PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemotherapy.

Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.

Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

Repeat sentinel lymph node surgery for locally recurrent breast cancer after prior mastectomy.

BACKGROUND AND OBJECTIVES: Current NCCN guidelines discourage repeat sentinel lymph node (SLN) surgery in patients with local recurrence (LR) of breast cancer following prior mastectomy. This study addresses the feasibility and therapeutic impact of this approach. METHODS: We identified 73 patients managed with repeat SLN surgery for post-mastectomy isolated LR. Lymphatic mapping was performed using radioisotope with or without lymphoscintigraphy and/or blue dye. Successful SLN surgery was defined as retrieval of ≥1 SLN. RESULTS: SLN surgery was successful in 65/73 (89%), identifying a median of 2 (range 1-4) SLNs, with 10/65 (15%) SLN-positive. Among these, 5/10 (50%) proceeded to ALND. In unsuccessful cases, 1/8 (13%) proceeded to ALND. Seven of 10 SLN-positive patients and 50/55 SLN-negative patients received adjuvant radiotherapy. Chemotherapy was administered in 31 (42%) and endocrine therapy in 50 of 57 HR+ patients (88%). After 28 months median follow-up, eight patients relapsed with the first site local in two, distant in five, and synchronous local/distant in one. No nodal recurrences were observed. CONCLUSIONS: SLN surgery for patients with LR post-mastectomy is feasible and informative. This approach appears oncologically sound, decreases axillary dissection rates and may be used to tailor adjuvant radiation target volumes and systemic therapies.

Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial.

BACKGROUND: Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25-28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. METHODS: We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov, NCT02783690, and is closed to accrual. FINDINGS: Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44-64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5-61·2). The median mean heart dose was 0·54 Gy (IQR 0·30-0·72) for the conventional fractionation group and 0·49 Gy (0·25-0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. INTERPRETATION: After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. FUNDING: The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute.

Clinical outcomes and prognostic factors in triple-negative invasive lobular carcinoma of the breast.

PURPOSE: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. METHODS: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. RESULTS: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p < 0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p = 0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p < 0.001). CONCLUSION: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

Surveillance mammography after treatment for male breast cancer.

PURPOSE: To identify the practice patterns related to use of surveillance mammography in male breast cancer (MaBC) survivors. METHODS: Using administrative claims data from OptumLabs Data Warehouse, we identified men who underwent surgery for breast cancer during 2007-2017. We calculated the proportion of men who had at least one mammogram (a) within 13 months for all patients and (b) within 24 months amongst those who maintained their insurance coverage for at least that length of time after surgery. Multivariate logistic regression modeling was used to identify factors associated with mammography within each timeframe. RESULTS: Out of 729 total MaBC survivors, 209 (29%) underwent mammography within 13 months after surgery. Among those who had lumpectomy, 41% underwent mammography, whereas among those who had mastectomy, 27% had mammography. Amongst 526 men who maintained consistent insurance coverage for 24 months after surgery, 215 (41%) underwent mammography at least once during that 24-month period. In this cohort, the proportion who had at least one mammogram during the 24-month period was 49% after lumpectomy and 40% after mastectomy. In a multivariate logistic regression model, more recent diagnosis (2015+) and older age at diagnosis were associated with lower odds of undergoing mammography, while receipt of radiation was associated with higher odds of undergoing mammography. CONCLUSIONS: Although recent ASCO guidelines recommend surveillance mammography after lumpectomy, a minority of MaBC survivors undergo surveillance mammography, even after lumpectomy. This is likely due to the paucity of data regarding the true benefits and harms of surveillance/screening mammography for MaBC.

Male breast cancer in the United States: Treatment patterns and prognostic factors in the 21st century.

BACKGROUND: Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. METHODS: Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan-Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. RESULTS: A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast-conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor-positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node-negative, estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy (P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor-positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. CONCLUSIONS: Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.

Carbon ion radiation therapy in breast cancer: a new frontier.

PURPOSE: Breast cancer is the most commonly diagnosed cancer in women, with many efforts aimed at reducing acute and late toxicity given the generally favorable clinical outcomes with the current standard of care. Carbon ion radiation therapy is an emerging technique that may reduce dose to adjacent organs at risk while allowing dose escalation to the target. Given the efficacy of the standard treatments for breast cancer, there have been few prospective studies to date investigating carbon ion radiation therapy in breast cancer. METHODS: PubMed/Medline, Ebsco, Cochrane, and Scopus were systematically reviewed using the search terms "carbon ion" and "breast" in November 2019. Out of the 76 articles screened, 26 articles were included. RESULTS: This comprehensive review describes the physical and biological properties of carbon ion radiation therapy, with an emphasis on how these properties can be applied in the setting of breast cancer. Studies investigating the role of carbon ion radiation therapy in early stage breast cancers are reviewed. Additionally, the use of carbon ion radiation therapy in locally advanced disease, recurrent disease, and radiation-induced angiosarcoma are discussed. CONCLUSION: Although the data is limited, the early clinical results are promising. Further clinical trials are needed, especially in the setting of locally advanced and recurrent disease, to fully define the potential role of carbon ion radiation therapy in the treatment of breast cancer.

A contemporary review of male breast cancer: current evidence and unanswered questions.

Male breast cancer is rare, accounting for 1% of all breast cancer diagnoses in the USA. Because of its rarity, most major breast cancer trials have included only female patients. This has resulted in limited prospective data to guide the clinical management of men with breast cancer. As a result, treatment decisions are typically extrapolated from data generated in female patients. This approach may be suboptimal, particularly considering the differing hormonal milieus between men and women with respect to both breast cancer development and treatment. Herein, we summarize current knowledge of the biology and clinicopathology of male breast cancer and review current approaches to locoregional and systemic management of this rare disease.

Patient-reported outcomes of catheter-based accelerated partial breast brachytherapy and whole breast irradiation, a single institution experience.

PURPOSE: Accelerated partial breast irradiation (APBI) and whole breast irradiation (WBI) are treatment options for early-stage breast cancer. The purpose of this study was to compare patient-reported-outcomes (PRO) between patients receiving multi-channel intra-cavitary brachytherapy APBI or WBI. METHODS: Between 2012 and 2015, 131 patients with ductal carcinoma in situ (DCIS) or early stage invasive breast cancer were treated with adjuvant APBI (64) or WBI (67) and participated in a PRO questionnaire. The linear analog scale assessment (LASA), harvard breast cosmesis scale (HBCS), PRO-common terminology criteria for adverse events- PRO (PRO-CTCAE), and breast cancer treatment outcome scale (BCTOS) were used to assess quality of life (QoL), pain, fatigue, aesthetic and functional status, and breast cosmesis. Comparisons of PROs were performed using t-tests, Wilcoxon rank-sum, Chi square, Fisher exact test, and regression methods. RESULTS: Median follow-up from completion of radiotherapy and questionnaire completion was 13.3 months. There was no significant difference in QoL, pain, or fatigue severity, as assessed by the LASA, between treatment groups (p > 0.05). No factors were found to be predictive of overall QoL on regression analysis. BCTOS health-related QoL scores were similar between treatment groups (p = 0.52).The majority of APBI and WBI patients reported excellent/good breast cosmesis, 88.5% versus 93.7% (p = 0.37). Skin color change (p = 0.011) and breast elevation (p = 0.01) relative to baseline were more common in the group receiving WBI. CONCLUSIONS: APBI and WBI were both associated with favorable patient-reported outcomes in early follow-up. APBI resulted in a lesser degree of patient-reported skin color change and breast elevation relative to baseline.

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immediate tissue expander or implant-based breast reconstruction does not compromise the oncologic delivery of post-mastectomy radiotherapy (PMRT).

PURPOSE: Increasingly, women are choosing immediate breast reconstruction (IBR) following mastectomy. Reports have indicated IBR may compromise post-mastectomy radiotherapy (PMRT). We investigated the impact of IBR on timing of PMRT, target coverage, and doses to organs at risk in a modern radiotherapy practice using advanced planning techniques. METHODS: Between 2013 and 2015, PMRT was delivered to 116 patients (66 mastectomy alone, 50 IBR). PMRT was delivered with a median dose of 50 Gy in 25 fractions. Left-sided patients were treated in breath-hold under image guidance. Differences in dosimetric parameters and time to the initiation of PMRT were assessed between patients with and without reconstruction. RESULTS: Reconstructed patients were younger and had lower clinical stage disease. Reconstruction did not significantly increase the mean time to PMRT initiation (51 days reconstructed vs. 45 days non-reconstructed, p = 0.14) or the number of patients who initiated PMRT within 12 weeks of the last therapeutic intervention (48/50 [96.0] vs. 61/66 [92.4%], p = 0.41). There was no significant difference in the percentage of patients in whom the internal mammary lymph nodes (IMNs) were targeted (72 vs. 80%, p = 0.29) or in IMN target coverage (mean IMN V40.5 Gy 92.6 vs. 94.1%, p = 0.62). Reconstruction did not significantly affect the mean ipsilateral lung V20 (25.4 vs. 26.4%, p = 0.37) or the mean heart dose (2.2 vs. 2.1 Gy, p = 0.63). CONCLUSIONS: In a specialized breast multidisciplinary practice, immediate breast reconstruction did not significantly delay PMRT, compromise target coverage, or increase dose to organs at risk.

Margin Proximity Correlates with Local Recurrence After Mastectomy for Patients Not Receiving Adjuvant Radiotherapy.

BACKGROUND: Although considerable evidence exists regarding margin status and reexcision for patients undergoing breast conservation therapy, few data address the impact of a close margin for patients undergoing mastectomy without postmastectomy radiotherapy. METHODS: This retrospective review identified 1147 patients who underwent 1206 mastectomies with negative final margins for breast cancer from 2006 to 2010. Margin distance was analyzed as a continuous variable and dichotomized variable ((≤2 vs >2 mm). Patients undergoing adjuvant radiation therapy were excluded from the study. Uni- and multivariable analyses were used to assess the association of reexcision, proximity of the final margin, adjuvant therapy, and other clinical and pathologic factors with local recurrence (LR). RESULTS: In 158 mastectomies (13.1%), a reexcision was performed for a close (n = 90) or positive (n = 68) margin. All but one were identified intraoperatively using frozen section analysis. The reexcision rates for skin- and nipple-sparing mastectomy (SSM/NSM) were higher than for simple mastectomy (SM) (19.8 vs 9.3%; p < 0.001). The overall 5-year risk for an LR was 3.8%. The risk was 3.1% for a margin greater than 2 mm and 11.2% for a margin of 2 mm or smaller. In the multivariable model, proximity of the final margin measured as a continuous variable was found to be a significant risk factor for LR (p = 0.009), whereas adjuvant endocrine therapy was found to be protective (p = 0.03). Intraoperative reexcision was not significant in the multivariable model (p = 0.23). CONCLUSIONS: For patients undergoing mastectomy for breast cancer, a wider final margin correlated with a reduced risk for LR. The rates for LR were similar between SSM/NSM and SM despite higher rates of intraoperative reexcision for SSM/NSM.

A Novel Treatment Schedule for Rapid Completion of Surgery and Radiation in Early-Stage Breast Cancer.

BACKGROUND: Data support the use of accelerated partial-breast irradiation (APBI) for early-stage breast cancer. We initiated a prospective protocol for intraoperative APBI catheter placement using a multi-lumen strut-based device. We hypothesized that with intraoperative pathology assessment of margins and sentinel nodes, all locoregional treatment (surgery and APBI) could be completed within 10 days with acceptable complication rates and cosmesis. METHODS: Eligible patients included women age 50 years or older with clinical T1 estrogen receptor positive (ER+) sentinel lymph node (SLN)-negative invasive ductal cancer or pure ductal carcinoma in situ. Patients were prospectively registered. Cosmesis was assessed using photographs graded independently by three investigators for patients with photos taken 6 months or longer after treatment. RESULTS: From October 2012 to August 2015, we enrolled 123 patients; 110 (90 %) underwent intraoperative catheter placement, whereas 13 did not due to intraoperative pathology findings. 109 APBI patients (99 %) completed their prescribed radiotherapy within 5 days, and all their locoregional therapy within 9 days, whereas one patient with a delayed positive SLN received only boost radiotherapy via catheter followed by conventional whole breast radiation. The 30-day complication rate was 6 %. In 81 patients with at least one-year followup, complications occurred in 14 (17 %) (including infection in five patients and symptomatic seroma in five patients) and correlated with device size (p = 0.05) but not with tumor size or location. The local recurrence rate was 1.8 % (two patients). Scored cosmesis was excellent or good in 88 % and fair in 12 % of patients. CONCLUSIONS: A protocol for intraoperative strut-based APBI catheter placement using careful patient selection and intraoperative pathology assessment can deliver efficient, effective treatment for early breast cancer.

Breast cancer after prophylactic mastectomy (bilateral or contralateral prophylactic mastectomy), a clinical entity: presentation, management, and outcomes.

Contralateral prophylactic mastectomy (CPM) and bilateral prophylactic mastectomy (BPM) markedly decrease the possibility of new breast cancer (BC) ipsilateral to the prophylactic mastectomy (PM). Given its relative infrequency, little is known about the clinical characteristics, presentation, and management of BC after PM. Between 1960 and 1993, 1065 women underwent BPM and 1643 women with unilateral BC treated with therapeutic mastectomy underwent CPM at our institution. Medical records were reviewed, and study-specific questionnaires were sent to all women. BC after PM included locoregional invasive BC or ductal carcinoma in situ ipsilateral to the PM. BC developed ipsilateral to the PM in 25 patients (13 after BPM; 12 after therapeutic mastectomy and CPM). Median follow-up after PM was 22 years (range 3-34 years). Presentations included clinically isolated local disease in 17 patients (68%); disease limited to the axilla without evidence of local primary disease in 4 (16%); synchronous local and axillary disease in 1 (4%); and synchronous local disease and distant metastases in 3 (12%). The 17 patients presenting with isolated local disease were most commonly managed with completion or redo mastectomy (65%) or local excision (29 %), followed by consideration of adjuvant therapy. The 5-year disease-free survival estimate was 69% (95% CI 52-94%) for the 22 patients who had isolated locoregional BC after PM and were treated with curative intent. Although rare, BC after PM can occur. The most common presentation, disease localized to the mastectomy site, can be managed with resection and consideration of adjuvant therapy.

Physician- and Patient-Reported Outcomes of the MC1635 Phase 3 Trial of Ultrahypofractionated Versus Moderately Hypofractionated Adjuvant Radiation Therapy After Breast-Conserving Surgery.

PURPOSE: Our aim was to report physician- and patient-reported outcomes of patients with localized breast cancer treated with moderate versus ultrahypofractionated whole breast irradiation (WBI) after breast-conserving surgery (BCS). METHODS AND MATERIALS: Between February 2018 and February 2020, patients with localized breast cancer (pT0-3 pN0-1 M0) were offered participation in a phase 3 randomized clinical trial assessing adjuvant moderate hypofractionation (MHF) to 40 Gy in 15 fractions versus ultrahypofractionation (UHF) to 25 Gy in 5 fractions after BCS, with an optional simultaneously integrated boost. Toxicities, cosmesis, and quality of life were assessed at baseline, end of treatment (EOT), and 3 months, 1 year, 2 years, and 3 years from irradiation using validated metric tools. RESULTS: One hundred seven patients were randomized to MHF (n = 54) or UHF (n = 53) adjuvant WBI. The median follow-up was 42.8 months. Grade 2 radiation dermatitis was experienced by 4 patients (7.4%) in the MHF arm and 2 patients (3.7%) in the UHF arm at EOT (P = .726). No grade 3 or higher toxicities were observed. Deterioration of cosmesis by physician assessment was observed in 2 (6.7%) patients treated in the UHF arm and 1 (1.9%) patient treated in the MHF arm at EOT (P = .534), whereas at 3 months, only 1 (1.8%) patient treated in the MHF arm demonstrated deterioration of cosmesis (P = .315). At EOT, 91% and 94% of patients reported excellent/good cosmesis among those treated with MHF and UHF regimens, respectively (P = .550). At 3 months, more patients within the MHF arm reported excellent/good cosmesis compared with those in the UHF arm (100% vs 91%; P = .030). However, the difference in patient-reported cosmesis disappeared at the 1-, 2-, and 3-year time points. CONCLUSIONS: UHF WBI showed similar treatment-related late toxicities and similar provider-scored cosmesis compared with MHF radiation in patients treated adjuvantly after BCS.

Validation of Patient-Reported Outcomes in Patients With Nonmetastatic Breast Cancer Receiving Comprehensive Nodal Irradiation in the RadComp Trial.

PURPOSE: Our purpose was to evaluate the measurement properties of patient-reported outcome (PRO) measures used in the ongoing RadComp pragmatic randomized clinical trial (PRCT). METHODS AND MATERIALS: The deidentified and blinded data set included 774 English-speaking female participants who completed their 6-month posttreatment assessment. Eleven PRO measures were evaluated, including the Trial Outcome Index from the Functional Assessment of Cancer Therapy-Breast (FACT-B), Satisfaction with Breast Cosmetic Outcomes, the BREAST-Q, and selected Patient-Reported Outcomes Measurement Information System (PROMIS) measures. PROs were measured at 3 timepoints: baseline, completion of radiation therapy (RT), and 6 months post-RT. Ten variables were used as validity anchors. Pearson or Spearman correlations were calculated between PROs and convergent validity indicators. Mean PRO differences between clinically distinct categories were compared with analysis of variance methods (known-groups validity). PRO change scores were mapped to change in other variables (sensitivity to change). RESULTS: Most correlations between PROs and validity indicators were large (≥0.5). Mean score for Satisfaction with Breast Cosmetic Outcomes was higher (better) for those with a lumpectomy compared with those with a mastectomy (P < .001). Mean scores for the FACT-B Trial Outcome Index and for PROMIS Fatigue and Ability to Participate in Social Roles and Activities were better for those with good baseline performance status compared with those with poorer baseline performance status (P < .05). At completion of RT and post-RT, mean scores for Satisfaction with Breast Cosmetic Outcomes and BREAST-Q Radiation were significantly different (P < .001) across categories for all Functional Assessment of Chronic Illness Therapy -Treatment Satisfaction - General items. There were medium-sized correlations between change scores for FACT-B Trial Outcome Index, Fatigue, Anxiety, and Ability to Participate in Social Roles and change scores in the Visual Analog Scale. CONCLUSIONS: For patients with nonmetastatic breast cancer receiving radiation in the RadComp PRCT, our findings demonstrate high reliability and validity for important PRO measures, supporting their psychometric strength and usefulness to reflect the effect of RT on health-related quality of life.

Secondary breast angiosarcoma following accelerated partial breast irradiation with intracavitary multicatheter applicator brachytherapy.

PURPOSE: Secondary angiosarcoma of the breast is a rare complication of breast radiotherapy and is associated with a poor prognosis. There are many reported cases of secondary angiosarcoma following whole breast irradiation (WBI), however development of secondary angiosarcoma following brachytherapy-based accelerated partial breast irradiation (APBI) is not as well characterized. METHODS AND MATERIALS: We reviewed and reported a case of a patient who developed secondary angiosarcoma of the breast following intracavitary multicatheter applicator brachytherapy APBI. RESULTS: A 69-year-old female was originally diagnosed with T1N0M0 invasive ductal carcinoma of the left breast and treated with lumpectomy followed by adjuvant intracavitary multicatheter applicator brachytherapy APBI. Seven years following her treatment, she developed secondary angiosarcoma. However, the diagnosis of secondary angiosarcoma was delayed due to nonspecific imaging findings and a negative biopsy. CONCLUSIONS: Our case highlights the need for secondary angiosarcoma to be considered in the differential diagnosis when patients present with symptoms such as breast ecchymosis and skin thickening following WBI or APBI. Prompt diagnosis and referral to a high-volume sarcoma treatment center for multidisciplinary evaluation is vital.

Study of linear energy transfer effect on rib fracture in breast patients receiving pencil-beamscanning proton therapy.

Purpose: To study the effect of proton linear energy transfer (LET) on rib fracture in breast cancer patients treated with pencil-beam scanning proton therapy (PBS) using a novel tool of dose-LET volume histogram (DLVH). Methods: From a prospective registry of patients treated with post-mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients that did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year.The DLVH index, V(d, l), defined as volume(V) of the structure with at least dose(d) and LET(l), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V(d, l) and the observed fracture at each combination of d and l. The p-value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p-value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results: Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5 to 14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p-value map demonstrated larger V(0-36Gy[RBE], 4.0-5.0 keV/µm) in patients experiencing fracture (p<0.1). For example, the p value for V(30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusions: In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LET may result in increased risk of rib fracture.