Overview
Breast cancer is the most common malignancy in females in the United States and is second only to lung cancer as a cause of cancer death. The American Cancer Society has estimated that 313,510 Americans will be diagnosed with breast cancer and 42,780 will die of disease in the United States in 2024.1,2 The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines have been developed and are updated continuously by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. This section focuses on systemic therapies (neoadjuvant/adjuvant) for nonmetastatic breast cancer.
Sensitive/Inclusive Language Usage
NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; antiracist, anticlassist, antimisogynist, antiageist, antiableist, and anti–weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate nongendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms “men,” “women,” “female,” and “male” when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.
Guidelines Update Methodology
The complete details of the “Development and Update of the NCCN Guidelines” are available at NCCN.org.
Literature Search Criteria
Prior to the update, an electronic search of the PubMed database was performed to obtain key literature in breast cancer. The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.3
The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. The potential relevance of the PubMed search was examined. The data from key PubMed articles selected by the panel for review during the Guidelines update meeting as well as articles from additional sources deemed as relevant to these Guidelines and discussed by the panel have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.
Systemic Therapies (Preoperative and Adjuvant)
Preoperative Systemic Therapy
The NCCN panel has outlined the rationale, appropriate patient selection, and response assessment for preoperative systemic therapy in a section titled, “Principles of Preoperative Chemotherapy” (Figures 1 and 2).
BINV M 1 of 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-M 2 of 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Randomized clinical trials have found no significant differences in long-term outcomes when systemic chemotherapy is given before or after surgery.4,5 Historically, a primary advantage of administering preoperative systemic therapy has been to improve surgical outcomes. Preoperative systemic therapy can convert inoperable tumors to operable and also downstage a significant number of patients with operable breast cancer to allow for more limited breast conservation procedures.6 Results from large clinical trials and retrospective reviews indicate that breast conservation rates are improved with preoperative systemic therapy.5,7 Clinicians need to carefully consider the extent of disease in the breast, tumor biology, and likelihood of adequate tumor response before recommending preoperative systemic therapy to improve the likelihood of successful breast conservation.
In addition, use of preoperative systemic therapy may provide important prognostic information based on response to therapy. Experiencing a pathologic complete response (pCR) to neoadjuvant therapy is associated with favorable disease-free survival (DFS) and overall survival (OS) in early-stage breast cancer. The correlation between pathologic response and long-term outcomes in patients with early-stage breast cancer is strongest for patients with triple-negative breast cancer (TNBC), less so for HER2-positive disease, and least for hormone-positive disease.8–10
Other benefits of preoperative systemic therapy include allowing time for appropriate genetic testing and for planning potential breast reconstruction in patients proceeding with mastectomy. For those with significant residual disease after standard preoperative systemic therapy, it may provide an opportunity to identify patients who may benefit from further adjuvant therapy after surgery. It may allow sentinel lymph node biopsy alone or allow for limited radiation fields if clinically node positive disease becomes clinically node negative after preoperative systemic therapy. In addition, preoperative systemic therapy also serves as an excellent research platform to test novel therapies and predictive biomarkers by providing tumor specimens and blood samples before and during systemic treatment.
Selection of Patients for Preoperative Therapy
Not all patients are appropriate candidates for preoperative systemic therapy (Figures 1 and 2). According to the NCCN panel, among those with inoperable breast tumors, preoperative systemic therapy is indicated in patients with locally advanced or inoperable breast cancer, including those with inflammatory breast cancer; those with bulky or matted cN2 axillary nodes; cN3 regional lymph node nodal disease; and cT4 tumors.
In patients with operable tumors, preoperative systemic therapy is the preferred approach for the following scenarios: for patients with TNBC and HER2-positive breast cancer that is clinical stage T2N0 and higher or is clinically node positive; if the patient’s breast cancer subtype is associated with a high likelihood of response; or if a patient desires breast-conserving surgery and the size of the tumor is large relative to that of the breast.
When preoperative systemic therapy is used to improve the likelihood of successful breast conservation, the surgical plan should consider the possibility that clear surgical margins may not always be obtained, and a follow-up mastectomy may be required, with or without breast reconstruction. This consideration is especially important when oncoplastic breast reduction techniques or contralateral breast symmetry procedures are added to the breast-conserving surgery to achieve optimal cosmetic outcomes.
The NCCN panel cautions that preoperative systemic therapy is not appropriate for certain patients. Preoperative systemic therapy should not be offered in patients with extensive in situ disease when the extent of invasive disease cannot be defined; in patients where the extent of the tumor is poorly delineated; or in those whose tumors are not clinically assessable. The decision to use preoperative therapy should be made in the context of a coordinated and collaborative multidisciplinary team.
For predicting the response of preoperative endocrine therapy for postmenopausal women with estrogen receptor (ER)–positive, HER2-negative, cN0 breast cancer, data from the TransNEOS study demonstrate a significant correlation between 21 gene assay recurrence score (RS) and clinical response to preoperative letrozole. Those whose tumors had an RS between 0 and 17 were significantly more likely to respond to preoperative letrozole compared with RS of 31 to 100.11
For predicting the response to preoperative chemotherapy for postmenopausal patients with ER-positive, HER2-negative disease with T1/T2, node-negative tumors, another study evaluated the role of the RS with pathologic response rates after preoperative systemic therapy. Their findings suggest high RS are associated with a higher likelihood of pCR after preoperative chemotherapy.12
Based on the 2 studies that showed the use of 21-gene RS in predicting response to preoperative chemotherapy,11,12 the NCCN panel has added a footnote for considering the use of a gene expression assay during workup when contemplating preoperative endocrine or systemic therapy for postmenopausal patients with cN0, operable ER-positive, HER2-negative disease, to aid in predicting response to preoperative therapy.
Preoperative Therapy Options
Chemotherapy
A number of chemotherapy regimens have activity in the preoperative setting. According to the NCCN panel, those regimens recommended in the adjuvant setting may be considered in the preoperative setting. In both settings, the underlying aim remains the same: eradication or control of undiscovered distant metastases.
Endocrine Therapy
Preoperative endocrine therapy alone may be offered to those with strongly HR-positive tumors based on comorbidities or low-risk luminal biology based on clinical characteristics and/or genomic signatures (until desired effect is achieved).13–20 The results of the ACOSOG Z1031 trial show that preoperative endocrine therapy is effective in reducing residual disease and enabling breast-conserving surgery for many patients with low rates of local-regional recurrence postsurgery.21
According to the NCCN panel, the endocrine therapy options include an aromatase inhibitor (AI) (with ovarian function suppression [OFS] for premenopausal patients) or tamoxifen (with or without OFS for premenopausal patients). The preferred endocrine therapy option for postmenopausal patients is an AI. The panel has added a comment that the optimal response to endocrine therapy, if achieved, is anywhere between 4 and 6 months based on the previously cited trials.
HER2-Targeted Therapy
For patients with HER2-positive breast cancer that are candidates for preoperative systemic therapy, chemotherapy and trastuzumab-based therapy is recommended.22 Chemotherapy and dual anti-HER2 blockade associated with trastuzumab plus pertuzumab has shown significant improvements in the pCR rate when compared with chemotherapy and trastuzumab in the preoperative setting.
In the TRYPHAENA trial, preoperative therapy with pertuzumab and trastuzumab given along with anthracycline-containing or anthracycline-free standard chemotherapy regimens to patients with operable, locally advanced, or inflammatory HER2-positive breast cancer showed pCR rates in all treatment arms ranging from 57% to 66%.23 In the Neosphere trial, the addition of pertuzumab to trastuzumab and docetaxel preoperatively led to a statistically significant increase in pCR in the breast, which in turn led to improved outcomes in those with node-positive disease.24,25 The NCCN panel supports the FDA-approved indication that a pertuzumab-containing regimen may be administered preoperatively to patients with greater than or equal to cT2, or greater than or equal to cN1, HER2-positive, early-stage breast cancer.
Immunotherapy
A randomized phase III multicenter, double-blind, placebo-controlled trial (KEYNOTE-522) compared preoperative carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide in combination with either pembrolizumab (n=784) or placebo (n=390), followed by pembrolizumab or placebo administered every 3 weeks for up to 9 cycles after surgery, in patients with previously untreated stage II–III TNBC.26 After a median follow-up of 39.1 months, a significant improvement in event-free survival (EFS) was seen with the addition of pembrolizumab compared with placebo plus chemotherapy. The 3-year EFS rates were 84.5% and 76.8%, respectively (hazard ratio [HR], 0.63, 95% CI, 0.48–0.82; P<.001).26
The 5-year follow-up of KEYNOTE-522 trial results showed an improvement in EFS rate in patients treated with chemotherapy plus pembrolizumab compared with the placebo arm (81.3% vs 72.3%), with reduction in risk for recurrence, progression, complications, or death of 37% (HR, 0.63; 95% CI, 0.49–0.81).27 Among patients in the trial who had a pCR and received adjuvant pembrolizumab, the 5-year EFS rate was 92.2% compared with 88.2% in patients who received only chemotherapy.27 There are no data comparing adjuvant pembrolizumab with other newer adjuvant therapies such as adjuvant capecitabine and/or olaparib in patients who meet criteria for treatment with one or more of these agents.
Response Assessment During Preoperative Chemotherapy
The NCCN panel recommends that tumor response be routinely assessed by clinical exam during the delivery of preoperative systemic therapy. Patients with operable breast cancer experiencing progression of disease while undergoing preoperative systemic therapy should be taken promptly to surgery. Imaging during preoperative systemic therapy should not be done routinely but may be considered if tumor progression is suspected. Imaging before surgery should be determined by a multidisciplinary team.
In a multicenter analysis of patients (n=5,161), the residual cancer burden (RCB) after preoperative chemotherapy was seen to be prognostic within each breast cancer subtype.28 Higher RCB scores were significantly associated with worse EFS, with hazard ratios ranging from 1.55 to 2.16 across different breast cancer subtypes.
This study highlights RCB as a prognostic factor for outcomes in patients with breast cancer undergoing preoperative chemotherapy.28
As noted under the “workup” section, to have a standardized method of pathology reporting, the NCCN endorses the CAP protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. On the “Principles of Preoperative Therapy” page, the panel encourages that the pathology report from definitive surgery after preoperative systemic therapy include the standardized tissue sampling and reporting elements of the RCB. However, since RCB reporting is currently not mandatory given its main purpose for prognostication only, there is inconsistent reporting of RCB across institutions and no uniform agreement among the panel that RCB is required in the pathology report, rendering it a category 2B recommendation.
Adjuvant Systemic Therapy
After surgical treatment, adjuvant systemic therapy should be considered. In patients with early-stage breast cancer, systemic adjuvant therapy is administered to reduce risk of cancer recurrence. The decision is often based on individual risk of relapse and predicted sensitivity to a particular treatment (eg, ER/progesterone receptor [PR] and HER2 status). The decision to use systemic adjuvant therapy requires considering and balancing risk for disease recurrence with local therapy alone, the magnitude of benefit from applying adjuvant therapy, toxicity of the therapy, and comorbidity. The decision-making process requires collaboration between the health care team and patient.
Stratification for Systemic Adjuvant Therapy
The NCCN Guidelines stratify patients with breast cancer based on their HR-status and HER2 expression. Patients are then further stratified based on risk of disease recurrence based on anatomic and pathologic characteristics (ie, tumor grade, tumor size, axillary lymph node [ALN] status, angiolymphatic invasion) (Figure 3).
BINV-4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Adjuvant Systemic Therapy for HR-Positive, HER2-Negative Tumors
Patients with HR positive, HER2-negative tumors receive adjuvant endocrine therapy to reduce the risk of recurrence, and those deemed at high risk for distant recurrence despite adjuvant endocrine therapy receive adjuvant chemotherapy. The NCCN Guidelines call for the determination of ER and PR content in all primary invasive breast cancers29 to determine whether a patient is a candidate for endocrine therapies. Patients with cancers with 1%–100% ER immunohistochemistry staining are considered ER-positive and eligible for endocrine therapies. Given the limited efficacy data on the ER-low-positive (1%–10%) group, with ER-low-positive cancers reported to be a heterogeneous group with a natural history/biologic behavior often similar to ER-negative cancers, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. Patients with ER-negative, PR-positive cancers may also be considered for endocrine therapies; however, the efficacy data on this group are also limited. The same overall interpretation principles apply, but PR should be interpreted as either positive (if 1%–100% of cells have nuclear staining) or negative (if <1% or 0% of cells have nuclear staining). For the purposes of this guideline, any ER and/or PR-positive tumors is referred to as “hormone receptor (HR)-positive,” given that the majority of all breast cancers are ER-positive or ER- and PR-positive and the subgroup of ER-negative/PR-positive tumors are relatively uncommon.
The magnitude of risk reduction from adjuvant endocrine therapy is dependent on level of ER expression and on RS of gene expression assay test results. Low level of ER expression is less likely to benefit from endocrine therapy and a high RS will gain less benefit with endocrine therapy alone versus those with low RS.
Patients with invasive breast cancers that are HR-positive should be considered for adjuvant endocrine therapy regardless of patient age, lymph node status, or whether adjuvant chemotherapy is to be administered.30 Selected studies suggest that HER2-positive breast cancers may be less sensitive to some endocrine therapies, although other studies have failed to confirm this finding.31–39 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.40 However, given the favorable toxicity profile of the available endocrine therapies, the panel recommends the use of adjuvant endocrine therapy in the majority of patients with HR-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor (Figure 4).
BINV-K 1 of 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Tamoxifen
The most firmly established adjuvant endocrine therapy is tamoxifen for both premenopausal and postmenopausal patients.41 In patients with ER-positive breast cancer, adjuvant tamoxifen decreases the annual odds of recurrence by 41% and the annual odds of death by 31% irrespective of the use of chemotherapy, patient age, menopausal status, or ALN status.41 In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first, followed by sequential tamoxifen.42 Prospective randomized trials have demonstrated that 5 years of tamoxifen is more effective than 1 to 2 years of tamoxifen.41,43
The ATLAS trial randomly allocated pre- and postmenopausal patients to 5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of 6,846 patients with ER-positive disease showed that by extending adjuvant treatment to 10 years, the risk of relapse and breast cancer-related mortality was reduced.44 The risk of recurrence during years 5 to 14 was 21.4% for patients receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction 3.7%). Patients who received tamoxifen for 10 years had a greater reduction in risk of progression, possibly due to 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 of treatment. There were decreases in the incidence of contralateral breast cancer as well. Furthermore, reduced mortality was also apparent after completion of 10 years of treatment with tamoxifen. With regards to toxicity, the most important adverse effects noted in all patients in the ATLAS trial after 10 years of tamoxifen treatment were an increased risk for endometrial cancer and pulmonary embolism.44 The results of the aTTom trial confirm the significant reduction in recurrence and death from breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen therapy.45
Aromatase Inhibitors
Several studies have evaluated AIs in the treatment of postmenopausal patients with early-stage breast cancer. These studies have used AI as initial adjuvant therapy, as sequential therapy after 2 to 3 years of tamoxifen, or as extended therapy after 4.5 to 6 years of tamoxifen. The AIs are not active in the treatment of patients with functioning ovaries and should not be used in patients whose ovarian function cannot reliably be assessed owing to treatment-induced amenorrhea.
The results from 2 prospective, randomized clinical trials have provided evidence of an OS 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-negative disease]) when compared with tamoxifen as the only endocrine therapy.46,47 In addition, the NCIC-CTG MA-17 trial showed a survival advantage with extended therapy with letrozole compared with placebo in patients with ALN-positive (but not lymph node-negative), ER-positive breast cancer.48 Tamoxifen and AIs have different side effect profiles. Both contribute to hot flashes and night sweats and may cause vaginal dryness. AIs are more commonly associated with musculoskeletal symptoms, osteoporosis, and increased rate of bone fracture, while 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 AI. The ATAC trial showed that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal patients with HR-positive breast cancer.49,50 With a median of 100 months follow-up, results in 5,216 postmenopausal patients with HR-positive, early-stage breast cancer enrolled in the ATAC trial demonstrated fewer recurrences (HR for DFS, 0.85; 95% CI, 0.76–0.94; P=.003) with anastrozole compared with tamoxifen.51 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.50 ATAC trial subprotocols show a lesser effect of anastrozole compared with tamoxifen on endometrial tissue52; similar effects of anastrozole and tamoxifen on quality of life, with most patients reporting that overall quality of life was not significantly impaired53; a greater loss of bone mineral density with anastrozole54; a small pharmacokinetic interference of anastrozole in the presence of tamoxifen of unclear significance55; and no evidence for an interaction between prior chemotherapy and anastrozole.56
BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 years, letrozole alone for 5 years, or 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 for those patients in the sequential arms during their first 2 years of treatment only.57 With 8,010 patients included in the analysis, DFS was superior in the letrozole-treated patients (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 OS was 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.58 In addition, a higher incidence of bone fracture was observed for patients in the letrozole arm compared with those in the tamoxifen arm (9.5% vs 6.5%).59 After a longer follow-up (median 71 months), no significant improvement in DFS was noted with either tamoxifen followed by letrozole or the reverse sequence as 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).60
Five trials have studied the use of tamoxifen for 2 to 3 years followed sequentially by a third-generation AI versus continued tamoxifen in postmenopausal patients. The Italian Tamoxifen Anastrozole (ITA) trial randomized 426 postmenopausal patients 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.61 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).61 Updated results from this study show the HR for relapse-free survival as 0.56 (95% CI, 0.35–0.89; P=.01); P value for OS analysis remained at 0.1.62 The IES trial randomized 4,742 postmenopausal patients with breast cancer who had completed a total of 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to exemestane to complete a total of 5 years of endocrine therapy.63 The results at a median of 55.7 months of follow-up demonstrated the superiority of sequential exemestane in DFS (HR, 0.76; 95% CI, 0.66–0.88; P=.0001) with a significant difference in OS in only patients with ER-positive tumors (HR, 0.83; 95% CI, 0.69–1.00; log rank P=.05). A prospectively planned, combined analysis of 3,224 patients enrolled in the ABCSG 8 trial and the ARNO 95 trial has also been reported.64 Patients in this combined analysis had been randomized following 2 years of tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of anastrozole. With 28 months of median follow-up available, EFS 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 demonstrated that switching from tamoxifen to anastrozole was associated with significant increases in both DFS (HR, 0.66; 95% CI, 0.44–1.00; P=.049) and OS (HR, 0.53; 95% CI, 0.28–0.99; P=.045).47 A meta-analysis of ABCSG 8, ARNO 95, and ITA studies showed significant improvement in OS (HR, 0.71; 95% CI, 0.52–0.98; P=.04) with a switch to anastrozole.65
The TEAM trial compared 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.66 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 is consistent with the data from the BIG 1-98 trial,60 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.
The NCCN panel finds no meaningful differences in terms of efficacy or toxicity between the available AIs: anastrozole, letrozole, and exemestane. All 3 have shown similar antitumor efficacy and toxicity profiles in randomized studies in the adjuvant settings.
Ovarian Function Suppression and Endocrine Therapy
OFS is achieved with a gonadotropin-releasing hormone (GnRH) agonist, oophorectomy, or ovarian irradiation. Available GnRH agonists in the United States include goserelin and leuprolide. OFS is generally considered in those who are premenopausal and for tumors with high enough recurrence risk where the additional absolute decrease in recurrence compared with tamoxifen alone is worth the additional toxicity (young age, high-grade tumor, lymph node involvement). A balanced discussion of the risks and benefits associated with OFS is critical, including the potential side effects of premature menopause.
In 2 randomized trials (TEXT and SOFT), premenopausal patients with HR-positive early-stage breast cancer were assigned to receive AI (exemestane) plus OFS or tamoxifen plus OFS for a period of 5 years.67 Suppression of ovarian estrogen production was achieved with the use of GnRH agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS was 92.8% in the exemestane plus OFS as compared with 88.8% in the tamoxifen plus OFS (HR for recurrence, 0.66; 95% CI, 0.55–0.80; P<.001).67 The OS did not differ significantly between the 2 groups (HR for death in the exemestane plus OFS group, 1.14; 95% CI, 0.86–1.51; P=.37).67
A 9-year median follow-up analysis of the TEXT-SOFT trials showed sustained improvements in DFS with exemestane plus OFS versus tamoxifen plus OFS (HR, 0.77; 95% CI, 0.67–0.90) and in distant recurrence-free interval but not OS (HR, 0.98; 95% CI, 0.79–1.22).68 Ultimately, with longer follow-up (median, 13 years), an OS was demonstrated for OFS plus exemestane in patients with high risk of recurrence, but not in exemestane plus OFS in patients with lower risk of relapse not receiving chemotherapy.69
The benefit of OFS in premenopausal patients with high risk of recurrence was also seen in the results of the ASTRRA trial. This trial studied premenopausal patients (n=1,483) with HR-positive breast cancer younger than 45 years treated with surgery and who received chemotherapy (as adjuvant or preoperative therapy) and received 5 years of tamoxifen alone or 5 years of tamoxifen with OFS for 2 years. The 8-year DFS with tamoxifen plus OFS was 85.4% versus 80.2% with tamoxifen alone (HR, 0.67; 95% CI, 0.51–0.87).70
The results of the TEXT–SOFT trials suggest an optimal OFS duration of 5 years, and data from the ASTRA trial suggests a benefit with a minimum of at least 2 years of OFS. The NCCN panel has included OFS plus endocrine therapy for 5 years as an option for premenopausal patients with HR-positive breast cancer at higher risk of recurrence (eg, young age, high-grade tumor, lymph node involvement). Premenopausal patients wishing to continue adjuvant endocrine therapy after ovarian suppression is stopped should continue with tamoxifen versus AI.
Duration of Adjuvant Endocrine Therapy
Adjuvant endocrine therapy is recommended for a minimum of 5 years. A recent retrospective analysis by the Oxford University studied risk of recurrence for years 5 through 20 after 5 years of endocrine therapy.71 These data showed a considerable risk of recurrence between years 5 and 20 in these patients treated with initial 5 years of endocrine therapy.71 Data have now emerged showing benefit of extended endocrine therapy in improving DFS.
Data from the ATLAS trial (discussed previously)44 and the aTTom trial confirm greater reduction in recurrence and death from breast cancer with 10 versus 5 years of tamoxifen therapy.45
For those treated initially with adjuvant tamoxifen, there is evidence for benefit from extended adjuvant endocrine therapy from several randomized trials. Results of the MA-17 trial in 5,187 patients who had completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that extended therapy with letrozole provides benefit in postmenopausal patients with HR-positive, early-stage breast cancer.48,72 With a median follow-up of 64 months, letrozole was associated with improved DFS (HR, 0.52; 95% CI, 0.45–0.61) and an improved OS (HR, 0.61; 95% CI, 0.52–0.71) compared with placebo.73
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 1,579 patients who had been randomly assigned to placebo after 4.5 to 6 years of tamoxifen.74,75 The median time since completion of tamoxifen was 2.8 years. Both DFS and distant DFS 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 years of tamoxifen therapy followed by no endocrine therapy for an extended period. A formal quality-of-life analysis demonstrated reasonable preservation of quality of life during extended endocrine therapy, although patients may experience ongoing menopausal symptoms and loss of bone mineral density.76,77 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 clear direction for treatment of postmenopausal patients.44 There are no data available to suggest that an AI for 5 years is better for long-term benefit than 10 years of tamoxifen.
In the extension study of ABCSG trial 6, HR-positive postmenopausal patients received 5 years of adjuvant tamoxifen and were randomized to 3 years of anastrozole or no further therapy.78 At a median follow-up of 62.3 months, patients who received anastrozole (n=387) were reported to have a statistically significantly reduced risk of recurrence compared with patients who received no further treatment (n=469; HR, 0.62; 95% CI, 0.40–0.96; P=.031).78
The differences in design and patient populations among the studies of the AIs do not allow for the direct comparison of the results of these studies. A meta-analysis of adjuvant trials of AIs versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented lower recurrence rates with the AI-containing regimen, with no clear impact on OS.79 It is not known whether initial, sequential, or extended use of adjuvant AIs is the optimal strategy.
In patients initially treated with an AI, a randomized phase III trial (MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to 10 years.80 Postmenopausal patients who had completed 4.5 to 6 years of therapy with an AI (with a median duration of prior tamoxifen of 5 years), were randomized to letrozole or placebo for an additional 5 years.80 Improvement was seen in 5-year DFS in those receiving letrozole compared with those who received placebo (95% [95% CI, 93%–96%] vs 91% [95% CI, 89%−93%]). The annual rate of contralateral breast cancer reported was lower with letrozole (0.49% vs 0.21%; HR, 0.42; 95% CI, 0.22%–0.81%). However, longer duration of AI resulted in more frequent bone-related adverse effects compared with those who received placebo, and no improvement was observed with respect to OS. Bone-related adverse effects included bone pain (18% vs 14%), fractures (14% vs 9%), and new-onset osteoporosis (11% vs 6%).80 Patients with high-risk of recurrence (eg those with lymph node involvement) may benefit from extended AI duration (7.5–10 years total).81,82
NCCN Recommendations
The decision of whether to extend adjuvant treatment based on the evidence available should be individualized. When considering endocrine therapy, the panel recommends the following adjuvant endocrine therapy options for patients with early-stage breast cancer (Figure 5).
BINV-K 2 of 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Adjuvant Endocrine Therapy for Postmenopausal Patients
The NCCN panel recommends AI as initial adjuvant therapy for 5 years (category 1); and tamoxifen for 2 to 3 years followed by one of the following options: an AI to complete 5 years of adjuvant endocrine therapy (category 1) or 5 years of AI therapy (category 2B); or tamoxifen for 4.5 to 6 years followed by 5 years of AI (category 1) or consideration of tamoxifen for up to 10 years. In postmenopausal patients, 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 AIs.
Adjuvant Endocrine Therapy for Premenopausal Patients
For patients who are premenopausal at diagnosis, the NCCN panel recommend 5 years of tamoxifen alone (category 1) or tamoxifen with OFS (category 1) or OFS plus AI for 5 years (category 1). Patients who are premenopausal at diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries without menses. Menopausal status cannot be determined while receiving OFS. AI can stimulate ovarian function. To assure a true postmenopausal status, serial assessment of circulating luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory when considering this subset for AI therapy.83,84 Frequency of testing of estradiol and follicle-stimulating hormone/luteinizing hormone levels should be individualized.
After 5 years of initial endocrine therapy, for patients who are postmenopausal at that time (including those who have become postmenopausal during the 5 years of tamoxifen therapy), the NCCN panel recommends considering extended therapy with an AI 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 continuing up to 10 years of tamoxifen therapy.
Additional Considerations During Adjuvant Endocrine Therapy
Symptom management for patients on adjuvant endocrine therapies often requires treatment of hot flashes and the treatment of concurrent depression.
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, has been studied and is an effective intervention in decreasing hot flashes.85–88 There is evidence suggesting that concomitant use of tamoxifen with certain selective serotonin reuptake inhibitors (SSRIs) (eg, paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.89,90 These SSRIs/serotonin-norepinephrine reuptake inhibitors s may interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of cytochrome P-450 (CYP450) enzyme. Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. The mild CYP2D6 inhibitors such as citalopram, escitalopram, sertraline, and venlafaxine appear to have no or only minimal effect on tamoxifen metabolism.83,91,92
With respect to CYP2D6 mutation status, a large retrospective study of 1,325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen.93 However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects.94 A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes.95,96 Given the limited and conflicting evidence at this time,97 the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines.98 When prescribing an SSRI, it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists.
For those on tamoxifen, although age-appropriate gynecologic screening is recommended, the use of routine annual pelvic ultrasound is not recommended. For those receiving AI 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 panel discourages the selective ER modulators to treat osteoporosis or osteopenia in patients with breast cancer. The use of a bisphosphonate (oral/intravenous) or denosumab is recommended to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant AI therapy. Optimal duration of either therapy has not been established. The optimal duration and benefits beyond 3 years is not known. Factors to consider for duration of antiosteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with bisphosphonates or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D.
The incremental benefit of adding adjuvant chemotherapy to endocrine therapy in patients with low clinical risk of recurrence such as those with very small, low grade, lymph node-negative tumors is relatively small.99 The decision whether to administer adjuvant chemotherapy in patients with HR-positive, HER2-negative tumors is based on many factors including lymph node status, size, grade, lymphovascular invasion, age, comorbid conditions and/or the results of a gene expression profile test using multigene assays.
Several commercially available gene-based assays are useful in determining prognosis by predicting distant recurrence, local recurrence, or survival. Of these, only one, the 21-gene assay (Oncotype Dx) has been clinically validated for predicting the benefit of adding adjuvant chemotherapy to further reduce the risk of recurrence.
21-Gene Assay (Oncotype DX) in Node-Negative, HR-Positive, HER2-Negative Disease
The 21-gene RS is one of the most validated multigene assays. The RS is helpful in determining the prognosis in patients with HR-positive, HER2-negative tumors treated with endocrine therapy alone by predicting locoregional and distant recurrence.100–102 This assay has also been validated to predict the benefit from adding adjuvant chemotherapy to adjuvant endocrine therapy for patients with HR-positive, HER2-negative, node-negative breast cancer.39,103,104
Among patients with T1b/c and T2, lymph node-negative, HR-positive, HER2-negative tumors with RS between 0 and 10, the risk of distant recurrence is low and these patients derive no incremental benefit from the addition of adjuvant chemotherapy to endocrine therapy.39,105 At the other end of the spectrum, patients with lymph node-negative, HR-positive, HER2-negative cancers with high RS (≥31) have a higher risk of distant recurrence, and secondary analyses of prospective studies demonstrate a clear benefit from adjuvant chemotherapy.39,106
For those with intermediate RS (11–25), the TAILORx trial of postmenopausal patients (n=6,711) with lymph node-negative, HR-positive, HER2-negative breast cancer, showed similar DFS rates at 9 years in those who received adjuvant chemotherapy followed by endocrine therapy compared with endocrine therapy alone.106 However, in a subset analysis, patients 50 years of age or younger with RS 16 to 25 had lower rates of distance recurrence with the addition of adjuvant chemotherapy to endocrine therapy.106 The cutoff for low, intermediate, and high RS was different in TAILORx versus NSABP B-20. The NSABP-B20 was the first trial to validate the 21-gene assay both as a prognostic and as a predictive tool and identified RS cutoffs to predict the magnitude of chemotherapy benefit in patients with node-negative, HR-positive breast cancer.7
21-Gene Assay (Oncotype DX) in Node-Positive, HR-Positive, HER2-Negative Disease
In the West German Plan B study, patients (n=110) with node-positive, HR-positive, HER2-negative tumors, and an RS of ≤11 were found to have a 5-year DFS of 94.4% when treated with endocrine therapy alone.107 In a secondary analysis of a prospective registry of patients with HR-positive, HER2-negative, node-positive tumors, the 5-year risk of distant recurrence in patients with an RS of <18 treated with endocrine therapy alone was 2.7%.108 These results suggest that in patients with limited nodal disease (1–3 positive lymph nodes) and a low RS, the absolute benefit from chemotherapy is likely to be very small.108,109
There is a clear benefit from adjuvant chemotherapy in patients with node positive, HR-positive, HER2-negative tumors, if the RS is high (≥31). In a secondary analysis of the SWOG 8814 trial of patients with HR-positive, node-positive tumors, high RS (≥31) was predictive of chemotherapy benefit. This study evaluated breast cancer specimens from postmenopausal patients with node-positive, HR-positive disease (n=367) randomized to endocrine therapy with tamoxifen alone or chemotherapy with CAF (cyclophosphamide, doxorubicin hydrochloride [Adriamycin], and fluorouracil) followed by tamoxifen.103 Compared with tamoxifen alone, treatment with CAF among patients with a high RS (≥31) resulted in improved 10-year DFS (55% vs 43%; HR, 0.59; 95% CI, 0.35–1.01) and OS (73% vs 54%; HR, 0.56; 95% CI 0.31–1.02).103
The Southwest Oncology Group (SWOG) S1007 RxPONDER trial (ClinicalTrials.gov identifier: NCT01272037) assigned patients with 1 to 3 node-positive, HR-positive, HER2-negative breast cancer and an RS ≤25 to standard endocrine therapy with or without adjuvant chemotherapy. The results showed that the addition of adjuvant chemotherapy to endocrine therapy improved invasive DFS among premenopausal—but not postmenopausal—women with HR-positive, HER2-negative, node-positive breast cancer and a 21-gene assay RS up to 25.110
70-Gene Assay (MammaPrint)
Results from the randomized MINDACT trial111 demonstrated that the 70-gene assay can identify a subset of patients who have a low likelihood of distant recurrence despite high-risk clinical features (based on tumor size, grade, nodal status). In this trial, 79% had node-negative disease and 21% had 1 to 3 positive lymph nodes and all patients underwent risk assessment by clinical criteria (using Adjuvant! Online) and genomic risk assessment by the 70-gene assay.
Patients with low-risk disease according to both clinical criteria and genomic assay results did not receive adjuvant chemotherapy, whereas patients categorized as high risk by both assessments received chemotherapy. Patients with discordant results (ie, either high clinical risk/low genomic risk or low clinical risk/high genomic risk) were randomized to the chemotherapy group or the no-chemotherapy group on the basis of either the clinical result or the genomic result. The primary outcome of the study was met with the demonstration that among those with high clinical risk/low genomic risk, the 5-year rate of survival without distant metastasis in those did not receive adjuvant chemotherapy was 94.7% (95% CI, 92.5–96.2).111
In the intention-to-treat population, among patients at high clinical risk/low genomic risk by the 70-gene assay, the 5-year rate of survival with no distant metastasis in those who received chemotherapy was 95.9% (95% CI, 94.0–97.2) versus 94.4% (95% CI, 92.3–95.9) in those who did not receive chemotherapy (adjusted HR for distant metastasis or death with chemotherapy vs no chemotherapy 0.78; 95% CI, 0.50–1.21).111 Among patients at low clinical risk/high genomic risk, 5-year survival with no distant metastasis was 95.8% with chemotherapy (95% CI, 92.9–97.6), compared with a rate of 95.0% (95% CI, 91.8%–97.0%) without chemotherapy (adjusted HR for distant metastasis or death with chemotherapy vs no chemotherapy, 1.17; 95% CI, 0.59–2.28). These data suggest that the results of the 70-gene signature do not provide evidence for making recommendations regarding chemotherapy for patients at low clinical risk.111
In a subgroup analysis by nodal status, among node-negative patients with high clinical risk/low genomic risk, the 5-year rate of survival with no distant metastasis was 95.7% (95% CI, 93.0–97.4) in those who received adjuvant chemotherapy compared with 93.2% (95% CI, 90.1–95.4) in those who did not receive chemotherapy.111 Among patients with 1 to 3 positive lymph nodes, the rates of survival without distant metastases were 96.3% (95% CI, 93.1–98.1) in those who received adjuvant chemotherapy versus 95.6 (95% CI, 92.7–97.4) in those who did not receive adjuvant chemotherapy.111 These data suggest that the additional benefit of adjuvant chemotherapy in patients with high clinical risk/low genomic risk is likely to be small.
50-Gene Assay (PAM50)
The 50-gene assay (PAM-50) risk of recurrence (ROR) score stratifies patients with HR-positive disease into high-, medium-, and low-risk groups. Several studies have shown the prognostic value of ROR score in estimating risk of disease recurrence.112–114
In a study from the Danish Breast Cancer Cooperative Group database, patients with node-negative tumors and low ROR had a distant recurrence risk of 5.0% (95% CI, 2.9%–8.0%) whereas tumors with high ROR had a distant recurrence risk of 17.8% (95% CI, 14.0%–22.0%).113 Based on these analyses, patients with T1 and T2, HR-positive, HER2-negative, node-negative tumors, a ROR score in the low range, regardless of tumor size, places the individual into the same prognostic category as those with T1a–T1b, N0, M0 tumors.113
In patients with 1 to 3 node-positive, HR-positive, HER2-negative disease with low ROR score, the distant recurrence risk was less than 3.5% at 10 years with endocrine therapy alone.113 In TransATAC study, no distant recurrence was seen at 10 years in a similar group.114
12-Gene Assay (EndoPredict)
This assay uses 12 genes to calculate a prognostic score. This assay appears to be useful in identifying a subgroup of patients with ER-positive, HER2-negative tumors with very low risk of recurrence without adjuvant chemotherapy and helpful in identifying patients at low risk for a late recurrence.115 Based on results of 2 Austrian Breast Cancer Study Group trials-ABCSG-6 and ABCSG-8, patients with HR-positive, HER2-negative, and node-negative disease with a low-risk score by the 12-gene assay had risk of distant recurrence of 4% at 10 years.115 The prognostic value of the risk score from the 12-gene assay was found to be independent of conventional clinicopathological factors. Patients with T1 and T2 HR-positive, HER2-negative, and node-negative tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a–T1b, N0, M0.
In TransATAC study, patients with 1 to 3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years,114 suggesting that chemotherapy would be of limited benefit in these patients.
Breast Cancer Index
The Breast Cancer Index (BCI) is a combination of 2 profiles, the HOXB13-to-IL17BR expression ratio (H:I ratio) and the molecular grade index. Compared with clinical prognostic factors (eg, age, tumor size, tumor grade, and lymph node status), the H:I ratio has been shown to be prognostic in the setting of adjuvant tamoxifen monotherapy.115,116 The addition of the molecular grade index to H:I was determined to provide additional prognostic discrimination, leading to the BCI assay.116 In a secondary analysis of the ATAC trial, BCI was prognostic in node-negative breast cancer for both early (years 0–5) and late (years 5–10) distant recurrence.117 For patients with T1 and T2 HR-positive, HER2-negative, and node-negative tumors, a BCI in the low-risk range, regardless of T size, places the tumor into the same prognostic category as T1a-T1b, N0, M0. Secondary analyses of the MA.17, TransaTTom, and IDEAL trials showed that in patients with HR-positive T1–T3 tumors that are lymph-node negative or positive, those that had a high BCI (H:I) demonstrated significant improvements in DFS when adjuvant endocrine therapy was extended, compared with the control arm.118–120 Considering the ability of the multigene assays to predict benefit of adjuvant systemic chemotherapy and ability to determine prognosis by predicting risk of distant recurrence, the NCCN panel has summarized the treatment implications based on risk scores and nodal status.
Multigene Assays for Axillary Lymph Node–Negative HR-Positive, HER2-Negative Tumors
Small tumors (up to 0.5 cm in greatest diameter) that do not involve the lymph nodes have a favorable prognosis, so adjuvant chemotherapy is not recommended. According to the NCCN panel, adjuvant endocrine therapy may be considered in this group of patients to reduce the risk for a second contralateral breast cancer, as well as the small benefit in reducing the risk of local/regional and distant recurrence (category 2B).
For patients with invasive ductal or lobular tumors greater than 0.5 cm in diameter and no lymph node involvement (node-negative), the NCCN panel recommends strongly considering the 21-gene reverse transcriptase–polymerase chain reaction assay to help estimate likelihood of recurrence and benefit from chemotherapy (category 1). The panel has noted that on an exploratory analysis from the TAILORx study,106 adjuvant chemotherapy may be considered in patients 50 years of age or younger with a 21-gene RS of 16 to 25. Also, patients with T1b tumors with low-grade histology should be considered for endocrine monotherapy, as the TAILORx study106 did not include patients with such tumors.
The panel notes that other prognostic multigene assays may be considered to help estimate risk of recurrence, but these assays have not been validated to predict the benefit of systemic chemotherapy. Also, among the other assays, the panel has listed the 70-gene assay as a category 1 option based on the results of the prospective MINDACT111 trial demonstrating the ability of the 70-gene assay to identify a good genomic risk population despite a high clinical risk, in whom chemotherapy may be omitted without a detrimental effect. High clinical risk in the MINDACT trial was defined for grade 1 tumors as >3 cm N0 or T2N1, for grade 2 tumors T2N0–1, and for grade 3 tumors T1c–2N0–1.
Furthermore, given no difference in outcomes with or without chemotherapy in the discordant low clinical risk/high genomic risk group, the MINDACT study suggests that the 70-gene panel is not useful guiding systemic chemotherapy decisions in this subgroup of patients.
Since results of different assays may not be concordant with each other and these assays have not been compared head-to-head prospectively, clinicians should only order one of the available assays for a specific patient and tumor.
Multigene Assays for Axillary Lymph Node–Positive HR-Positive, HER2-Negative Tumors
For patients with 4 or more involved nodes, the panel recommends systemic adjuvant chemotherapy followed by endocrine therapy (category 1).
Patients with fewer than 4 involved nodes or with pN1mi and less than or equal to 2 mm axillary node metastasis are most often candidates for chemotherapy in addition to endocrine therapy. The panel recommends that clinical decision making for adjuvant chemotherapy be based on elements of clinical risk stratification such as clinical characteristics, tumor stage, pathology, and comorbid conditions. If the patient is not a candidate for chemotherapy, the panel recommends adjuvant endocrine therapy alone (category 2A).
For those who are candidates for systemic adjuvant chemotherapy based on clinical characteristics, tumor stage, and pathology, the panel recommends consideration of multigene assays to assess prognosis as a tool to assist with treatment decision making. The panel notes in those with N1mi and N1 tumors, while multigene assays have yet to be proven to be predictive for adjuvant chemotherapy benefit, they are prognostic and can be used to identify low-risk patients who are likely to derive little or no absolute benefit from addition of adjuvant chemotherapy to adjuvant endocrine therapy. A secondary analysis of the prospective SWOG 8814 trial using the 21-gene assay demonstrated no benefit for chemotherapy for patients with 1 to 3 involved axillary lymph nodes and a low RS, and a significant benefit for the addition of adjuvant chemotherapy in those with high RS (≥31).103 The phase III RxPONDER trial prospectively demonstrated that for premenopausal patients with HR-positive, HER2-negative, node-positive breast cancer, a 21-gene assay RS up to 25 had an addition benefit of adjuvant chemotherapy to endocrine therapy for improving invasive DFS.110 In the MINDACT trial, among patients with 1 to 3 positive nodes who had a high clinical risk of recurrence but low risk by the 70-gene assay, the rates of survival were similar between those who received adjuvant chemotherapy in addition to adjuvant endocrine therapy versus those received adjuvant endocrine therapy alone, suggesting that chemotherapy could be omitted in this group.111 Other multigene assays have not proven to be predictive of benefit from chemotherapy.
For those who are candidates for systemic adjuvant chemotherapy based on clinical characteristics, tumor stage, and pathology, if multigene assay is not available, the panel recommends systemic adjuvant chemotherapy followed by endocrine therapy (category 1).
Adjuvant Targeted Therapies for HR-Positive, HER2-Negative Tumors
Adjuvant therapies are rapidly evolving, and cyclin-dependent kinase (CDK) 4/6 inhibitors and poly-ADP ribose polymerase inhibitors are now indicated in this setting (Figures 5–9).
BINV-6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-16. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Adjuvant CDK 4/6 Inhibitors
In the MonarchE study, the addition of 2 years of abemaciclib to endocrine therapy reduced the absolute risk of recurrence at 4 years by 6.4% (HR, 0.664; 95% CI, 0.578–0.762; P<.0001) in patients with HR-positive/HER2-negative, high-risk breast cancer, defined as 4 or more pathologically involved lymph nodes confirmed preoperatively and/or at surgery, or 1 to 3 pathologically involved lymph nodes with additional high-risk features (grade 3 or size ≥5 cm based on preoperative imaging and/or pathologically at surgery).121
Two trials of palbociclib as adjuvant therapy in HR-positive, HER2-negative early breast cancer did not show benefit of adding palbociclib to adjuvant endocrine therapy in terms of invasive DFS.122,123
The results from the NATALEE trial reported after a median follow-up of 34 months, showed a statistically significant improvement (3.3%) in invasive DFS with the addition of ribociclib to adjuvant endocrine therapy (HR, 0.75; 95% CI, 0.62–0.91; P=.003) for stage II and stage III HR-positive, HER2-negative breast cancer.124 Additional follow-up is needed to characterize the long-term efficacy of ribociclib in this setting.
According to the current guidelines, 2 years of adjuvant CDK 4/6 therapy with abemaciclib should be considered in combination with endocrine therapy in patients with HR-positive/HER2-negative, high-risk breast cancer (as detailed previously). This is a category 1, preferred option for this setting.
Adjuvant Olaparib
In patients with germline BRCA 1/2 mutations and high-risk HER2-negative tumors, the results of the OlympiA trial showed that the 4-year OS in the group that received 1 year of adjuvant olaparib was 89.8% and 86.4% in the placebo group (95% CI, −0.1% to −6.8%). The 4-year invasive DFS for the olaparib group versus placebo group was 82.7% versus 75.4% (95% CI, 3.0%–11.5%) and 4-year distant DFS was 86.5% versus 79.1% (95% CI, 3.6%–11.3%).125
According to the NCCN panel, addition of adjuvant olaparib for 1 year may be considered for those with germline BRCA 1/2 mutations in patients with HR-positive, HER2-negative tumors with ≥4 positive lymph nodes after adjuvant chemotherapy or residual disease after preoperative therapy and a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3 (category 2A).
Adjuvant olaparib may be used concurrently with endocrine therapy.
In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequencing is not known. (For sequencing of olaparib and/or abemaciclib with radiotherapy [RT], see page BINV-I, available in these guidelines at NCCN.org).
Adjuvant Bisphosphonate Therapy
Antiresorptive agents (bisphosphonates and denosumab) have an established role as preventative and therapeutic agents for the management of osteoporosis, hypercalcemia of malignancy, and bone metastases.
Bisphosphonates
In the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) trial, for patients older than 40 years, zoledronic acid significantly reduced the risk of recurrence by 34% (HR, 0.66; P=.014) and the risk of death by 49% (HR, 0.51; P=.020). However, no improvement was seen in either DFS or OS in this post hoc analysis among patients younger than 40 years.126 In a planned subgroup analysis of the AZURE trial, zoledronic acid improved DFS in patients who were more than 5 years since menopause at trial entry.127 A meta-analysis of data from 7 adjuvant bisphosphonate trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN), including for only patients known to be older than 50 years, postmenopausal, or with ovarian suppression, showed a significant benefit for the use of adjuvant bisphosphonates in patients with a low-estrogen state and early-stage breast cancer.128 More recently, the Early Breast Cancer Trialists’ Collaborative Group (EBTCG) conducted a meta-analysis of all randomized adjuvant bisphosphonate studies (26 studies) and reported convincing evidence that adjuvant bisphosphonates provide benefits to postmenopausal (natural or induced) patients with breast cancer.129 With bisphosphonate therapy, the greatest improvement was seen in bone recurrence (RR, 0.83; P=.004) and bone fractures (RR, 0.85; P=.02). No effect was seen on distant recurrence outside bone (RR, 0.98; P=.69).129 In premenopausal patients, bisphosphonate therapy did not seem to have a significant effect on bone recurrence. However, in postmenopausal patients, zoledronic acid significantly reduced bone recurrence (3.4% vs 4.5%; RR, 0.73; 99% CI, 0.53–1.00); the difference in breast cancer mortality was not statistically significant (7.1% vs 7.9%; RR, 0.88; 99% CI, 0.69–1.11).129
Denosumab
In the adjuvant setting, the ABCSG-18 trial studied the effect of denosumab in postmenopausal patients treated with adjuvant AIs and showed a reduction in clinical fractures (HR, 0.5; P<.0001), which was the primary endpoint of this study.130 The final analysis after a median follow-up of 8 years continued to show a benefit with denosumab. Adjuvant denosumab improved bone metastasis-free survival (88.9% vs 86.4%; HR, 0.81; 95% CI, 0.65–1.00) and OS (90.9% vs 89.9%; HR, 0.80; 95% CI, 0.64–1.01).131 In contrast, results of the phase III trial (D-Care) failed to demonstrate a difference in bone metastasis-free survival in those receiving denosumab versus placebo.132
Due to these conflicting results from phase III trials, denosumab is currently not recommended in the adjuvant setting.131 The panel recommends considering adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3 to 5 years in patients with high-risk node-negative or node-positive tumors.
Adjuvant Therapy for HER2-Negative Tumors
Several combination chemotherapy regimens are appropriate to consider for HR-positive or HR-negative and HER2-negative tumors. All adjuvant chemotherapy regimens listed in the NCCN Guidelines have been evaluated in phase III clinical trials and are category 1 unless otherwise noted (Figures 6, 8, 10–13).
BINV-10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-L 1 of 9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-L 2 of 9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-L 3 of 9 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
Preferred Regimens
Regimens listed as preferred include dose-dense doxorubicin and cyclophosphamide (AC) followed or preceded by paclitaxel either weekly or biweekly; docetaxel plus cyclophosphamide (TC); olaparib for germline BRCA 1/2 mutations; pembrolizumab for high-risk ER-negative disease; and capecitabine for residual ER-negative disease after preoperative chemotherapy.
Meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group has shown that anthracycline and taxane-based combination chemotherapy reduces the risk of breast cancer mortality compared with no chemotherapy. The use of dose-dense schedules has shown to further reduce the risk of breast cancer recurrence or death without increasing mortality.133
The results of 2 randomized trials comparing AC chemotherapy with or without sequential paclitaxel chemotherapy in patients with axillary node-positive breast cancer suggest improved disease-free rates and results from one of the trials showed an improvement in OS with the addition of paclitaxel.134,135 On retrospective analysis, the apparent advantage of the paclitaxel-containing regimen appears greater in patients with ER-negative breast cancers.
A randomized trial evaluated the use of concurrent versus sequential chemotherapy (doxorubicin followed by paclitaxel followed by cyclophosphamide vs doxorubicin plus cyclophosphamide followed by paclitaxel) given either every 2 weeks with filgrastim support or every 3 weeks. The results show no significant difference between the 2 chemotherapy regimens but demonstrate a 26% reduction in hazard of recurrence (P=.01) and a 31% reduction in the hazard of death (P=.013) for the dose-dense regimens.136
The ECOG E1199 study was a 4-arm trial that randomized 4,950 patients to receive AC chemotherapy followed by either paclitaxel or docetaxel given by either an every-3-week schedule or a weekly schedule.137 In a secondary series of comparisons, weekly paclitaxel was superior to every-3-week paclitaxel in DFS (HR, 1.27; 95% CI, 1.03–1.57; P=.006) and OS (HR, 1.32; 95% CI, 1.02–1.72; P=.01), and every-3-week docetaxel was superior to every-3-week paclitaxel in DFS (HR, 1.23; 95% CI, 1.00–1.52; P=.02) but not in OS.137 Based on these results and the findings from the CALGB 9741 trial that showed dose-dense AC followed by paclitaxel every 2 weeks to have a survival benefit when compared with the regimen of AC followed by every-3-week paclitaxel,136 the every-3-week paclitaxel regimen has been removed from the guidelines.
Combination TC was compared with AC chemotherapy in a trial that randomized 1,016 patients with stage I–III breast cancer.138 At a median follow-up of 7 years, overall DFS (81% vs 75%; HR, 0.74; 95% CI, 0.56–0.98; P=.033) and OS (87% vs 82%; HR, 0.69; 95% CI, 0.50–0.97; P=.032) were significantly improved with TC compared with AC. Nonanthracycline, taxane-based regimens such as TC may be preferred options in patients for whom anthracyclines are contraindicated.
Residual disease after preoperative systemic therapy indicates higher risk (20%–30%) of disease relapse.9,139 CREATE-X, a multicenter, open-label, randomized phase III trial evaluated the efficacy and safety of adjuvant capecitabine in patients with HER2-negative primary breast cancer who had residual invasive disease after standard (anthracycline and/or taxane-based) preoperative chemotherapy. The results showed improved DFS (HR, 0.70; 95% CI, 0.53–0.92; P=.01) and OS (HR for death, 0.59; 95% CI, 0.39–0.90; P=.01) with adjuvant capecitabine. The OS was higher in those with TNBC (HR for death, 0.52). Results of 2 other similar trials with adjuvant capecitabine have showed a similar impact with adjuvant capecitabine in patients with TNBC with no significant impact in those with HR-positive disease.140,141 Based on these trial results, the NCCN panel has included adjuvant capecitabine as an adjuvant therapy option for those with TNBC and residual disease after preoperative therapy. For those with germline BRCA 1/2 mutations and TNBC, according to the NCCN panel, based on the results of the OlympiA trial (discussed in the sections on adjuvant therapy for HR-positive, HER2-negative disease) adjuvant olaparib for 1 year may be considered if tumors ≥ pT2 or ≥ pN1 disease after adjuvant chemotherapy or in those with residual disease after preoperative chemotherapy (catgeory1). Patients in the OlympiA trial did not receive capecitabine; thus, no data are available on sequencing or to guide selection of one agent over the other. (For sequencing of capecitabine or Olaparib with RT, see BINV-I, available in these guidelines at NCCN.org)
If pembrolizumab was given in combination with chemotherapy in the preoperative setting, based on the KEYNOTE-522 trial data, the panel recommends adjuvant pembrolizumab.27
Other Recommended Regimens
Other recommended regimens in the guidelines include: AC; epirubicin and cyclophosphamide (EC); docetaxel, doxorubicin, and cyclophosphamide (TAC); paclitaxel and carboplatin (various schedules); and docetaxel and carboplatin.
A trial compared 2 dose levels of EC chemotherapy with CMF chemotherapy in patients with node-positive breast cancer.142 This study showed that higher-dose EC chemotherapy was equivalent to CMF chemotherapy and superior to moderate-dose EC in EFS and OS.
Final results from a randomized trial of TAC versus FAC chemotherapy in node-positive breast cancer demonstrated that TAC is superior to FAC.143 Estimated 5-year DFS was 75% with TAC and 68% with FAC (HR, 0.72; 95% CI, 0.59–0.88; P=.001); survival was 87% with TAC and 81% with FAC (HR, 0.70; 95% CI, 0.53–0.91; P=.008). DFS favored TAC in both ER-positive and ER-negative tumors. At a median follow-up of 73 months, results from the 3-arm randomized NSABP B-30 trial comparing TAC versus AT versus AC followed by docetaxel (AC followed by T) demonstrated that AC followed by T had a significant advantage in DFS (HR, 0.83; P=.006) but not in OS (HR, 0.86; P=.086) when compared with TAC. In addition, both DFS (HR, 0.080; P=.001) and OS (HR, 0.83; P=.034) were significantly increased when AC followed by T was compared with AT, with AT demonstrating noninferiority compared with TAC.144
Useful in Certain Circumstances
Regimens in this category include dose-dense AC; AC every 3 weeks (category 2B); CMF; AC followed by weekly paclitaxel; and capecitabine as maintenance therapy for TNBC after adjuvant chemotherapy.
The phase III E1199 trial compared patients with node-positive or high-risk node-negative breast cancer who received 4 cycles of AC every 3 weeks, followed by either paclitaxel or docetaxel, either weekly or every 3 weeks. The 10-year updated results of this trial showed that incorporation of weekly paclitaxel and docetaxel every 3 weeks was associated with significant improvements in DFS and marginal improvements in OS, compared with paclitaxel given every 3 weeks. Among patients with TNBC, the 10-year DFS rate with weekly paclitaxel was 69% and the 10-year OS rate was 75%.145
The AC regimen for 4 cycles has been studied in randomized trials, resulting in relapse-free survival and OS equivalent to CMF chemotherapy.146,147 No benefit from dose escalation of either doxorubicin or cyclophosphamide was shown.134,148 Studies of CMF chemotherapy versus no chemotherapy have shown DFS and OS advantages with CMF chemotherapy.41,149
Results of a randomized trial in patients with TNBC (n=434) who received standard adjuvant chemotherapy demonstrated that maintenance therapy with low-dose capecitabine (dose of 650 mg/m2 twice a day by mouth for 1 year) improved 5-year DFS and OS. The invasive DFS in those who receive adjuvant low-dose capecitabine was 85.8% compared with 75.8% in those who did not (HR for risk of distant metastasis or death, 0.60; 95% CI, 0.38–0.92; P=.02), the estimated 5-year OS with maintenance capecitabine was 85.5% versus 81.3% (HR for risk of death, 0.75; 95% CI, 0.47–1.19; P=.22).150
Adjuvant Therapy for HER2-Positive Tumors
Trastuzumab-containing chemotherapy regimens followed by 1 year of HER2-targeted therapy are a backbone of adjuvant therapy for patients with HER2-positive disease (Figures 1, 2, 9, 14, and 15).
BINV-5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
BINV-9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
The panel recommends HER2-targeted therapy in patients with HER2-positive tumors (see “Principles of HER2 Testing,” available in these guidelines at NCCN.org). Preoperative systemic therapy incorporating HER2-targeted agent(s) should be considered for patients with HER2-positive disease presenting with clinical node-positive tumors or those measuring ≥2 cm (cT2) at presentation (Figures 1 and 2).
The NCCN panel suggests trastuzumab and chemotherapy be used for patients with HER2-positive, node-negative tumors measuring 0.6 to 1.0 cm (T1b) and for smaller tumors that have less than or equal to 2 mm axillary node metastases (pN1mi). Some support for this recommendation comes from studies showing a higher risk of recurrence for patients with HER2-positive, node-negative tumors less than or equal to 1 cm compared with those with HER2-negative tumors of the same size.151
Ten-year breast cancer-specific survival and 10-year recurrence-free survival were 85% and 75%, respectively, in patients with tumors characterized as HER2-positive, ER-positive tumors, and 70% and 61%, respectively, in patients with HER2-positive, ER-negative tumors. Two additional retrospective series report recurrence-free survival in this subpopulation of HER2-positive, node-negative tumors measuring 0.6 to 1.0 cm (T1b) and/or pN1mi. all treated without trastuzumab. In the first study, 5-year recurrence-free survival rates of 77.1% and 93.7% (P<.001) were observed for patients with HER2-positive and HER2-negative T1a–bN0M0 breast tumors, respectively, with no recurrence-free survival differences seen in the HER2-positive group when hormonal receptor status was considered.152 In the other retrospective study of patients with small HER2-positive tumors, the risk of recurrence at 5 years was low (99% [95% CI, 96%–100%] for HER2-negative disease and 92% [95% CI, 86%–99%] for HER2-positive disease).153 Subgroup analyses from several of the randomized trials have shown consistent benefit of trastuzumab irrespective of tumor size or nodal status.154,155
Preferred Regimens
The NCCN panel has included paclitaxel and trastuzumab as an option for patients with low-risk, HER2-positive, stage I tumors, based on a trial of 406 patients with small, node-negative, HER2-positive tumors treated with this combination. The 3-year rate of DFS was 98.7% (95% CI, 97.6–99.8) and the risk of serious toxic effects with this regimen was low (incidence of heart failure reported was 0.5%).156 The long-term follow-up data reported 10-year invasive DFS of 91.3%, breast cancer-specific survival of 98.8% and OS rates of 94.3%.157 Accordingly, NCCN panel has listed paclitaxel and trastuzumab as a less intensive therapeutic option, preferred for patients with low-risk T1,N0,M0, HER2-positive disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.157
The BCIRG 006 study randomized 3,222 patients with HER2-positive, 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, docetaxel, and trastuzumab for 1 year.155 At 65-month follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC-TH) had an HR for DFS 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 DFS was 0.75 (P=.04) when patients in the carboplatin/docetaxel/trastuzumab (TCH)-containing arm were compared with patients in the control arm. No statistically significant difference in the HR for DFS was observed between the 2 trastuzumab-containing arms. An OS 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% 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).155 In the FinHer trial, 1,010 patients 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.158 Patients (n=232) with HER2-positive cancers that were either node-positive or node-negative and greater than or equal to 2 cm and PR-negative were further randomized to receive or not receive 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 OS (HR, 0.41; 95% CI, 0.16–1.08; P=.07) or cardiac toxicity were observed with the addition of trastuzumab.158 At 5-year follow-up, a comparison of the 2 arms (ie, chemotherapy with and without trastuzumab) demonstrated that the HRs for distant DFS (HR, 0.65; 95% CI, 0.38–1.12; P=.12) and OS (HR, 0.55; 95% CI, 0.27–1.11; P=.094) were higher relative to those reported at 3 years.159 The TCH regimen is a preferred regimen, especially for those with risk factors for cardiac toxicity, based on the results of the BCIRG 006 study.
The APHINITY trial compared adjuvant trastuzumab plus pertuzumab with trastuzumab–placebo, both in combination with standard adjuvant chemotherapy in patients with node-positive or high-risk node-negative HER2-positive, operable tumors. The study demonstrated that trastuzumab plus pertuzumab significantly improved 3-year invasive DFS (HR, 0.81; 95% CI, 0.66–1.00; P=.045).160 With long-term (8-year) follow-up, the node-positive subgroup maintained a clear invasive DFS benefit favoring the dual HER2 agent arm demonstrating 8-year invasive DFS of 86% versus 81% (HR, 0.72; 95% CI, 0.60–0.87) with no OS difference; no benefit was seen in the node-negative subgroup.161 These updated results from the adjuvant APHINITY trial confirm the long-term benefit of adding pertuzumab to trastuzumab plus chemotherapy for node-positive disease. The panel has designated use of trastuzumab with chemotherapy as a category 1 recommendation for all HER2-positive tumors >1 cm, and based on the data above, chemotherapy plus trastuzumab and pertuzumab as a category 1, preferred regimen for HER2-positive, node-positive disease.
The data from the phase III KATHERINE trial reported improved outcomes in patients who had residual invasive cancer and received adjuvant trastuzumab emtansine (T-DM1). Invasive DFS at 3 years was 88.3% with T-DM1 versus 77.0% with trastuzumab.162 T-DM1 significantly decreased the invasive breast cancer recurrence risk or death (HR, 0.50; 95% CI, 0.39–0.64; P<.001).162
The ATEMPT trial was designed to determine whether T-DM1 was more toxic than paclitaxel/trastuzumab. The long-term follow-up data of patients who received 1 year of adjuvant T-DM1 (n=383) or trastuzumab/paclitaxel (n=114) reported the 5-year invasive DFS rate with T-DM1 of 97.0% (95% CI, 95.2%–98.7%), the 5-year recurrence-free interval of 98.3% (95% CI, 96.3%–99.0%), and the 5-year OS rate of 97.8% (95% CI, 96.3%–99.3%).163 The study was not powered to evaluate the efficacy of paclitaxel/trastuzumab; among those who received it, the reported 5-year invasive DFS with this combination was 91.3% (95% CI, 86.0%–96.9%), 5-year recurrence free interval was 93.3% (95% CI, 88.6%–98.2%), and 5-year OS was 97.9% (95% CI, 95.2%–100%).163 Based on these data, T-DM1 may be considered an alternative for these patients ineligible for paclitaxel/trastuzumab.
Other Recommended Regimens
Anthracycline followed by taxane-containing chemotherapy regimens were used in the NSABP trial B-31,164 NCCTG trial,165 and BCIRG 006 trial.155
In the NOAH trial, patients were given concurrent taxane and anthracycline, then taxane alone followed by cyclophosphamide–methotrexate–fluorouracil.166 In the FinHER study, patients were randomized to docetaxel or vinorelbine before anthracyclines,158 and PACS 04 randomized patients to fluorouracil/epirubicin/cyclophosphamide or to epirubicin plus docetaxel.167 The HERA trial did not mandate the choice of chemotherapy, 94% receiving anthracyclines and 26% receiving a taxane in addition to an anthracycline.
All of the previously noted adjuvant trials of trastuzumab have demonstrated clinically significant improvements in DFS. Furthermore, the HERA trial168 and the combined analysis of the NSABP B31 and NCCTG N9831 trials169 showed significant improvement in OS with the use of trastuzumab. A more recent meta-analysis of all the previously noted studies (excluding the BCIRG 006 trial) showed that addition of trastuzumab resulted in an average absolute reduction in 10-year risk of recurrence of 9.0% (95% CI, 7.4–10.7; P<.0001), a reduction in 10-year breast cancer mortality by 6.4% (4.9–7.8; P<.0001), and a reduction in mortality (all causes) by 6.5% (5.0–8.0; P<.0001).170 The benefits of trastuzumab are independent of ER status.164,171
The NCCN panel considers it reasonable to incorporate pertuzumab into these adjuvant regimens.25,172,173
The results of the TRAIN-2 trial showed high pCR rates after treatment regimens with anthracycline plus trastuzumab and pertuzumab (67%) and also without anthracycline plus trastuzumab and pertuzumab (68%).172 Patients who received anthracycline-containing regimen experienced more febrile neutropenia, hypokalemia, and left ventricular ejection fraction decline to grade 2 or worse (≥10% or to <50%).172
A follow-up analysis of the TRAIN-2 study showed similar 3-year EFS and OS with or without anthracyclines in patients with stage II and III HER2-positive breast cancer. Based on these results, considering the added toxicity of anthracycline-containing regimens, the panel has added nonanthracycline-containing regimens with trastuzumab and pertuzumab as treatment options.174
The NCCN panel has included the following regimen as other recommended regimens for HER2-positive disease: doxorubicin/cyclophosphamide (AC) followed by docetaxel plus trastuzumab (followed by docetaxel plus trastuzumab); AC followed by docetaxel and trastuzumab and pertuzumab and paclitaxel/carboplatin and trastuzumab and pertuzumab.
Regimens Useful in Certain Circumstances
One year of extended therapy with neratinib after completion of 1 year of adjuvant trastuzumab without pertuzumab was evaluated in the phase III ExteNET trial. Neratinib improved invasive DFS (HR, 0.73; 95% CI, 0.57–0.92; P=.0083) primarily in the subgroup of HR-positive tumors (HR, 0.60; 95% CI, 0.43–0.83; P=.063). Neratinib is associated with moderate to severe diarrhea.
Based on the trials listed in the section for “other recommended regimen and the above data from ExteNET, the NCCN panel has included following regimens have been included as useful in certain circumstances: Docetaxel and cyclophosphamide and trastuzumab; AC followed by paclitaxel and trastuzumab followed by paclitaxel plus trastuzumab, various schedules); AC followed by paclitaxel and trastuzumab and pertuzumab, various schedules); paclitaxel and trastuzumab and pertuzumab; adjuvant neratinib and adjuvant T-DM1.
Therapeutic Duration and Other Considerations in Those Receiving HER2-Targeted Therapy
The length of trastuzumab administration in the adjuvant setting trials listed above is 12 months. The HERA trial demonstrated no additional benefit extending trastuzumab to 2 years compared with 1 year.
With respect to a duration less than 12 months, the results of the PERSEPHONE trial showed noninferiority for 6 months versus 12 months of trastuzumab treatment,175 However, the PHARE study observed more events in the 6 month cohort compared with the 12 month cohort, and noninferiority was not established.176 Furthermore, adverse events over time remained similar in both arms, and comparable to data reported in other trials.
Considering the conflicting results between PERSEPHONE and PHARE, in addition to the protocol design of the majority of the randomized trials establishing the benefits of trastuzumab which used 12 months of therapy, the NCCN panel recommends up to 1 year of HER2-targeted therapy with trastuzumab. Based on the updated APHINITY trial data, the addition of pertuzumab may be considered with trastuzumab in those with node-positive disease.
Increased cardiac toxicity has been observed in patients treated with trastuzumab.164,177,178 In addition, anthracycline and taxane-based regimens in combination with HER2-targeted agents are associated with further increased risk of cardiac toxicity.179 The panel recommends evaluation of left ventricular ejection fraction prior to and during treatment. The optimal frequency of left ventricular ejection fraction assessment during adjuvant trastuzumab therapy is not known. The FDA label recommends left ventricular ejection fraction measurements prior to initiation of trastuzumab and every 3 months during therapy.
According to the panel, use of an FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab and hyaluronidase-oysk injection approved for subcutaneous use may be substituted for intravenous trastuzumab. It is important to note that it has a different dosage and administration compared with intravenous trastuzumab.
Adjuvant Therapy for Tumors of Favorable Histologies
The guidelines provide systemic treatment recommendations for the favorable histology of invasive breast cancers (including pure tubular and pure mucinous cancers, pure cribriform, adenoid cystic secretory carcinoma and other salivary carcinoma, rare low-grade forms of metaplastic carcinoma) based on ER/PR status, tumor size and ALN status (Figure 16). If used, the treatment options for endocrine therapy, chemotherapy, and sequencing of treatment with other modalities are similar to those of the usual histology of breast cancers. There are rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that have a favorable prognosis even without administration of adjuvant systemic therapies.
BINV-11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0035
The vast majority of pure tubular, pure mucinous, and pure cribriform breast cancers are both ER-positive and HER2-negative. To be associated with favorable prognosis, the favorable histologic type should not be high grade, should be pure (>90% as classified on the surgical excision, not core biopsy alone), and should be HER2-negative. If atypical pathologic or clinical features are present, consider treating as ductal/no special type.
The pathology evaluation and accuracy of the ER and/or HER2 determination should be reviewed if these are ER-negative and/or HER2-positive, or if a tumor with an ER- and PR-negative status is grade 1.29 Should a breast cancer be histologically identified as a pure tubular or mucinous breast cancer and be confirmed as ER-negative, then the tumor should be treated according to the guideline for the usual histology, ER-negative breast cancers. The panel acknowledges that prospective data regarding systemic adjuvant therapy of pure tubular and mucinous histologies are lacking.
References
- 3.↑
US National Library of Medicine. Key MEDLINE indicators. Accessed April 16, 2020. Available at: http://www.nlm.nih.gov/bsd/bsd_key.html
- 4.↑
Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005;97:188–194.
- 5.↑
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778–785.
- 6.↑
Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 2008;26:814–819.
- 7.↑
Killelea BK, Yang VQ, Mougalian S, et al. Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg 2015;220:1063–1069.
- 8.↑
Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275–1281.
- 9.↑
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–172.
- 10.↑
von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796–1804.
- 11.↑
Iwata H, Masuda N, Yamamoto Y, et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study. Breast Cancer Res Treat 2019;173:123–133.
- 12.↑
Pease AM, Riba LA, Gruner RA, et al. Oncotype DX recurrence score as a predictor of response to neoadjuvant chemotherapy. Ann Surg Oncol 2019;26:366–371.
- 13.↑
Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the pre-operative “arimidex” compared to tamoxifen (PROACT) trial. Cancer 2006;106:2095–2103.
- 14.↑
Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5108–5116.
- 15.↑
Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12:1527–1532.
- 16.↑
Ellis MJ, Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat 2007;105(Suppl 1):33–43.
- 17.↑
Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol 2011;29:2342–2349.
- 18.↑
Masuda N, Sagara Y, Kinoshita T, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol 2012;13:345–352.
- 19.↑
Torrisi R, Bagnardi V, Rotmensz N, et al. Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer. Breast Cancer Res Treat 2011;126:431–441.
- 20.↑
Fontein DB, Charehbili A, Nortier JW, et al. Efficacy of six month neoadjuvant endocrine therapy in postmenopausal, hormone receptor-positive breast cancer patients--a phase II trial. Eur J Cancer 2014;50:2190–2200.
- 21.↑
Hunt KK, Suman VJ, Wingate HF, et al. Local-regional recurrence after neoadjuvant endocrine therapy: Data from ACOSOG Z1031 (Alliance), a randomized phase 2 neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-positive clinical stage 2 or 3 breast cancer. Ann Surg Oncol 2023;30:2111–2118.
- 22.↑
Petrelli F, Borgonovo K, Cabiddu M, et al. Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs 2011;22:128–135.
- 23.↑
Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278–2284.
- 24.↑
Gianni L, Pienkowski T, Im YH, et al. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol 2015;33(Suppl):Abstract 505.
- 25.↑
Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791–800.
- 26.↑
Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 2022;386:556–567.
- 27.↑
Schmid P, Cortés J, Dent RA, et al. Pembrolizumab or placebo plus chemotherapy followed by pembrolizumab or placebo for early-stage TNBC: Updated EFS results from the phase III KEYNOTE-522 study. Ann Oncol 2023;34:S1257.
- 28.↑
Yau C, Osdoit M, van der Noordaa M, et al. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol 2022;23:149–160.
- 29.↑
Allred DC, Carlson RW, Berry DA, et al. NCCN Task Force report: estrogen receptor and progesterone receptor testing in breast cancer by immunohistochemistry. J Natl Compr Canc Netw 2009;7(Suppl 6):S1–21; quiz S22–23.
- 30.↑
Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–1467.
- 31.↑
Arpino G, Green SJ, Allred DC, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clin Cancer Res 2004;10:5670–5676.
- 32.↑
Berry DA, Muss HB, Thor AD, et al. HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptor-positive, node-positive breast cancer. J Clin Oncol 2000;18:3471–3479.
- 33.↑
De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 2005;11:4741–4748.
- 34.↑
Eppenberger-Castori S, Kueng W, Benz C, et al. Prognostic and predictive significance of ErbB-2 breast tumor levels measured by enzyme immunoassay. J Clin Oncol 2001;19:645–656.
- 35.↑
Knoop AS, Bentzen SM, Nielsen MM, et al. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol 2001;19:3376–3384.
- 36.↑
Mass R. The role of HER-2 expression in predicting response to therapy in breast cancer. Semin Oncol 2000;27(6 Suppl 11):46–52; discussion 92–100.
- 37.↑
Pegram MD, Pauletti G, Slamon DJ. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 1998;52:65–77.
- 38.↑
Piccart MJ, Di Leo A, Hamilton A. HER2. a ‘predictive factor’ ready to use in the daily management of breast cancer patients? Eur J Cancer 2000;36:1755–1761.
- 39.↑
Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24:3726–3734.
- 40.↑
Dowsett M, Allred C, Knox J, et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the arimidex, tamoxifen, alone or in combination trial. J Clin Oncol 2008;26:1059–1065.
- 41.↑
Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–1717.
- 42.↑
Albain KS, Barlow WE, Ravdin PM, et al. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine- responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374:2055–2063.
- 43.↑
Davies C, Godwin J, Gray RG, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378:771–784.
- 44.↑
Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805–816.
- 45.↑
Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(Suppl):Abstract 5.
- 46.↑
Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007;369:559–570.
- 47.↑
Kaufmann M, Jonat W, Hilfrich J, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study. J Clin Oncol 2007;25:2664–2670.
- 48.↑
Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262–1271.
- 49.↑
Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131–2139.
- 50.↑
Howell A, Cuzick J, Baum M, et al. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–62.
- 51.↑
Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53.
- 52.↑
Duffy S, Jackson TL, Lansdown M, et al. The ATAC (‘arimidex’, tamoxifen, alone or in combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment. Hum Reprod 2006;21:545–553.
- 53.↑
Fallowfield L, Cella D, Cuzick J, et al. Quality of life of postmenopausal women in the arimidex, tamoxifen, alone or in combination (ATAC) adjuvant breast cancer trial. J Clin Oncol 2004;22:4261–4271.
- 54.↑
Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol 2008;26:1051–1057.
- 55.↑
Dowsett M, Cuzick J, Howell A, et al. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the ‘arimidex and tamoxifen alone or in combination’ (ATAC) trial. Br J Cancer 2001;85:317–324.
- 56.↑
Buzdar AU, Guastalla JP, Nabholtz JM, et al. Impact of chemotherapy regimens prior to endocrine therapy: results from the ATAC (anastrozole and tamoxifen, alone or in combination) trial. Cancer 2006;107:472–480.
- 57.↑
Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747–2757.
- 58.↑
Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol 2007;25:5715–5722.
- 59.↑
Rabaglio M, Sun Z, Price KN, et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 2009;20:1489–1498.
- 60.↑
Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 2009;361:766–776.
- 61.↑
Boccardo F, Rubagotti A, Puntoni M, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 2005;23:5138–5147.
- 62.↑
Boccardo F, Rubagotti A, Guglielmini P, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 2006;17(Suppl 7):vii10–14.
- 63.↑
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–1092.
- 64.↑
Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005;366:455–462.
- 65.↑
Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 2006;7:991–996.
- 66.↑
van de Velde CJ, Rea D, Seynaeve C, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321–331.
- 67.↑
Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371:107–118.
- 68.↑
Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 2018;379:122–137.
- 69.↑
Pagani O, Walley BA, Fleming GF, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer: long-term follow-up of the combined TEXT and SOFT trials. J Clin Oncol 2023;41:1376–1382.
- 70.↑
Baek SY, Noh WC, Ahn SH, et al. Adding ovarian suppression to tamoxifen for premenopausal women with hormone receptor-positive breast cancer after chemotherapy: an 8-year follow-up of the ASTRRA trial. J Clin Oncol 2023;41:4864–4871.
- 71.↑
Pan H, Gray R, Davies C, et al. Predictors of recurrence during years 5–14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET). J Clin Oncol 2016;34(Suppl):Abstract 505.
- 72.↑
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–1802.
- 73.↑
Jin H, Tu D, Zhao N, et al. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol 2012;30:718–721.
- 74.↑
Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol 2008;26:1948–1955.
- 75.↑
Ingle JN, Tu D, Pater JL, et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol 2008;19:877–882.
- 76.↑
Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 2006;24:3629–3635.
- 77.↑
Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:6931–6940.
- 78.↑
Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst 2007;99:1845–1853.
- 79.↑
Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010;28:509–518.
- 80.↑
Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 2016;375:209–219.
- 81.↑
Del Mastro L, Mansutti M, Bisagni G, et al. Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:1458–1467.
- 82.↑
Gnant M, Fitzal F, Rinnerthaler G, et al. Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer. N Engl J Med 2021;385:395–405.
- 83.↑
Smith IE, Dowsett M, Yap YS, et al. Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. J Clin Oncol 2006;24:2444–2447.
- 84.↑
Yu B, Douglas N, Ferin MJ, et al. Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy. Cancer 2010;116:2099–2105.
- 85.↑
Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059–2063.
- 86.↑
Boekhout AH, Vincent AD, Dalesio OB, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2011;29:3862–3868.
- 87.↑
Kaplan M, Mahon S, Cope D, et al. Putting evidence into practice: evidence-based interventions for hot flashes resulting from cancer therapies. Clin J Oncol Nurs 2011;15:149–157.
- 88.↑
Bordeleau L, Pritchard KI, Loprinzi CL, et al. Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 2010;28:5147–5152.
- 89.↑
Garber K. Tamoxifen pharmacogenetics moves closer to reality. J Natl Cancer Inst 2005;97:412–413.
- 90.↑
Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97:30–39.
- 91.↑
Henry NL, Stearns V, Flockhart DA, et al. Drug interactions and pharmacogenomics in the treatment of breast cancer and depression. Am J Psychiatry 2008;165:1251–1255.
- 92.↑
Ahern TP, Pedersen L, Cronin-Fenton DP, et al. No increase in breast cancer recurrence with concurrent use of tamoxifen and some CYP2D6-inhibiting medications. Cancer Epidemiol Biomarkers Prev 2009;18:2562–2564.
- 93.↑
Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 2009;302:1429–1436.
- 94.↑
Regan MM, Leyland-Jones B, Bouzyk M, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst 2012;104:441–451.
- 95.↑
Rae JM, Drury S, Hayes DF, et al. Lack of correlation between gene variants in tamoxifen metabolizing enzymes with primary endpoints in the ATAC trial. Cancer Res 2010;70(24 Suppl):Abstract S1-7.
- 96.↑
Park HS, Choi JY, Lee MJ, et al. Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. J Korean Med Sci 2011;26:1007–1013.
- 97.↑
Higgins MJ, Stearns V. Pharmacogenetics of endocrine therapy for breast cancer. Annu Rev Med 2011;62:281–293.
- 98.↑
Visvanathan K, Chlebowski RT, Hurley P, et al. American society of clinical oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009;27:3235–3258.
- 99.↑
Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006;295:1658–1667.
- 100.↑
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817–2826.
- 101.↑
Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 2010;28:1829–1834.
- 102.↑
Mamounas EP, Tang G, Fisher B, et al. Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 2010;28:1677–1683.
- 103.↑
Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 2010;11:55–65.
- 104.↑
Tang G, Shak S, Paik S, et al. Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat 2011;127:133–142.
- 105.↑
Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379:111–121.
- 106.↑
Sparano J, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol 2018;36(Suppl):Abstract LBA1.
- 107.↑
Nitz U, Gluz O, Christgen M, et al. Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial. Breast Cancer Res Treat 2017;165:573–583.
- 108.↑
Stemmer SM, Steiner M, Rizel S, et al. Clinical outcomes in ER+ HER2-node-positive breast cancer patients who were treated according to the recurrence score results: evidence from a large prospectively designed registry. NPJ Breast Cancer 2017;3:32.
- 109.↑
Gluz O, Nitz UA, Christgen M, et al. West German Study Group Phase III PlanB Trial: first prospective outcome data for the 21-gene recurrence score assay and concordance of prognostic markers by central and local pathology assessment. J Clin Oncol 2016;34:2341–2349.
- 110.↑
Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 2021;385:2336–2347.
- 111.↑
Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 2016;375:717–729.
- 112.↑
Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013;31:2783–2790.
- 113.↑
Lænkholm AV, Jensen MB, Eriksen JO, et al. PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish cohort of postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor-positive early breast cancer. J Clin Oncol 2018;36:735–740.
- 114.↑
Sestak I, Buus R, Cuzick J, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor–positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol 2018;4:545–553.
- 115.↑
Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 2011;17:6012–6020.
- 116.↑
Ma XJ, Wang Z, Ryan PD, et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004;5:607–616.
- 117.↑
Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 2013;14:1067–1076.
- 118.↑
Noordhoek I, Treuner K, Putter H, et al. Breast Cancer Index predicts extended endocrine benefit to individualize selection of patients with HR+ early-stage breast cancer for 10 years of endocrine therapy. Clin Cancer Res 2021;27:311–319.
- 119.↑
Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst 2018;110:40–48.
- 120.↑
Bartlett JMS, Sgroi DC, Treuner K, et al. Breast Cancer Index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the adjuvant tamoxifen-to offer more? (aTTom) trial. Ann Oncol 2019;30:1776–1783.
- 121.↑
Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 2020;38:3987–3998.
- 122.↑
Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib for early breast cancer: the PALLAS trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol 2022;40:282–293.
- 123.↑
Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the Penelope-B trial. J Clin Oncol 2021;39:1518–1530.
- 124.↑
Slamon D, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. N Engl J Med 2024;390:1080–1091.
- 125.↑
Geyer CE Jr, Garber JE, Gelber RD, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol 2022;33:1250–1268.
- 126.↑
Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 2011;12:631–641.
- 127.↑
Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011;365:1396–1405.
- 128.↑
Valachis A, Polyzos NP, Coleman RE, et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 2013;18:353–361.
- 129.↑
Coleman R, Gray R, Powles T, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015;386:1353–1361.
- 130.↑
Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386:433–443.
- 131.↑
Gnant M, Frantal S, Pfeiler G, et al. Long-term outcomes of adjuvant denosumab in breast cancer. NEJM Evidence 2022;1:EVIDoa2200162.
- 132.↑
Coleman R, Finkelstein DM, Barrios C, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21:60–72.
- 133.↑
Gray R, Bradley R, Braybrooke J, et al. Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 2019;393:1440–1452.
- 134.↑
Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential Paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–983.
- 135.↑
Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005;23:3686–3696.
- 136.↑
Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431–1439.
- 137.↑
Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008;358:1663–1671.
- 138.↑
Jones S, Holmes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 2009;27:1177–1183.
- 139.↑
Kuroi K, Toi M, Ohno S, et al. Prognostic significance of subtype and pathologic response in operable breast cancer; a pooled analysis of prospective neoadjuvant studies of JBCRG. Breast Cancer 2015;22:486–495.
- 140.↑
Martín M, Ruiz Simón A, Ruiz Borrego M, et al. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol 2015;33:3788–3795.
- 141.↑
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, et al. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol 2012;30:11–18.
- 142.↑
Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 2001;19:3103–3110.
- 143.↑
Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302–2313.
- 144.↑
Swain SM, Jeong JH, Geyer CE, et al. NSABP B-30: definitive analysis of patient outcome from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer. Cancer Res 2009;69(Suppl 2):75.
- 145.↑
Sparano JA, Zhao F, Martino S, et al. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol 2015;33:2353–2360.
- 146.↑
Bang SM, Heo DS, Lee KH, et al. Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma. Cancer 2000;89:2521–2526.
- 147.↑
Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483–1496.
- 148.↑
Fisher B, Anderson S, Wickerham DL, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 1997;15:1858–1869.
- 149.↑
Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930–942.
- 150.↑
Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage triple-negative breast cancer who had received standard treatment: the SYSUCC-001 randomized clinical trial. JAMA 2021;325:50–58.
- 151.↑
Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 2008;26:5697–5704.
- 152.↑
Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol 2009;27:5700–5706.
- 153.↑
Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol 2009;27:5693–5699.
- 154.↑
Untch M, Gelber RD, Jackisch C, et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 2008;19:1090–1096.
- 155.↑
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273–1283.
- 156.↑
Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015;372:134–141.
- 157.↑
Tolaney SM, Tarantino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol 2023;24:273–285.
- 158.↑
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820.
- 159.↑
Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol 2009;27:5685–5692.
- 160.↑
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 2017;377:122–131.
- 161.↑
Loibl S, Jassem J, Sonnenblick A, et al. VP6-2022: adjuvant pertuzumab and trastuzumab in patients with early HER-2 positive breast cancer in APHINITY: 8.4 years’ follow-up. Ann Oncol 2022;33:986–987.
- 162.↑
von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019;380:617–628.
- 163.↑
Tarantino P, Tayob N, Dang CT, et al. Adjuvant trastuzumab emtansine versus paclitaxel plus trastuzumab for stage I HER2+ breast cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033). Cancer Res 2023;83(5 Suppl):Abstract PD18-01.
- 164.↑
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.
- 165.↑
Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 2005;6:425–432.
- 166.↑
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 2010;375:377–384.
- 167.↑
D’Hondt V, Canon JL, Roca L, et al. UCBG 2-04: long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer 2019;122:91–100.
- 168.↑
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.
- 169.↑
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29:3366–3373.
- 170.↑
Bradley R, Braybrooke J, Gray R, et al. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol 2021;22:1139–1150.
- 171.↑
Romond EH, Suman VJ, Jeong JH, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Res 2012;72(24 Suppl):S5.
- 172.↑
van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1630–1640.
- 173.↑
Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR-phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 2017;28:2768–2772.
- 174.↑
van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual ERBB2 blockade in patients with ERBB2-positive breast cancer: a secondary analysis of the train-2 randomized, phase 3 trial. JAMA Oncol 2021;7:978–984.
- 175.↑
Earl HM, Hiller L, Vallier AL, et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet 2019;393:2599–2612.
- 176.↑
Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet 2019;393:2591–2598.
- 177.↑
Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008;26:1231–1238.
- 178.↑
Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811–7819.
- 179.↑
Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30:3792–3799.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN CATEGORIES OF PREFERENCE
Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation).
All recommendations are considered appropriate.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
