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As the use of breast reconstruction and postmastectomy radiotherapy (PMRT) has increased over the past decade, the typical approach to integrating radiotherapy with breast reconstruction has provoked intense controversy in the management of breast cancer. PMRT can lead to an increased frequency of complications in the reconstructed breast. Conversely, the reconstructed breast can increase the complexity of radiotherapy delivery. How to minimise the frequency of complications without compromising oncological or cosmetic outcomes of the reconstructed breast is an important shared multidisciplinary goal for oncologists and their patients. Several questions remain, however, regarding the type of reconstruction that should be used with PMRT, when reconstruction should be done relative to PMRT and whether radiotherapy treatment should be directed towards the tissue expander or the implant for women who opt for a two-stage expander–implant reconstruction. Following advances in the planning of radiotherapy treatment, new questions about the application of these technologies in the setting of breast reconstruction have arisen. In this Review, we address these questions by reviewing contemporary evidence on the optimal integration of radiotherapy and breast reconstruction in the management of breast cancer.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS–STING-mediated signalling and tumour suppression 1 – 3 . However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA) 4 – 10 . Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11–RAD50–NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1–RIPK3–MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis. The double-strand break sensor MRE11 is identified as a pivotal mediator of cGAS activation in response to multiple types of DNA damage.

In this issue of the Journal , Kunkler and colleagues 1 report the highly anticipated 10-year results of the PRIME II trial, which show that omission of radiotherapy did not affect survival after breast-conserving surgery in women 65 years of age or older with T1 or T2 (tumors ≤3 cm in the largest dimension), node-negative, estrogen receptor (ER)–positive breast cancer. These data offer a response to the long-standing problem of overtreatment in older women with low-risk breast cancer. 2 The ability to omit radiotherapy is one of many options in a lengthy list that also includes the use of abbreviated radiotherapy regimens and . . .

Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients' race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.

Purpose Immune checkpoint inhibition (ICI) has demonstrated clinically significant efficacy when combined with chemotherapy in triple negative breast cancer (TNBC). Although many patients derived benefit, others do not respond to immunotherapy, therefore relying upon innovative combinations to enhance response. Local therapies such as radiation therapy (RT) and cryotherapy are immunogenic and potentially optimize responses to immunotherapy. Strategies combining these therapies and ICI are actively under investigation. This review will describe the rationale for combining ICI with targeted local therapies in breast cancer. Methods A literature search was performed to identify pre-clinical and clinical studies assessing ICI combined with RT or cryotherapy published as of August 2021 using PubMed and ClinicalTrials.gov. Results Published studies of ICI with RT and IPI have demonstrated safety and signals of early efficacy. Conclusion RT and cryotherapy are local therapies that can be integrated safely with ICI and has shown promise in early trials. Randomized phase II studies testing both of these approaches, such as P-RAD (NCT04443348) and ipilimumab/nivolumab/cryoablation for TNBC (NCT03546686) are current enrolling. The results of these studies are paramount as they will provide long term data on the safety and efficacy of these regimens.

Background Conflicting data exist regarding optimum local therapy for early-stage triple-negative breast cancer (TNBC). We examined outcomes according to local treatment type in a large cohort of node-negative TNBC patients. Methods A total of 1,242 consecutive patients with TNBC treated at a single institution from 1999 to 2008 were identified. Of these, 646 with pathologic stage T1-2N0 TNBC underwent breast-conserving therapy (BCT) ( N  = 448) or total mastectomy (TM) without postmastectomy radiation ( N  = 198) and comprised the study population. Locoregional recurrence (LRR), distant metastasis (DM), and overall recurrence were investigated with a competing risk analysis using Gray’s test and multivariable Fine and Gray competing risk regression. Overall survival was assessed using standard Kaplan–Meier methods and a Cox proportional hazards analysis. Results Median follow-up was 78.3 months (range 1–156). Eight-one percent of patients received adjuvant chemotherapy. TM patients were younger, were more likely to have lymphovascular invasion, and had larger tumors than patients undergoing BCT (all P  ≤ 0.05). The 5-year cumulative incidence of LRR was 4.2 and 5.4 % for patients undergoing BCT and TM, respectively. There was no significant difference in LRR, DM, overall recurrence, disease free survival, or overall survival between groups on univariate analysis, or after adjusting for other variables in multivariate models. Lack of chemotherapy and high tumor stage independently predicted for decreased overall survival (both P  < 0.001). Conclusions A low, 5-year risk of LRR (4.7 %) was achieved in a large group of women with T1-2N0 TNBC treated with multimodality therapy. BCT was as equally effective as TM for local and distant control.

Background Despite dosimetric benefits of volumetric modulated arc therapy (VMAT) in breast cancer patients with implant reconstruction receiving regional nodal irradiation (RNI), low dose to the thoracic structures remains a concern. Our goal was to report dosimetric effects of adding deep inspiration breath hold (DIBH) to VMAT in left-sided breast cancer patients with tissue expander (TE)/permanent implant (PI) reconstruction receiving RNI. Methods Ten consecutive breast cancer patients with unilateral or bilateral TE/PI reconstruction who were treated with a combination of VMAT and DIBH to the left reconstructed chest wall and regional nodes were prospectively identified. Free breathing (FB) and DIBH CT scans were acquired for each patient. VMAT plans for the same arc geometry were compared for FB versus DIBH. Prescription dose was 50 Gy in 25 fractions. Dosimetric differences were tested for statistical significance. Results For comparable coverage and target dose homogeneity, the mean dose to the heart reduced on average by 2.9 Gy (8.2 to 5.3 Gy), with the addition of DIBH ( p  < 0.05). The maximum dose to the left anterior descending (LAD) artery was reduced by 9.9 Gy ( p  < 0.05), which related closely to the reduction in the maximum heart dose (9.4 Gy). V05 Gy to the heart, ipsilateral lung, contralateral lung and total lung ( p  < 0.05) decreased on average by 29.6%, 5.8%, 15.4% and 10.8% respectively. No significant differences were seen in the ipsilateral lung V20 Gy or mean dose as well as in the mean contralateral breast/implant dose. However, V04 Gy and V03 Gy of the contralateral breast/implant were respectively reduced by 13.2% and 18.3% using DIBH ( p  < 0.05). Conclusion Combination of VMAT and DIBH showed significant dosimetric gains for low dose to the heart, lungs and contralateral breast/implant. Not surprisingly, the mean and maximum dose to the heart and to the LAD were also reduced. DIBH should be considered with the use of VMAT in breast cancer patients with implant reconstructions receiving RNI.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Study Objectives: While neck circumference (NC) is a useful predictor of obstructive sleep apnea (OSA) in adults, childhood OSA is difficult to predict clinically. We utilized the neck circumference-height ratio (NHR) to normalize NC in growing children. Our study aimed to determine if (1) NC is a reproducible clinical measurement; (2) NHR predicts OSA in children; (3) this metric translates to adults. Methods: For this retrospective study, paired NC measurements (from clinic and sleep laboratory) in 100 consecutive adult subjects were used to confirm inter-observer reproducibility. Polysomnographic (PSG) and anthropometric data from children aged 5–18 years presenting consecutively between July 2007 and February 2012 was obtained. Children with genetic syndromes, severe neurological disorders, craniofacial abnormalities, tracheostomy, past adenotonsillectomy, in-hospital PSG or sleep efficiency < 80% were excluded. Data were analyzed using χ 2 test and logistic and linear regression models. These analyses were also applied to 99 adult patients with similar exclusion criteria. Results: Adult NC measurement had inter-observer correlation of 0.85 (N = 100). Among children, after correcting for BMI-Z scores, NHR conferred additional predictive value, in both logistic regression and linear models, for both apnea-hypopnea index (AHI) > 2 and > 5 (N = 507). In children, for NHR > 0.25, the odds ratio of AHI > 2 was 3.47. In adults, for NHR > 0.25, the odds ratio of AHI > 5 was 18. Conclusions: NHR can be included as a simple screening tool for OSA in children and adults, which along with other predictors, may improve the ability of clinicians to triage children and adults at risk for OSA for further evaluation with PSG. Citation: Ho AW, Moul DE, Krishna J. Neck circumference-height ratio as a predictor of sleep related breathing disorder in children and adults. J Clin Sleep Med 2016;12(3):311–317.

Purpose Patients undergoing external beam accelerated partial breast irradiation (APBI) receive permanent tattoos to aid with daily setup alignment and verification. With the advent of three‐dimensional (3D) body surface imaging and two‐dimensional (2D) x‐ray imaging‐based matching to surgical clips, tattoos may not be necessary to ensure setup accuracy. We compared the accuracy of conventional tattoo‐based setups to a patient setup without tattoos. Materials/methods Twenty consecutive patients receiving APBI at our institution from July 10, 2017 to February 13, 2018 were identified. All patients received tattoos per standard of care. Ten patients underwent setup using tattoos for initial positioning followed by surface imaging and 2D matching of surgical clips. The other ten patients underwent positioning using surface imaging followed by 2D matching without reference to tattoos. Overall setup time and orthogonal x‐ray‐based shifts after surface imaging per fraction were recorded. Shift data were used to calculate systematic and random error. Results Among ten patients in the “no tattoo” group, the average setup time per fraction was 6.83 min vs 8.03 min in the tattoo cohort (P < 0.01). Mean 3D vector shifts for patients in the “no tattoo” group were 4.6 vs 5.9 mm in the “tattoo” cohort (P = NS). Mean systematic errors in the “no tattoo” group were: 1.2 mm (1.5 mm SD) superior/inferior, 0.5 mm (1.6 mm SD) right/left, and 2.3 mm (1.9 mm SD) anterior/posterior directions. Mean systematic errors in the “tattoo” group were: 0.8 mm (2.2 mm SD) superior/inferior, 0.3 mm (2.5 mm SD) right/left, and 1.4 mm (4.4 mm SD) anterior/posterior directions. The random errors in the “no tattoo” group ranged from 0.6 to 0.7 mm vs 1.2 to 1.7 mm in the “tattoo” group. Conclusions Using both surface imaging and 2D matching to surgical clips provides excellent accuracy in APBI patient alignment and setup verification with reduced setup time relative to the tattoo cohort. Skin‐based tattoos may no longer be warranted for patients receiving external beam APBI.