Prediction of breast cancer-related lymphedema by dermal backflow detected with near-infrared fluorescence lymphatic imaging.

PURPOSE: Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%-10% increase in arm volume, typically measured no earlier than 3-6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL. METHODS: In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4-8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI. RESULTS: By 18 months after RT, 30 of 42 study subjects (71%) developed mild-moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by "dermal backflow" of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL. CONCLUSION: BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes.

Exclusion of Men from Randomized Phase III Breast Cancer Clinical Trials.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer.

Inflammatory breast cancer: a proposed conceptual shift in the UICC-AJCC TNM staging system.

In the absence of histological criteria that distinguish between inflammatory and non-inflammatory breast cancer, diagnosis of inflammatory breast cancer relies entirely on the existence of clinical criteria as outlined by the TNM classification. This classification restricts patients presenting with clinical criteria characteristic of inflammatory breast cancer to subcategory T4d, which immediately relegates all patients with non-metastatic inflammatory breast cancer to stage 3, regardless of tumour size or nodal spread. Patients who present with metastatic disease are consigned to stage 4, and the TNM classification does not distinguish patients on the basis of the presence of inflammatory criteria. Evidence by our group and others suggests that patients with inflammatory breast cancer have significantly reduced overall survival among those who present with distant metastasis at diagnosis (stage 4). In light of these results, this Personal View addresses whether the current TNM staging classification accurately represents a distinction between patients with inflammatory and those with non-inflammatory breast cancer.

A 10-Year Experience with Mastectomy and Tissue Expander Placement to Facilitate Subsequent Radiation and Reconstruction.

BACKGROUND: An integrated approach to skin sparing mastectomy with tissue expander placement followed by radiotherapy and delayed reconstruction was initiated in our institution in 2002. The purpose of this study was to assess the surgical outcomes of this strategy. METHODS: Between September 2002 and August 2013, a total of 384 reconstructions had a tissue expander placed at the time of mastectomy and subsequently underwent radiotherapy. Rates and causes of tissue expander explantation before, during, and after radiotherapy, as well as tumor specific outcomes and reconstruction approaches, were collected. RESULTS: Median follow-up after diagnosis was 5.6 (range 1.3-13.4) years. In the study cohort, 364 patients (94.8%) had stage II-III breast cancer, and 7 patients (1.8%) had locally recurrent disease. The 5-year rates of actuarial locoregional control, disease-free survival, and overall survival were 99.2, 86.1, and 92.4%, respectively. The intended delayed-immediate reconstruction was subsequently completed in 325 of 384 mastectomies (84.6% of the study cohort). Of the remaining 59 tissue expanders, 1 was explanted before radiotherapy, 1 during radiotherapy, and 7 patients (1.8%) were lost to follow-up. Fifty patients (13.0%) required tissue expander explantation after radiation and before their planned final reconstruction, primarily due to cellulitis. Nonetheless, the cumulative rate of completed reconstructions was 89.6%. The median time from placement of the tissue expander until reconstruction was 12 (interquartile range 9-15) months. CONCLUSIONS: Tissue expander placement at skin-sparing mastectomy in patients who require radiotherapy appears to be a viable strategy for combining reconstruction and radiotherapy.

Longitudinal analysis of patient-reported outcomes and cosmesis in a randomized trial of conventionally fractionated versus hypofractionated whole-breast irradiation.

BACKGROUND: The authors compared longitudinal patient-reported outcomes and physician-rated cosmesis with conventionally fractionated whole-breast irradiation (CF-WBI) versus hypofractionated whole-breast irradiation (HF-WBI) within the context of a randomized trial. METHODS: From 2011 to 2014, a total of 287 women with American Joint Committee on Cancer stage 0 to stage II breast cancer were randomized to receive CF-WBI (at a dose of 50 grays in 25 fractions plus a tumor bed boost) or HF-WBI (at a dose of 42.56 grays in 16 fractions plus a tumor bed boost) after breast-conserving surgery. Patient-reported outcomes were assessed using the Breast Cancer Treatment Outcome Scale (BCTOS), the Functional Assessment of Cancer Therapy-Breast, and the Body Image Scale and were recorded at baseline and 0.5, 1, 2, and 3 years after radiotherapy. Physician-rated cosmesis was assessed at the same time points. Outcomes by treatment arm were compared at each time point using a 2-sided Student t test. Multivariable mixed effects growth curve models assessed the effects of treatment arm and time on longitudinal outcomes. RESULTS: Of the 287 patients enrolled, 149 were randomized to CF-WBI and 138 were randomized to HF-WBI. At 2 years, the Functional Assessment of Cancer Therapy-Breast Trial Outcome Index score was found to be modestly better in the HF-WBI arm (mean 79.6 vs 75.9 for CF-WBI; P = .02). In multivariable mixed effects models, treatment arm was not found to be associated with longitudinal outcomes after adjusting for time and baseline outcome measures (P≥.14). The linear effect of time was significant for BCTOS measures of functional status (P = .001, improved with time) and breast pain (P = .002, improved with time). CONCLUSIONS: In this randomized trial, longitudinal outcomes did not appear to differ by treatment arm. Patient-reported functional and pain outcomes improved over time. These findings are relevant when counseling patients regarding decisions concerning radiotherapy. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2886-2894. © 2016 American Cancer Society.

Nomograms for Predicting Axillary Response to Neoadjuvant Chemotherapy in Clinically Node-Positive Patients with Breast Cancer.

BACKGROUND: Many patients with clinically node-positive breast cancer receive neoadjuvant chemotherapy (NAC). Recent trials suggest the potential for limiting axillary surgery in patients who convert to pathologically node-negative disease. The authors developed a nomogram to predict axillary response to NAC in patients with cN1 disease that can assist clinicians in treatment planning. METHODS: Patients with cT1-4N1M0 breast cancer who received NAC and underwent axillary lymph node dissection from 2001 through 2013 were identified (n = 584). Uni- and multivariate logistic regression analyses were performed to determine factors predictive of nodal conversion. A nomogram to predict the likelihood of nodal pathologic complete response (pCR) was constructed based on clinicopathologic variables and validated using an external dataset. RESULTS: Axillary pCR was achieved for 217 patients (37 %). Patients presenting with high nuclear grade [grade 3 vs. 1, odds ratio (OR) 13.4], human epidermal growth factor receptor 2-positive (OR 4.7), estrogen receptor (ER)-negative (OR 3.5), or progesterone receptor-negative (OR 4.3) tumors were more likely to achieve nodal pCR. These factors, together with clinically relevant factors including presence of multifocal/centric disease, clinical T stage, and extent of nodal disease seen on regional nodal ultrasound at diagnosis were used to create nomograms predicting nodal conversion. The discrimination of the nomogram using ER+ status (>1 % staining) versus ER- status [area under the curve (AUC) 78 %] was improved slightly using the percentage of ER staining (AUC 78.7 %). Both nomograms were validated using an external cohort. CONCLUSION: Nomograms incorporating routine clinicopathologic parameters can predict axillary pCR in node-positive patients receiving NAC and may help to inform treatment decisions.

Prognosis for patients with metastatic breast cancer who achieve a no-evidence-of-disease status after systemic or local therapy.

BACKGROUND: This study sought to determine outcomes for patients with metastatic breast cancer (MBC) with no evidence of disease (NED) after treatment and to identify factors predictive of outcomes once the status of NED was attained. METHODS: This study reviewed 570 patients with MBC who were consecutively treated between January 2003 and December 2005. Ninety patients (16%) attained NED, which was defined as a complete metabolic response on positron emission tomography or sclerotic healing of bone metastases on computed tomography or magnetic resonance imaging. The median follow-up for patients attaining NED was 100 months (range, 14-134 months). RESULTS: The 3- and 5-year overall survival (OS) rates were 44% and 24%, respectively, for the entire group and 96% and 78%, respectively, for those attaining NED. According to a landmark analysis, NED status was significantly associated with survival at 2 (P < .001; hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34) and 3 years (P < .001; HR, 0.20; 95% CI, 0.14-0.30). From the time of NED, the median survival was 102 months (range, 14-134 months) with 5-year OS and progression-free survival (PFS) rates of 77% and 40%, respectively. According to a multivariate analysis, human epidermal growth factor receptor 2 positivity was significantly associated with OS in comparison with estrogen receptor positivity (P = .02; HR, 0.44; 95% CI, 0.21-0.90), and trastuzumab use was significantly associated with PFS (P = .007; HR, 0.48; 95% CI, 0.28-0.82). Thirty-one patients (34%) with NED remained in remission at the last follow-up. CONCLUSIONS: MBC patients who attain the status of NED have significantly prolonged survival with a durable response to therapy. Ultimately, this study provides essential outcome data for clinicians and patients living with MBC.

Radiation for inflammatory breast cancer: Updates.

Inflammatory breast cancer (IBC) is a diagnosis based on a constellation of clinical features of edema (peau d'orange) of a third or more of the skin of the breast with a palpable border and a rapid onset of breast erythema. Incidence of IBC has increased over time, although it still makes up only 1-4% of all breast cancer diagnoses. Despite recent encouraging data on clinical outcomes, the published local-regional control rates remain consistently lower than the rates for non-IBC. In this review, we focus on radiotherapy, provide a framework for multi-disciplinary care for IBC, describe local-regional treatment techniques for IBC; highlight new directions in the management of patients with metastatic IBC and offer an introduction to future directions regarding the optimal treatment and management of IBC.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation.

PURPOSE: Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. METHODS AND MATERIALS: We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. RESULTS: All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P = .004), breast pain (P = .004), and physician-reported cosmesis (P < .001). CONCLUSIONS: Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer.

PURPOSE: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRF-LI) signals preclinical lymphedema that precedes the development of volumetrically defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). METHODS AND MATERIALS: Patients with breast cancer planned for axillary dissection and RNI prospectively underwent perometry, NIRF-LI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey [LSIDS] and QuickDASH) at baseline, after surgery, and at 6, 12, and 18 months after radiation. Clinical lymphedema was defined as an arm volume increase ≥5% over baseline. Trends over time were assessed using analysis of variance testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. RESULTS: Sixty participants completed at least 2 sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a body mass index >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18 months. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all P < .05). Both dermal backflow and lymphedema were associated with QuickDASH score (P < .05). CONCLUSIONS: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRF-LI use to identify patients for early intervention trials after RNI.

Prospective, early longitudinal assessment of lymphedema-related quality of life among patients with locally advanced breast cancer: The foundation for building a patient-centered screening program.

BACKGROUND: We examined how breast cancer-related lymphedema (BCRL) affects health-related quality of life (HRQOL), productivity, and compliance with therapeutic interventions to guide structuring BCRL screening programs. METHODS: We prospectively followed consecutive breast cancer patients who underwent axillary lymph node dissection (ALND) with arm volume screening and measures assessing patient-reported health-related quality of life (HRQOL) and perceptions of BCRL care. Comparisons by BCRL status were made with Mann-Whitney U, Chi-square, Fisher's exact, or t tests. Trends over time from ALND were assessed with linear mixed-effects models. RESULTS: With a median follow-up of 8 months in 247 patients, 46% self-reported ever having BCRL, a proportion that increased over time. About 73% reported fear of BCRL, which was stable over time. Further in time from ALND, patients were more likely to report that BCRL screening reduced fear. Patient-reported BCRL was associated with higher soft tissue sensation intensity, biobehavioral, and resource concerns, absenteeism, and work/activity impairment. Objectively measured BCRL had fewer associations with outcomes. Most patients reported performing prevention exercises, but compliance decreased over time; patient-reported BCRL was not associated with exercise frequency. Fear of BCRL was positively associated with performing prevention exercises and using compressive garments. CONCLUSIONS: Both incidence and fear of BCRL were high after ALND for breast cancer. Fear was associated with improved therapeutic compliance, but compliance decreased over time. Patient-reported BCRL was more strongly associated with worse HRQOL and productivity than was objective BCRL. Screening programs must support patients' psychological needs and aim to sustain long-term compliance with recommended interventions.

Stereotactic radiosurgery for patients with recurrent intracranial ependymomas.

The objective of the study is to define the tumor control rate and complications associated with stereotactic radiosurgery (SRS) for patients with recurrent intracranial ependymoma. Retrospective review of 26 patients (49 tumors) having SRS between 1990 and 2008. Twenty-five patients (96 %) had undergone one or more craniotomies; one patient underwent SRS for a metastatic tumor after resection of a spinal ependymoma. Nineteen patients (73 %) had received cranial external beam radiotherapy (median dose, 54 Gy). Eight patients (31 %) were less than 18 years old. The median target volume was 2.2 cm(3) (range, 0.3-66.6); the median tumor margin dose was 18 Gy (range, 12-24). The median follow-up after SRS was 3.1 years (range, 3 months-13.1 years). The median overall survival after SRS was 5.5 years. The 1-year and 3-year survival rates were 96 and 69 %, respectively. Local tumor control (LC) was achieved in 33 of 49 lesions (67 %) with a median time to progression of 14.7 months (range, 2.9 months-11.2 years). The 1-year and 3-year progression-free survival rates were 80 and 66 %, respectively. The 1-year and 3-year LC rate was 85 and 72 %, respectively. On univariate analysis, higher tumor grade was associated with worse OS (grade 3-4, 27 % vs grade 2, 82 %, p = 0.04). Seven patients (27 %) had distant tumor progression and two patients (8 %) had symptomatic radiation necrosis after SRS. SRS for recurrent intracranial ependymoma provided good LC and may improve survival for patients with limited recurrent disease after prior treatment.

Locoregional Management and Prognostic Factors in Breast Cancer With Ipsilateral Internal Mammary and Axillary Lymph Node Involvement.

PURPOSE: Patients with breast cancer and ipsilateral axillary and internal mammary (IM) lymph node involvement (cN3b) often forgo IM node resection. Therefore, radiation is important for curative therapy. However, prognosis is not well described in the era of modern systemic therapy, and limited data exist to guide optimal locoregional treatment recommendations. METHODS AND MATERIALS: We retrospectively reviewed 117 patients with nonmetastatic cN3b breast cancer treated at our institution between 2014 and 2019. Staging included ultrasound evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy, resection of the breast primary, and axillary nodal dissection, followed by adjuvant radiation to the breast/chest wall and regional nodes. Institutional guidelines recommend a 10-Gy boost to radiographically resolved nodes, and a 16-Gy boost to unresolved nodes. Overall survival, recurrence-free survival (RFS), locoregional RFS, internal mammary RFS, and distant metastasis-free survival were evaluated with Kaplan-Meier analysis. A multivariable model for RFS was constructed. RESULTS: Median follow-up for 117 patients was 3.82 years. Median age at diagnosis was 46 years and 56 patients (48%) were receptor group ER+/HER2-. Mastectomy was performed in 96 patients (82%), 38 (32%) had biopsy-confirmed IMC involvement, and 8 (7%) had IM node dissection. The median initial radiation dose was 50 Gy (range, 50-55 Gy) and IMC boost 10 Gy (range, 0-16 Gy). The 5-year overall survival, IM RFS, locoregional RFS, distant metastasis-free survival, and RFS were 74%, 98%, 89%, 68%, and 67%, respectively. On multivariable analysis, a clinical complete response of the IM nodes or ypN0 (pathologic complete response of nodes) status had improved 5-year RFS with hazard ratios of 0.24 (P = .006) and 0.27 (P = .05), respectively. Extranodal extension or lymphovascular invasion were associated with worse 5-year RFS with hazard ratios of 4.13 (P = .001) and 2.25 (P = .04), respectively. CONCLUSIONS: Multimodality therapy provides excellent locoregional control of 89% at 5 years for patients with cN3b breast cancer. Adjuvant radiation yields a 5-year IM RFS of 98%. Clinical and pathologic response of IM nodes are independently prognostic for RFS.

Adoption of Ultrahypofractionated Radiation Therapy in Patients With Breast Cancer.

Introduction: The first high-quality clinical trial to support ultrahypofractionated whole-breast irradiation (ultra-HF-WBI) for invasive early-stage breast cancer (ESBC) was published in April 2020, coinciding with the beginning of the COVID-19 pandemic. We analyzed adoption of ultra-HF-WBI for ductal carcinoma in situ (DCIS) and ESBC at our institution after primary trial publication. Methods and Materials: We evaluated radiation fractionation prescriptions for all patients with DCIS or ESBC treated with WBI from March 2020 to May 2021 at our main campus and regional campuses. Demographic and clinical characteristics were extracted from the electronic medical record. Treating physician characteristics were collected from licensure data. Hierarchical logistic regression models identified factors correlated with adoption of ultra-HF-WBI (26 Gy in 5 daily factions [UK-FAST-FORWARD] or 28.5 Gy in 5 weekly fractions [UK-FAST]). Results: Of 665 included patients, the median age was 61.5 years, and 478 patients (71.9%) had invasive, hormone-receptor-positive breast cancer. Twenty-one physicians treated the included patients. In total, 249 patients (37.4%) received ultra-HF-WBI, increasing from 4.3% (2 of 46) in March-April 2020 to a high of 45.5% (45 of 99) in July-August 2020 (P < .001). Patient factors associated with increased use of ultra-HF-WBI included older age (≥50 years old), low-grade WBI without inclusion of the low axilla, no radiation boost, and farther travel distance (P < .03). Physician variation accounted for 21.7% of variance in the outcome, with rate of use of ultra-HF-WBI by the treating physicians ranging from 0% to 75.6%. No measured physician characteristics were associated with use of ultra-HF-WBI. Conclusions: Adoption of ultra-HF-WBI at our institution increased substantially after the publication of randomized evidence supporting its use. Ultra-HF-WBI was preferentially used in patients with lower risk disease, suggesting careful selection for this new approach while long-term data are maturing. Substantial physician-level variation may reflect a lack of consensus on the evidentiary standards required to change practice.

Outcomes After Breast Radiation Therapy in a Diverse Patient Cohort With a Germline BRCA1/2 Mutation.

PURPOSE: BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations. METHODS AND MATERIALS: This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status. RESULTS: Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively. CONCLUSIONS: Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation.

Breast Radiation Therapy-Related Treatment Outcomes in Patients With or Without Germline Mutations on Multigene Panel Testing.

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing. METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival, locoregional recurrence, disease-specific death, and radiation-related toxicities in 3 groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations. RESULTS: PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval, 3.8-4.9 years). No differences were found in overall survival, locoregional recurrence, or disease-specific death between groups (P > .1 for all). Acute and late toxicities were comparable across groups. CONCLUSION: Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated.

Excellent local control and survival after intraoperative and external beam radiotherapy for pediatric solid tumors: long-term follow-up of the Mayo Clinic experience.

Use of external beam radiotherapy (EBRT) for pediatric solid malignancies is generally limited by the tolerance of normal tissue in developing organs. Intraoperative electron radiotherapy (IOERT) allows a more focal delivery of radiation dose because vital organs can be displaced and avoided during treatment. From February 1983 to July 2003, 20 children underwent IOERT for treatment of locally advanced or recurrent malignancies of the extremity or abdominopelvic area. All patients underwent EBRT and received IOERT doses of 7.5 to 25 Gy with 6-MeV to 15-MeV electrons. At a median follow-up of 11.6 years (range, 2.1 to 25.5 y), 13 patients (65%) were alive and without evidence of disease. Patients who underwent gross total resection had better local control (88% vs. 67%) and survival (71% vs. 33%) than patients for whom the resection was not achieved. Among 7 patients, 11 grade 3 toxicity events were reported. No grade >3 toxicities or second malignancies were observed during follow-up. Use of IOERT in combination with surgery and EBRT in management of pediatric solid malignancies provides excellent local control with reasonable toxicity. IOERT should be considered as an integral part of a multimodality regimen for pediatric solid malignancies, especially for patients with abdominopelvic malignancies.

How should radiation be done for inflammatory breast cancer patients?-a narrative review of modern literature.

OBJECTIVE: This review highlights the considerations of the radiation oncologist when managing patients with inflammatory breast cancer (IBC) as well as the radiation oncologist's role as a member of the multi-disciplinary team. BACKGROUND: IBC makes up only 1-4% of all breast cancer diagnoses but incidence is increasing. IBC is diagnosed based on a constellation of clinical features, including the rapid onset of breast erythema and edema (peau d'orange) of one-third or more of the skin of the breast and with a palpable border to the edema. Most published IBC local-regional control rates are consistently lower than those observed in non-IBC, which the highlights the need for deliberate treatment techniques to maximize clinical outcomes. METHODS: For this narrative review, we discuss the principles of radiation target delineation and dose escalation; highlight new findings in the local-regional management of IBC; provide a critical evaluation of the recent literature evaluating local-regional treatment of IBC; and offer a brief introduction to possible future directions regarding the optimal treatment and management of IBC based on our institutional experience. CONCLUSIONS: IBC is an aggressive type of breast cancer that warrants multi-disciplinary care from breast surgical, medical, and radiation oncology. Several strategies exist to enhance the effect of radiation therapy (RT) on local-regional control, including hyperfractionation, use of bolus, increased total RT dose, and radiosensitizers, which are currently being tested in randomized trials. With an individualized patient approach, local-regional control rates are improving for IBC.

Proton Accelerated Partial Breast Irradiation: Clinical Outcomes at a Planned Interim Analysis of a Prospective Phase 2 Trial.

PURPOSE: To perform a planned interim analysis of acute (within 12 months) and late (after 12 months) toxicities and cosmetic outcomes after proton accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: A total of 100 patients with pTis or pT1-2 N0 (≤3cm) breast cancer status after segmental mastectomy were enrolled in a single-arm phase 2 study from 2010 to 2019. The clinically determined postlumpectomy target volume, including tumor bed surgical clips and operative-cavity soft-tissue changes seen on imaging plus a radial clinical expansion, was irradiated with passively scattered proton APBI (34 Gy in 10 fractions delivered twice daily with a minimum 6-hour interfraction interval). Patients were evaluated at protocol-specific time intervals for recurrence, physician reports of cosmetic outcomes and toxicities, and patient reports of cosmetic outcomes and satisfaction with the treatment or experience. RESULTS: Median follow-up was 24 months (interquartile range [IQR], 12-43 months). Local control and overall survival were 100% at 12 and 24 months. There were no acute or late toxicities of grade 3 or higher; no patients experienced fat necrosis, fibrosis, infection, or breast shrinkage. Excellent or good cosmesis at 12 months was reported by 91% of patients and 94% of physicians; at the most recent follow-up, these were 94% and 87%, respectively. The most commonly reported late cosmetic effect was telangiectasis (17%). The total patient satisfaction rate for treatment and results at 12 and 24 months was 96% and 100%, respectively. Patients' mean time away from work was 5 days (IQR, 2-5 days), and the median out-of-pocket cost was $700 (IQR, $100-$1600). The mean left-sided heart dose was 2 cGy (range, 0.2-75 cGy), and the mean ipsilateral lung dose was 19 cGy (range, 0.2-164 cGy). CONCLUSIONS: Proton APBI is a maturing treatment option with high local control, favorable intermediate-term cosmesis, high treatment satisfaction, low treatment burden, and exceptional heart and lung sparing.

Five-Year Longitudinal Analysis of Patient-Reported Outcomes and Cosmesis in a Randomized Trial of Conventionally Fractionated Versus Hypofractionated Whole-Breast Irradiation.

PURPOSE: There are limited prospective data on predictors of patient-reported outcomes (PROs) after whole-breast irradiation (WBI) plus a boost. We sought to characterize longitudinal PROs and cosmesis in a randomized trial comparing conventionally fractionated (CF) versus hypofractionated (HF) WBI. METHODS AND MATERIALS: From 2011 to 2014, women aged ≥40 years with Tis-T2 N0-N1a M0 breast cancer who underwent a lumpectomy with negative margins were randomized to CF-WBI (50 Gray [Gy]/25 fractions plus boost) versus HF-WBI (42.56 Gy/16 fractions plus boost). At baseline (pre-radiation), at 6 months, and yearly thereafter through 5 years, PROs included the Breast Cancer Treatment Outcome Scale (BCTOS), Functional Assessment of Cancer Therapy-Breast (FACT-B), and Body Image Scale; cosmesis was reported by the treating physician using Radiation Therapy Oncology Group cosmesis values. Multivariable mixed-effects growth curve models evaluated associations of the treatment arm and patient factors with outcomes and tested for relevant interactions with the treatment arm. RESULTS: A total of 287 patients were randomized, completing a total of 14,801 PRO assessments. The median age was 60 years, 37% of patients had a bra cup size ≥D, 44% were obese, and 30% received chemotherapy. Through 5 years, there were no significant differences in PROs or cosmesis by treatment arm. A bra cup size ≥D was associated with worse BCTOS cosmesis (P < .001), BCTOS pain (P = .001), FACT-B Trial Outcome Index (P = .03), FACT-B Emotional Well-being (P = .03), and Body Image Scale (P = .003) scores. Physician-rated cosmesis was worse in patients who were overweight (P = .02) or obese (P < .001). No patient subsets experienced better PROs or cosmesis with CF-WBI. CONCLUSIONS: Both CF-WBI and HF-WBI confer similar longitudinal PROs and physician-rated cosmesis through 5 years of follow-up, with no relevant subsets that fared better with CF-WBI. This evidence supports broad adoption of hypofractionation with boost, including in patients receiving chemotherapy and in a population with a high prevalence of obesity. The associations of large breast size and obesity with adverse outcomes across multiple domains highlight the opportunity to engage at-risk patients in lifestyle intervention strategies, as well as to consider alternative radiation treatment regimens.