Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

American Radium Society Appropriate Use Criteria Postmastectomy Radiation Therapy: Executive Summary of Clinical Topics.

PURPOSE: To conduct an appropriate use criteria expert panel update on clinical topics relevant to current clinical practice regarding postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An analysis of the medical literature from peer-reviewed journals was conducted from May 4, 2010 to May 4, 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to search the PubMed database to retrieve a comprehensive set of relevant articles. A well-established methodology (modified Delphi) was used by the expert panel to rate the appropriate use of procedures. RESULTS: Evidence for key questions in PMRT regarding benefit in special populations and technical considerations for delivery was examined and described. Risk factors for local-regional recurrence in patients with intermediate-risk disease that indicate benefit of PMRT include molecular subtype, age, clinical stage, and pathologic response to neoadjuvant chemotherapy. Use of hypofractionated radiation in PMRT has been examined in several recent randomized trials and is under investigation for patients with breast reconstruction. The use of bolus varies significantly by practice region and has limited evidence for routine use. Adverse effects occurred with both PMRT preimplant and postimplant exchange in 2-staged breast reconstruction. CONCLUSIONS: Most patients with even limited nodal involvement will likely benefit from PMRT with significant reduction in local-regional recurrence and potential survival. Patients with initial clinical stage III disease and/or any residual disease after neoadjuvant chemotherapy should be strongly considered for PMRT. Growing evidence supports the use of hypofractionated radiation for PMRT with equivalent efficacy and decreased acute side effects, but additional evidence is needed for special populations. There is limited evidence to support routine use of bolus in all patients. Timing of PMRT regarding completion of 2-staged breast reconstruction requires a discussion of increased risks with radiation postimplant exchange compared with increased risk of failure of reconstruction or surgical complications with radiation preimplant exchange.

Reduced Survival Outcome After Receiving a New Cancer Diagnosis in the Emergency Department: Findings from a Hospital Network in Rural Eastern North Carolina.

PURPOSE: Patients whose cancer was found during an Emergency Department (ED) visit often present at later stages when survival outcomes are worse. Limited research has characterized the survival experience of cancer patients who receive their diagnosis through the ED versus those who do not. METHODS: A retrospective cohort study identified all patients presenting to the ED between 2014 and 2015 in a rural, regional hospital system with a visit or resulting admission associated with an oncologic ICD-9 code. The chart was abstracted to determine a new cancer diagnosis versus an existing case. Cox proportional hazards (HR) estimated survival time. Patient and cancer characteristics were compared between those who were newly diagnosed through the ED and patients who were not. FINDINGS: Thirty-nine percent of patients in our sample received their new cancer diagnosis as a result of an ED visit. The median survival was lower in cancer cases diagnosed through the ED (13 vs. 39 months, P < .001), men (20 vs. 32 months, P < .001), and patients aged ≥ 65 (22 months vs. 32 months, P < .001). Factors associated with lower survival were having a type of cancer location other than breast (HR = 1.96; P < .001), followed by being newly diagnosed with cancer through the ED (HR = 1.71; P < .001), and stage IV at diagnosis (HR = 1.70; P < .001). CONCLUSIONS: Patients who received a new cancer diagnosis through the ED and required subsequent hospitalization had shorter overall survival and presented with advanced disease. Future research should address socioeconomic factors that may influence these patterns of cancer presentation.

Navigator-assisted hypofractionation (NAVAH) to address radiation therapy access disparities facing African-Americans with breast cancer.

Background: African-Americans have the highest overall cancer death rate and shortest survival time of any racial or ethnic group in the United States. The most common cancer studied in African-American radiation therapy (RT) access disparities research is breast cancer. The goal of this study is to evaluate the impact of patient navigation on RT access for African-American breast cancer patients. Material and methods: This study is a prospective survey-based evaluation of the impact of patient navigation on access to hypofractionated RT and financial toxicity in African-American breast cancer patients. The impact of patient navigation on RT access will be collated and analyzed from survey results pre-RT versus post-RT as well as for patients with versus without receipt of patient navigation. The validated COST-Functional Assessment of Chronic Illness Therapy score will be used to compare hypofractionation versus standard fractionated RT financial toxicity for patients with early-stage breast cancer who have received lumpectomy. Conclusion: This is the first study to investigate the impact of patient navigation on reducing RT access disparities facing African-American breast cancer patients. The natural progression of this work will be to expand this model to include additional breast cancer populations most vulnerable to suffering RT access disparities (Native American, Hispanic American, Appalachian) within the United States.

Partial Breast Reirradiation for Patients With Ipsilateral Breast Tumor Recurrence After Initial Treatment With Breast Conservation for Early Stage Breast Cancer.

PURPOSE: Accelerated partial breast irradiation (APBI), including intraoperative radiation therapy (IORT), is an evidence-based treatment option in patients undergoing breast conserving surgery (BCS) for early-stage breast cancer. However, literature regarding reirradiation for patients with ipsilateral breast tumor recurrences (IBTR) is limited. This prospective study assessed the feasibility and efficacy of using APBI in patients who had prior whole breast irradiation. METHODS AND MATERIALS: This was a single institution, prospective study of patients who were previously treated with BCS and adjuvant whole breast radiation. At the time of enrollment, all had unifocal IBTR, histologically confirmed invasive ductal carcinoma with negative margins after repeat BCS. Patients received either IORT in a single fraction at time of BCS or MammoSite brachytherapy twice daily over 5 days. Follow-up data and patient surveys were collected at 1, 3, 6, 9, and 12 months, then annually for at least a 5-year period. RESULTS: From 2008 to 2014, 13 patients were enrolled. Median time to recurrence after initial course of radiation was 12.5 years. Median follow-up after retreatment was 7.8 years. One patient in the IORT group had a subsequent tumor bed recurrence, yielding a local control of 92%. One patient had distant recurrence. At baseline, 680 reported excellent-good cosmesis compared with 42% at 5 years. All patients indicated total satisfaction with overall treatment experience. CONCLUSIONS: APBI using IORT was well tolerated with excellent local control and may be a reasonable alternative to mastectomy for IBTR. Further study is needed to determine the most suitable candidates for this approach.

Breast Radiation and the Heart: Cardiac Toxicity and Cardiac Avoidance.

The purpose of this invited review is to discuss the most recent and relevant outcome studies assessing the risk of late cardiac toxicity in women treated with radiotherapy for breast cancer and to describe the evidence-based technical factors associated with late cardiac toxicity. This review will also discuss the common radiation techniques for reducing radiation dose to the heart, which will lead to better outcomes and lower rates of late toxicity that can cause morbidity and mortality in women who have been cured of their breast cancer.

Genomically Guided Breast Radiation Therapy: A Review of the Current Data and Future Directions.

PURPOSE: To highlight the current evidence and the limitations in data to support a personalized approach in breast oncology radiation therapy management and define steps needed for clinical implementation. METHODS AND MATERIALS: A critical review of the current literature on the use of genomics in breast radiation therapy was undertaken by a group of breast radiation oncologists to discuss current data, future directions, and challenges. RESULTS: A summary of the existing data, ongoing clinical trials, and future directions is provided. The authors note many groups have developed radiation-specific genomic assays, which demonstrate promise in prediction of local control and benefit from radiation therapy; however, prospective validation of their utility is needed. Limitations continue to exist in our understanding of tumor biology and how it can be integrated into clinical practice. CONCLUSIONS: Given the relative ubiquity of breast radiation therapy, the variety of dose and fractionation approaches, and the current data to support a personalized approach, it is our belief that the delivery of breast radiation therapy is uniquely poised for a genomically personalized radiation therapy approach. Prospective clinical trials implementing genomic signatures are needed at this time to advance the field.

Utilizing the genomically adjusted radiation dose (GARD) to personalize adjuvant radiotherapy in triple negative breast cancer management.

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.

Precision Medicine for Breast Cancer: The Paths to Truly Individualized Diagnosis and Treatment.

Precision medicine in oncology seeks to individualize each patient's treatment regimen based on an accurate assessment of the risk of recurrence or progression of that person's cancer. Precision will be achieved at each phase of care, from detection to diagnosis to surgery, systemic therapy, and radiation therapy, to survivorship and follow-up care. The precision arises from detailed knowledge of the inherent biological propensities of each tumor, rather than generalizing treatment approaches based on phenotypic, or even genotypic, categories. Extensive research is being conducted in multiple disciplines, including radiology, pathology, molecular biology, and surgical, medical, and radiation oncology. Clinical trial design is adapting to the new paradigms and moving away from grouping heterogeneous patient populations into limited treatment comparison arms. This review touches on several areas invested in clinical research. This special issue highlights the specific work of a number of groups working on precision medicine for breast cancer.

Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement.

PURPOSE: To update the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy (IORT) for partial breast irradiation in early-stage breast cancer, based on published evidence complemented by expert opinion. METHODS AND MATERIALS: A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles; 44 articles were selected. The authors synthesized the published evidence and, through a series of conference calls and e-mails, reached consensus regarding the recommendations. RESULTS: The new recommendations include lowering the age in the "suitability group" from 60 to 50 years and in the "cautionary group" to 40 years for patients who meet all other elements of suitability (Table 1). Patients with low-risk ductal carcinoma in situ, as per Radiation Therapy Oncology Group 9804 criteria, were categorized in the "suitable" group. The task force agreed to maintain the current criteria based on margin status. Recommendations for the use of IORT for breast cancer patients include: counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation; the need for prospective monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up; and restriction of IORT to women with invasive cancer considered "suitable." CONCLUSION: These recommendations will provide updated clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients.

Intraoperative Radiotherapy for Breast Cancer.

Intraoperative radiotherapy (IORT) for early stage breast cancer is a technique for partial breast irradiation. There are several technologies in clinical use to perform breast IORT. Regardless of technique, IORT generally refers to the delivery of a single dose of radiation to the periphery of the tumor bed in the immediate intraoperative time frame, although some protocols have performed IORT as a second procedure. There are two large prospective randomized trials establishing the safety and efficacy of breast IORT in early stage breast cancer patients with sufficient follow-up time on thousands of women. The advantages of IORT for partial breast irradiation include: direct visualization of the target tissue ensuring treatment of the high-risk tissue and eliminating the risk of marginal miss; the use of a single dose coordinated with the necessary surgical excision thereby reducing omission of radiation and the selection of mastectomy for women without access to a radiotherapy facility or unable to undergo several weeks of daily radiation; favorable toxicity profiles; patient convenience and cost savings; radiobiological and tumor microenvironment conditions which lead to enhanced tumor control. The main disadvantage of IORT is the lack of final pathologic information on the tumor size, histology, margins, and nodal status. When unexpected findings on final pathology such as positive margins or positive sentinel nodes predict a higher risk of local or regional recurrence, additional whole breast radiation may be indicated, thereby reducing some of the convenience and low-toxicity advantages of sole IORT. However, IORT as a tumor bed boost has also been studied and appears to be safe with acceptable toxicity. IORT has potential efficacy advantages related to overall survival related to reduced cardiopulmonary radiation doses. It may also be very useful in specific situations, such as prior to oncoplastic reconstruction to improve accuracy of adjuvant radiation delivery, or when used as a boost in higher risk patients to improve tumor control. Ongoing international clinical trials are studying these uses and follow-up data are accumulating on completed studies.

Integration of a Radiosensitivity Molecular Signature Into the Assessment of Local Recurrence Risk in Breast Cancer.

PURPOSE: Recently, we developed radiosensitivity (RSI), a clinically validated molecular signature that estimates tumor radiosensitivity. In the present study, we tested whether integrating RSI with the molecular subtype refines the classification of local recurrence (LR) risk in breast cancer. METHODS AND MATERIALS: RSI and molecular subtype were evaluated in 343 patients treated with breast-conserving therapy that included whole-breast radiation therapy with or without a tumor bed boost (dose range 45-72 Gy). The follow-up period for patients without recurrence was 10 years. The clinical endpoint was LR-free survival. RESULTS: Although RSI did not uniformly predict for LR across the entire cohort, combining RSI and the molecular subtype identified a subpopulation with an increased risk of LR: triple negative (TN) and radioresistant (reference TN-radioresistant, hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.15-0.92, P=.02). TN patients who were RSI-sensitive/intermediate had LR rates similar to those of luminal (LUM) patients (HR 0.86, 95% CI 0.47-1.57, P=.63). On multivariate analysis, combined RSI and molecular subtype (P=.004) and age (P=.001) were the most significant predictors of LR. In contrast, integrating RSI into the LUM subtype did not identify additional risk groups. We hypothesized that radiation dose escalation was affecting radioresistance in the LUM subtype and serving as a confounder. An increased radiation dose decreased LR only in the luminal-resistant (LUM-R) subset (HR 0.23, 95% CI 0.05-0.98, P=.03). On multivariate analysis, the radiation dose was an independent variable only in the LUMA/B-RR subset (HR 0.025, 95% CI 0.001-0.946, P=.046), along with age (P=.008), T stage (P=.004), and chemotherapy (P=.008). CONCLUSIONS: The combined molecular subtype-RSI identified a novel molecular subpopulation (TN and radioresistant) with an increased risk of LR after breast-conserving therapy. We propose that the combination of RSI and molecular subtype could be useful in guiding radiation therapy-based decisions in breast cancer.

ACR Appropriateness Criteria® Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) is a breast neoplasm with potential for progression to invasive cancer. Management commonly involves excision, radiotherapy, and hormonal therapy. Surgical assessment of regional lymph nodes is rarely indicated except in cases of microinvasion or mastectomy. Radiotherapy is employed for local control in breast conservation, although it may be omitted for select low-risk situations. Several radiotherapy techniques exist beyond standard whole-breast irradiation (ie, partial-breast irradiation [PBI], hypofractionated whole-breast radiation); evidence for these is evolving. We present an update of the American College of Radiology (ACR) Appropriateness Criteria® for the management of DCIS. The ACR Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions, which are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria local-regional recurrence (LRR) and salvage surgery-breast cancer.

Although both breast-conserving surgery and mastectomy generally provide excellent local-regional control of breast cancer, local-regional recurrence (LRR) does occur. Predictors for LRR include patient, tumor, and treatment-related factors. Salvage after LRR includes coordination of available modalities, including surgery, radiation, chemotherapy, and hormonal therapy, depending on the clinical scenario. Management recommendations for breast cancer LRR, including patient scenarios, are reviewed, and represent evidence-based data and expert opinion of the American College of Radiology Appropriateness Criteria Expert Panel on LRR.The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel.The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Evaluation of bolus electron conformal therapy compared with conventional techniques for the treatment of left chest wall postmastectomy in patients with breast cancer.

Postmastectomy radiation (PMRT) lowers local-regional recurrence risk and improves survival in selected patients with breast cancer. The chest wall and lower axilla are technically challenging areas to treat with homogenous doses and normal tissue sparing. This study compares several techniques for PMRT to provide data to guide selection of optimal treatment techniques. Twenty-five consecutive left-sided patients treated postmastectomy were contoured using Radiation Therapy Oncology Group (RTOG) atlas guidelines then planned using 4 different PMRT techniques: opposed tangents with wedges (3-dimensional [3D] wedges), opposed tangents with field-in-field (FiF) modulation, 8-field intensity modulation radiotherapy (IMRT), and custom bolus electron conformal therapy (BolusECT, .decimal, Inc., Sanford, FL). Required planning target volume (PTV) coverage was held constant, and then dose homogeneity and normal tissue dose parameters were compared among the 4 techniques. BolusECT achieved clincally acceptable PTV coverage for 22 out of 25 cases. Compared with either tangential technique, IMRT and BolusECT provided the lowest heart V25 doses (3.3% ± 0.9% and 6.6% ± 3.2%, respectively with p < 0.0001). FiF had the lowest mean total lung dose (7.3 ± 1.1Gy, with p = 0.0013), IMRT had the lowest total lung V20 (10.3% ± 1.6%, p < 0.0001), and BolusECT had the lowest mean heart dose (7.3 ± 2.0Gy, p = 0.0002). IMRT provided the optimal dose homogeneity and normal tissue sparing compared with all other techniques for the cases in which BolusECT could not achieve acceptable PTV coverage. IMRT generally exposes contralateral breast and lung to slightly higher doses. Optimal PMRT technique depends upon patient anatomy. Patients whose maximal target volume depth is about 5.7cm or less can be treated with BolusECT-assisted 12 or 15MeV electron beams. At these energies, BolusECT has comparable dose-volume statistics as IMRT and lower heart V25 than opposed tangential beams. Patients with larger depths are best treated with IMRT, which provides significant advantages in both dose homogeneity and normal tissue sparing compared with all other techniques.

The impact of the size of nodal metastases on recurrence risk in breast cancer patients with 1-3 positive axillary nodes after mastectomy.

PURPOSE: Use of postmastectomy radiation therapy (PMRT) in breast cancer patients with 1-3 positive nodes is controversial. The objective of this study was to determine whether the size of nodal metastases in this subset could predict who would benefit from PMRT. METHODS AND MATERIALS: We analyzed 250 breast cancer patients with 1-3 positive nodes after mastectomy treated with contemporary surgery and systemic therapy at our institution. Of these patients, 204 did not receive PMRT and 46 did receive PMRT. Local and regional recurrence risks were stratified by the size of the largest nodal metastasis measured as less than or equal to 5 mm or greater than 5 mm. RESULTS: The median follow-up was 65.6 months. In the whole group, regional recurrences occurred in 2% of patients in whom the largest nodal metastasis measured 5 mm or less vs 6% for those with metastases measuring greater than 5 mm. For non-irradiated patients only, regional recurrence rates were 2% and 9%, respectively. Those with a maximal nodal size greater than 5 mm had a significantly higher cumulative incidence of regional recurrence (P=.013). The 5-year cumulative incidence of a regional recurrence in the non-irradiated group was 2.7% (95% confidence interval [CI], 0.7%-7.2%) for maximal metastasis size of 5 mm or less, 6.9% (95% CI, 1.7%-17.3%) for metastasis size greater than 5 mm, and 16% (95% CI, 3.4%-36.8%) for metastasis size greater than 10 mm. The impact of the maximal nodal size on regional recurrences became insignificant in the multivariable model. CONCLUSIONS: In patients with 1-3 positive lymph nodes undergoing mastectomy without radiation, nodal metastasis greater than 5 mm was associated with regional recurrence after mastectomy, but its effect was modified by other factors (such as tumor stage). The size of the largest nodal metastasis may be useful to identify high-risk patients who may benefit from radiation therapy after mastectomy.

Accelerated partial breast irradiation: a review and description of an early North American surgical experience with the intrabeam delivery system.

BACKGROUND: Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. METHODS: Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. RESULTS: Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. CONCLUSIONS: While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery.