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PURPOSE To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS Patients with newly diagnosed BC and BRCA1/ 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/ 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/ 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/ 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines .

We queried the National Cancer Database for nonmetastatic breast angiosarcoma, yielding 808 patients (202 de novo, 606 secondary). The median survival was 53.7 months. Secondary tumors were more likely to undergo mastectomy than de novo lesions (OR = 3.99, P 0.001). Treatments included lumpectomy (10%), lumpectomy/radiation (3%), mastectomy alone (73%), or mastectomy/radiation (14%), with no difference in survival (P = 0.68). Lumpectomy correlated with positive margin rate (OR 3.29), which was a predictor for death (HR = 2.37, P 0.01), along with older age, higher comorbidity scores, size5 cm, and high-grade disease (P 0.05). While breast angiosarcoma is usually treated with mastectomy, lumpectomy may be feasible for well-selected tumors.

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis., Graphical Abstract, Permanent salivary hypofunction is a major complication due to irradiation therapy in head and neck cancer patients. Lombaert et al. present a key translational advance where retro-ductal infusion of an adeno-associated virus serotype 2 (AAV2) vector expressing neurotrophic factor neurturin (CERE-120) into mouse and porcine salivary glands before irradiation reduces fibrosis, restores immune homeostasis, and prevents loss of saliva.

Purpose To develop a summary of recommendations regarding locoregional management of patients with breast cancer and germline mutations in breast cancer susceptibility genes based on the American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology Guideline on Management of Hereditary Breast Cancer. Methods The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an expert panel to develop recommendations based on a systematic review of the literature and a formal consensus process. A total of 58 articles met the eligibility criteria and formed the evidentiary basis for the locoregional therapy recommendations. Additionally, 6 randomized controlled trials of systemic therapy also met eligibility criteria. Results A joint evidence-based guideline was developed by a multidisciplinary panel, which has been separately published. From this guideline, the radiation-oncologist authors of the panel extracted pertinent surgical and radiation-specific recommendations of findings that are hereby presented. Conclusions Patients with newly diagnosed breast cancer and BRCA1/2 mutations may be considered for breast conserving therapy (BCT), expecting similar rates of local control of the index cancer as noncarriers. The significant risk of contralateral breast cancer in these women (especially younger women), coupled with the higher risk of new cancers in the ipsilateral breast, warrant discussion of bilateral mastectomy. For women with mutations in BRCA1/2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or contralateral breast cancer events from radiation exposure in BRCA1/2 carriers. Patients with mutations in moderate-risk genes should be offered BCT as one choice after appropriate counseling. Radiation therapy should not be withheld in ATM carriers if BCT is planned. For patients with germline TP53 mutations, mastectomy is advised and radiation therapy is contraindicated except for those with a significant risk of locoregional recurrence.

PURPOSE: Surgical excision of keloids can result in an insidious cycle of tissue injury and repeat keloid formation unless combined with adjuvant therapy to halt this cycle. We present our results of postoperative radiation therapy for keloids with various dose regimens. METHODS AND MATERIALS: A retrospective review of 124 patients with 250 keloid lesions treated with postoperative radiation therapy was analyzed. In this institutional review board—approved study, 125 keloids were treated to 20 Gy in 5 fractions and 125 keloids were treated to 12 to 16 Gy in 3 to 4 fractions. Local failure was defined as redevelopment of any clinically apparent keloid at the treated site. The median age was 34 years (14-84 years). Keloids were located on the ear (34%), neck/shoulder (19%), abdomen (13%), chest (10%), face (9%), breast (7%), extremities (4%), and back (3%). Median keloid size was 4 cm (0.5-20 cm). RESULTS: At a median follow-up of 40 months, the recurrence rate for all lesions was 5.6%. Lesions treated to 20 Gy had a recurrence rate of 1.6% compared with 9.6% with 60 (20 Gy in 5 fractions) yielded superior local control over lower dose regimens.

Purpose: The goal of this ongoing project is to develop and integrate a comprehensive electronic health record (EHR) throughout a multi-facility radiation oncology network to facilitate more efficient workflow and improve overall patient care and safety. Methodology: We required that the EHR provide pre-defined record and verify capability for radiation treatment while still providing a robust clinical health record. In 1996, we began to integrate the Local Area Network Treatment Information System (LANTIS®) across the West Penn Allegheny Radiation Oncology Network (currently including 9 sites). By 2001, we began modifying and expanding the assessment components and creating user-defined templates and have developed a comprehensive electronic health record across our network. Results: In addition to access to the technical record and verify information and imaging obtained for image-guided therapy, we designed and customized 6 modules according to our networks needs to facilitate information acquisition, tracking, and analysis as follows: 1) Demographics/scheduling; 2) Charge codes; 3) Transcription/clinical documents; 4) Clinical/technical assessments; 5) Physician orders 6) Quality assurance pathways. Each module was developed to acquire specific technical/clinical data prospectively in an efficient manner by various staff within the department in a format that facilitates data queries for outcomes/statistical analyses and promotes standardized quality guidelines resulting in a more efficient workflow and improved patient safety and care. Conclusions: Development of a comprehensive EHR across a radiation oncology network is feasible and can be customized to promote clinical/technical standards, facilitate outcomes studies, and improve communication and peer review. The EHR has improved patient care and network integration across a multi-facility radiation oncology system and has markedly reduced the flow and storage of paper across the network.

Rationale Xerostomia is a common side effect of ionizing radiation used to treat head and neck cancer. A groundbreaking Phase I human clinical trial utilizing Adenoviral gene transfer of Aquaporin-1 (AQP1) to a single salivary gland of individuals suffering from radiation-induced xerostomia has recently been reported. Unfortunately, the limitations of the Adenoviral vector system utilized in this pioneering trial preclude its advancement to a Phase II trial and we have thus undertaken to evaluate the therapeutic potential of ultrasound-assisted non-viral gene transfer (UAGT) as an alternative means of delivering AQP1 gene therapy to the salivary gland by comparing head-to-head with the canonical Adenoviral vector in a swine model. Findings Swine irradiated unilaterally with a 10Gy electron beam targeted at the parotid gland suffered from significant, sustained hyposalivation that was bilateral, despite irradiation being confined to the targeted gland. Unilateral AQP1 gene therapy with UAGT resulted in bilateral restoration of stimulated salivary flow at 48 hours and one week post-treatment (1.62+/−0.48ml, 1.87+/−0.45ml) to pre-injury levels (1.34+/−0.14ml) in a manner comparable to Adenoviral delivery (2.32+/−0.6ml, 1.33+/−0.97ml). Conclusions UAGT can replace the Adenoviral vector as a means of delivering AQP1 gene therapy in the irradiated swine model and is a candidate for advancement to a Phase I human clinical trial.

An objective method was proposed and compared with a manual selection method to determine planner-independent skin and rib maximal dose in balloon-based high dose rate (HDR) brachytherapy planning.The maximal dose to skin and rib was objectively extracted from a dose volume histogram (DVH) of skin and rib volumes. A virtual skin volume was produced by expanding the skin surface in three dimensions (3D) external to the breast with a certain thickness in the planning computed tomography (CT) images. Therefore, the maximal dose to this volume occurs on the skin surface the same with a conventional manual selection method. The rib was also delineated in the planning CT images and its maximal dose was extracted from its DVH. The absolute (Abdiff = [D(max) Man - D (max)DVH]) and relative (Rediff[%] = 100 x ([D(max)Man-D(max)DVH])/D(max)DVH) maximal skin and rib dose differences between the manual selection method (D(max)Man) and the objective method (D(max)DVH) were measured for 50 balloon-based HDR (25 MammoSite and 25 Contura) patients.The average +/- standard deviation of maximal dose difference was 1.67% +/- 1.69% of the prescribed dose (PD). No statistical difference was observed between MammoSite and Contura patients for both Abdiff and Rediff[%] values. However, a statistically significant difference (p value0.0001) was observed in maximal rib dose difference compared with maximal skin dose difference for both Abdiff (2.30% +/- 1.71% vs 1.05% +/- 1.43%) and Rediff[%] (2.32% +/- 1.79% vs 1.21% +/- 1.41%). In general, rib has a more irregular contour and it is more proximally located to the balloon for 50 HDR patients. Due to the inverse square law factor, more dose difference was observed in higher dose range (D(max)90%) compared with lower dose range (D(max)90%): 2.16% +/- 1.93% vs 1.19% +/- 1.25% with p value of 0.0049. However, the Rediff[%] analysis eliminated the inverse square factor and there was no statistically significant difference (p value = 0.8931) between high and low dose ranges.The objective method using volumetric information of skin and rib can determine the planner-independent maximal dose compared with the manual selection method. However, the difference was2% of PD, on average, if appropriate attention is paid to selecting a manual dose point in 3D planning CT images.

A dosimetric comparison was performed on external-beam three-dimensional conformal partial breast irradiation (PBI) and whole breast irradiation (WBI) plans for patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 protocol at our institution. Twenty-four consecutive patients were treated with either PBI (12 patients) or WBI (12 patients). In the PBI arm, the lumpectomy cavity was treated to a total dose of 38.5 Gy at 3.85 Gy per fraction twice daily using a four-field noncoplanar beam setup. A minimum 6 h interval was required between fractions. In the WBI arm, the whole breast including the entirety of the lumpectomy cavity was treated to a total dose of 50.4 Gy at 1.8 Gy per fraction daily using opposed tangential beams. The lumpectomy cavity volume, planning target volume for evaluation (PTV_EVAL), and critical structure volumes were contoured for both the PBI and WBI patients. Dosimetric parameters, dose volume histograms (DVHs), and generalized equivalent uniform dose (gEUD) for target and critical structures were compared. Dosimetric results show the PBI plans, compared to the WBI plans, have smaller hot spots in the PTV_EVAL (maximum dose: 104.2% versus 110.9%) and reduced dose to the ipsilateral breast (V50: 48.6% versus 92.1% and V100: 10.2% versus 50.5%), contralateral breast (V3: 0.16% versus 2.04%), ipsilateral lung (V30: 5.8% versus 12.7%), and thyroid (maximum dose: 0.5% versus 2.0%) with p valuesor = 0.01. However, similar dose coverage of the PTV_EVAL (98% for PBI and 99% for WBI, on average) was observed and the dose difference for other critical structures was clinically insignificant in both arms. The gEUD data analysis showed the reduction of dose to the ipsilateral breast and lung, contralateral breast and thyroid. In addition, preliminary dermatologic adverse event assessment data suggested reduced skin toxicity for patients treated with the PBI technique.