NCCN Guidelines® Insights: Breast Cancer, Version 4.2023.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

The Impact of Radiotherapy Delay in Breast Conservation Patients Not Receiving Chemotherapy and the Rationale for Dichotomizing the Radiation Oncology Time-Dependent Standard into Two Quality Measures.

INTRODUCTION: The Commission on Cancer/National Quality Forum breast radiotherapy quality measure establishes that for women < 70 years, adjuvant radiotherapy after breast conserving surgery (BCS) should be started < 1 year from diagnosis. This was intended to prevent accidental radiotherapy omission or delay due to a long interval between surgery and chemotherapy completion, when radiation is delivered. However, the impact on patients not receiving chemotherapy, who proceed from surgery directly to radiotherapy, remains unknown. PATIENTS AND METHODS: Patients aged 18-69, diagnosed with stage I-III breast cancer as their first and only cancer diagnosis (2004-2016), having BCS, for whom this measure would be applicable, were reviewed from the National Cancer Database. RESULTS: Among 308,521 patients, the median age was 57.0 years, and > 99% of all patients were compliant with the measure. The cohort of interest included 186,650 (60.5%) patients not receiving chemotherapy, with a mean age of 57.9 years. Of these, 90.5% received external beam radiotherapy (EBRT) and 9.5% brachytherapy. Among them, 24.9% started radiotherapy > 8 weeks after surgery. In a multivariable model, delay from surgery to radiotherapy increased the hazard ratios for overall survival to 9.0% (EBRT) per month and 3.0% (brachytherapy) per week. CONCLUSION: While 99.9% of patients undergoing BCS without chemotherapy remain compliant with the current quality measure, 25% have delays > 8 weeks to start radiation, which is associated with impaired survival. These data suggest that the current quality measure should be dichotomized into two, with or without chemotherapy, in order to impel prompt radiotherapy initiation and maximize outcomes in all patients.

Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male 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. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.

The COVID-19 pandemic presents clinicians a unique set of challenges in managing breast cancer (BC) patients. As hospital resources and staff become more limited during the COVID-19 pandemic, it becomes critically important to define which BC patients require more urgent care and which patients can wait for treatment until the pandemic is over. In this Special Communication, we use expert opinion of representatives from multiple cancer care organizations to categorize BC patients into priority levels (A, B, C) for urgency of care across all specialties. Additionally, we provide treatment recommendations for each of these patient scenarios. Priority A patients have conditions that are immediately life threatening or symptomatic requiring urgent treatment. Priority B patients have conditions that do not require immediate treatment but should start treatment before the pandemic is over. Priority C patients have conditions that can be safely deferred until the pandemic is over. The implementation of these recommendations for patient triage, which are based on the highest level available evidence, must be adapted to current availability of hospital resources and severity of the COVID-19 pandemic in each region of the country. Additionally, the risk of disease progression and worse outcomes for patients need to be weighed against the risk of patient and staff exposure to SARS CoV-2 (virus associated with the COVID-19 pandemic). Physicians should use these recommendations to prioritize care for their BC patients and adapt treatment recommendations to the local context at their hospital.

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Hypofractionated radiation treatment for breast cancer: The time is now.

While there is now Level I data with long-term follow-up supporting the routine use of hypofractionated (HF) whole-breast radiation therapy (WBRT) after breast-conserving surgery, its adoption has been slow and variable. This article will review the literature supporting the efficacy and safety of hypofractionated radiation for breast cancer, discuss the radiobiological rationale specific to breast tumors, and make an argument for justifying the routine adoption of shorter, HF-WBRT courses when delivering breast radiation. Data using HF with regional nodal irradiation and in the post-mastectomy setting will also be reviewed. The aim is to provide an in-depth understanding of the use of hypofractionated radiation therapy for breast cancer, its applicability, and topics warranting future research.

Individualized Prediction of Survival Benefit from Postmastectomy Radiotherapy for Patients with Breast Cancer with One to Three Positive Axillary Lymph Nodes.

PURPOSE: There still exist some arguments regarding the use of postmastectomy radiotherapy (PMRT) for patients with breast cancer carrying one to three positive axillary lymph nodes considering the heterogeneity of this cohort. Here, we developed a prognostic nomogram to estimate the probability of long-term outcome in patients receiving or not receiving PMRT in order to assist in making individually locoregional treatment decisions for this particular cohort. METHODS: Altogether, 20,336 women, aged 18 to 80 years, diagnosed with breast cancer, and carrying one to three positive nodes were identified in the Surveillance, Epidemiology, and End Results (SEER) database. We applied multivariant Cox hazard model to determine the impact of covariates on disease-specific survival (DSS) and overall survival (OS). Then, the nomogram was built accordingly. Internal and external validations were performed to examine the accuracy of nomograms. RESULTS: Age of diagnosis, tumor grade, size, estrogen and progesterone receptor status, and number of positive nodes were independent factors of DSS and OS in the multivariate analysis. Incorporating these factors into the constructed nomogram showed high accuracy when predicting 5- and 10-year survival, with internally and externally bootstrap-corrected concordance indexes in the range of 0.6 to 0.8. CONCLUSION: Besides the number of involved nodes, extra variables existed as predictors of survival outcomes in this cohort; therefore, the recommendation of PMRT or no PMRT requires comprehensive consideration. This clinically validated nomogram provided a useful tool that could aid decision making by estimating DSS and OS benefits from PMRT, useful in predicting 5- and 10-year DSS and OS for patients with one to three positive nodes after mastectomy. IMPLICATIONS FOR PRACTICE: This study evaluated population-based data to identify prognostic factors associated with patients with breast cancer with one to three lymph nodes and help clinicians to weigh the benefit of postmastectomy radiotherapy (PMRT). Surveillance, Epidemiology, and End Results (SEER) data were used to develop a prognostic nomogram to predict the likelihood of long-term survival with and without PMRT in order to optimize the individual locoregional control strategy for this particular cohort. This clinically validated nomogram provides a useful tool to predict 5- and 10-year disease-specific survival and overall survival for patients with one to three positive nodes and can aid tailored clinical decision making by estimating predicted benefit from PMRT.

Treatment delays from transfers of care and their impact on breast cancer quality measures.

PURPOSE: Despite delays between diagnosis and surgery adversely affecting survival, patients frequently transfer their breast cancer care between institutions. This study was performed to assess the prevalence and effect of such transfers of care (TsOC) on the time to surgery, and its impact on current time-dependent breast cancer quality metrics at Commission on Cancer (CoC) and National Accreditation Program for Breast Centers (NAPBC)-accredited institutions. METHODS: Patients having non-metastatic invasive breast cancer diagnosed between 2006 and 2015 at CoC and NAPBC centers ("reporting facilities") in the National Cancer Database were reviewed. TsOC refer to transferring into or out of a reporting facility between diagnosis and surgery. RESULTS: Among 622,793 patients, 36.6% of patients transferred care. TsOC add 7.3, 7.8, 8.7, and 9.8 days in time to surgery, chemotherapy, radiotherapy, and endocrine therapy, respectively (p's < 0.0001). On multivariable analysis, the odds of surgery occurring > 90 days from diagnosis were greatest for patients undergoing unilateral or bilateral mastectomy, Black or Hispanic patients, and those having TsOC (ORs > 1.73, p's < 0.0001). TsOC increase the odds of non-compliance, per patient, for chemotherapy, radiotherapy and endocrine therapy time-dependent measures by 65.4%, 25.6%, and 56.5%, respectively (p < 0.0001). CONCLUSIONS: TsOC for newly diagnosed breast cancers to or from an accredited facility result in delays in time to surgery which can affect compliance with time-dependent quality measures. Facilities frequently receiving transferred patients may be most adversely affected. Although non-compliance with these quality measures is low, institutions and accrediting bodies should be aware of these associations in order to comply with time-dependent standards.

NCCN Guidelines Insights: Breast Cancer, Version 3.2018.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

American Society of Breast Surgeons' Practice Patterns After Publication of the SSO-ASTRO-ASCO DCIS Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation.

BACKGROUND: The SSO-ASTRO-ASCO consensus guideline on margins for breast-conserving surgery with whole breast irradiation in ductal carcinoma in situ (DCIS) recommended a 2-mm margin. We sought to determine the impact of guideline publication on clinician practice. METHODS: A total of 3081 members of the American Society of Breast Surgeons (ASBrS) received a survey. Respondents' clinical practice type and duration, guideline familiarity, and margin width preferences before and after publication were assessed. Clinical practice pattern differences before and after publication were investigated using McNemar's test. RESULTS: A total of 767 (24.9%) of those surveyed responded. Most (92.4%) indicated guideline familiarity. Of those familiar, re-excision preference for DCIS and a positive margin remained the same before (94.4%) and after (94.3%) publication (McNemar's test p = 1.0). Following publication, surgeons were more likely to avoid re-excision to achieve margins wider than 2-mm (82.3% pre versus 87.5% post, p = 0.002). More surgeons performed re-excision for a close margin with pure DCIS (25.9% pre versus 36.5% post, p < 0.001) and with DCIS with microinvasion (DCIS-M) (40.7% pre versus 52.3% post, p < 0.001). For patients with invasive disease with extensive intraductal component (EIC) and a close margin, preference to avoid re-excision was similar (51.2% per versus 55.2% post, p = 0.071). CONCLUSION: Since guideline publication, surgeons are less likely to perform re-excision to obtain a margin greater than 2-mm and more likely to perform re-excision to obtain a 2-mm margin for both pure DCIS and DCIS-M. Preference to avoid re-excision with a close margin and EIC was similar before and after publication.

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Advancements and Personalization of Breast Cancer Treatment Strategies in Radiation Therapy.

Significant technologic advances in radiation treatment delivery now allow for more personalized delivery considerations which incorporate individual patient characteristics (such as tumor location and patient anatomy) and more precise delivery in the breast conservation or post-mastectomy setting. The combined advancements with other treatment modalities (i.e., systemic therapy, surgical management) have had direct effects on local-regional management and outcomes such that currently, local-regional relapses after definitive treatment for localized disease are now rarely experienced. Recent advances in the radiation therapy field have come from careful patient selection for a variety of three-dimensional treatment delivery techniques and alternatives to conventional tangential radiation. These advances have been demonstrated to diminished acute/long-term toxicity, minimized dose to surrounding normal tissue structures such as the heart and lung, and ultimately result in an improvement in the therapeutic ratio for radiation treatment. This chapter discusses recent radiation innovations and appropriate patient selection for their application, for a more personalized approach to radiation therapy for breast cancer patients.

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.

Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma In Situ.

PURPOSE: Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation. METHODS: A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7,883 patients and other published literature as the evidence base for consensus. RESULTS: Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2-mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2-mm margins. Negative margins narrower than 2 mm alone are not an indication for mastectomy, and factors known to affect rates of IBTR should be considered in determining the need for re-excision. CONCLUSION: Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.

Radiation therapy in the locoregional treatment of triple-negative breast cancer.

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks (relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for post-mastectomy radiation, and accelerated delivery methods for TNBC should be offered on clinical trials. Preliminary data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard locoregional management principles should be adhered to.

Predictive factors of nipple involvement in breast cancer: a systematic review and meta-analysis.

Nipple-sparing mastectomy (NSM) provides a cosmetic and psychological benefit for patients, but concerns on nipple involvement (NI) of tumor continue to persist. Several studies have reported factors for predicting NI, but the results were inconsistent and uncomprehensive, making patient selection difficult. The aim of the systematic review was to pool the published data to further discern factors associated with NI. A literature review was conducted of PubMed database, following the PRISMA guidelines. Relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using random-effect or fix-effect model. Publication bias and Chi-square test were also calculated. From 1978 to 2014, 27 clinical studies with 7971 patients met the inclusion criteria. Predictive factors suggest higher rates of NI including the following: tumor-to-nipple distance (TND) ≤ 2.5 cm (3.65, 1.42-9.33); positive lymph node status (2.09, 1.71-2.57); stage III or IV disease (2.41, 1.93-3.00); tumor size > 5 cm (2.42, 1.95-3.02); estrogen receptor (ER)-negative status (1.19, 1.01-1.40); progesterone receptor (PR)-negative status (1.52, 1.25-1.84); HER-positive status (1.76, 1.46-2.12); patients with ductal carcinoma in situ (DCIS) compared with invasive ductal carcinoma (1.55, 1.16-2.08). Due to the statistical heterogeneity detected with certain parameters, further investigations to confirm their association with NI will be needed. Patients with one or more risk factors such as centrally located tumors; higher tumor stage; large tumors; ER-negative/PR-negative/HER-positive status and associated DCIS have higher risk of NI. Taking these factors into consideration comprehensively may help with decision-making process for NSM.

Assessment of Practice Patterns Following Publication of the SSO-ASTRO Consensus Guideline on Margins for Breast-Conserving Therapy in Stage I and II Invasive Breast Cancer.

BACKGROUND: The recently published SSO-ASTRO consensus guideline on margins concluded "no ink on tumor" is the standard for an adequate margin. This study was conducted to determine how this guideline is aligned with current clinical practice. METHODS: A survey was sent to 3057 members of the American Society of Breast Surgeons. Questions assessed respondents' clinical practice type and duration, familiarity with the guideline, and preferences for margin re-excision. RESULTS: Of those surveyed, 777 (25%) responded. Most (92%) indicated familiarity with the guideline. Of these respondents, the majority (n = 678, or 94.7%) would re-excise all or most of the time when tumor extended to the inked margin. Very few (n = 9, or 1.3%) would re-excise all or most of the time when tumor was within 2 mm of the margin. Over 12 % (n = 90) would re-excise all or most of the time for a triple-negative tumor within 1 mm of the margin, whereas 353 (49.6%) would re-excise all or most of the time when imaging and pathology were discordant, and tumor was within 1 mm of multiple margins. Finally, 330 (45.8%) would re-excise all or most of the time when multiple foci of ductal carcinoma in situ extended to within 1 mm of multiple inked margins. CONCLUSIONS: Surgeons are in agreement to re-excise margins when tumor touches ink and generally not to perform re-excisions when tumor is close to (but not touching) the inked margin. For more complex scenarios, surgeons are utilizing their individual clinical judgment to determine the need for re-excision.

Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer.

PURPOSE: Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer. METHODS: A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus. RESULTS: Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. CONCLUSION: The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.

Prognostic significance of calcium-sensing receptor in breast cancer.

The calcium-sensing receptor (CaSR) is a G-protein coupled receptor that is involved in tumor suppression of cancers. However, its role in breast cancer remains largely unknown. The aim of the study was to investigate the expression of CaSR in breast cancers and to evaluate its prognostic significance. We found that the protein levels of CaSR were significantly reduced in cancer lesion compared with its paired non-tumor tissues. By analyzing the expression of CaSR in a 148 cases of breast cancer tissue microarray (TMA) by immunohistochemistry, we found that patients with lower expression of CaSR were significantly associated with poor overall survival, cause-specific survival, and distant metastasis-free survival. The Cox multivariate analysis showed that CaSR was an independent prognostic significance for both overall survival and cause-specific survival of breast cancer patients. Our data confirmed the tumor suppressor role of CaSR and suggested that CaSR is an independent prognostic indicator of breast cancer.