Breast Cancer Version 3.2014

ER/PR Testing

ER and PR tumor status is normally determined through immunohistochemistry (IHC) testing. Although this method is considered reliable when performed by experienced pathology personnel, several reports have indicated that the reliability of ER and PR determinations can vary widely among laboratories.^7-9 These interlaboratory differences may be attributable to the diverse methodologies and interpretation schema used to evaluate tumor hormonal status. An NCCN Task Force and a panel of ASCO and CAP members have reviewed this topic and issued recommendations on ER and PR testing in breast cancer.^10,11 Breast cancers that have at least 1% of cells staining positive for ER should be considered ER-positive.^10-12

HER2 Testing

The determination of HER2 tumor status is also recommended for all newly diagnosed invasive breast cancers and for first recurrences of breast cancer whenever possible. The NCCN Breast Cancer Panel endorses CAP accreditation for anatomic pathology laboratories performing HER2 testing.

HER2 status can be assessed through measuring the number of HER2 gene copies using in situ hybridization (ISH) techniques or a complementary method in which the quantity of HER2 cell surface receptors is assessed with IHC.¹³ Assignment of HER2 status based on mRNA assays or multigene arrays is not recommended. The accuracy of HER2 assays used in clinical practice is a major concern, and results from several studies have shown that false-positive^14-18 as well as false-negative^14,19 HER2 test results are common. A joint panel from ASCO and CAP issued updated HER2 testing guidelines to avoid these false-positive or false-negative results. These updated guidelines have been published in the Archives of Pathology & Laboratory Medicine and the Journal of Clinical Oncology.^20,21 The NCCN Panel endorses these updated ASCO/CAP recommendations for quality HER2 testing, and has outlined them in the algorithm.

Staging and Workup

The recommended workup and staging of invasive breast cancer includes a history and physical examination; a CBC count; liver function tests; bilateral diagnostic mammography; breast ultrasonography, if necessary; determination of tumor ER and PR status; determination of tumor HER2 status; and pathology review. Genetic counseling is recommended if the patient is considered to be at high risk for hereditary breast cancer, as defined by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast and Ovarian (to view the most recent version of these guidelines, visit NCCN.org).

Use of MRI during initial workup is optional and may be specially considered for mammographically occult tumors. MRI may be used to define the extent of cancer or presence of multifocal or multicentric cancer in the ipsilateral breast, or for screening of the contralateral breast (category 2B). It may be helpful for breast cancer evaluation before and after neoadjuvant therapy to define extent of disease, response to treatment, and potential for breast-conserving therapy. MRI of the breast should be performed using a dedicated breast coil, with consultation with the multidisciplinary treatment team, and by a breast imaging team capable of performing MRI-guided biopsy. The limitations of breast MRI include a high percentage of false-positive findings.^24-26 Therefore, MRI should generally be considered for staging breast cancer in patients whose breasts cannot be imaged adequately with mammography and ultrasound (eg, women with very dense breast tissue; women with positive axillary nodal status and occult primary tumor presumed to originate in the breast; to evaluate the chest wall).²⁷ No randomized, prospective assessment of the utility of MRI in staging of or treatment decision-making in breast cancer is available. One retrospective study suggested an outcome benefit,²⁸ whereas another did not.²⁹ One systematic review reported that breast MRI staging altered surgical treatment in 7.8% to 33.3% of women.²⁶ However, no differences in outcome, if any, can be demonstrated in that analysis. Patients should not be denied the option of breast-conservation therapy based on MRI findings alone without tissue sampling.

Optional Studies as Directed by Signs and Symptoms for All Stages: Additional tests may be considered based on the signs and symptoms. A bone scan is indicated for patients presenting with localized bone pain or elevated alkaline phosphatase. If pulmonary symptoms are present, chest diagnostic CT is indicated. Abdominal imaging using diagnostic CT or MRI is indicated if the patient has elevated alkaline phosphatase, abnormal results on liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis. These studies are not indicated in patients with stage I disease without signs/symptoms of metastatic disease, nor are they needed in many other patients with early-stage breast cancer.³⁰ These recommendations are supported by a study evaluating patients with newly diagnosed breast cancer by bone scan, liver ultrasonography, and chest radiography.³¹ Metastases were identified by bone scan in 5.1%, 5.6%, and 14.0% of patients with stage I, II, and III disease, respectively, and no evidence of metastasis was detected by liver ultrasonography or chest radiography in patients with stage I or II disease.³¹

Additional Workup for Patients With Locally Advanced Disease: Locally advanced breast cancer describes a subset of invasive breast cancer for which the initial clinical and radiographic evaluation documents advanced disease confined to the breast and regional lymph nodes. The AJCC clinical staging system used in these guidelines and for the determination of operability is recommended, and locally advanced disease is represented by the stage III category. Patients with stage III disease may be further divided into those for whom the initial surgical approach is unlikely to successfully remove all disease or to provide long-term local control, and those for whom a reasonable initial surgical approach is likely to achieve pathologically negative margins and provide long-term local control. Thus, patients with stage IIIA disease are divided into those who have clinical T3N1M0 disease versus those who have clinical TanyN2M0 disease, based on evaluation by a multidisciplinary team. For patients diagnosed with clinical stage III disease, systemic staging should be considered with tests such as a bone scan or sodium fluoride PET/CT (category 2B), and abdominal imaging with diagnostic CT (with or without pelvic CT) or MRI.

Fluorodeoxyglucose (FDG)/PET scan is optional (category 2B). FDG-PET scan can be considered at the same time as diagnostic CT. If FDG-PET and diagnostic CT are performed and both clearly indicate bone metastases, bone scan or sodium fluoride PET/CT may not be needed. The consensus of the panel is that FDG-PET/CT is most helpful when standard imaging results are equivocal or suspicious. However, limited studies^32-38 support a potential role for FDG-PET/CT to detect regional node involvement and distant metastases in locally advanced breast cancer, including T3N1M0 disease. A retrospective study comparing bone scan with integrated FDG-PET/CT in women with stages I-III breast cancer with suspected metastasis observed a high concordance (81%) between the studies for reporting osseous metastases.³⁹ The panel suggests that bone scan may be omitted if FDG-PET/CT results are positive for bone metastases.

Equivocal or suspicious sites identified by PET/CT scanning should be biopsied for confirmation whenever possible and if the disease site would impact the course of treatment. In the past decade, the advent of PET/CT scanners has significantly changed the approach to PET imaging.⁴⁰ However, the terminology has also created confusion regarding the nature of the scans obtained from a PET/CT device. PET/CT scanners have both a PET and CT scanner in the same gantry that allows precise coregistration of molecular (PET) and anatomic (CT) imaging. Almost all current clinical PET imaging is performed using combined PET/CT devices.

In PET/CT tomographs, the CT scanner has a second important role beyond diagnostic CT scanning.⁴⁰ For PET applications, the CT scan is also used for photon attenuation correction and for anatomic localization of the PET imaging findings. For these tasks, the CT scan is usually taken without breathholding, to match PET image acquisition, and typically uses low-dose (nondiagnostic) CT. Radiation exposure for these nondiagnostic CT scans is lower than for diagnostic CT. Intravenous contrast is not needed for this task.

PET/CT scanners typically include a high-quality CT device that can also be used for stand-alone, optimized, and fully diagnostic CT. Diagnostic CT scans are acquired using breathholding for optimal chest imaging and are often performed with intravenous contrast. For fully diagnostic CT, the CT beam current, and therefore patient radiation exposure, is considerably higher than for the low-dose CT needed for PET requirements. Radiation exposures associated with fully diagnostic CT are often greater than for the emission (PET) component of the study.

Currently, the approach to clinical PET/CT imaging varies widely across centers.⁴¹ Many centers perform low-dose CT as part of a PET/CT scan, and perform optimized, fully diagnostic CT only when diagnostic CT has also been requested in addition to PET/CT. Other centers combine diagnostic CT scans with PET on all of their PET/CT images. The CT scans described in the workup section of the guidelines refer to fully optimized diagnostic CT scans, whereas the PET or PET/CT scans refer to scans primarily directed toward the PET component, not necessarily using diagnostic-quality CT. Referring physicians must understand the differences between PET/CT performed primarily for PET imaging and fully optimized CT performed as a stand-alone diagnostic CT examination.⁴¹ It may be convenient to perform PET/CT and diagnostic CT at the same time.

Fertility Counselling

Numerous epidemiologic studies have shown that childbearing after treatment of invasive breast cancer does not increase rates of recurrence or death from breast cancer.⁴² The offspring of pregnancies after treatment of breast cancer do not have an increased rate of birth defects or other serious childhood illness. However, treatment of breast cancer, especially with cytotoxic agents, may impair fertility. Therefore, it is reasonable and appropriate to consider fertility preservation before breast cancer treatment in young women who desire to bear children.^43-47 No high-level evidence shows that ovarian suppression or other interventions decrease the toxicity of cytotoxic chemotherapy on the premenopausal ovary.⁴⁸ However, many women, especially those younger than 35 years, regain menstrual function within 2 years of completing chemotherapy.⁴⁹ Resumption of menses does not necessarily correlate with fertility, and fertility may be preserved without menses.

All premenopausal patients should be informed about the potential impact of chemotherapy on fertility and asked about their desire for potential future pregnancies. Premenopausal women with newly diagnosed breast cancer who desire to bear children after breast cancer treatment should undergo consultation with a physician with expertise in fertility before initiation of chemotherapy.^47,50 Multiple factors must be considered when making a decision about fertility preservation, including patient preference, patient age, risk of premature ovarian failure based on anticipated chemotherapy, and length of optimal endocrine therapy. It is important for fetal safety that women do not become pregnant during breast cancer treatment. Also see NCCN Guidelines for Adolescent and Young Adult Oncology (to view the most recent version of these guidelines, visit NCCN.org).

Preoperative Systemic Therapy

Preoperative chemotherapy should be considered for women with locally advanced invasive breast cancer (stage III) and those with large clinical stage IIA, stage IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size and wish to undergo breast-conserving therapy. In the available data from clinical trials of preoperative systemic therapy, pretreatment biopsies have been limited to core needle biopsy or fine-needle aspiration (FNA) cytology. Therefore, according to the NCCN panel, in patients anticipated to receive preoperative systemic therapy, core biopsy of the breast tumor and placement of image-detectable markers should be considered to demarcate the tumor bed for any future (postchemotherapy) surgical management. Clinically positive ALNs should be sampled through FNA or core biopsy, and the positive nodes must be removed after preoperative systemic therapy at the time of definitive surgery. Patients with clinically negative ALNs should undergo axillary ultrasound before neoadjuvant treatment. For those with clinically suspicious ALNs, the panel recommends consideration of either a core biopsy or FNA of these nodes.⁵¹ If FNA or core biopsy indicates any positive nodes, these should be removed after neoadjuvant therapy at the time of definitive surgery.

According to the panel, axillary staging after preoperative systemic therapy may include sentinel node biopsy or level I/II dissection. Level I/II dissection should be performed when patients are proven node-positive before neoadjuvant therapy (category 2B). The false-negative rate of sentinel lymph node (SLN) biopsy in either the pre- or postchemotherapy setting is low.^52-54 Nevertheless, the possibility remains that a pathologic complete response after chemotherapy may occur in lymph node metastases previously undetected in the clinical examination. SLN excision can be considered before preoperative systemic therapy is administered, because it provides additional information to guide local and systemic treatment decisions.^55,56 If SLN resection is performed after administration of preoperative systemic therapy, both the prechemotherapy clinical and the postchemotherapy pathologic nodal stages must be used to determine the risk of local recurrence. Close communication between members of the multidisciplinary team, including the pathologist, is particularly important when any treatment strategy involving preoperative systemic therapy is planned.

In some patients, preoperative systemic therapy results in sufficient tumor response to make breast-conserving therapy possible. Because complete or near-complete clinical responses are common, the use of percutaneously placed clips into the breast under mammographic or ultrasound guidance or other method of localizing prechemotherapy tumor volume aids in the postchemotherapy resection of the original area of tumor and is encouraged. The results of the NSABP B-18 trial show that breast conservation rates are higher after preoperative systemic therapy.⁵⁷ However, preoperative systemic therapy has no demonstrated disease-specific survival advantage over postoperative adjuvant chemotherapy in patients with stage II tumors. NSABP B-27 was a 3-arm, randomized, phase III trial of women with invasive breast cancer treated with preoperative systemic therapy with AC (doxorubicin/cyclophosphamide) for 4 cycles followed by local therapy alone, preoperative AC followed by preoperative docetaxel for 4 cycles followed by local therapy, or AC followed by local therapy followed by 4 cycles of postoperative docetaxel.⁵⁸ Results from this study, which involved 2411 women, documented a higher rate of complete pathologic response at the time of local therapy in patients treated preoperatively with 4 cycles of AC followed by 4 cycles of docetaxel versus 4 cycles of preoperative AC. This trial did not show disease-free and overall survivals to be superior with the addition of docetaxel treatment.⁵⁸ A disease-free survival advantage was observed (hazard ratio [HR], 0.71; 95% CI, 0.55-0.91; P=.007) favoring preoperative versus postoperative docetaxel in the subset of patients experiencing a clinical partial response to AC. For patients with inoperable, noninflammatory, locally advanced disease at presentation (clinical stages IIIA [except for T3N1M0], IIIB, or IIIC), the initial use of anthracycline-based preoperative systemic therapy with or without a taxane is standard therapy.⁵⁹

Several chemotherapy regimens have been studied as preoperative systemic therapy. The panel believes that the regimens recommended in the adjuvant setting are appropriate to consider in the preoperative systemic therapy setting. The benefits of “tailoring” preoperative systemic therapy (ie, switching following limited response) or using preoperative systemic therapy to evaluate disease responsiveness have not been well studied.⁶⁰

Preoperative Systemic Therapy in Patients With HER2⁺ Tumors: In women with HER2⁺ tumors treated with neoadjuvant chemotherapy, the addition of neoadjuvant trastuzumab to paclitaxel followed by chemotherapy with FEC (fluorouracil/epirubicin/cyclophosphamide) was associated with an increase in the pathologic complete response rate from 26.0% to 65.2% (P=.016).⁶¹ Thus, the incorporation of trastuzumab into neoadjuvant chemotherapy regimens seems to be important in HER2⁺ tumors.⁶²

The GeparQuinto phase III trial led by the German Breast Group studied 620 women with untreated, HER2⁺, primary invasive breast cancer.⁶³ Patients were randomized to receive 4 cycles of epirubicin/cyclophosphamide followed by docetaxel administered concurrently with either trastuzumab or lapatinib. The primary end point, pathologic complete response, was achieved in 30.3% of patients who received trastuzumab plus chemotherapy, compared with 22.7% of patients who received lapatinib plus chemotherapy (odds ratio, 0.68; 95% CI, 0.47-0.97; P<.04).⁶³ Edema and dyspnea occurred more frequently in the trastuzumab group, whereas diarrhea and skin rash occurred more frequently in the lapatinib group.

The NeoALTTO trial randomized 455 patients with HER2⁺ primary breast cancer to receive lapatinib plus paclitaxel or trastuzumab plus paclitaxel or a combination of lapatinib and trastuzumab plus paclitaxel.⁶⁴ The results showed that the pathologic complete response rate was 51.3% (95% CI, 43.1-59.5) in the lapatinib plus trastuzumab combination arm, compared with a rate of 24.7% (95% CI, 18.1-32.3) for the lapatinib arm and 29.5% (95% CI, 22.4-37.5) for the trastuzumab arm. The difference in pathologic complete response rate between the lapatinib plus trastuzumab arm and the trastuzumab arm was statistically significant (difference, 21.1%; range, 9.1-34.2; P=.0001). The pathologic complete response rate difference between the lapatinib and trastuzumab arms was not statistically significant (difference, -4.8%; range, -17.6-8.2; P=.34).⁶⁴ Grade 3/4 liver enzyme abnormalities occurred more frequently with trastuzumab plus lapatinib or lapatinib alone compared to trastuzumab alone.⁶⁴ Updated preliminary data presented at the 2013 San Antonio Breast Cancer Symposium showed that patients who experienced a pathologic complete response had a better outcome than those who did not.⁶⁵ These studies thus confirm that the use of HER2-targeted therapy is important in the preoperative treatment of HER2⁺ primary breast cancer. Significant uncertainty remains regarding the optimal regimen of HER2 targeting. The NeoALTTO study results confirm the potential of dual HER2-targeted therapy in the neoadjuvant setting.

Pertuzumab is a recombinant humanized monoclonal antibody that inhibits the ligand-dependent dimerization of HER2 and its downstream signaling. Pertuzumab and trastuzumab bind to different epitopes of HER2 receptor and have complementary mechanisms of action. When administered together in HER2⁺ tumor models and in humans, they provide a greater overall antitumor effect than either alone.^66,67 Because the combination of pertuzumab and trastuzumab showed significant overall survival benefit in the metastatic setting,⁶⁸ it was also examined in the neoadjuvant setting.^69,70

The FDA recently granted accelerated approval for pertuzumab in combination with trastuzumab and docetaxel as neoadjuvant treatment for patients with HER2⁺ early-stage breast cancer, including those with either tumors greater than 2 cm in diameter (≥T2) or positive nodes (≥N1). The accelerated approval was based on the results of 2 phase II trials, the NeoSphere trial⁷⁰ and the TRYPHAENA study,⁶⁹ which showed significant improvement in pathologic complete response in patients receiving pertuzumab, trastuzumab, and docetaxel. Pathologic complete response is defined by the FDA as “the absence of invasive cancer in the breast and lymph nodes.”

In the NeoSphere trial, 417 patients were randomized 1:1:1:1 to receive trastuzumab plus docetaxel; pertuzumab and trastuzumab plus docetaxel; pertuzumab and trastuzumab; or pertuzumab plus docetaxel. A total of 45.8% (95% CI, 36.1-55.7) of patients who received pertuzumab plus trastuzumab and docetaxel experienced a pathologic complete response, compared with only 29% (CI, 20.6-38.5) who experienced a pathologic complete response on the trastuzumab plus docetaxel regimen (P=.0063).⁷⁰ The TRYPHAENA was a phase II randomized multicenter trial designed to evaluate the safety and tolerability of trastuzumab and pertuzumab in combination with anthracycline- or carboplatin-based neoadjuvant chemotherapy. A total of 225 patients with HER2⁺, locally advanced (T2-3, N2-3, M0; T4a-cNanyM0), inflammatory (T4dNanyM0) or early-stage breast cancer (tumors >2 cm) were enrolled and randomized 1:1:1 to receive 6 cycles of neoadjuvant therapy with FEC plus trastuzumab and pertuzumab followed by docetaxel, trastuzumab, and pertuzumab; FEC followed docetaxel, trastuzumab, and pertuzumab; or docetaxel, carboplatin, trastuzumab along with pertuzumab. Based on the assessment of pathologic complete response, all 3 regimens seem active. The reported pathologic complete response ranged from 57.3% to 66.2%, with the highest seen in patients who received pertuzumab, trastuzumab, docetaxel, and carboplatin chemotherapy. The adverse events reported in the trial were consistent with those seen with each of the 3 agents, and low rates of symptomatic left ventricular systolic dysfunction were reported.

The panel has included pertuzumab-based regimens as neoadjuvant therapy options for patients with early-stage (≥T2 or ≥N1) HER2⁺ tumors.

Preoperative Systemic Endocrine Therapy: Several randomized trials have assessed the value of neoadjuvant endocrine therapy in postmenopausal women with ER⁺ breast cancer. These studies have generally compared the rates of objective response and breast-conserving surgery among treatment with tamoxifen, anastrozole, anastrozole plus tamoxifen, and letrozole. These studies consistently show that the use of either anastrozole or letrozole alone provides superior rates of breast-conserving surgery and usually objective response when compared with tamoxifen.^71,72 Based on these trials, the panel recommends that if preoperative endocrine therapy is to be used, an aromatase inhibitor is preferred in the treatment of postmenopausal women with hormone receptor-positive disease.

Locoregional Treatment After Preoperative Systemic Therapy

For large stage II tumors and IIIA (T3N1M0), local therapy after a complete or partial response to preoperative systemic therapy is usually lumpectomy, if possible, along with surgical axillary staging. If lumpectomy is not possible or progressive disease is confirmed, mastectomy is performed along with surgical axillary staging with or without breast reconstruction. Surgical axillary staging may include SLN biopsy or level I/II dissection. If SLN biopsy was performed before administering preoperative systemic therapy and the findings were negative, then further ALN staging is not necessary. If an SLN procedure was performed before administering preoperative systemic therapy and the findings were positive, then a level I/II ALN dissection should be performed. Local therapy for clinical stages IIIA (except for T3N1M0), IIIB, or IIIC after a clinical response to preoperative systemic therapy usually consists of total mastectomy with level I/II ALN dissection, with or without delayed breast reconstruction or lumpectomy and level I/II axillary dissection.

If an inoperable tumor fails to respond, or the response is minimal, after several cycles of preoperative systemic therapy, or the disease progresses at any point, an alternative chemotherapy agent and/or preoperative radiation therapy could be considered followed by local therapy, usually a mastectomy plus axillary dissection, with or without breast reconstruction. Postsurgical adjuvant treatment for these patients consists of completion of planned chemotherapy if not completed preoperatively, followed by endocrine therapy (category 1) in women with ER^- and/or PR⁺ tumors. Up to 1 year of trastuzumab therapy should be completed if the tumor is HER2⁺ (category 1).

Radiation therapy is recommended based on prechemotherapy characteristics to the chest wall and supraclavicular lymph nodes (see “Principles of Radiation Therapy” [available online, in these guidelines, at NCCN.org] and “Radiation After Mastectomy” on page 562). The panel recommends strong consideration of including the internal mammary lymph nodes in the radiation therapy field (category 2B). Endocrine therapy and trastuzumab can be administered concurrently with radiation therapy if indicated.

Surgical Axillary Staging

Pathologic confirmation of malignancy using ultrasound-guided FNA or core biopsy must be considered in patients with clinically positive nodes to determine whether axillary lymph node dissection is needed.

Performance of SLN mapping and resection in the surgical staging of the clinically negative axilla is recommended by the panel for assessment of the pathologic status of the ALNs in patients with clinical stage I or II breast cancer.^54,73-81 This recommendation is supported by results of randomized clinical trials showing decreased arm and shoulder morbidity (eg, pain, lymphedema, sensory loss) in patients with breast cancer undergoing SLN biopsy compared with patients undergoing standard ALN dissection.^81,82 No significant differences in the effectiveness of the SLN procedure or level I and II dissection in determining the presence or absence of metastases in axillary nodes were seen in these studies. However, not all women are candidates for SLN resection. An experienced SLN team is mandatory for the use of SLN mapping and excision.^83,84 Women who have clinical stage I or II disease and do not have immediate access to an experienced SLN team should be referred to an experienced SLN team for the definitive surgical treatment of the breast and surgical ALN staging. In addition, potential candidates for SLN mapping and excision should have clinically negative ALNs at the time of diagnosis, or a negative core or FNA biopsy of any clinically suspicious ALNs.

In many institutions, SLNs are assessed for the presence of metastases using both hematoxylin-eosin (H&E) staining and cytokeratin IHC. The clinical significance of a lymph node that is negative on H&E staining but positive on cytokeratin IHC is not clear. Because the historical and clinical trial data on which treatment decisions are based have relied on H&E staining, the panel does not recommend routine cytokeratin IHC to define node involvement and believes that current treatment decisions should be made based solely on H&E staining. This recommendation is further supported by a randomized clinical trial (ACOSOG Z0010) of patients with H&E-negative nodes, in which further examination by cytokeratin IHC was not associated with improved overall survival over a median of 6.3 years.⁸⁵ In the uncommon situation in which H&E staining is equivocal, reliance on the results of cytokeratin IHC is appropriate.

Multiple attempts have been made to identify cohorts of women with involved SLNs who have a low enough risk for non-SLN involvement that complete axillary dissection might be avoided if the SLN is positive. None of the early studies identified a low risk group of patients with positive SLN biopsies but consistently negative nonsentinel nodes.^86-92 Nonetheless, a randomized trial (ACOSOG Z0011) compared SLN resection alone with ALN dissection in women aged 18 years or older with T1/T2 tumors, fewer than 3 positive SLNs, and undergoing breast-conserving surgery and whole-breast irradiation, and found no difference in local recurrence, disease-free survival, or overall survival between the treatment groups. Only ER^- status, age younger than 50 years, and lack of adjuvant systemic therapy were associated with decreased overall survival.⁹³ At a median follow-up of 6.3 years, locoregional recurrences were noted in 4.1% of the ALN dissection patients (n=420) and 2.8% of the SLN dissection patients (n=436; P=.11). Median overall survival was approximately 92% in each group.⁹⁴ Therefore, based on these results after SLN mapping and excision, if a patient has a T1 or T2 tumor with 1 to 2 positive SLNs, did not receive neoadjuvant therapy, and is treated with lumpectomy and whole breast radiation, the panel recommends considering either level I and II axillary dissection or no further axillary surgery.

The panel recommends level I or II axillary dissection when patients have clinically positive nodes at the time of diagnosis, which is confirmed by FNA or core biopsy, and when sentinel nodes are not identified. Traditional level I and II evaluation of ALN requires that at least 10 lymph nodes should be provided for pathologic evaluation to accurately stage the axilla.^95,96 ALN should be extended to include level III nodes only if gross disease is apparent in the level II nodes. In the absence of gross disease in level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle (level I/II). Furthermore, according to the panel, without definitive data demonstrating superior survival with ALN dissection or SLN resection, these procedures may be considered optional in patients who have particularly favorable tumors, those for whom the selection of adjuvant systemic therapy will not be affected by the results of the procedure, those who are elderly, and those with serious comorbid conditions. Women who do not undergo ALN dissection or ALN irradiation are at increased risk for ipsilateral lymph node recurrence.⁹⁷ Women who undergo mastectomy are appropriate candidates for breast reconstruction (see next section).

Radiation Therapy After Mastectomy

Node-Positive Disease: Three randomized clinical trials have shown that a disease-free and overall survival advantage is conferred by irradiation of the chest wall and regional lymph nodes in women with positive ALNs after mastectomy and ALN dissection.^98-102 In these trials, the ipsilateral chest wall and ipsilateral locoregional lymph nodes were irradiated. Based on these studies, the current guidelines recommend postmastectomy irradiation in women with 4 or more positive ALNs, and strong consideration of postmastectomy irradiation in women with 1 to 3 positive ALNs. Two retrospective analyses have provided evidence for the benefit of radiation therapy in only selected patients receiving preoperative systemic therapy before mastectomy.^103,104

However, the panel recommends that decisions related to administration of radiation therapy for patients receiving neoadjuvant chemotherapy should be made based on prechemotherapy tumor characteristics, irrespective of tumor response to preoperative systemic therapy (ie, radiation therapy is recommended in patients with clinical stage III disease and a pathologic complete response to neoadjuvant chemotherapy).

Women with 4 or more positive ALNs are at substantially increased risk for locoregional recurrence of disease. The use of prophylactic chest wall irradiation in this setting substantially reduces the risk of local recurrence.¹⁰⁵ The use of postmastectomy, postchemotherapy chest wall irradiation, and regional lymph node irradiation is recommended (category 1).

The recommendation for strong consideration of chest wall and supraclavicular irradiation in women with 1 to 3 involved ALNs generated substantial controversy among panel members. The use of regional nodal irradiation is supported by a subgroup analysis of studies from the Danish Breast Cancer Cooperative Group.¹⁰⁶ In this analysis, a substantial survival benefit was associated with postmastectomy radiation therapy for women with 1 to 3 positive ALNs. Some panel members believe chest wall and supraclavicular irradiation should be used routinely after mastectomy and chemotherapy in this subgroup of patients. However, other panel members believe radiation should be considered in this setting but should not be mandatory, because studies do not show an advantage. This is an unusual situation in which high-level evidence exists but is contradictory.^{100-102,105,106} Women with 1 to 3 involved ALNs and tumors larger than 5 cm or tumors with pathologic margins postmastectomy should receive radiation therapy to the chest wall and supraclavicular area.

The panel also recommends strong consideration of ipsilateral internal mammary field radiation therapy in women with positive ALNs (category 2B).

Results from the randomized NCIC-CTG MA.20 trial show that additional regional node irradiation reduces the risk of locoregional and distant recurrence and improves disease-free survival.¹⁰⁷ The study enrolled 1832 women; most (85%) had 1 to 3 positive lymph nodes, and a smaller proportion (10%) had high-risk, node-negative breast cancer. All women had been treated with breast-conserving surgery and adjuvant chemotherapy or endocrine therapy. The participants were randomized to receive either whole-breast radiation therapy alone or whole-breast radiation plus regional node radiation therapy. The interim data found that after a median follow-up of 62 months, statistically significant benefits were seen in the group receiving the added regional node radiation therapy, including improved disease-free survival (HR, 0.68; P=.003; 5-year risk, 89.7% and 84.0%) and overall survival (HR, 0.76; P=.07; 5-year risk, 92.3% and 90.7%).¹⁰⁷ The consensus of the panel is that radiation therapy should be given to clinically or pathologically positive ipsilateral internal mammary lymph nodes, with a strong consideration of treatment of the internal mammary lymph nodes.

Postmastectomy irradiation should be performed using CT-based treatment planning to assure reduced radiation dose to the heart and lungs. The recommended radiation dose for whole-breast radiation is 45 to 50 Gy in fractions of 1.8 to 2.0 Gy, or 42.5 Gy in fractions of 2.55 Gy to the ipsilateral chest wall, mastectomy scar, and drain sites. An additional boost dose of 10 to 16 Gy radiation in 2-Gy single doses is recommended patients who are at high risk for disease recurrence (eg, age <50 years with high-grade tumors).^108-110

Node-Negative Disease: Features in node-negative tumors that predict a high rate of local recurrence include primary tumors greater than 5 cm and close (<1 mm) or positive pathologic margins. Chest wall irradiation is recommended for these patients.¹¹¹ Consideration should be given to radiation to the ipsilateral supraclavicular area and to the ipsilateral internal mammary lymph nodes (category 2B), especially in patients with inadequate axillary evaluation or extensive lymphovascular invasion. Postmastectomy radiation therapy is not recommended for patients with tumors 5 cm or smaller, margins greater than or equal to 1 mm, and no positive ALNs.

The panel recommends that decisions related to administration of radiation therapy for patients receiving preoperative systemic therapy should be made based on preoperative systemic therapy tumor characteristics irrespective of response to neoadjuvant chemotherapy. Endocrine therapy and trastuzumab can be administered concurrently with radiation therapy if indicated.

Breast Reconstruction

Breast reconstruction may be an option for any woman receiving surgical treatment for breast cancer. Therefore, all women undergoing breast cancer treatment should be educated about breast reconstructive options appropriate for their individual clinical situation. However, breast reconstruction should not interfere with the appropriate surgical management of the cancer.

Factors to be considered when deciding the type of reconstruction include patient preference, body habitus, smoking history, comorbidities, plans for irradiation, and expertise and experience of the reconstruction team. Reconstruction is an optional procedure that does not impact the probability of recurrence or death, but it is associated with an improved quality of life for many patients. It is sometimes necessary to perform surgery on the contralateral breast (eg, breast reduction, implantation) to achieve optimal symmetry between the ipsilateral reconstructed breast and the contralateral breast.

Breast Reconstruction After Mastectomy: Mastectomy results in loss of the breast for breastfeeding, loss of sensation in the skin of the breast and nipple areolar complex (NAC), and loss of the breast for cosmetic, body image, and psychosocial purposes. The loss of the breast for cosmetic, body image, and psychosocial issues may be partially overcome through the performance of breast reconstruction with or without reconstruction of the NAC. Reconstruction can be performed either immediately after mastectomy and under the same anesthetic or in a delayed fashion after mastectomy. In many cases, breast reconstruction involves a staged approach requiring more than one procedure, such as surgery on the contralateral breast to improve symmetry, revision surgery involving the breast and/or donor site, and/or nipple and areola reconstruction and tattoo pigmentation.

Many factors must be considered in the decision-making about breast reconstruction after mastectomy. Several different types of breast reconstruction include the use of implants, autogenous tissues, or both.^112-114 Reconstruction with implants can be performed either through immediate placement of a permanent subpectoral implant or initial placement of a subpectoral expander implant followed by gradual expansion of the implant envelope with stretching of the pectoralis major muscle and overlying skin, followed by replacement of the expander with a permanent implant. A wide variety of implants are available that contain saline, silicone gel, or a combination of saline and silicone gel inside a solid silicone envelope. Autogenous tissue methods of reconstruction use various combinations of fat, muscle, skin, and vasculature from donor sites (eg, abdomen, buttock, back) that may be brought to the chest wall with their original blood supply (pedicle flap) or as free flaps with microvascular anastomoses to blood supply from the chest wall/thorax.¹¹⁵ Several procedures using autologous tissue are available, including transverse rectus abdominis myocutaneous flap, latissimus dorsi flap, and gluteus maximus myocutaneous flap reconstruction. Composite reconstruction techniques use implants in combination with autogenous tissue reconstruction to provide volume and symmetry. Patients with underlying diabetes or who smoke tobacco have increased rates of complications after autogenous tissue breast cancer reconstruction, presumably because of underlying microvascular disease.

Skin-Sparing Mastectomy: Skin-sparing mastectomy procedures are appropriate for some patients and involve removal of the breast parenchyma, including the NAC, while preserving most of the original skin envelope and are followed by immediate reconstruction with autogenous tissue, a prosthetic implant, or a composite of autogenous tissue and an implant. Skin-sparing mastectomy involving preservation of the skin of the NAC has become the subject of increased attention. Possible advantages of this procedure include improvements in breast cosmesis, body image, and nipple sensation after mastectomy, although the impact of this procedure on these quality-of-life issues has not been well studied.^116-118 Limited data from surgical series, with short follow-up, suggest that performance of NAC-sparing mastectomy in selected patients is associated with low rates of both occult involvement of the NAC with breast cancer and local recurrence of disease.^117,119,120 NAC-sparing procedures may be an option in patients who are carefully selected by experienced multidisciplinary teams. According to the panel, assessment of nipple margins is mandatory when considering NAC-sparing procedures. Retrospective data support the use of NAC-sparing procedures for patients with breast cancer, with low rates of nipple involvement and local recurrence because of early-stage, biologically favorable (eg, Nottingham grade I or 2, node-negative, HER2^-, no lymphovascular invasion), invasive cancers and/or ductal carcinoma in situ that are peripherally located in the breast (>2 cm from nipple).^121,122 Contraindications for nipple preservation include evidence of nipple involvement, such as Paget disease or bloody nipple discharge. Several prospective trials are underway to evaluate NAC-sparing mastectomy in the setting of cancer, and enrollment in such trials is encouraged.

Advantages of a skin-sparing mastectomy procedure include an improved cosmetic outcome resulting in a reduction in the size of the mastectomy scar and a more natural breast shape, especially when autologous tissue is used in reconstruction,¹²³ and the ability to perform immediate reconstruction. Although no randomized studies have been performed, results of several mostly retrospective studies have indicated that the risk of local recurrence is not increased in patients undergoing skin-sparing mastectomies compared with those undergoing non-skin-sparing procedures; however, strong selection biases almost certainly exist in the identification of patients appropriate for skin-sparing procedures.^124-128 Reconstruction of the NAC may also be performed in a delayed fashion if desired by the patient. Reconstructed nipples are devoid of sensation. According to the panel, skin-sparing mastectomy should be performed by an experienced breast surgery team that works in a coordinated, multidisciplinary fashion to guide proper patient selection for skin-sparing mastectomy, determine optimal sequencing of the reconstructive procedures in relation to adjuvant therapies, and perform a resection that achieves appropriate surgical margins. Postmastectomy radiation should still be applied in patients treated with skin-sparing mastectomy based on the same selection criteria as for standard mastectomy.

Postmastectomy Radiation and Breast Reconstruction: Plans for postmastectomy radiation therapy can impact decisions related to breast reconstruction because there is a significantly increased risk of implant capsular contracture after irradiation of an implant. Furthermore, postmastectomy irradiation may have a negative impact on breast cosmesis when autologous tissue is used in immediate breast reconstruction, and may interfere with the targeted delivery of radiation when immediate reconstruction is performed using either autologous tissue or breast implants.^129,130 Some studies, however, have not found a significant compromise in reconstruction cosmesis after irradiation.¹³¹ The preferred approach to breast reconstruction for these patients was a subject of controversy among the panel. Although some experienced breast cancer teams have used protocols in which immediate tissue reconstructions are followed by radiation therapy, it is generally preferred that the radiation therapy precede the placement of the autologous tissue, because of reported loss in reconstruction cosmesis (category 2B).

When implant reconstruction is planned in a patient requiring radiation therapy, the panel prefers a staged approach with immediate tissue expander placement, followed by implant placement. Surgery to exchange the tissue expanders with permanent implants can be performed before radiation or after completion of radiation therapy. Tissue expansion of irradiated skin can result in a significantly increased risk of capsular contracture, malposition, poor cosmesis, and implant exposure. The use of tissue expanders/implants is relatively contraindicated in patients who have been previously irradiated. Immediate placement of an implant in patients requiring postoperative radiation has an increased rate of capsular contracture, malposition, poor cosmesis, and implant exposure.

Several reconstructive approaches are summarized for these patients in “Principles of Breast Reconstruction Following Surgery,” available online, in these guidelines, at NCCN.org.

Breast Reconstruction After Lumpectomy: Issues related to breast reconstruction also pertain to women who undergo or have undergone a lumpectomy, particularly when the surgical defect is large and/or expected to be cosmetically unsatisfactory. An evaluation of the likely cosmetic outcome of lumpectomy should be performed before surgery. Oncoplastic techniques for breast conservation can extend breast-conserving surgical options in situations in which the resection, itself, would likely yield an unacceptable cosmetic outcome.¹³² The evolving field of oncoplastic surgery includes the use of “volume displacement” techniques performed in conjunction with a large partial mastectomy.¹³³ Oncoplastic volume displacement procedures combine the removal of generous regions of breast tissue (typically designed to conform to the segmentally distributed cancer in the breast) with “mastopexy” techniques in which remaining breast tissues are shifted together within the breast envelope to fill the resulting surgical defect and thereby avoid the creation of significant breast deformity. Volume displacement techniques are generally performed during the same operative setting as the breast-conserving lumpectomy by the same surgeon who is performing the cancer resection.^133,134

Advantages of oncoplastic volume displacement techniques are that they permit the removal of larger regions of breast tissue, thereby achieving wider surgical margins around the cancer, and at the same time better preserve the natural shape and appearance of the breast than standard breast resections.¹³⁵

Limitations of oncoplastic volume displacement techniques include lack of standardization among centers, performance at only a limited number of sites in the United States, and the possible need for subsequent mastectomy if pathologic margins are positive when further breast-conserving attempts are deemed impractical or unrealistic. Nevertheless, panel consensus is that these issues should be considered before surgery for women who are likely to have a surgical defect that is cosmetically unsatisfactory, and that women who undergo lumpectomy and are dissatisfied with the cosmetic outcome after treatment should be offered a consultation with a plastic surgeon to address the repair of resulting breast defects. Patients should be informed of the possibility of positive margins and potential need for secondary surgery, which could include reexcision segmental resection or could require mastectomy with or without loss of the nipple. Oncoplastic procedures can be combined with surgery on the contralateral unaffected breast to minimize long-term asymmetry.

Finally, it is important to note that the primary focus should be on treatment of the tumor, and such treatment should not be compromised when decisions regarding breast reconstruction are made.

Systemic Adjuvant Therapy

After surgical treatment, adjuvant systemic therapy should be considered. The decision is often based on individual risk of relapse and predicted sensitivity to a particular treatment (eg, ER/PR and HER2 status).

The published results of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview analyses of adjuvant polychemotherapy and tamoxifen show convincing reductions in the odds of recurrence and death in all age groups for chemotherapy and for endocrine therapy.^2,136 Thus, the current guidelines recommend adjuvant therapy without regard to patient age (category 1). The decision to use systemic adjuvant therapy requires considering and balancing the risk for disease recurrence with local therapy alone, the magnitude of benefit from applying adjuvant therapy, the toxicity of the therapy, and comorbidity.^137,138 The decision-making process requires a collaboration involving the health care team and the patient. Panel consensus is that data are insufficient to make definitive chemotherapy recommendations for patients older than 70 years. Although AC or CMF (cyclophosphamide/methotrexate/fluorouracil) was superior to capecitabine in a randomized trial of women aged 65 years or older with early-stage breast cancer, enrollment in that study was discontinued early.¹³⁹ A possibility also exists that AC/CMF is not superior to any chemotherapy in this cohort. Therefore, treatment should be individualized for women in this age group, with consideration given to comorbid conditions.

Estimating Risk of Relapse or Death and Benefits of Systemic Treatment

Several prognostic factors predict for future recurrence or death from breast cancer. The strongest prognostic factors are patient age, comorbidity, tumor size, tumor grade, number of involved ALNs, and possibly HER2 tumor status. Algorithms have been published estimating rates of recurrence,¹³⁷ and a validated computer-based model to estimate 10-year disease-free and overall survivals is available (Adjuvant! Online; www.adjuvantonline.com) that incorporates all of the above prognostic factors except for HER2 tumor status.^138,140 These tools help clinicians objectively estimate outcome with local treatment only, and also help estimate the absolute benefits expected from systemic adjuvant endocrine therapy and chemotherapy. These estimates may be used by the clinician and patient in their shared decision-making regarding the toxicities, costs, and benefits of systemic adjuvant therapy.¹⁴¹

A determination of the HER2 status of the tumor is recommended for prognostic purposes for patients with node-negative breast cancer.¹⁴² More importantly, HER2 tumor status also provides predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease (category 1). For example, retrospective analyses have shown that anthracycline-based adjuvant therapy is superior to non-anthracycline-based adjuvant chemotherapy in patients with HER2⁺ tumors,^143-147 and that the dose of doxorubicin may be important in the treatment of tumors that are HER2⁺.¹⁴⁸ Prospective evidence of the predictive utility of HER2 status in early-stage^149-154 and metastatic breast cancer^155-157 is available for trastuzumab-containing therapies.

Use of DNA microarray technologies to characterize breast cancer has allowed for the development of classification systems based on gene expression profiles.¹⁵⁸ Five major subtypes of breast cancer have been identified by DNA microarray gene expression profiling: ER⁺/HER2^- (luminal A and B subtypes); ER^-/HER2^- (basal subtype); HER2⁺; and tumors that have characteristics similar to normal breast tissue.^159-161 In retrospective analyses, these gene expression subtypes are associated with differing relapse-free survival and overall survival.

Another gene-based approach is the 21-gene assay using reverse transcription polymerase chain reaction (RT-PCR) on RNA isolated from paraffin-embedded breast cancer tissue (Oncotype Dx). On retrospective analysis of 2 trials (NSABP B-14 and B-20) performed in women with hormone receptor-positive, ALN-negative invasive breast cancer, this assay system was able to quantify risk of recurrence as a continuous variable (eg, Oncotype Dx recurrence score) and to predict responsiveness to both tamoxifen and CMF or methotrexate/5-fluorouracil/leucovorin chemotherapy.^162,163 A comparison of simultaneous analyses of breast cancer tumors using 5 different gene expression models indicated that 4 of these methods (including MammaPrint and Oncotype Dx) provided similar predictions of clinical outcome.¹⁶⁴

A similar approach has been used to define more limited sets of genes for prognostic and predictive purposes.¹⁶⁵ For example, the MammaPrint assay uses microarray technology to analyze a 70-gene expression profile from breast tumor tissue as a means of selecting patients with early-stage breast cancer who are more likely to develop distant metastases.^166-172 MammaPrint is approved by the FDA for helping to assign women with ER⁺ or ER^- breast cancer into a high versus low risk for recurrence, but not for predicting benefit from adjuvant systemic therapy. Studies using MammaPrint as a prognostic and predictive tool are small and/or retrospective in nature.

Multiple other multigene or multigene expression assay systems have been developed. These systems are generally based on small, retrospective studies, and the panel believes that none are currently sufficiently validated to warrant inclusion in the guidelines.

Although many of the DNA microarray technologies are able to stratify patients into prognostic and/or predictive subsets on retrospective analysis, the gene subsets differ from study to study, and prospective clinical trials testing the utility of these techniques have yet to be reported. Currently, prospective randomized clinical trials are addressing the use of Oncotype DX and MammaPrint as predictive and/or prognostic tools in populations of women with early-stage, lymph node-negative breast cancer.^173,174 Pending the results of the prospective trials, the panel considers the 21-gene RT-PCR assay to be an option when evaluating patients with primary tumors characterized as 0.6 to 1.0 cm with unfavorable features or greater than 1.0 cm, and node-negative, hormone receptor-positive, and HER2^- (category 2A). In this circumstance, the recurrence score may be determined to help estimate the likelihood of recurrence and benefit from chemotherapy. The panel emphasizes that the recurrence score should be used for decision-making only in the context of other elements of risk stratification for an individual patient. Unplanned, retrospective subset analysis from a single randomized clinical trial in postmenopausal, ALN-positive, ER⁺ breast cancer found that the 21-gene RT-PCR assay may provide predictive information for chemotherapy benefit in addition to tamoxifen.¹⁷⁵ Patients with a high score in the study benefited from chemotherapy, whereas patients with a low score did not seem to benefit from the addition of chemotherapy, regardless of the number of positive lymph nodes.¹⁷⁵ Patient selection for assay use remains controversial.

The additional benefit from adjuvant chemotherapy in addition to endocrine therapy is currently unclear for intermediate-risk patients (as assessed by the gene-based assays). The TAILORx and RxPONDER trials are being conducted to help answer this question. In the TAILORx trial, patients with node-negative, hormone receptor-positive breast cancer classified as being at low risk based on the gene signature or Adjuvant! Online estimates receive endocrine therapy alone, whereas patients deemed to be at high risk based on gene signature profiles or other characteristics receive chemotherapy in addition to endocrine therapy. Those classified as intermediate risk are randomized to receive chemotherapy or no chemotherapy.¹⁷⁶ The RxPONDER trial will confirm the SWOG-8814 trial data for women with ER⁺, node-positive disease treated with endocrine therapy with or without chemotherapy based on risk scores.¹⁷³ The findings from these trials will help determine the benefit of treating patients at intermediate risk with adjuvant chemotherapy. The MINDACT trial is underway in Europe to compare the 70-gene signature with the commonly used clinicopathologic criteria in selecting patients with breast cancer with 0 to 3 positive nodes for adjuvant chemotherapy.¹⁷⁴ The findings from this trial will help determine the prognostic value of MammaPrint and the benefit of treating intermediate-risk patients with adjuvant chemotherapy.

Stratification for Systemic Adjuvant Therapy

The guidelines recognize subsets of patients who have early breast cancer with the usual histologies based on responsiveness to endocrine therapy and trastuzumab (ie, hormone receptor status, HER2 status). Patients are then further stratified according to risk of disease recurrence based on anatomic and pathologic characteristics (ie, tumor grade, tumor size, ALN status, angiolymphatic invasion).

Endocrine therapy may be considered to reduce the risk for a second contralateral breast cancer, especially in those with ER⁺ disease. The NSABP database demonstrated a correlation between the ER status of a new contralateral breast tumor and the original primary tumor, which reinforced the notion that endocrine therapy is not an effective strategy to reduce the risk for contralateral breast cancer in patients diagnosed with ER^- tumors.¹⁷⁷ Unfavorable prognostic features include intramammary angiolymphatic invasion, high nuclear grade, high histologic grade, HER2⁺ status, or hormone receptor-negative status (category 2B).

ALN-Negative Tumors

For women with lymph node-negative, hormone receptor-negative tumors greater than 1 cm in diameter, systemic adjuvant chemotherapy is recommended (category 1). For those with lymph node-negative, hormone receptor-positive breast cancer tumors greater than 1 cm, endocrine therapy with chemotherapy is recommended (category 1). Incremental benefit of combination chemotherapy in patients with lymph node-negative, hormone receptor-positive breast cancer may be relatively small.¹⁷⁸ Therefore, the panel recommends that tumor hormone receptor status be included as one of the factors considered when making chemotherapy-related treatment decisions for patients with node-negative, hormone receptor-positive breast cancer. Patients for whom this evaluation may be especially important are those with tumors characterized as 0.6 to 1.0 cm and hormone receptor-positive that are grade 2 or 3 or have unfavorable features, or greater than 1 cm and hormone receptor-positive and HER2^-. However, chemotherapy should not be withheld from these patients solely based on ER⁺ tumor status.^2,178,179

The use of genomic/gene expression array data that also incorporate additional prognostic/predictive biomarkers (eg, Oncotype Dx recurrence score) may provide additional prognostic and predictive information beyond anatomic staging and determination of ER/PR and HER2 status. Assessment of the role of the genomic/gene expression array technology is difficult because of the retrospective nature of the studies, the evolution of chemotherapy and hormone therapy regimens, and the overall more favorable prognosis of the patients with lymph node-negative disease compared with those enrolled in the historically controlled clinical trials. Some NCCN Member Institutions consider performing RT-PCR analysis (eg, Oncotype DX assay) to further refine risk stratification for adjuvant chemotherapy in patients with node-negative, ER⁺, HER2^- breast cancers greater than 0.5 cm, whereas others do not.

ALN-Positive Tumors

Patients with lymph node-positive disease are candidates for chemotherapy and, if the tumor is hormone receptor-positive, for the addition of endocrine therapy (category 1). In postmenopausal women with hormone receptor-positive disease, an aromatase inhibitor should be used either as initial adjuvant therapy, sequentially with tamoxifen, or as extended therapy after tamoxifen, unless a contraindication exists or the woman declines this therapy. In premenopausal women, adjuvant tamoxifen is recommended. If both chemotherapy and tamoxifen are administered, data from the Intergroup trial 0100 suggest that delaying initiation of tamoxifen until after completion of chemotherapy improves disease-free survival compared with concomitant administration.¹⁷⁹ Consequently, chemotherapy followed by endocrine therapy should be the preferred therapy sequence.

Adjuvant Endocrine Therapy

The guidelines call for the determination of ER and PR content in all primary invasive breast cancers.¹⁰ Patients with invasive breast cancers that are ER⁺ or PR⁺ should be considered for adjuvant endocrine therapy regardless of patient age, lymph node status, or whether adjuvant chemotherapy is to be administered.¹⁸⁰ Selected studies suggest that HER2⁺ breast cancers may be less sensitive to some endocrine therapies, although other studies have failed to confirm this finding.^145,181-188 A retrospective analysis of tumor blocks collected in the ATAC trial indicated that HER2 amplification is a marker of relative endocrine resistance independent of type of endocrine therapy.¹⁸⁹ However, given the favorable toxicity profile of the available endocrine therapies, the panel recommends the use of adjuvant endocrine therapy in most women with hormone receptor-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor. Possible exceptions to this recommendation are patients with lymph node-negative cancers 0.5 cm or less or 0.6 to 1.0 cm in diameter with favorable prognostic features for whom the prognosis is so favorable that the benefits of adjuvant endocrine therapy are very small.

The most firmly established adjuvant endocrine therapy is tamoxifen for both premenopausal and postmenopausal women.² In women with ER⁺ breast cancer, adjuvant tamoxifen decreases the annual odds of recurrence by 39% and the annual odds of death by 31% irrespective of the use of chemotherapy, patient age, menopausal status, or ALN status.² In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first, followed by sequential tamoxifen.¹⁷⁹ Prospective, randomized trials have shown that 5 years of tamoxifen is more effective than 1 to 2 years.^190,191

The ATLAS trial randomly allocated 12894 women who had completed 5 years of tamoxifen to either continue tamoxifen up to 10 years or discontinue at 5 years (control). The outcome analyses of 6846 women with ER⁺ disease showed that extending adjuvant treatment up to 10 years reduced the risk of relapse and breast cancer-related mortality.¹⁹² The risk of recurrence during years 5 to 14 was 21.4% for women receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction, 3.7%). Patients receiving tamoxifen beyond 10 years of treatment had a greater reduction in risk of progression, possibly because of a carryover effect. The reduction in risk of recurrence was 0.90 (95% CI, 0.79-1.02) during 5 to 9 years of tamoxifen treatment and 0.75 (0.62-0.90) after 10 years. Furthermore, reduced mortality was apparent after completion of 10 years of treatment with tamoxifen. With regard to toxicity, the most important adverse effects noted in all women in ATLAS were an increased risk of endometrial cancer after treatment with 10 years of tamoxifen and pulmonary embolism. The recurrence rate ratios for incidence of adverse events (hospitalization or death) were: pulmonary embolus, 1.87 (95% CI, 1.13-3.07; P=.01 [including 0.2% mortality in both treatment groups]); stroke, 1.06 (0.83-1.36); ischemic heart disease, 0.76 (0.60-0.95; P=.02); and endometrial cancer, 1.74 (1.30-2.34; P=.0002). The cumulative risk for endometrial cancers during 5 to 14 years was 3.1%, with a mortality of 0.4% associated with endometrial cancer, higher than what was noted in the control group of patients receiving only 5 years of therapy (cumulative risk, 1.6%; mortality, 0.2%).¹⁹²

Results are expected in the near future of other ongoing trials of extended tamoxifen, such as the aTTom trial of 5 versus 10 years tamoxifen among approximately 7000 women. Preliminary results of this trial have shown that continuation of tamoxifen beyond 5 years resulted in a nonsignificant reduction in recurrences.¹⁹³

The role of adjuvant ovarian ablation or suppression in premenopausal women with hormone receptor-positive breast cancer is incompletely defined.^194-196 Ovarian ablation may be accomplished through surgical oophorectomy or ovarian irradiation. Ovarian suppression uses luteinizing hormone-releasing hormone (LH-RH) agonists that cause suppression of luteinizing hormone (LH) and release of follicle stimulating hormone (FSH) from the pituitary and reduction in ovarian estrogen production. Available LH-RH agonists in the United States include goserelin and leuprolide. When used for ovarian suppression, both agents should be given as monthly injections.

The EBCTCG performed a meta-analysis of randomized studies of ovarian ablation or suppression alone versus no adjuvant treatment in women older than 50 years, with many of the subjects in the trials unselected based on hormone receptor status. Reductions in the annual odds of recurrence and death favored ovarian ablation/suppression over no adjuvant treatment (age <40 years: 25% reduction in recurrence rate and 29% reduction in death rate; age 40-49 years: 29% reduction in recurrence rate and 29% reduction in death rate).¹⁹⁵ Analysis of ovarian suppression versus no adjuvant therapy did not show a significant reduction in recurrence (HR reduction, 28.4; 95% CI, 50.5-3.5; P=.08) or death (HR reduction, 22; 95% CI, 4.1-6.4; P=.11).¹⁹⁷

Studies in premenopausal women of ovarian ablation or suppression alone versus CMF chemotherapy alone generally demonstrate similar antitumor efficacy in patients with hormone receptor-positive tumors, and superior outcomes with CMF in patients with hormone receptor-negative tumors.^197-205 Findings also suggest that the benefits of ovarian suppression/ablation may be greater in the younger premenopausal group. Studies of ovarian ablation/suppression plus tamoxifen versus chemotherapy alone in premenopausal women generally demonstrate no difference in rates of recurrence or survival between the treatments.^195,206,207

A large Intergroup study in premenopausal women with hormone receptor-positive, node-positive breast cancer studied adjuvant CAF chemotherapy versus CAF plus ovarian suppression with goserelin (CAF-Z) versus CAF-Z plus tamoxifen (CAF-ZT).¹⁹⁸ The results showed no improvement in time to recurrence or overall survival between CAF with CAF-Z. There was improvement in time to recurrence (HR 0.73, 95% CI 0.59-0.90; P < .01) but not overal survival with CAF-Z compared with CAF-ZT (HR, 0.91, 95% CI, 0.71-1.15; P=.21). This study did not include a CAF plus tamoxifen arm, so the contribution of the goserelin to the improved time to recurrence in the CAF-ZT arm cannot be assessed. The EBCTCG also conducted a meta-analysis examining the addition of ovarian suppression/ablation.¹⁹⁵ They identified no statistically significant reduction in annual rates of recurrence or death with the addition of ovarian suppression or ablation to chemotherapy in women younger than 40 years or aged 40 to 49 years.

Thus, selected studies currently suggest benefit from the use of ovarian ablation or suppression in the adjuvant treatment of premenopausal women with hormone receptor-positive breast cancer. However, the benefit of ovarian suppression or ablation when added to combination chemotherapy or tamoxifen, as would be widely used in the United States, is uncertain.

Several studies have evaluated aromatase inhibitors in the treatment of postmenopausal women with early-stage breast cancer. These studies have used aromatase inhibitors as initial adjuvant therapy, as sequential therapy after 2.0 to 3.0 years of tamoxifen, or as extended therapy after 4.5 to 6.0 years of tamoxifen. The aromatase inhibitors are not active in the treatment of women with functioning ovaries and should not be used in women whose ovarian function cannot be assessed reliably because of treatment-induced amenorrhea. The results from 2 prospective randomized clinical trials have provided evidence of an overall survival benefit for patients with early-stage breast cancer receiving initial endocrine therapy with tamoxifen followed sequentially by anastrozole (HR, 0.53; 95% CI, 0.28-0.99; P=.045) or exemestane (HR, 0.83; 95% CI, 0.69-1.00; P=.05 [excluding patients with ER^- disease]) when compared with tamoxifen as the only endocrine therapy.^208,209 In addition, the NCIC-CTG MA-17 trial showed a survival advantage for extended therapy with letrozole compared with placebo in women with ALN-positive (but not lymph node-negative), ER⁺ breast cancer.²¹⁰ However, no survival differences have been reported for patients receiving initial adjuvant therapy with an aromatase inhibitor versus first-line tamoxifen.^211,212

Tamoxifen and aromatase inhibitors have different side effect profiles. Both contribute to hot flashes and night sweats and may cause vaginal dryness. Aromatase inhibitors are more commonly associated with musculoskeletal symptoms, osteoporosis, and increased rate of bone fracture, whereas tamoxifen is associated with an increased risk for uterine cancer and deep venous thrombosis.

Two studies have examined initial adjuvant endocrine treatment with either tamoxifen or an aromatase inhibitor. The ATAC trial showed that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal women with hormone receptor-positive breast cancer.^213,214 With a median of 100 months follow-up, results in 5216 postmenopausal women with hormone receptor-positive, early-stage breast cancer enrolled in the ATAC trial demonstrated fewer recurrences (HR for disease-free survival, 0.85; 95% CI, 0.76-0.94; P=.003) with anastrozole compared with tamoxifen.²¹¹ No difference in survival has been observed (HR, 0.90; 95% CI, 0.75-1.07; P=.2). Patients in the combined tamoxifen and anastrozole group gained no benefit over those in the tamoxifen group, suggesting a possible deleterious effect from the weak estrogenic effect of tamoxifen in patients with near-complete elimination of endogenous estrogen levels.²¹⁴ ATAC trial subprotocols show that anastrozole has a lesser effect on endometrial tissue than tamoxifen²¹⁵; anastrozole and tamoxifen have similar effects on quality of life, with most patients reporting no significant impairment of overall quality of life²¹⁶; anastrozole is associated with a greater loss of bone mineral density²¹⁷; anastrozole shows a small pharmacokinetic interference of unclear significance in the presence of tamoxifen²¹⁸; and no evidence supports an interaction between prior chemotherapy and anastrozole.²¹⁹

BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 years, letrozole alone for 5 years, tamoxifen for 2 years followed sequentially by letrozole for 3 years, or letrozole for 2 years followed sequentially by tamoxifen for 3 years. An early analysis compared tamoxifen alone versus letrozole alone, including in patients in the sequential arms during their first 2 years of treatment only.²¹² With 8010 women included in the analysis, disease-free survival was superior in the women treated with letrozole (HR, 0.81; 95% CI, 0.70-0.93; log rank P=.003). No interaction between PR expression and benefit was observed. No difference in overall survival has been observed. A comparison of the cardiovascular side effects in the tamoxifen and letrozole arms of the BIG 1-98 trial showed that the overall incidence of cardiac adverse events was similar (letrozole, 4.8%; tamoxifen, 4.7%). However, the incidence of grade 3 to 5 cardiac adverse events was significantly higher in the letrozole arm, and both the overall incidence and incidence of grade 3 to 5 thromboembolic events was significantly higher in the tamoxifen arm.²²⁰ In addition, a higher incidence of bone fracture was observed for women in the letrozole arm compared with those in the tamoxifen arm (9.5% vs 6.5%).²²¹ After a longer follow-up (median, 71 months), no significant improvement in disease-free survival was noted with either tamoxifen followed by letrozole or the reverse sequence compared with letrozole alone (HR for tamoxifen followed by letrozole, 1.05; 99% CI, 0.84-1.32; HR for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76-1.21).²²²

Five trials have studied the use of tamoxifen for 2 to 3 years followed sequentially by a third-generation aromatase inhibitor versus continued tamoxifen. The Italian Tamoxifen Anastrozole (ITA) trial randomized 426 postmenopausal women with breast cancer who had completed 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to anastrozole to complete a total of 5 years of endocrine therapy.²²³ The HR for relapse strongly favored sequential treatment with anastrozole (HR, 0.35; 95% CI, 0.18-0.68; P=.001), with a trend toward fewer deaths (P=.10).²²³ Updated results from this study show the HR for relapse-free survival as 0.56 (95% CI, 0.35-0.89; P=.01); the P value for overall survival analysis remained at 0.1.²²⁴ The IES trial randomized 4742 postmenopausal women with breast cancer who had completed a total of 2 to 3 years of tamoxifen to either continue tamoxifen or switch to exemestane to complete a total of 5 years of endocrine therapy.²²⁵ The results at a median of 55.7 months of follow-up demonstrated the superiority of sequential exemestane in terms of disease-free survival (HR, 0.76; 95% CI, 0.66-0.88; P=.0001), with a significant difference in overall survival in only patients with ER⁺ tumors (HR, 0.83; 95% CI 0.69-1.00; log rank P=.05). A prospectively planned, combined analysis of 3224 patients enrolled in the ABCSG trial 8 and the Arimidex Nolvadex (ARNO 95) trial has also been reported.²²⁶ Patients in this combined analysis had been randomized after 2 years of tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of anastrozole. With 28 months of median follow-up available, event-free survival was superior with crossover to anastrozole (HR, 0.60; 95% CI, 0.44-0.81; P=.0009). No statistically significant difference in survival has been observed. An analysis of the ARNO 95 trial alone after 58 months of median follow-up showed that switching from tamoxifen to anastrozole was associated with significant increases in both disease-free survival (HR, 0.66; 95% CI, 0.44-1.00; P=.049) and overall survival (HR, 0.0.53; 95% CI, 0.28-0.99; P=.045).²⁰⁹ A meta-analysis of the ABCSG 8, ARNO 95, and ITA studies showed significant improvement in overall survival (HR, 0.71; 95% CI, 0.52-0.98; P=.04) with a switch to anastrozole.²²⁷

The TEAM trial compared sequential treatment of exemestane alone versus sequential therapy of tamoxifen for 2.5 to 3.0 years followed by exemestane to complete 5 years of hormone therapy.²²⁸ At the end of 5 years, 85% of patients in the sequential group versus 86% in the exemestane group were disease-free (HR, 0.97; 95% CI, 0.88-1.08; P=.60). This finding is consistent with the data from the BIG 1-98 trial,²²² in which tamoxifen followed by letrozole or the reverse sequence of letrozole followed by tamoxifen was not associated with significant differences in efficacy versus letrozole monotherapy after a median follow-up of 71 months.

Results of the MA-17 trial in 5187 women who had completed 4.5 to 6.0 years of adjuvant tamoxifen showed that extended therapy with letrozole provides benefit in postmenopausal women with hormone receptor-positive, early-stage breast cancer.^210,229 At a median follow-up of 2.5 years, the results showed fewer recurrences or new contralateral breast cancers with extended letrozole (HR, 0.58; 95% CI, 0.45-0.76; P<.001). No difference in overall survival was observed (HR, 0.82; 95% CI, 0.57-1.19; P=.3), although a survival advantage was seen in the subset of patients with ALN-positive disease (HR 0.61; 95% CI, 0.38-0.98; P=.04). In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole versus placebo was evaluated after unblinding of the study in the 1579 women who had been randomly assigned to placebo after 4.5 to 6.0 years of tamoxifen.^230,231 The median time since completion of tamoxifen was 2.8 years. Both disease-free survival and distant disease-free survival were significantly improved in the group receiving letrozole, thereby providing some evidence for the efficacy of letrozole in patients who had received 4.5 to 6.0 years of tamoxifen therapy followed by no endocrine therapy for an extended period. A formal quality-of-life analysis showed reasonable preservation of quality of life during extended endocrine therapy, although women may experience ongoing menopausal symptoms and loss of bone mineral density.^232,233 No data are available regarding use of aromatase inhibitors for more than 5 years or long-term toxic effects from extended treatment. In addition, the ATLAS trial data do not provide a clear direction regarding treatment of postmenopausal women.¹⁹² No available data suggest that an aromatase inhibitor for 5 years provides a better long-term benefit than 10 years of tamoxifen.

In the extension study of ABCSG trial 6, postmenopausal patients with hormone receptor-positive breast cancer received 5 years of adjuvant tamoxifen and were randomized to 3 years of anastrozole or no further therapy.²³⁴ At a median follow-up of 62.3 months, women who received anastrozole (n=387) were reported to have a statistically significantly reduced risk of recurrence compared with women who received no further treatment (n=469; HR, 0.62; 95% CI, 0.40-0.96; P=.031).²³⁴

The differences in design and patient populations among the studies of aromatase inhibitors do not allow for the direct comparison of the results of these studies. A meta-analysis of adjuvant trials of aromatase inhibitors versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented lower recurrence rates with the aromatase inhibitor-containing regimen, with no clear impact on overall survival.²³⁵ Whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy is unknown.

The optimal duration of aromatase inhibitor treatment is also not known, nor is the optimal use vis-à-vis chemotherapy established. Furthermore, the long-term (>5-year) safety and efficacy of these agents are still under investigation. The various studies are consistent in demonstrating that the use of a third-generation aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer lowers the risk of recurrence, including ipsilateral breast tumor recurrence, contralateral breast cancer, and distant metastatic disease, when used as initial adjuvant therapy, sequential therapy, or extended therapy. The panel finds no compelling evidence of meaningful efficacy or toxicity differences between the aromatase inhibitors anastrozole, letrozole, and exemestane. All 3 have shown similar antitumor efficacy and toxicity profiles in randomized studies in the adjuvant settings. These guidelines recommend the following adjuvant endocrine therapy options for women with early-stage breast cancer who are postmenopausal at diagnosis: an aromatase inhibitor as initial adjuvant therapy for 5 years (category 1); tamoxifen for 2 to 3 years followed by one of the following options: an aromatase inhibitor to complete 5 years of adjuvant endocrine therapy (category 1) or 5 years of aromatase inhibitor therapy (category 2B); or tamoxifen for 4.5 to 6.0 years followed by 5 years of an aromatase inhibitor (category 1) or consideration of tamoxifen for up to 10 years. In postmenopausal women, the use of tamoxifen alone for 5 years (category 1) or up to 10 years is limited to those who decline or who have a contraindication to aromatase inhibitors.

In premenopausal women, aromatase inhibitors are associated with the development of benign ovarian pathology and do not adequately suppress ovarian estrogen synthesis. Premenopausal women should not be given adjuvant initial therapy with an aromatase inhibitor outside the confines of a clinical trial. Women who are premenopausal at diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries without menses. Serial assessment of circulating LH, FSH, and estradiol to assure a true postmenopausal status is mandatory if this subset of women is to be considered for therapy with an aromatase inhibitor.^236,237 After 5 years of tamoxifen (category 1), for women postmenopausal at that time (including those who have become postmenopausal during the 5 years of tamoxifen therapy), the panel recommends considering extended therapy with an aromatase inhibitor for up to 5 years (category 1) or, based on the data from the ATLAS trial, considering tamoxifen for an additional 5 years. For those who remain premenopausal after the initial 5 years of tamoxifen, the panel recommends considering continuation of tamoxifen therapy for up to 10 years.

Measurement of the nuclear antigen Ki67 using IHC gives an estimate of the tumor cells in the proliferative phase (G1, G2, and M phases) of the cell cycle. Studies have shown the prognostic value of Ki67 as a biomarker and its usefulness in predicting response and clinical outcome.²³⁸ One small study suggests that measurement of Ki67 after short-term exposure to endocrine treatment may be useful in selecting patients resistant to endocrine therapy and those who may benefit from additional interventions.²³⁹ However, these data require larger analytic and clinical validation. In addition, standardization of tissue handling and processing is required to improve the reliability and value of Ki67 testing. No conclusive evidence currently shows that Ki67 alone, especially baseline Ki67 as an individual biomarker, helps in selecting the type of endocrine therapy for an individual patient. Therefore, the panel does not currently recommend assessment of Ki67.

The cytochrome P-450 (CYP) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. More than 100 allelic variants of CYP2D6 have been reported in the literature.²⁴⁰ Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with 1 or 2 variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen.²⁴¹ However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive early-stage invasive breast cancer.²⁴² The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects.²⁴² A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes.²⁴³ Given the limited and conflicting evidence at this time,²⁴⁴ the panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO guidelines.²⁴⁵ When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists.

Adjuvant Cytotoxic Chemotherapy

Several combination chemotherapy regimens are appropriate to consider when adjuvant cytotoxic chemotherapy is used. All adjuvant chemotherapy regimens listed in these guidelines have been evaluated in phase III clinical trials, and the current version of the adjuvant chemotherapy guideline does not distinguish between options for chemotherapy regimens by ALN status.

The adjuvant chemotherapy guidelines also include specific representative doses and schedules for the recommended adjuvant chemotherapy regimens. The regimens have been categorized as “preferred” or “other.”

The purpose of distinguishing the adjuvant chemotherapy regimens as preferred and other adjuvant chemotherapy regimens is to convey the sense of the panel regarding the relative efficacy and toxicity of the regimens.²⁴⁶ Factors considered by the panel include the efficacy, toxicity, and treatment schedules of the regimens. The following sections summarize clinical trial results focusing on treatment efficacy.

Adjuvant HER2-Targeted Therapy

The panel recommends HER2-targeted therapy in patients with HER⁺ tumors. Trastuzumab is a humanized monoclonal antibody with specificity for the extracellular domain of HER2.²⁷⁰ Results of several randomized trials testing trastuzumab as adjuvant therapy have been reported.^{149-154,271-273}

NSABP B-31 patients with HER2⁺, node-positive breast cancer were randomly assigned to 4 cycles of AC every 3 weeks followed by paclitaxel for 4 cycles every 3 weeks or the same regimen with 52 weeks of trastuzumab commencing with paclitaxel. In the NCCTG N9831 trial, patients with HER2⁺ breast cancer that was node-positive, or, if node-negative, with primary tumors greater than 1 cm if ER^- and PR^- or greater than 2 cm if ER⁺ or PR⁺, were similarly randomized except that paclitaxel was given on a low-dose weekly schedule for 12 weeks and a third arm delayed trastuzumab until the completion of paclitaxel.

The NSABP B-31 and NCCTG N9831 trials have been jointly analyzed with the merged control arms for both trials compared with the merged arms using trastuzumab begun concurrently with paclitaxel. A total of 4045 patients were included in the joint analysis performed at 3.9 years median follow-up. A 48% reduction in the risk of recurrence (HR, 0.52; 95% CI, 0.45-0.60; P<.001) and a 39% reduction in the risk of death (HR, 0.61; 95% CI, 0.50-0.75; log-rank P=.001) were documented.²⁷² Similar significant effects on disease-free survival were observed when results of the NSABP B-31 and NCCTG N9831 trials were analyzed separately. Cardiac toxicity was increased in patients treated with trastuzumab.^152,274,275 In the adjuvant trastuzumab trials, the rates of grade III/IV congestive heart failure (CHF) or cardiac-related death in patients receiving treatment regimens containing trastuzumab ranged from 0% (FinHer trial) to 4.1% (NSABP B-31 trial).^{149,150,152,154,274,275} The frequency of cardiac dysfunction seems to be related to both age and baseline left ventricular ejection fraction. An analysis of data from N9831 showed the 3-year cumulative incidence of CHF or cardiac death to be 0.3%, 2.8%, and 3.3% in the trial arms without trastuzumab, with trastuzumab following chemotherapy, and with trastuzumab initially combined with paclitaxel, respectively.²⁷⁴ The acceptable rate of significant cardiac toxicity observed in the trastuzumab adjuvant trials partly reflects rigorous monitoring for cardiac dysfunction. Furthermore, concerns have been raised regarding the long-term cardiac risks associated with trastuzumab therapy based on follow-up evaluations of cardiac function in patients enrolled in some of these trials.^276,277

A third trial (HERA) (N=5081) tested trastuzumab for 1 or 2 years compared with none in patients with HER2⁺ and either node-positive disease or node-negative disease with tumors 1 cm or greater who had completed all local therapy and a variety of standard chemotherapy regimens.¹⁵⁰ At a median follow-up of 1 year, a 46% reduction in the risk of recurrence in those who received trastuzumab compared with those who did not (HR 0.54; 95%, CI 0.43-0.67; P<.0001), no difference in overall survival, and acceptable cardiac toxicity were reported. The 2-year data indicate that 1 year of trastuzumab therapy is associated with an overall survival benefit when compared with observation (HR for risk of death, 0.66; 95% CI, 0.47-0.91; P=.0115).²⁷⁸ After this initial analysis, patients randomized to chemotherapy alone were allowed to crossover to trastuzumab. Intention-to-treat analysis including crossover patients was reported at 4-year median follow-up.²⁷³ The primary end point of disease-free survival continued to be significantly higher in the trastuzumab-treated group (78.6%) versus the observation group (72.2; HR, 0.76; 95%, CI 0.66-0.87; P<.0001). At a median follow-up of 8 years, the study reported no significant difference in the secondary end point of disease-free survival in patients treated with trastuzumab for 2 years compared with 1 year.¹⁵¹ Therefore, 1 year of adjuvant trastuzumab remains the current standard of treatment.

The BCIRG 006 study randomized 3222 women with HER2⁺, node-positive, or high-risk node-negative breast cancer to AC followed by docetaxel, AC followed by docetaxel plus trastuzumab for 1 year, or carboplatin and docetaxel plus trastuzumab for 1 year.¹⁵⁴ At 65-month follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC-TH) had an HR for disease-free survival of 0.64 (P<.001) when compared with the group of patients in the control arm receiving the same chemotherapy regimen without trastuzumab (AC-T). The HR for disease-free survival was 0.75 (P=.04) when patients in the carboplatin/docetaxel/trastuzumab (TCH)-arm were compared with patients in the control arm. No statistically significant difference in the HR for disease-free survival was observed between the 2 trastuzumab-containing arms. An overall survival advantage was reported for patients in both trastuzumab-containing arms relative to the control arm (HR for AC-TH vs AC-T, 0.63; P=.001; HR for TCH vs AC-T, 0.77; P=.04). Cardiac toxicity was significantly lower in the TCH arm (9.4% patients with >10% relative decline in left ventricular ejection fraction) compared with the AC-TH arm (18.6%; P<.0001). CHF was also more frequent with AC-TH than TCH (2.0% vs 0.4%; P<.001). Analysis of this trial by critical clinical event revealed more distant breast cancer recurrences with TCH (144 vs 124), but fewer cardiac events with TCH compared with AC-TH (4 vs 21).¹⁵⁴

In the FinHer trial, 1010 women were randomized to 9 weeks of vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel for 3 cycles followed by 3 cycles of FEC chemotherapy.¹⁴⁹ Patients (n=232) with HER2⁺ cancers that were either node-positive or were node-negative, 2 cm or greater, and PR^- were further randomized to treatment with or without trastuzumab for 9 weeks during the vinorelbine or docetaxel portions of the chemotherapy only. With a median follow-up of 3 years, the addition of trastuzumab was associated with a reduction in risk of recurrence (HR, 0.42; 95% CI, 0.21-0.83; P=.01). No statistically significant differences in overall survival (HR, 0.41; 95% CI, 0.16-1.08; P=.07) or cardiac toxicity were observed with the addition of trastuzumab.¹⁴⁹ At 5-year follow-up, a comparison of the arms (ie, chemotherapy with and without trastuzumab) showed that the HRs for distant disease-free survival (HR, 0.65; 95% CI, 0.38-1.12; P=.12) and overall survival (HR, 0.55; 95% CI, 0.27-1.11; P=.094) were higher relative to those reported at 3 years.²⁷¹

All of the adjuvant trials of trastuzumab have demonstrated clinically significant improvements in disease-free survival, and the combined analysis from the NSABP B31 and NCCTG N9831 trials,²⁷² and the HERA trial,¹⁵⁰ showed significant improvement in overall survival with the use of trastuzumab in patients with high-risk HER2⁺ breast cancer. Therefore, regimens from each of these trials are included as trastuzumab-containing adjuvant regimen choices in the guidelines. The benefits of trastuzumab are independent of ER status.^152,153 In the FNCLCC-PACS-04 trial, 528 women with HER2⁺, node-positive breast cancer were randomly assigned to receive trastuzumab or observation after completion of adjuvant anthracycline-based chemotherapy with or without docetaxel.²⁷⁹ No statistically significant disease-free survival or overall survival benefit was observed with the addition of trastuzumab. These results suggest that the sequential administration of trastuzumab after chemotherapy is not as efficacious as a schedule involving concomitant chemotherapy and trastuzumab.

Retrospective analyses of low-risk patients with small tumors show that in T1a-b,N0 breast cancers, HER2 overexpression added a 15% to 30% risk for recurrence.^280-283 These risks rates are substantially higher than those seen among similarly sized HER2^- tumors.

A recent single-arm, multicenter trial studied the benefit of trastuzumab-based chemotherapy in patients with HER2⁺ node-negative tumors 3 cm or less. All patients received trastuzumab and weekly paclitaxel for 12 weeks, followed by completion of a year of trastuzumab monotherapy.²⁸⁴ Among patients enrolled, 50% had tumors 1.0 cm or less and 9% of patients had tumors between 2 and 3 cm. The end point of the study was disease-free survival. The results presented at the 2013 San Antonio Breast Cancer Symposium showed that the 3-year disease-free survival rate in the overall population was 98.7% (95% CI, 97.6-99.8; P<.0001).

Dual anti-HER2 blockade associated with trastuzumab plus lapatinib, trastuzumab plus pertuzumab has shown significant improvements in the pathologic complete response rate when compared with chemotherapy associated with one anti-HER2 agent in the neoadjuvant setting. The results of the ongoing ALTTO trial are expected to provide additional data on the long-term outcome in the adjuvant setting with dual HER2 blockade (lapatinib plus trastuzumab).

NCCN Recommendation for Adjuvant HER2-Targted Therapy: Based on these studies, the panel has designated the use of trastuzumab with chemotherapy as a category 1 recommendation in patients with HER2⁺ tumors greater than 1 cm.

The panel suggests that trastuzumab and chemotherapy be used for women with HER2⁺ node-negative tumors measuring 0.6 to 1.0 cm (ie, T1b) and for smaller tumors that have 2 mm or less axillary node metastases (pN1mi). Some support for this recommendation comes from studies showing a higher risk of recurrence for patients with HER2⁺ node-negative tumors 1 cm or less compared with those with HER2^- tumors of the same size. Results of a retrospective study of 1245 women with early-stage breast cancer tumors characterized as T1pN0.²⁸⁵ Rates of 10-year breast cancer-specific and recurrence-free survivals were 85% and 75%, respectively, in women with tumors characterized as HER2⁺/ER⁺, and 70% and 61%, respectively, in women with HER2⁺/ER^- tumors.

Two additionals retrospective studies have also investigated recurrence-free survival in this patient population. In one large study, 5-year recurrence-free survival rates of 77.1% and 93.7% (P<.001) were observed for patients with HER2⁺ and HER2^- T1a-bN0M0 breast tumors, respectively, with no recurrence-free survival differences seen in the HER2⁺ group when hormonal receptor status was considered.²⁸¹ In another retrospective study of women with small HER2⁺ tumors, the risk of recurrence at 5 years was low, although disease-free survival was inferior in the group with HER2⁺, hormone receptor-positive disease.²⁸⁶ None of the patients in these 2 retrospective studies had received trastuzumab. Subgroup analyses from several of the randomized trials have shown a consistent benefit with trastuzumab irrespective of tumor size or nodal status.^154,287,288

The panel recommends AC followed by paclitaxel with trastuzumab, commencing with the first dose of paclitaxel, for 1 year as a preferred HER2-targeting adjuvant regimen. The TCH regimen is also a preferred regimen, especially in those with risk factors for cardiac toxicity, given the results of the BCIRG 006 study that showed superior disease-free survival in patients receiving either TCH or AC followed by docetaxel plus trastuzumab both compared with AC followed by docetaxel alone.

Other trastuzumab-containing regimens included in these guidelines are AC followed by docetaxel and trastuzumab,¹⁵⁴ and docetaxel plus trastuzumab followed by FEC.¹⁴⁹

Based on the recent data presented at the 2013 San Antonio Breast Cancer Symposium,²⁸⁴ the panel has included paclitaxel and trastuzumab as an option for patients with low-risk HER2⁺ stage 1 tumors.

Considering the unprecedented improvement in overall survival in the metastatic setting⁶⁸ and the significant improvement in pathologic complete response seen in the neoadjuvant setting,^69,70 the panel considers it reasonable to incorporate pertuzumab to the above adjuvant regimens, if the patient has not received pertuzumab as a part of their neoadjuvant therapy An ongoing study is evaluating pertuzumab and trastuzumab with standard chemotherapy regimens in the adjuvant setting.^289,290

Posttherapy Surveillance and Follow-up

Posttherapy follow-up is optimally performed by members of the treatment team and includes the performance of regular history/physical examinations every 4 to 6 months for the first 5 years after primary therapy and annually thereafter. Mammography should be performed annually.

The routine performance of alkaline phosphatase and liver function tests are not included in the guidelines.^291-293 In addition, the Panel notes no evidence to support the use of “tumor markers” for breast cancer, and routine bone scans, CT scans, MRI scans, PET scans, or ultrasound examinations in the asymptomatic patient provide no advantage in survival or ability to palliate recurrent disease and are, therefore, not recommended.^35,294

The use of dedicated breast MRI may be considered an option for posttherapy surveillance and follow-up in women at high risk for bilateral disease, such as carriers of BRCA1/2 mutations. Rates of contralateral breast cancer after either breast-conserving therapy or mastectomy have been reported to be increased in women with BRCA1/2 mutations compared with patients with sporadic breast cancer.^295-297 (see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian and NCCN Guidelines for Breast Cancer Screening and Diagnosis; to view the most recent version of these guidelines, visit NCCN.org).

The panel recommends that women with an intact uterus who are taking adjuvant tamoxifen should have yearly gynecologic assessments and rapid evaluation of any vaginal spotting that might occur, because of the risk of tamoxifen-associated endometrial carcinoma in postmenopausal women.²⁹⁸ The performance of routine endometrial biopsy or ultrasonography in the asymptomatic woman is not recommended. Neither test has demonstrated utility as a screening test in any population of women. Most women with tamoxifen-associated uterine carcinoma have early vaginal spotting.

If an adjuvant aromatase inhibitor is considered in women with amenorrhea after treatment, baseline levels of estradiol and gonadotropin followed by serial monitoring of these hormones should be performed if endocrine therapy with an aromatase inhibitor is initiated.²³⁶ Bilateral oophorectomy assures postmenopausal status in young women with therapy-induced amenorrhea and may be considered before initiating therapy with an aromatase inhibitor in a young woman.

Symptom management for women on adjuvant endocrine therapies often requires treatment of hot flashes and the treatment of concurrent depression. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), has been studied and is an effective intervention in decreasing hot flashes.^299-302 Evidence suggests that concomitant use of tamoxifen with certain SSRIs (eg, paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.^303,304 These SSRIs/SNRIs may interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of CYP2D6. However, the mild CYP2D6 inhibitors, such as citalopram, escitalopram, sertraline, and venlafaxine, seem to have no or only minimal effect on tamoxifen metabolism.^236,305,306

Follow-up also includes assessment of patient adherence to ongoing medication regimens, such as endocrine therapies. Predictors of poor adherence to medication include the presence of side effects associated with the medication, and incomplete understanding by the patient of the benefits associated with regular administration of the medication.³⁰⁷ The panel recommends the implementation of simple strategies to enhance patient adherence to endocrine therapy, such as direct questioning of the patient during office visits and brief, clear explanations on the value of taking the medication regularly and the therapeutic importance of longer durations of endocrine therapy.

Evidence suggests that a healthy lifestyle may lead to better breast cancer outcomes. A nested case control study of 369 women with ER⁺ tumors who developed a second primary breast cancer compared with 734 matched control patients who did not develop a second primary tumor showed an association between obesity (body mass index [BMI] ≥30), smoking, and alcohol consumption and contralateral breast cancer.³⁰⁸ A prospective study of 1490 women diagnosed with stage I-III breast cancer showed an association among high fruit and vegetable consumption and physical activity and improved survivorship, regardless of obesity.³⁰⁹ Thus, the panel recommends an active lifestyle and ideal body weight (BMI, 20-25) for optimal overall health and breast cancer outcomes.

Many young women treated for breast cancer remain or regain premenopausal status after treatment for breast cancer. For these women, the panel discourages the use of hormonal birth control methods, regardless of the hormone receptor status of the tumor.³¹⁰ Alternative birth control methods are recommended, including intrauterine devices, barrier methods, and, for those with no intent of future pregnancy, tubal ligation or vasectomy for the partner. Breastfeeding during endocrine or chemotherapy treatment is not recommended by the panel because of risks to the infant. Breastfeeding after breast-conserving treatment for breast cancer is not contraindicated. However, lactation from an irradiated breast may not be possible, or may occur only with a diminished capacity.^310,311

The panel recommends that women on an adjuvant aromatase inhibitor or who experience ovarian failure secondary to treatment should have monitoring of bone health, with a bone mineral density determination at baseline and periodically thereafter. The use of estrogen, progesterone, or selective ER modulators to treat osteoporosis or osteopenia in women with breast cancer is discouraged. The use of a bisphosphonate is generally the preferred intervention to improve bone mineral density. Optimal duration of bisphosphonate therapy has not been established. Factors to consider for duration of antiosteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. Women treated with a bisphosphonate should undergo a dental examination with preventive dentistry before the initiation of therapy, and should take supplemental calcium and vitamin D.

Individual Disclosures for the NCCN Breast Cancer Panel

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