NCCN Guidelines Insights: Breast Cancer, Version 1.2017

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor–positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

Abstract

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor–positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.

Accreditation Statement

Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-17-004-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/80546; and 3) view/print certificate.

Release date: April 10, 2017; Expiration date: April 10, 2018

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to NCCN Guidelines for Breast Cancer

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Breast Cancer

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

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 noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The American Cancer Society estimates that 255,180 Americans will be diagnosed with breast cancer and 41,070 will die of the disease in the United States in 2017.1 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 up-to-date guidelines for the clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, phyllodes tumor, inflammatory breast cancer, and breast cancer during pregnancy. These guidelines are developed 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.

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

In the most recent version of NCCN Breast Cancer Guidelines, Version 1.2017, the NCCN panel included updated recommendations for situations where axillary lymph node dissection (ALND) can be omitted in women with stages I, II, and IIIA (T3N1M0) breast cancer; for whole-breast radiation therapy (WBRT) using hypofractionation, updates regarding accelerated partial breast irradiation (APBI) and regional nodal irradiation (RNI) in women with early-stage breast cancer; and systemic therapy for women with hormone receptor–positive breast cancer in the adjuvant and metastatic settings. The full version of these guidelines is available online (NCCN.org).

Surgical Axillary Staging for Stages I, IIA, IIB, and IIIA (T3N1M0)

ALND is the standard of care for patients with clinically positive nodes. However, ALND is associated with lymphedema and other significant morbidities,24 and therefore sentinel lymph node biopsy (SLNB) has replaced axillary evaluation for patients with clinically node-negative disease.

Based on several randomized trials, it is now accepted that patients with a negative sentinel lymph node (SLN) do not need an ALND.58

The ACOSOG Z0011 trial randomized women ≥18 years of age with T1/T2 tumors, <3 positive SLNs, undergoing lumpectomy and WBRT to either SLNB alone (n=436) or ALND (n=420). In this study, no difference was seen in local recurrence, disease-free survival (DFS), or overall survival (OS) between women with positive SLNs undergoing a completion ALND versus no ALND. Only estrogen receptor (ER)–negative status, age <50 years, and lack of adjuvant systemic therapy were associated with decreased OS.9 At a median follow-up of 6.3 years, locoregional recurrences were noted in 4.1% of patients in the ALND group and 2.8% of those in the SLNB group (P=.11). Median OS was approximately 92% in each group.10 Long term follow-up

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

(median, 9.25 years) results of the ACOSOG Z0011 study showed no statistically significant difference in local recurrence-free survival between the groups (P=.13).11 The cumulative incidence of ipsilateral axillary recurrences at 10 years was 0.5% (2 patients) in those who underwent ALND and 1.5% (5 patients) in those who underwent SLNB alone (P=.28).11 The 10-year cumulative incidence of local regional recurrences was 6.2% with ALND and 5.3% with SLNB alone (P=.36).11 Results of the ACOSOG Z0011 trial show that ALND is not needed in women with early-stage breast cancer who have only 1 or 2 SLN metastases who will receive WBRT as part of breast-conserving therapy.

Another randomized trial (IBCSG 23-01) was specifically designed to compare outcomes in patients with sentinel micrometastases (≤2 mm) treated with ALND versus no ALND.12 Although the ACOSOG Z0011 trial was limited to those undergoing breast-conserving therapy, this trial included patients undergoing mastectomy (9%).12 No differences were seen in the group treated with ALND versus those not treated with ALND in 5-year DFS rate (84.4% [95% CI, 80.7%–88.1%] vs 87.8% [95% CI, 84.4%–91.2%]); cumulative incidence of breast cancer events, including local, regional, contralateral breast, and distant recurrence (10.8% [95% CI, 7.6–14.0] vs 10.6% [95% CI, 7.5–13.8]); or OS rate (97.6% [95% CI, 96.0%–99.2%] vs 97.5% [95% CI, 95.8%–99.1%]).12 Regional recurrence was <1% for those who underwent ALND and 1% for those who did not.12 Results of this trial show that in patients with only micrometastases in the SLNs, ALND is not needed.

The results of a trial by the European EORTC group (AMAROS) assessed whether axillary radiation therapy (RT) provides regional control with fewer side effects compared with ALND.13 This trial included patients (n=4,823) with T1 or T2 breast cancer and positive SLNs (micrometastatic or macrometastatic), and included a small fraction of patients (n=248) treated with mastectomy.13 The results reported no difference in 5-year OS or DFS for

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Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

patients randomized to ALND versus axillary RT.13 The 5-year DFS was 86.9% (95% CI, 84.1–89.3) in the ALND group and 82.7% (95% CI, 79.3–85.5) in the axillary RT group. The 5-year OS was 93.3% (95% CI, 91.0–95.0) in the ALND group and 92.5% (95% CI, 90.0–94.4) in the axillary RT group.13 At the end of 5 years, lymphedema was less frequent in the group treated with axillary RT versus ALND (11% vs 23%).13 The results of this trial show that axillary RT is an acceptable alternative to ALND for axillary control in patients found to have positive SLNs, with significantly less lymphedema-related morbidity.

NCCN Recommendations

In patients with clinically positive nodes, to determine whether ALND is needed, the panel recommends pathologic confirmation of malignancy using ultrasound-guided fine-needle aspiration (FNA)14 or core biopsy of suspicious nodes. According to the NCCN panel, the recommendation for axillary dissection of level I and II nodes is limited to patients with biopsy-proven axillary metastases. Traditional level I and II ALND requires that ≥10 lymph nodes be provided for pathologic evaluation to accurately stage the axilla.15,16 ALND should be extended to include level III nodes only if gross disease is apparent in the level II and III nodes. In the absence of gross disease in level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle (level I and II) (see BINV-D; page 440).

If axillary lymph nodes are clinically negative at diagnosis or if FNA/core biopsy results of suspicious nodes are negative, the panel recommends SLN mapping and excision. SLNs can be assessed for the presence of metastases by both hematoxylineosin (H&E) staining and cytokeratin immunohistochemistry (IHC). The clinical significance of a lymph node that is negative on H&E staining but positive on cytokeratin IHC is not clear. Because the historical and clinical trial data on which treatment

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

decisions are based have relied on H&E staining, the panel does not recommend routine cytokeratin IHC to define node involvement and believes that current treatment decisions should be made based solely on H&E staining. This recommendation is further supported by a randomized clinical trial (ACOSOG Z0010) for patients with H&E-negative nodes in whom further examination by cytokeratin IHC was not associated with improved OS over a median of 6.3 years.17 In the uncommon situation in which H&E staining is equivocal, reliance on the results of cytokeratin IHC is appropriate.

Based on the ACOSOG Z0011 trial results, for patients with T1 or T2 tumors and 1 to 2 positive SLNs, treated with lumpectomy but no preoperative systemic therapy, and who receive WBRT, the NCCN panel recommends no further axillary surgery. If any of these criteria are not met, the panel recommends level I and II axillary dissection. In the 2017 version of the NCCN Guidelines, based on the results of the IBCSG 23-01 trial, the NCCN panel recommends no ALND for patients with positive SLNs when disease is only micrometastatic (see BINV-D; page 440). According to AJCC staging, micrometastatic nodal involvement is defined as a metastatic deposit >0.2 mm but ≤2.0 mm.18

When SNLs are not successfully identified, the panel recommends level I and II axillary dissection be performed for axillary staging.

For mastectomy patients with clinically negative axillae but with positive SLNs, the panel notes that for regional control of disease, axillary RT may replace ALND (see BINV-D; page 440).

Adjuvant RT for Stages I, IIA, IIB, and IIIA (T3N1M0)

Adjuvant RT After Lumpectomy

Whole-Breast Radiation Therapy: WBRT reduces the risk of local recurrence and has been shown to have a beneficial effect on survival. Results of a

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed reduction in 10-year risk of recurrence in those who received WBRT versus those who did not (19% vs 35%; relative risk [RR], 0.52; 95% CI, 0.48–0.56).19 In addition, a significant reduction in 15-year risk of breast cancer death (21% vs 25%; RR, 0.82; 95% CI, 0.75–0.90) was also observed.19

Dose and Fractionation: The conventional dose for WBRT is 46 to 50 Gy in 23 to 25 fractions. Four randomized clinical trials including more than 7,000 patients have investigated hypofractionated WBRT schedules (39–42.9 Gy in daily fractions of 2.6–3.3 Gy) compared with standard 50 Gy doses in fractions of 2 Gy.2023 The 10-year follow-up data from the START trials24 are consistent with the 10-year results of the Canadian trial,23 which reported at least equivalent local tumor control and breast cosmesis between both conventional and hypofractionated regimens.23 The START trials reported that radiation-related effects to normal breast tissue, such as breast shrinkage, telangiectasia, and breast edema, were less common with the hypofractionated fraction regimen.24

RT Boost to the Tumor Bed: Randomized trials have demonstrated a reduction in local recurrence with the addition of a boost to the tumor bed in patients with higher-risk characteristics (eg, age <50 years, high-grade disease, or focally positive margins).2430 Boost treatment may be delivered using photons, electrons, or brachytherapy.

NCCN Recommendations for WBRT With or Without Boost to Tumor Bed: After breast-conserving surgery, WBRT is recommended with or without a boost to the tumor bed (category 1). The panel recommends that WBRT include the breast tissue in its entirety. CT-based treatment planning is recommended to assure adequate target coverage of the breast tissue and lumpectomy site and limit dose to normal tissues, especially the heart and lungs.

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

Compensators such as tissue wedges, forward planning using segments, and intensity-modulated RT (IMRT) may provide improved homogeneity of target dose and normal tissue sparing.31,32 Treatment techniques such as respiratory control using deep inspiration breath-hold and prone positioning can further reduce dose to adjacent normal tissues, particularly the heart and lungs.33

The NCCN panel recommends a dose of 46 to 50 Gy in 23 to 25 fractions or 40 to 42.5 Gy in 15 to 16 fractions for WBRT. Based on the results from the Canadian and START trials and overall convenience, hypofractionated courses are the NCCN-preferred option for treating patients receiving WBRT. Use of hypofractionation is not recommended for RNI. A boost to the tumor bed is recommended in patients with higher-risk characteristics (eg, age <50 years, high-grade disease, or focally positive margins). Typical boost doses are 10 to 16 Gy in 4 to 8 fractions.

RNI After Lumpectomy: RNI includes treatment of the supraclavicular, infraclavicular nodes, axillary bed at risk, and internal mammary nodes.

Use of RNI was shown to reduce risk of locoregional and distant recurrence and improve DFS in the MA.20 and EORTC 22922/10925 trials.34,35 In the MA.20 trial, women (n=1,800) who had undergone lumpectomy were randomly assigned to WBRT with or without RNI. An improvement in 10-year DFS was seen with the addition of regional RT compared with WBRT alone (82% vs 77%; hazard ratio [HR], 0.76; 95% CI, 0.61–0.94). Distant recurrences were reduced from 17.3% to 13.4% in those receiving WBRT alone versus those who also received RNI.35 No improvement was seen in 10-year OS with the addition of RNI compared with WBRT alone (82.8% vs 81.8%; HR, 0.91; 95% CI, 0.72–1.13).

In the EORTC 22922/10925 trial, women (n=4,000) were treated with lumpectomy plus WBRT or mastectomy plus chest wall radiation (n=955) and were randomly assigned to radiation

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NCCN Guidelines Insights: Breast Cancer, Version 1.2017

Version 1.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 4; 10.6004/jnccn.2017.0044

to the internal mammary and medial supraclavicular nodes or no RNI.34 At a median follow-up of 10.9 years, the addition of RNI resulted in a significant reduction in breast cancer mortality compared with no additional treatment (12.5% vs 14.4%; HR, 0.82; 95% CI, 0.70–0.97). An improved was seen in DFS as well (72.1% vs 69.1%; HR, 0.89; 95% CI, 0.80–1.00; P=.04).

Both the MA.20 and EORTC 22922/10925 trials included patients with high-risk, node-negative disease.34,35 In MA.20, patients with high-risk node-negative disease (n=177; 10% of total enrolled) included those with a primary tumor measuring ≥5 cm, or ≥2 cm with <10 axillary nodes removed, and at least one of the following: grade 3 histology, ER negativity, or lymphovascular invasion (LVSI). For those with high-risk, node-negative disease, the 10-year DFS was 83.7% with WBRT plus RNI versus 72.4% with WBRT alone (HR, 0.55; 95% CI, 0.28–1.09).35 The EORTC study eligibility included patients with stage I, II, III central/medial breast cancers irrespective of lymph node involvement, of which 44.4% (n=1,778) were node-negative. DFS in patients who received RNI was 76% versus 72% in those who did not (HR, 0.85; 95% CI, 0.70–1.02).34

NCCN Recommendations for RNI After Lumpectomy: For patients with ≥4 positive lymph nodes, the NCCN panel recommends RNI to the supraclavicular and infraclavicular areas, internal mammary nodes, and any part of the axillary bed at risk (category 1). For those with 1 to 3 positive axillary nodes, the panel recommends strong consideration of RNI to these areas (category 2A).

RNI for patients with negative axillary nodes is not routinely recommended by the panel. However in patients with central/medial primary tumors or tumors >2 cm with other high-risk features such as young age or extensive LVSI, according to the updated NCCN Guidelines, RNI may be considered on the basis of assessed individual risk for locoregional recurrence. The guidelines updates reflect these changes based on results of the MA-20 and EORTC trials (see BINV-2; page 435).

NCCN Recommendations and Other RT Considerations for Those Undergoing Lumpectomy: Accelerated Partial Breast Irradiation: Studies of APBI suggest that rates of local control in selected patients with early-stage breast cancer may be comparable to those treated with standard WBRT. Patients are encouraged to participate in clinical trials. The NCCN panel accepts the updated 2016 version of the ASTRO APBI consensus statement, which now defines criteria for patients “suitable” for APBI as one of the following: (1) age of ≥50 years with invasive ductal carcinoma measuring ≤2 cm (T1 disease) with negative margins by ≥2 mm, no LVSI, hormone receptor–positive, and BRCA-negative, or (2) low to intermediate grade screen-detected ductal carcinoma in situ measuring ≤2.5 cm with negative margins by ≥3 mm.36

Recent results from a randomized study of APBI using interstitial brachytherapy versus WBRT (50 Gy with 10 Gy boost) after lumpectomy in patients with low-risk disease demonstrated that APBI was not inferior to WBRT with respect to 5-year local control, DFS, and OS.37 Overall recurrence rates were low in both arms. Toxicity profiles and cosmetic results were also found to be similar in both trial groups at the end of 5 years, with fewer grade 2/3 late skin side effects observed in those receiving APBI.38 The applicability of these results using interstitial brachytherapy and doses of the trial to other APBI techniques is uncertain.

Dose and Schedule: A treatment course of 34 Gy in 10 fractions delivered twice per day with brachytherapy or 38.5 Gy in 10 fractions delivered twice per day with external-beam RT is typically prescribed to the tumor bed. Other fractionation schemes are currently under investigation.

RT After Lumpectomy in Older Adults: RT may be omitted after breast-conserving surgery in selected older women at overall low risk of recurrence. A study of women aged ≥70 years at diagnosis with clinical stage I, node-negative, ER-positive breast cancer with negative margins who were to receive adjuvant tamoxifen randomized patients to receive lumpectomy with WBRT or lumpectomy alone. With a median follow up of 12.6 years, the WBRT group experienced a significantly longer time to locoregional recurrence (HR, 0.18; 95% CI, 0.07–0.42; P<.001) compared with those who did not receive RT. At 10 years, the incidence of locoregional recurrence was 8% lower in those receiving RT. Of patients receiving RT, 98% were free from local and regional recurrences (95% CI, 96%–99%) compared with 90% of those receiving tamoxifen (95% CI, 85%–93%).39,40 No differences were seen in OS, DFS, or need for mastectomy between the 2 groups.39,40

Similar results have been obtained in other studies of similar design.41,42 In the Postoperative Radiotherapy in Minimum-Risk Elderly (PRIME) II study, women (n=1,326) aged ≥65 years with node-negative breast cancers that were <3 cm were randomly assigned to RT versus no RT.43 After a median follow-up of 5 years, ipsilateral breast tumor recurrences were lower in women assigned to RT (1.3% vs 4.1%). However, no differences in OS, regional recurrence, distant metastases, or contralateral breast cancers were observed between the groups.43

In the NCCN Guidelines, breast RT may be omitted after breast-conserving surgery for women ≥70 years of age with ER-positive, clinically node-negative T1 breast cancers who will receive endocrine therapy (tamoxifen or an aromatase inhibitor [AI]; category 1).

Adjuvant RT After Mastectomy

Multiple trials have reported decrease in locoregional recurrence and OS benefit in patients receiving postmastectomy RT (PMRT).4446 The indications for RT after mastectomy depend on the presence of risk factors for locoregional recurrence, such as large or advanced tumor (≥T3 disease or T3–4), close or positive margins, positive lymph nodes, and/or multiple other high-risk factors. After mastectomy, RT is most commonly delivered to chest wall with RNI.

RT to Chest Wall (Including Breast Reconstruction): The target for chest wall irradiation includes the ipsilateral chest wall and mastectomy scar, and may include the drain sites when indicated.

RT for Node-Positive Disease After Mastectomy: Randomized clinical trials of postmastectomy RT (PMRT) have shown that a DFS and OS advantage is conferred by irradiation of chest wall and regional lymph nodes.44,4649 In these trials, PMRT target volumes include the ipsilateral chest wall and regional lymph nodes, including supraclavicular, axillary apex, and internal mammary nodes.

The results of EBCTCG meta-analyses50 show that RT after mastectomy and ALND reduced both recurrence and breast cancer mortality in the women with 1 to 3 positive lymph nodes even when systemic therapy was administered.34 The data from EORTC 22922/10925 trial, which included patients (n=955) who had undergone a mastectomy, further support the role of PMRT in women with positive lymph nodes.34 For women with 1 to 3 involved ALNs, the most recent jointly updated guidelines by ASCO, ASTRO, and Society of Surgical Oncology recommend PMRT to reduce the risk of recurrence and improve survival taking an individualized approach based on patient preference and high-risk features.51

RT for Node-Negative Disease After Mastectomy: Prior retrospective analyses suggest a benefit of RT after mastectomy in reducing risk of recurrence in patients with node-negative disease with high-risk factors, such as close margins, tumors ≥2 cm, premenopausal status, triple-negative intrinsic subtype, and/or LVSI.52,53 Additional features of node-negative tumors that predict a higher rate of local recurrence include primary tumors >5 cm or positive pathologic margins. The Danish Breast Cancer Cooperative Group studies included patients with node-positive as well as high-risk, node-negative disease (defined as tumors that were >5 cm or invaded the skin or fascia) and demonstrated improved DFS and OS associated with RT (including the axillary, supra/infraclavicular, and ipsilateral internal mammary nodes) after mastectomy.43,45,48

NCCN Recommendations for RT After Mastectomy: The NCCN Guidelines recommend PMRT to the chest wall and regional nodes in patients with ≥4 positive ALNs (category 1). For patients with 1 to 3 positive nodes, PMRT should be strongly considered (category 2A). RNI should include the infraclavicular and supraclavicular regions, internal mammary nodes, and the axillary bed at risk.

In patients with negative axillary nodes and tumors >5 cm, or positive surgical margins, chest wall irradiation should be considered with or without RNI.

For negative axillary nodes, tumors ≤5 cm, and negative margins but <1 mm according to the NCCN panel, RT should be considered to the chest wall with or without regional nodal RT in patients with central/medial primary tumor or tumor >2 cm with other high-risk features, such as young age or extensive lymphovascular invasion.

In patients with negative axillary nodes, tumors ≤5 cm, and clear margins ≥1 mm, RT is generally not recommended. However, the panel has noted that in this group, RT may be considered for those with multiple risks of recurrence, including central/medial primary tumors or tumors >2 cm with other high-risk features, such as young age or extensive LVSI (see BINV-3; page 436).

CT-based treatment planning is recommended to assure adequate target coverage of the breast tissue and lumpectomy site and to limit dose to normal tissues, especially the heart and lungs.

Treatment Planning and Dose: CT-based treatment planning is recommended to assure adequate target coverage of the chest wall and regional lymph nodes and limit dose to normal tissues, especially the heart and lungs.

Compensators such as tissue wedges, forward planning using segments, and IMRT may provide improved homogeneity of target dose and normal tissue sparing.31,32 Treatment techniques, such as respiratory control using deep inspiration breath-hold, can further reduce dose to adjacent normal tissues, particularly the heart and lungs.33 The NCCN panel recommends a dose of 45 to 50 Gy in 23 to 25 fractions to the chest wall and regional lymph nodes. A scar boost of 10 Gy, at 2 Gy per fraction, to a total dose of approximately 60 Gy may be considered in patients at increased risk for recurrence.

Adjuvant Bisphosphonate Therapy

The 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

Oral clodronate, which is not commercially available in this country, has been studied in several randomized trials in patients with early-stage breast cancer for preventing bone metastases and improving survival. The studies have reported mixed results, with variable effects on DFS and OS.5457 However, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial, although DFS was similar in older and younger women, improvements in skeletal metastasis–free interval (P=.027) and nonskeletal metastasis–free interval (P=.014) were noted with adjuvant clodronate in women >50 years of age.57 Patients aged >60 years appeared to derive the most benefit from adjuvant clodronate, including an almost 60% reduction in skeletal metastases and a 40% to 50% reduction in nonskeletal metastases.57

Similarly, zoledronic acid seems to have a different effect in patients with high versus low estrogen environments (postmenopausal vs premenopausal patients). In the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) trial, for patients >40 years of age, 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 <40 years of age.58 In a planned subgroup analysis of the AZURE trial, zoledronic acid improved DFS in women who were >5 years since menopause at trial entry.59 A meta-analysis of data from 7 adjuvant bisphosphonate trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN), including only those known to be aged ≥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.60 More recently, the EBCTCG 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.61 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).61 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).61

With respect to other bisphosphonates, one trial that studied adjuvant oral ibandronate showed no effect on DFS or OS in patients with node-positive, early-stage breast cancer treated with dose-dense chemotherapy.62 Data on adjuvant oral pamidronate show no benefit on either reducing fractures or recurrence to bone in patients with breast cancer receiving adjuvant chemotherapy.63

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 end point of this study.64 Subsequently, in an interim analysis, an improvement in DFS—a secondary end point of the trial—was reported.65 However, unlike the bisphosphonates, which have demonstrated an OS benefit when used as adjuvant therapy, no available data show an OS benefit with denosumab. Results of the ABCSG-18 and the ongoing D-CARE66 trials may provide evidence for the use of denosumab in the adjuvant setting.

NCCN Recommendations for Use of Bisphosphonates as Adjuvant Therapy

The recently updated guidelines include new indications for bisphosphonates based on the EBCTCG meta-analysis.61 The panel recommends considering adjuvant bisphosphonate therapy for postmenopausal (natural or induced) women receiving adjuvant endocrine therapy (see BINV-5, BINV-6, and BINV-9; pages 437, 438, and 439, respectively).

Adjuvant Endocrine Therapy

Duration of Adjuvant Endocrine Therapy for Hormone Receptor–Positive Breast Cancer

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.67 These data showed a considerable risk of recurrence between years 5 and 20 in these patients treated with an initial 5 years of endocrine therapy.67 Data have now emerged showing benefit of extended endocrine therapy in improving DFS.

For those treated initially with adjuvant tamoxifen, evidence from several randomized trials shows benefit from extended adjuvant endocrine therapy. In the MA-17 trial, postmenopausal women with hormone receptor–positive, early-stage breast cancer who had completed 4.5 to 6 years of adjuvant tamoxifen were randomized to extended therapy with letrozole or not.6870 With a median follow-up of 64 months, letrozole was associated with improved DFS (HR, 0.52; 95% CI, 0.45–0.61) and OS (HR, 0.61; 95% CI, 0.52–0.71) compared with placebo.70

The ATLAS trial randomly allocated premenopausal and postmenopausal women to either 5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of 6,846 women with ER-positive disease showed that by extending adjuvant treatment to 10 years, the risk of relapse and breast cancer–related mortality was reduced.71 The risk of recurrence during years 5 to 14 was 21.4% for women receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction, 3.7%). Patients 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 (95% CI, 0.62–0.90) after 10 years of treatment. There were also decreases in the incidence of contralateral breast cancer. Furthermore, reduced mortality was also apparent after completion of 10 years of tamoxifen treatment. With regard to toxicity, the most important adverse effects noted in all women in the ATLAS trial after 10 years of tamoxifen treatment were an increased risk for endometrial cancer and pulmonary embolism.71 The results of the aTTom trial confirm the reduction in recurrence and death from breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen therapy.72

In women initially treated with an AI, a recent randomized phase III trial (MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to 10 years.73 Postmenopausal women 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.73 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 treatment resulted in more frequent bone-related adverse effects compared with 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%).73

NCCN Recommendations for Adjuvant Endocrine Therapy

Postmenopausal Women: The NCCN Guidelines for Breast Cancer recommend the following adjuvant endocrine therapy options for women with early-stage breast cancer who are postmenopausal at diagnosis: (1) an AI as initial adjuvant therapy for 5 years (category 1), with consideration of an additional 5 years on AI therapy based on data from the recent MA17.R trial; (2) an AI for 2 to 3 years (category 1) followed by tamoxifen to complete 5 years of endocrine therapy (category 1); (3) 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 (4) tamoxifen for 4.5 to 6 years followed by 5 years of an AI (category 1), or consideration of tamoxifen for up to 10 years. In postmenopausal women, the use of tamoxifen alone for 5 years (category 1) or up to 10 years is limited to those who decline or have a contraindication to AIs (see BINV-J; page 441).

Premenopausal Women: For women who were premenopausal at diagnosis, the NCCN Guidelines for Breast Cancer recommend 5 years of tamoxifen (category 1) with or without ovarian suppression (category 1), or ovarian suppression plus an AI for 5 years (category 1). Women who are premenopausal at diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries without menses. Serial assessment of circulating luteinizing hormone, follicle-stimulating hormone, and estradiol to assure a true postmenopausal status is mandatory if this subset of women is to be considered for therapy with an AI74,75 (see BINV-J; page 441).

After 5 years of initial endocrine therapy, for women 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 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 (see BINV-J; page 441).

First-Line Endocrine Therapy for Metastatic Hormone Receptor–Positive Breast Cancer

Editor's Note: Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

Women with recurrent or metastatic disease characterized by tumors that are hormone receptor–positive are appropriate candidates for endocrine therapy. First-line endocrine treatment is for women presenting with metastatic disease >12 months after completion of adjuvant endocrine therapy or those presenting with de novo metastatic breast cancer.

In premenopausal women, first-line endocrine treatment is typically with a selective ER modulator (SERM) alone or with ovarian suppression/ablation and endocrine therapy listed for postmenopausal women.76 Tamoxifen is the commonly used SERM for premenopausal women.

In postmenopausal women, AIs appear to have superior outcome compared with tamoxifen, although the differences are modest.7780 A Cochrane review has also suggested a survival benefit favoring the AIs over other endocrine therapies, although the advantage is small.81 A randomized phase III trial comparing tamoxifen with exemestane as first-line endocrine therapy for postmenopausal women with metastatic breast cancer showed no significant differences in progression-free survival (PFS) or OS between the 2 arms.79

Fulvestrant is an ER antagonist and was originally approved as a monthly intramuscular injection (250 mg per month); higher dose has been proven to be more effective in subsequent randomized trials. In the first-line setting, fulvestrant was found to be as effective as anastrozole in terms of overall response (36.0% vs 35.5%; odds ratio, 1.02; 95% CI, 0.56–1.87; P=.947) in evaluable patients (n=89 for fulvestrant and n=93 for anastrozole).82 An improved time to progression was seen with fulvestrant compared to anastrazole (median time to progression was 23.4 months for fulvestrant vs 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39–1.00; P=.0496).83 This study also used a higher loading dose of 500 mg every 2 weeks for 3 doses and then a maintenance dose of 500 mg monthly.82 The median OS was observed to be longer in the fulvestrant group than in the anastrozole group (54.1 vs 48.4 months; HR, 0.70; P=.041).84

Results from a recent phase III trial (FALCON) of first-line treatment with fulvestrant compared with anastrozole in women with metastatic ER-positive breast cancer demonstrated improved PFS with fulvestrant (at the higher dose, 500 mg) over anastrazole at a median follow-up of 25.0 months (16.6 vs 13.8 months; HR for progression or death, 0.797; 95% CI, 0.637–0.999).85 Quality-of-life outcomes were similar between the groups, with the most common adverse effects being arthralgia (17% vs 10%) and hot flashes (11% vs 10%) for fulvestrant and anastrazole, respectively.85 Importantly, patients in the FALCON trial had not received any prior endocrine therapy in any setting.

Combination of 2 endocrine agents as first-line treatment in postmenopausal women with hormone receptor–positive, metastatic breast cancer has been reported from 2 studies comparing single-agent anastrozole versus anastrozole plus fulvestrant. In one study (FACT), combination endocrine therapy was not superior to single-agent anastrozole (time to progression: HR, 0.99; 95% CI, 0.81–1.20; P=.91).86 In the second study (S0226) by SWOG, PFS (HR, 0.80; 95% CI, 0.68–0.94; stratified log-rank P=.007) and OS (HR, 0.81; 95% CI, 0.65–1.00; stratified P=.049) were superior with combination anastrozole plus fulvestrant.87 An unplanned subset analysis in this trial suggested that patients without prior adjuvant tamoxifen experienced the greatest benefit. The reason for the divergent outcomes in these 2 studies is not known.

The CDK 4/6 inhibitor, palbociclib in combination with letrozole received accelerated approval by the FDA as first-line therapy for metastatic, ER-positive, HER2-negative breast cancer. This approval was based on a phase II, open-label, randomized, multicenter trial (PALOMA-1) that evaluated the safety and efficacy of palbociclib in combination with letrozole versus letrozole alone as first-line treatment for patients with advanced ER-positive, HER2-negative breast cancer.88 Median PFS reported was double with the combination regimen compared with letrozole alone (20.2 months for the palbociclib plus letrozole group vs 10.2 months for the letrozole alone group; HR, 0.488; 95% CI, 0.319–0.748).88 Grade 3/4 adverse reactions reported at a higher incidence in the palbociclib plus letrozole versus letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%).

In a subsequent phase III study (PALOMA-2), the combination of palbociclib and letrozole demonstrated improved PFS (24.8 vs 14.5 months; HR, 0.58, 95% CI, 0.46–0.72) and objective response rate (42% vs 35%) compared with letrozole alone.89 The most commonly reported adverse events in the palbociclib and letrozole group compared with the letrozole alone group included neutropenia (79.5% vs 6.3%), fatigue (37.4% vs 27.5%) and nausea (35.1% vs 26.1%) and grade 1 and 2 alopecia (32.9% vs 15.8%).89

NCCN Recommendations for Endocrine Therapy for Metastatic Breast Cancer

All of the endocrine therapy options recommended by the NCCN panel for premenopausal and postmenopausal women with hormone receptor–positive metastatic breast cancer are listed on BINV-N (page 442).

In the recently updated guidelines, based on the results of the PALOMA-2 study, the NCCN panel included the combination of palbociclib with letrozole as a category 1 first-line endocrine therapy option for postmenopausal patients with hormone receptor–positive, HER2-negative metastatic breast cancer.

Fulvestrant and palbociclib may be offered to patients who experienced progression during prior treatment with AIs with or without one line of prior chemotherapy (category 1), because PFS was improved compared with fulvestrant alone in a phase III trial (PALOMA-3).90 The NCCN panel notes that treatment should be limited to those without prior exposure to cyclin-dependent kinase 4/6 inhibitors.

Conclusions

This report highlights the updates to the surgical axillary staging, RT, and systemic therapy recommendations for hormone receptor–positive disease in the 2017 version of the NCCN Guidelines for Breast Cancer. The NCCN Guidelines are in continuous evolution. They are updated annually, and sometimes more often if/when new high-quality clinical data become available in the interim. The recommendations in the NCCN Guidelines, with few exceptions, are based on the evidence from clinical trials. Expert medical clinical judgment is required to apply these guidelines in the context of an individual patient to provide optimal care. Ultimately, the physician and patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials.

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