. An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without 5-FU) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS.[96]
   • For the dose-density comparison, DFS at 5 years was 81% (95% CI, 79–84) in patients treated every 2 weeks and 76% (95% CI, 74–79) in patients treated every 3 weeks (HR, 0.77; 95% CI, 0.65–0.92; P = .004).
   • OS rates at 5 years were 94% (95% CI, 93–96) and 89% (95% CI, 87–91; HR, 0.65; 0.51–0.84; P = .001).[96][Level of evidence: 1iiA]
3. A meta-analysis of dose-dense versus standard dosing included data from eight trials including 17,188 patients.[97]
   • The patients who received dose-dense chemotherapy had better OS (HR, 0.86; 95% CI, 0.79–0.93; P = .0001) and DFS (HR, 0.84; 95% CI, 0.77–0.91; P < .0001) than those on the conventional schedule. A statistically significant OS benefit was observed in patients with ER-negative tumors (HR, 0.8; P = .002) but not in those with ER-positive breast cancer (HR, 0.93; 95% CI, 0.82–1.05; P = .25).
4. A randomized, phase III, double-blinded study (NCT01519700) demonstrated noninferiority for the duration of severe neutropenia of a biosimilar filgrastim, EP2006, compared with the U.S.-licensed product.[98][Level of evidence: 1iDiv]

Docetaxel and cyclophosphamide

Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):

1. The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.[99,100][Level of evidence: 1iiA]
   1. At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS.[100]
      • DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033).
      • OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032).
   2. Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.[99]

Timing of postoperative chemotherapy

The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:

1. A single-institution study of early-stage breast cancer patients diagnosed between 1997 and 2011 revealed that delays in initiation of adjuvant chemotherapy adversely affected survival outcomes.[101][Level of evidence: 3iiiA]
   • Initiation of chemotherapy 61 days or more after surgery was associated with adverse outcomes among patients with stage II breast cancer (distant relapse-free survival: HR, 1.20; 95% CI, 1.02–1.43) and stage III breast cancer (OS: HR, 1.76; 95% CI, 1.26–2.46; RFS: HR, 1.34; 95% CI, 1.01–1.76; and distant relapse-free survival: HR, 1.36; 95% CI, 1.02–1.80).
   • Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.
   • Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.

Toxic effects of chemotherapy

Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include the following:

• Nausea and vomiting.
• Myelosuppression.
• Alopecia.
• Mucositis.

Less common, but serious, toxic effects include the following:

• Heart failure (if an anthracycline is used).
• Thromboembolic events.[102]
• Premature menopause.[103]
• Second malignancy (leukemia).[104-106]

(Refer to the PDQ summary on Treatment-Related Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)

The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[104,105] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).[106]

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[107] However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer.[84] This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.

HER2/neu–negative breast cancer

For HER2/neu–negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.[108]

Triple-negative breast cancer (TNBC)

TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Combination chemotherapy

Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.[109]

Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):

1. A prospective analysis studied 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC.[110][Level of evidence: 3iiDiv]
   • The study observed that patients with TNBC had higher pathologic complete response (pCR) rates than did non-TNBC patients (22% vs. 11%; P = .034). Improved pCR rates may be important because in some studies, pCR is associated with improved long-term outcomes.

Platinum agents

Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[111][Level of evidence: 3iiiDiv] A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.

Poly (ADP-ribose) polymerase (PARP) inhibitor agents

The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC.[112] PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.

HER2/neu–positive breast cancer

Treatment options for HER2-positive early breast cancer:

Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.

Trastuzumab

Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.

Evidence (duration of trastuzumab therapy):

1. The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[113][Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:
   • Observation (n = 1,693).
   • 1 year of trastuzumab (n = 1,694).
   • 2 years of trastuzumab (n = 1,694).
   Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.[114]
   1. One year of trastuzumab versus observation:
      • After a median follow-up of 11 years,[114] the finding was that 1 year of trastuzumab improved DFS (HR, 0.76; 95% CI, 0.68–0.86; 10-year DFS, 72% vs. 66%; P < .0001), despite a crossover of 52% of the patients on observation.
      • One year of trastuzumab also improved OS (HR, 0.74; 95% CI, 0.64–0.86; 12-year OS, 79% vs. 73%; P < .0001).[114][Level of evidence: 1iiA]
   2. One year versus 2 years of trastuzumab:
      • After a median follow-up of 11 years, there was no benefit to an additional year of trastuzumab for DFS (HR, 1.02; 95% CI, 0.89–1.17).
   3. Symptomatic cardiac events occurred in 1% of the patients on trastuzumab and in 0.1% of the observation group.
2. In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[115,116][Level of evidence: 1iiA]
   • The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%) was observed, as was a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS, 91.4% in the trastuzumab group vs. 86.6% in the control group).[115]
   • Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).[115]
   • In an updated analysis with a median follow-up of 8.4 years, the addition of trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR, 0.63; 95% CI, 0.54–0.73; P < .001) and an increase in the 10-year OS rate from 75.2% to 84%.[117]
3. In the BCIRG-006 (NCT00021255) trial, 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a nonanthracycline-containing regimen).[118][Level of Evidence: 1iiA]
   • A significant DFS and OS benefit was seen in both groups treated with trastuzumab compared with the control group that did not receive trastuzumab.
   • For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04). The control group had a 5-year DFS rate of 75% and an OS rate of 87%.
   • The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.
   • The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).
   • These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.
   • This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.
4. The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[119][Level of evidence: 1iiA]
   • At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3-year DFS, 89% vs. 78%).
   • The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).
5. In contrast, another study failed to demonstrate that 6 months of adjuvant trastuzumab was noninferior to 12 months of treatment.[120][Level of evidence: 1iiA]
   • A 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).
   • Similar results were noted in a larger, multicenter, randomized study led by the Hellenic Oncology Research Group.[121][Level of evidence: 1iiA]
   • Therefore, 12 months remains the standard duration of trastuzumab adjuvant therapy.

Several studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.

Cardiac toxic effects with adjuvant trastuzumab

Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:

• In the HERA (BIG-01-01) trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab.[113] Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.
• In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.[122] The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).
• In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).
• In the AVENTIS-TAX-GMA-302 (BCIRG 006) (NCT00021255) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm.[123] There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.
• In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.[119]

Lapatinib

Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu–positive breast cancer.

Evidence (against the use of lapatinib for HER2-positive early breast cancer):

1. In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO[NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting was investigated.[124][Level of evidence: 1iiA]
   • In the primary analysis, at the median follow-up of 4.5 years (range, 1 day–6.4 years), a 16% reduction in the HR for DFS was observed in the lapatinib-plus-trastuzumab arm, compared with the trastuzumab-alone arm (555 DFS events; HR, 0.84; 97.5% CI, 0.70–1.02; P = .048), which was not statistically significant at the .025 significance level.
   • The HR for DFS for the superiority comparison of trastuzumab to lapatinib versus trastuzumab alone in the intention-to-treat population was 0.96 (97.5% CI, 0.80–1.15; P = .61).
   • The 4-year OS was 95% for the lapatinib-plus-trastuzumab arm, 95% for the trastuzumab-to-lapatinib arm, and 94% for the trastuzumab-alone arm. The HR for OS was 0.80 (95% CI, 0.62–1.03; P = .078) for the comparison of lapatinib plus trastuzumab versus trastuzumab alone and 0.91 (95% CI, 0.71–1.16; P = .433) for the comparison of trastuzumab to lapatinib versus trastuzumab alone.
   • The lapatinib-versus-trastuzumab component of the study was closed because, at interim analysis, the HR for DFS was 1.52 in favor of trastuzumab alone and noninferiority was excluded.
   • Combination therapy with lapatinib and trastuzumab also resulted in worsened grade 3 diarrhea (15% vs. 1%), grade 3 rash (5% vs. 1%), and grade 3 hepatobiliary adverse events (3% vs. 1%) compared with trastuzumab alone.

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Its use, in combination with trastuzumab, has been evaluated in a randomized trial in the postoperative setting.

Evidence (pertuzumab):

1. The Breast Intergroup (BIG) trial enrolled 4,805 women with HER2-positive cancer cells in a blinded comparison study for 12 months of trastuzumab plus placebo versus 12 months of trastuzumab plus pertuzumab, which were given in conjunction with standard chemotherapy and hormone therapy.[125]
   • At the time of the final analysis of the primary endpoint (breast cancer, RFS), there was a significant difference in favor of the combination regimen (HR, 0.81; 95% CI, 0.66–1.00; P = .045; 3-year invasive DFS, 94.1% vs. 93.2%).
   • There was no statistically significant difference in OS at the first interim analysis for this endpoint.
   • Patients receiving pertuzumab had more grade 3 diarrhea (9.8% vs. 3.7%) and were more likely to develop heart failure (0.6% vs. 0.2%).

Neratinib

Neratinib is an irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4, which has been approved by the FDA for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.

Evidence (Neratinib):

1. In the ExteNET (NCT00878709) trial, the safety and efficacy of 12 months of adjuvant neratinib was investigated in patients with early-stage HER2-positive breast cancer (n = 2,840) who had completed neoadjuvant trastuzumab up to 2 years before randomization. Patients received neratinib 240 mg oral daily for 1 year or a placebo.[126][Level of evidence: 1iiA]
   • The primary endpoint was invasive DFS.
   • After a median follow-up of 5.2 years (interquartile range, 2.1–5.3), patients in the neratinib group had significantly fewer invasive DFS events than those in the placebo group (neratinib group, 116 events vs. placebo group, 163 events; stratified HR, 0.73; 95% CI, 0.57–0.92; P = .0083). The 5-year invasive DFS was 90.2% (95% CI, 88.3–91.8) in the neratinib group and 87.7% (85.7–89.4) in the placebo group.[127]
   • OS data are not mature.
   • The most common grade 1 to 2 adverse events included diarrhea (neratinib, 55% vs. placebo, 34%), nausea (41% vs. 21%), fatigue (25% vs. 20%), vomiting (23% vs. 8%), and abdominal pain (22% vs. 10%). Prophylactic loperamide is recommended on the FDA label during the first 56 days of therapy, and as needed thereafter to help manage diarrhea.
   • The most common grade 3 to 4 adverse event was diarrhea (neratinib, 40% vs. placebo, 2%). All other grade 3 to 4 adverse events occurred in 2% or less of patients.

Hormone receptor–positive breast cancer

Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients.[128] Five years of adjuvant endocrine therapy has been shown to substantially reduce the risks of locoregional and distant recurrence, contralateral breast cancer, and death from breast cancer.

The optimal duration of endocrine therapy is unclear, with the preponderance of evidence supporting at least 5 years of endocrine therapy. A meta-analysis of 88 clinical trials involving 62,923 women with hormone receptor–positive breast cancer who were disease free after 5 years of endocrine therapy showed a steady risk of late recurrence 5 to 20 years after diagnosis.[129][Level of evidence: 3iiiD] The risk of distant recurrence correlated with the original tumor (T) and node (N) status, with risks ranging from 10% to 41%.

Tamoxifen

Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

Evidence (tamoxifen for hormone receptor–positive early breast cancer):

1. The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. An analysis published in 2005 included information on 80,273 women in 71 trials of adjuvant tamoxifen.[83][Level of evidence: 1iiA]
   • In this analysis, the benefit of tamoxifen was found to be restricted to women with hormone receptor–positive or hormone receptor–unknown breast tumors. In these women, the 15-year absolute reduction associated with 5 years of use was 12% for recurrence and 9% for mortality.
   • Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.
   • The meta-analysis also confirmed the benefit of adjuvant tamoxifen in hormone receptor–positive premenopausal women. Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the node-positive breast cancer group (5.3% vs. 12.5% with 5 years of use).
2. Similar results were found in the IBCSG-13-93 trial.[130] Of 1,246 women with stage II disease, only the women with hormone receptor–positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials.[83,131-134] Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.

Evidence (duration of tamoxifen therapy):

1. The EBCTCG meta-analysis demonstrated that 5 years of tamoxifen was superior to shorter durations. The following results were reported:[83]
   • A highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01) was observed.
2. Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS[NCT00003016]) trial demonstrated that 10 years of tamoxifen therapy was superior to 5 years of tamoxifen therapy. Between 1996 and 2005, 12,894 women with early breast cancer were randomly assigned to receive 10 years or 5 years of tamoxifen therapy. The following results were reported:[134][Level of Evidence: 1iiA]
   1. Study results revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences for 10 years of tamoxifen vs. 711 recurrences for 5 years of tamoxifen; P = .002), reduced breast-cancer mortality (331 deaths for 10 years of tamoxifen vs. 397 deaths for 5 years of tamoxifen; P= .01), and reduced overall mortality (639 deaths for 10 years of tamoxifen vs. 722 deaths for 5 years of tamoxifen; P = .01).
   2. Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% at 10 years and 12.2% at 5 years.
   3. Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:
      • Pulmonary embolus RR, 1.87; (95% CI, 1.13–3.07; P = .01).
      • Stroke RR, 1.06; (95% CI, 0.83–1.36).
      • Ischemic heart disease RR, 0.76; (95% CI, 0.6–0.95; P = .02).
      • Endometrial cancer RR, 1.74; (95% CI, 1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.
   The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial.[134] Women who have become menopausal after 5 years of tamoxifen may also be treated with AI. (Refer to the Aromatase inhibitors section in the Hormone receptor-positive therapy section of this summary for more information.)

Tamoxifen and chemotherapy

Because of the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy.[83] However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.[135]

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.[136-140] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.[138,140-143]

Evidence (tamoxifen plus ovarian suppression):

1. The largest study (SOFT [NCT00066690]) to examine the addition of ovarian ablation to tamoxifen with or without chemotherapy randomly assigned 2,033 premenopausal women (53% of whom had received previous chemotherapy) to receive tamoxifen or tamoxifen plus ovarian suppression with triptorelin or ablation with surgery or radiation therapy.[144][Level of evidence: 1iiDii]
   1. Upon initial report, with a median follow-up of 5.6 years, there was no significant difference in the primary outcome of DFS (HR, 0.83; 95% CI, 0.66–1.04; P = .10); 5-year DFS was 86% in the tamoxifen-plus-ovarian-suppression group versus 84.7% in the tamoxifen-alone group. However, updated results with a median follow-up of 8 years, demonstrated improved DFS with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.76; 95% CI, 0.62–0.93, P = .009); the 8-year DFS was 83.2% in the tamoxifen-plus-ovarian-suppression group versus 78.9% in the tamoxifen-alone group. In addition, OS at 8 years was improved with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.67; 95% CI, 0.48–0.92; P = .01); 8-year OS was 93.3% in the tamoxifen-plus-ovarian-suppression group versus 91.5% in the tamoxifen-alone group.
      Despite overall negative initial results, subgroup analysis suggested a benefit with ovarian suppression in women who underwent chemotherapy and remained premenopausal afterwards. Follow-up results at 8 years, however, did not demonstrate heterogeneity of treatment effect according to whether chemotherapy was administered, although recurrences were more frequent among patients who received chemotherapy.

Aromatase inhibitors (AI)

Premenopausal women

AI have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Evidence (comparison of an AI with tamoxifen in premenopausal women):

1. In one study (NCT00295646), 1,803 women who received goserelin were randomly assigned to a 2 × 2 factorial design trial that compared anastrozole and tamoxifen, with or without zoledronic acid.[145]
   • At a median follow-up of 62 months, there was no difference in DFS (HR, 1.08; 95% CI, 0.81–1.44; P = .59).
   • OS was superior with tamoxifen (HR, 1.75; 95% CI, 1.08–2.83; P = .02).
2. In two unblinded studies that were analyzed together (TEXT [NCT00066703] and SOFT[NCT00066690]), exemestane was also compared with tamoxifen in 4,690 premenopausal women who underwent ovarian ablation.[146]
   1. The use of exemestane resulted in a significant difference in DFS (HR, 0.77; 95% CI, 0.67–0.90; P < .001; 8-year DFS, 86.8% in the exemestane-ovarian suppression group vs. 82.8% in the tamoxifen-ovarian-suppression group).[146][Level of evidence: 1iDii]
   2. The 8-year rate of freedom from distant recurrence was also higher in the exemestane-ovarian-suppression group (HR, 0.80; 95% CI, 0.66–0.96; P = .02); 8-year rate of freedom from distant recurrence was 91.8% in the exemestane-ovarian-suppression group versus 89.7% in the tamoxifen-ovarian-suppression group.
   3. Despite improvements in DFS and freedom from distant recurrence, no difference in OS was observed with the use of exemestane in combination with ovarian suppression compared with tamoxifen in combination with ovarian suppression (HR 0.98; 95% CI, 0.79–1.22; P = .84; 8-year OS, 93.4% in the exemestane-ovarian suppression group vs. 93.3% in the tamoxifen-ovarian-suppression group).[146][Level of evidence: 1iiA]
   4. A follow-up report on the differences in QOL for the exemestane-ovarian-suppression group versus the tamoxifen-ovarian-suppression group observed the following (the differences cited below were all significant at P < .001 and occurred in patients who did and did not receive chemotherapy):[147]
      • Patients who received tamoxifen plus ovarian function suppression were more affected by hot flushes and sweats over 5 years than were those who received exemestane plus ovarian function suppression, although these symptoms improved.
      • Patients who received exemestane plus ovarian function suppression reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients who received tamoxifen plus ovarian function suppression; these differences persisted over time.
      • An increase in bone or joint pain was more pronounced, particularly in the short term, in patients who received exemestane plus ovarian function suppression than in patients who received tamoxifen plus ovarian function suppression.
      • Changes in global QOL indicators from baseline were small and similar between treatments over the 5 years.[147][Level of evidence: 1iC]

Postmenopausal women

In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.[148]

Initial therapy

Evidence (AI vs. tamoxifen as initial therapy in postmenopausal women):

1. A large, randomized trial of 9,366 patients compared the use of the AI anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with lymph node-negative or lymph node-positive disease. Most (84%) of the patients in the study were hormone receptor-positive. Slightly more than 20% had received chemotherapy.[149]; [150][Level of evidence: 1iDii]
   • With a median follow-up of 33.3 months, no benefit in DFS was observed for the combination arm relative to tamoxifen alone.[149]
   • Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted after a median follow-up of 100 months among hormone receptor-positive patients, DFS was significantly (P = .003) longer in patients on anastrozole (HR, 0.85; 95% CI, 0.76–0.94), but OS was not improved (HR, 0.97; 95% CI, 0.86–1.11; P = .7).[150]
   • Patients on tamoxifen more frequently developed endometrial cancer and cerebrovascular accidents, whereas patients on anastrozole had more fracture episodes. The frequency of myocardial infarction was similar in both groups. Except for a continued increased frequency of endometrial cancer in the tamoxifen group, these differences did not persist in the posttreatment period.[150]
2. A large, double-blinded, randomized trial of 8,010 postmenopausal women with hormone receptor-positive breast cancer compared the use of letrozole with tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years.[151] An updated analysis from the International Breast Cancer Study Group (IBCSG-1-98 [NCT00004205]) reported results on the 4,922 women who received tamoxifen or letrozole for 5 years at a median follow-up of 51 months.[152][Level of evidence: 1iDii]
   • DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS, 84.0% vs. 81.1%).
   • OS was not significantly different in patients treated with letrozole (HR, 0.91; 95% CI, 0.75–1.11; P = .35).
3. In the meta-analysis, which included 9,885 women from multiple trials, the 10-year recurrence risk was 19.1% in the AI group versus 22.7% in the tamoxifen group (RR, 0.80; 95% CI, 0.73–0.88; P < .001). The overall 10-year mortality rate was also reduced from 24.0% to 21.3%. (RR, 0.89; 95% CI, 0.8–0.97; P = .01).[148][Level of evidence: 1A]

Sequential tamoxifen and AI versus 5 years of tamoxifen

Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[153-155] The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.

Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):

1. Two trials carried out in sequence by the same group enrolled a total of 828 patients and were reported together; one trial used aminoglutethimide as the AI, and the other trial used anastrozole. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed in the AI groups.[155][Level of evidence: 1iiA]
2. Two other trials were reported together.[154] A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. There was a significant difference in event-free survival (EFS) (HR, 0.80; 95% CI, P = .0009), but not in OS (5-year OS, 97% CI for the switched arm vs. 96% CI for the tamoxifen-alone arm; P = .16).[155][Level of evidence: 1iDii]
3. A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) (NCT00003418) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[156][Level of evidence: 1iDii]
   • After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.[156]
   • After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[157][Level of evidence: 1iA]
   • At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).[157]

In the meta-analysis, which included 11,798 patients from six trials, the 10-year recurrence rate was reduced from 19% to 17% in the AI-containing groups (RR, 0.82; 95% CI, 0.75–0.91; P = .0001). The overall 10-year mortality was 17.5% in the tamoxifen group and 14.6% in the AI-containing group (RR, 0.82; 95% CI, 0.73–0.91; P = .0002).[148][Level of evidence: 1A]

Sequential tamoxifen and AI for 5 years versus 5 years of an AI

The evidence indicates that there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.

Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):

1. A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years. The primary endpoints were DFS at 2.75 years and 5.0 years.[158][Level of evidence: 1iDii]
   • Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).
2. Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole.[159][Level of evidence: 1iDii]
   • There was no difference in DFS when the two sequential arms were compared with 5 years of letrozole (letrozole to tamoxifen HR, 1.06; 95% CI, 0.91–1.23; P = .45 and tamoxifen to letrozole HR, 1.07; 95% CI, 0.92–1.25; P = .36).
3. The FATA-GIM3 (NCT00541086) trial, which was not included in the meta-analysis, compared 2 years of tamoxifen followed by 3 years of one of the three AIs with 5 years of an AI. No significant difference in 5-year DFS was found between the two approaches (88.5% for switching; 89.8% for upfront AI; HR, 0.89; 95% CI, 0.73–1.08; P = .23).[160]

In the meta-analysis, which included 12,779 patients from the trials, the 7-year recurrence rate was slightly reduced from 14.5% to 13.8% in the groups that received 5 years of an AI (RR, 0.90; 95% CI, 0.81–0.99; P = .045). Overall mortality at 7 years was 9.3% in the tamoxifen-followed-by-AI groups and 8.2% in the AI-alone groups (RR, 0.89; 95% CI, 0.78–1.03; P = .11).[148][Level of evidence: 1A]

One AI versus another for 5 years

1. The mild androgen activity of exemestane prompted a randomized trial that evaluated whether exemestane might be preferable to anastrozole, in terms of its efficacy (i.e., EFS) and toxicity, as upfront therapy for postmenopausal women diagnosed with hormone receptor-positive breast cancer.[161][Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.
   • At a median follow-up of 4.1 years, no difference in efficacy was seen (HR, 1.02; 95% CI, 0.87–1.18; P = .86).[161][Level of evidence: 1iiD]
   • The two therapies also were not significantly different in terms of impact on bone mineral density or fracture rates.[162][Level of evidence: 1iiD]
2. In the Femara Versus Anastrozole Clinical Evaluation (FACE [NCT00248170]) study, 4,136 patients with hormone receptor-positive disease were randomly assigned to receive either letrozole or anastrozole.[163]
   • There was no significant difference in DFS (HR, 0.93; 95% CI, 0.80–1.07; P = .3150) at the time of a final analysis that was conducted when there were 709 of the planned 959 events.
   • There were no substantial differences in adverse events between the arms.
3. In the FATA-GIM3 trial, 3,697 patients with HR-positive disease were randomly assigned among the three AIs either for 5 years or after 2 years of tamoxifen. No significant difference in 5-year DFS (90.0% for anastrozole, 88.0% for exemestane, and 89.4% for letrozole; P = .24) was noted among the three AIs.[160]

Switching to an AI after 5 years of tamoxifen

The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.

1. A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 years (range, 4.5–6.0) years.[164][Level of evidence: 1iDii]
   • After the first planned interim analysis, when median follow-up for patients in the study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57), favoring the letrozole arm.[164]
   • After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[165,166]
   • An updated analysis including all events before unblinding confirmed the results of the interim analysis.[167] In addition, a statistically significant improvement in distant DFS was found for patients who received letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no statistically significant difference was found in the total study population, the lymph node-positive patients who received letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), although the P value was not corrected for multiple comparisons.
2. The NSABP B-33 (NCT00016432) trial that was designed to compare 5 years of exemestane with placebo after 5 years of tamoxifen was stopped prematurely when the results of CAN-NCIC-MA17 became available. At the time of analysis, 560 of the 783 patients who were randomly assigned to receive exemestane remained on that drug and 344 of the 779 patients who were randomly assigned to receive placebo had crossed over to exemestane.[168][Level of evidence: 1iDii]
   • An intent-to-treat analysis of the primary study endpoint, DFS, demonstrated a nonsignificant benefit of exemestane (HR, 0.68; P = .07).

Duration of AI therapy

The optimal duration of AI therapy is unclear, although the preponderance of evidence supports at least 5 years of endocrine therapy. A meta-analysis of 88 clinical trials involving 62,923 women with hormone receptor–positive breast cancer who were disease free after 5 years of endocrine therapy (tamoxifen and/or AI) showed a steady risk of late recurrence 5 to 20 years from diagnosis.[129][Level of evidence: 3iiiD]

Evidence regarding extension of endocrine therapy beyond 5 years of initial AI–based adjuvant therapy:

1. A double-blind, randomized, phase III trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[169] Patients who received previous tamoxifen therapy were included. Most women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI.
   1. At a median follow-up of 6.3 years, DFS, the primary study endpoint, was significantly improved in patients randomly assigned to receive letrozole (HR, 0.66; 95% CI, 0.48–0.91; P = .01), and 5-year DFS was improved from 91% to 95%.[169][Level of evidence: 1iDii]
   2. OS rates showed no difference (HR, 0.97; 95% CI, 0.73–1.28; P = .83). Some patients on letrozole had fractures (14%) compared with the patients on placebo with fractures (9%) (P = .001).
   3. QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.
      • No between-group differences were found on the four MENQOL subscales or on the SF-36 summary score.
      • SF-36 role-emotional and bodily pain scores were statistically significantly worse (P = .03) among patients receiving letrozole, but the differences observed were fewer than the minimum clinically important differences for the SF-36 instrument.
2. A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[170][Level of evidence: 1iiDii]
   • DFS events were similar in both groups (HR, 0.92; 95% CI, 0.74–1.16). The distant metastasis-free interval was also similar (HR, 1.06; 95% CI, 0.78–1.45).
   • A subgroup analysis did not identify patients who benefited from 5-year extended therapy.
   • This study did not show that 10 years of AI therapy was superior to 7.5 years of AI therapy.

The optimal duration of adjuvant AI therapy and whether it should be extended beyond a duration of 5 years remains unclear.

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.

Evidence (bisphosphonates in the treatment of early breast cancer):

1. A meta-analysis has been conducted that included the individual patient data of 18,766 patients from 26 adjuvant trials of bisphosphonates of any type.[171] Overall, reductions associated with bisphosphonate use in recurrence (RR, 0.94; 95% CI, 0.87–1.01; 2P = .08), distant recurrence (RR, 0.92; 95% CI, 0.85–0.99; 2P = .03), and breast cancer mortality (RR, 0.91; 95% CI, 0.83–0.99; 2P = .04) were of only borderline significance, but the reduction in bone recurrence was more definite (RR, 0.83; 95% CI, 0.73–0.94; 2P = .004).
   • In a prespecified subgroup analysis, among premenopausal women, treatment had no apparent effect on any outcome, but among 11,767 postmenopausal women, it produced highly significant reductions in recurrence (RR, 0.86; 95% CI, 0.78–0.94; 2P = .002), distant recurrence (RR, 0.82; 95% CI, 0.74–0.92; 2P = .0003), bone recurrence (RR, 0.72; 95% CI, 0.60–0.86; 2P = .0002), and breast cancer mortality (RR, 0.82; 95% CI, 0.73–0.93; 2P = .002).[171]

An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.

Preoperative Systemic Therapy

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple, randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[172][Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[173,174][Level of evidence: 1iiDiv]

A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains.

pCR has been utilized as a surrogate endpoint for long-term outcomes, such as DFS, EFS, and OS, in preoperative clinical trials in breast cancer. A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), provided a better association with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is).[175] pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.[175][Level of evidence: 3iiiD] Because of a strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the FDA has supported use of pCR as an endpoint in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.

Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.

Patient selection, staging, treatment, and follow-up

Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

• Patient selection.
• Choice of systemic therapy.
• Management of the axilla and surgical approach.
• Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone-receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline-taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:[176]

• CT scan of the chest and abdomen and a bone scan.
• Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.

The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:

• If suspicious lymph nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.[177][Level of evidence: 2Div]; [178][Level of evidence: 3iiD]; [179][Level of evidence: 3iiDiv] Alternatively, it is acceptable in this circumstance to perform ALND, based on the possibility of undetected positive nodes.
• In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy.[180] If the SLN biopsy is negative, ALND can be omitted.
• If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.

When considering preoperative therapy, treatment options include the following:

• For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.
• For HER2-positive disease, chemotherapy and HER2-targeted therapy.
• Ideally, the entire treatment regimen is administered before surgery.
• For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.
• For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.

Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible.[181,182] Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

HER2/neu–negative breast cancer

Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Evidence (preoperative anthracycline-based regimen):

1. A randomized clinical trial (NSABP-B-18) was designed to determine whether the preoperative combination of four cycles of AC would more effectively prolong DFS and OS than the same chemotherapy given in the adjuvant setting.[183-185][Level of evidence: 1iiA]
   • After preoperative therapy, 36% of the patients had a complete clinical response.
   • More patients treated with preoperative chemotherapy were able to have breast-conserving procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%; P = .001).
   • No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.
2. An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[186][Level of evidence: 1iiA]

To improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.

Evidence (anthracycline-taxane–based chemotherapy regimen):

1. In an effort to improve on the results observed with AC alone, the NSABP (NSABP B-27[NCT00002707]) trial was conducted.[173][Level of evidence: 1iiD]
   • The administration of preoperative AC followed by docetaxel was associated with a higher clinical complete response rate compared with the administration of AC alone (63.6% for AC followed by docetaxel and 40.1% for AC alone; P < .001); a higher pCR rate was also observed (26.1% for AC followed by docetaxel and 13.7% for AC alone; P < .001).
2. Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline-taxane–based regimens in women with initial response or with relative resistance to anthracyclines.[181]
3. Alternative anthracycline-taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.[187][Level of evidence: 1iiDiv]
4. The phase III GeparSepto (NCT01583426) trial investigated an alternative taxane (nab-paclitaxel) in patients with untreated primary breast cancer.[188] Patients (n = 1,229) were randomly assigned to receive 12 weeks of nab-paclitaxel or paclitaxel followed by epirubicin and cyclophosphamide (EC) for four cycles. The pCR rate was higher in the nab-paclitaxel arm (233 patients, 38%; 95% CI, 35%–42%) when compared with the paclitaxel arm (174 patients, 29%; 95% CI, 25%–33%).[188][Level of evidence: 1iiDiv]
5. The incorporation of many additional cytotoxic agents to anthracycline-taxane–based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[189][Level of evidence: 1iiDiv]

Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Evidence (adding carboplatin to an anthracycline-taxane–based chemotherapy regimen in patients with TNBC):

1. In the GeparSixto (NCT01426880) trial, carboplatin was added to an anthracycline-taxane–based backbone.[190][Level of evidence: 1iiDiv]
   • Higher pCR rates were observed with the addition of carboplatin to an anthracycline-taxane–based backbone compared with anthracycline-taxane alone (36.9% vs. 53.2%; P = .005) in patients with TNBC.
   • The more intensive regimen was also associated with increased toxicity and treatment discontinuations (39% vs. 48%).
2. The CALGB 40603 (NCT00861705) trial compared an anthracycline-taxane backbone alone with an anthracycline-taxane backbone-plus-carboplatin in patients with stage II and stage III TNBC.[191][Level of evidence: 1iiDiv]
   • The pCR rate for the breast and axilla was 54% for the anthracycline-taxane backbone-plus-carboplatin group versus 41% for the anthracycline-taxane backbone-alone group (P = .0029)

Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[192,193][Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.

HER2/neu-positive breast cancer

After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline-taxane–based regimens.[194][Level of evidence: 1iiDiv] This has been confirmed in phase III studies.[195,196]

Trastuzumab

Evidence (trastuzumab):

1. The phase III NeOAdjuvant Herceptin (NOAH) study randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to undergo preoperative chemotherapy with or without 1 year of trastuzumab therapy.[196][Level of evidence:1iiA]
   • Study results confirmed that the addition of trastuzumab to preoperative chemotherapy resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.[196][Level of evidence:1iiA]
   • After a median follow-up of 5.4 years, the EFS benefit was 58% with the addition of trastuzumab to chemotherapy (95% CI, 48–66) and 43% (95% CI, 34–52) in patients in the chemotherapy group. The unadjusted HR for EFS between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44–0.93; two-sided log-rank P = .016). EFS was strongly associated with pCR in patients who received trastuzumab.[197]
   • Symptomatic cardiac failure occurred in two patients who received concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (Refer to the Cardiac toxic effects with adjuvant trastuzumab section in this summary for more information.)[196][Level of evidence: 1iiD]
2. A phase III trial (Z1041 [NCT00513292]) randomly assigned patients with operable HER2-positive breast cancer to receive trastuzumab sequential to or concurrent with the anthracycline component (5-FU, epirubicin, cyclophosphamide) of the preoperative chemotherapy regimen.[198][Level of evidence: 1iiDiv]
   • There was no significant difference in pCR rate in the breast between the arms (56.5% sequential, 54.2% concurrent; difference, 2.3% with 95% CI, -9.3–13.9).
   • In addition, asymptomatic declines in LVEF during preoperative chemotherapy were identified in similar proportions of patients in each arm.
   • The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.

A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to undergo preoperative chemotherapy (anthracycline-taxane–based), with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[199][Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.

An ongoing trial, SafeHer (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.

Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.[200,201]

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):

1. In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial,[200] 417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:[200][Level of evidence: 1iiDiv]
   1. Docetaxel plus trastuzumab.
   2. Docetaxel plus trastuzumab and pertuzumab.
   3. Pertuzumab plus trastuzumab.
   4. Docetaxel plus pertuzumab.
   The following results were observed:
   • The pCR rates were 29% for docetaxel plus trastuzumab, 46% for docetaxel plus trastuzumab and pertuzumab, 17% for pertuzumab plus trastuzumab, and 24% for docetaxel plus pertuzumab. Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy.
   • The addition of pertuzumab to the docetaxel-plus-trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.
   • Despite the high pCR rate observed with dual HER2 blockade plus chemotherapy, PFS and DFS rates were not improved, although the NeoSPHERE trial was not powered to detect differences in long-term efficacy outcomes.[202]
2. The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.[203][Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens:
   1. Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.
   2. FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3).
   3. Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6).
   The following results were observed:
   • The pCR rate was equivalent across all three treatment arms: (62% for concurrent FEC plus trastuzumab plus pertuzumab followed by concurrent docetaxel plus trastuzumab plus pertuzumab; 57% for FEC alone followed by concurrent docetaxel plus trastuzumab plus pertuzumab; and 66% for concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab).
   • All three arms were associated with a low incidence of cardiac adverse events of 5% or less.

Because of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of a preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive.

The FDA approval of pertuzumab was subsequently converted to regular approval following the results of the confirmatory APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, which demonstrated improved invasive DFS with the combination of chemotherapy and dual HER2-targeted therapy with pertuzumab plus trastuzumab compared with chemotherapy and trastuzumab alone.[125] Pertuzumab is now approved both in combination with trastuzumab and chemotherapy for the neoadjuvant therapy of locally advanced, inflammatory, or early-stage HER2-positive breast cancer, which is larger than 2 cm or node-positive, as part of a complete treatment regimen and in combination with chemotherapy and trastuzumab as adjuvant treatment for HER2-positive early breast cancer at a high risk of recurrence.

Lapatinib

Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Evidence (against the use of lapatinib for HER2-positive early breast cancer):

1. The role of lapatinib in the preoperative setting was examined in the GeparQuinto[NCT00567554] trial.[193] This phase III trial randomly assigned women with HER2-positive early-stage breast cancer to receive chemotherapy with trastuzumab or chemotherapy with lapatinib, with pCR as the primary endpoint.[193][Level of evidence: 1iiDiv]
   • pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04).
   • Other endpoints of DFS, RFS, and OS have not been reported.
2. CALGB 40601 (NCT00770809) was a phase III trial that randomly assigned patients with stage II and III HER2-positive breast cancer to receive either paclitaxel plus trastuzumab or paclitaxel plus trastuzumab plus lapatinib. The primary endpoint of the study was pCR in the breast.[204] [Level of evidence: 1iiDiv]
   • pCR in patients who received paclitaxel plus trastuzumab was 46% (95% CI, 37%–55%), and pCR in the patients who received paclitaxel plus trastuzumab plus lapatinib was 56% (95% CI, 47%–65%; P = .13), indicating no benefit with the addition of lapatinib.
3. The NeoALTTO [NCT00553358] phase III trial randomly assigned 455 women with HER2-positive early-stage breast cancer (tumor size >2 cm) to receive preoperative lapatinib, or preoperative trastuzumab, or preoperative lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks. The primary endpoint of this study was pCR.
   • pCR was significantly higher in the lapatinib-plus-trastuzumab combination arm (51.3%; 95% CI, 43.1–59.5) than in the trastuzumab-alone arm (29.5%; 95% CI, 22.4–37.5).
   • No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference, -4.8%, -17.6 to 8.2; P = .34).
   • An updated analysis for the prespecified secondary endpoints of EFS and OS indicate no difference between the groups.[205]

More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to receive trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.[124] The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.

Cardiac toxic effects with pertuzumab and lapatinib

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[206][Level of evidence: 3iiiD]

• Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a nonanthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5).
• Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[207][Level of evidence: 3iiiD]

• LVEF decline was observed in 3.1% of the patients who received monotherapy (95% CI, 2.2%–4.4%) and 2.9% of the patients who received dual therapy (95% CI, 2.1%–4.1%).
• Symptomatic heart failure was observed in 0.88% of the patients who received monotherapy (95% CI, 0.47%–1.64%) and 1.49% of the patients who received dual therapy (95% CI, 0.98%–2.23%).

Preoperative endocrine therapy

Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor-positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[208][Level of Evidence: 1iDiv]

Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients.[209] A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P-value for trend < .04).[174][Level of Evidence: 1iiDiv]

The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women [208] or comparable to tamoxifen-associated outcomes.[174] An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy

Capecitabine

One clinical trial suggested that there is a benefit to using capecitabine as adjuvant therapy in patients who did not obtain a pCR after preoperative chemotherapy.

Evidence (capecitabine):

1. In a study conducted in Japan and Korea, 910 women with HER2/neu–negative breast cancers, who had residual disease after preoperative chemotherapy with anthracyclines, taxanes, or both, were randomly assigned in a nonblinded fashion to receive 6 to 8 four-weekly cycles of capecitabine or no further chemotherapy.[210] The study was terminated because of the results of a planned interim analysis, and a final analysis was done.
   • In the final analysis, which included 887 eligible patients, DFS, the primary endpoint, was statistically significantly prolonged (HR, 0.70; 95% CI, 0.53–0.92; P= .01; 5-year DFS, 74.1% vs. 67.6%).
   • OS, a secondary endpoint, was also longer in the capecitabine group (HR, 0.59; 95% CI, 0.39–0.90; P = .01; 5-year OS, 89.2% vs. 83.6%).
   • In the capecitabine group, 73.4% of the patients experienced hand-foot syndrome of varying degrees of severity.

This approach and participation in clinical trials of novel therapies should be considered for patients with residual disease after preoperative therapy. EA1131 (NCT02445391) is a randomized phase III clinical trial that randomly assigned patients with residual basal-like TNBC after preoperative therapy to receive platinum-based chemotherapy or capecitabine. S1418/BR006 (NCT02954874) is a phase III trial evaluating the efficacy of pembrolizumab as adjuvant therapy for patients with residual TNBC (≥1 cm invasive cancer or residual nodes) after preoperative therapy.

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor-positive disease and adjuvant trastuzumab for those with HER2-positive disease. (Refer to the Hormone receptor–positive breast cancer subsection in the Early/Localized/Operable Breast Cancer section of this summary for more information.)

Posttherapy Surveillance

The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations.[211-213] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[212] On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

• Physical examination.
• Annual mammography.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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