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Background: Pharmacy board certification provides pharmacists with formal recognition of their careers and their involvement in direct and comprehensive patient care. Credentialing as a board-certified pharmacist demonstrates that the pharmacist has specialized expertise and is able to provide advanced level patient care in a specific pharmacy practice specialty. There is currently not a community pharmacy board certification available in the United States. With the expanding role and clinical expectations of community pharmacists nationwide, perspectives regarding the utility of a community pharmacy specialty board certification are necessary. Methods: A cross-sectional survey with demographic and perception questions (5-point Likert scale) was distributed electronically via Qualtrics. A random sample of pharmacists registered in Rhode Island, Ohio, and Nebraska were selected and surveyed. Results: 53 survey responses were collected. There was a statistically significant difference in board certification history ( P = .001) and history of post-graduate training ( P < .001) between community pharmacists and non-community pharmacists. Community pharmacists were more likely to simultaneously see community pharmacists as general practitioners ( P = .030) and as pharmacy practice specialists ( P = .001). Non-community pharmacists were more likely to be familiar with current maintenance requirements for pharmacy board certifications ( P < .001) and to feel that a board certification is an appropriate indicator of experience in a pharmacy specialty area ( P = .016). Conclusion: Views regarding community pharmacy and board certification differed between community and non-community pharmacists. There was not a statistically significant difference in the perceived value of community pharmacy board certification between community and non-community pharmacist., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Contrast-enhanced breast MRI has an established role in aiding in the detection, evaluation, and management of breast cancer. This article discusses MRI sequences, the clinical utility of MRI, and how MRI has been evaluated for use in breast radiotherapy treatment planning. We highlight the contribution of MRI in the decision-making regarding selecting appropriate candidates for breast conservation therapy and review the emerging role of MRI-guided breast radiotherapy.

Purpose: Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer., Methods and Materials: This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival., Results: From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib., Conclusions: The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution., Methods: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses., Results: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated., Conclusions: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.

Purpose: Breast cancer-related lymphedema (BCRL) is a treatment complication that significantly reduces patient quality of life. Regional nodal irradiation (RNI) may increase the risk of BCRL. Recently, a region of the axilla known as the axillary-lateral thoracic vessel juncture (ALTJ) was identified as a potential organ at risk (OAR). Here, we set out to validate whether radiation dose to the ALTJ is associated with BCRL., Methods and Materials: We identified patients with stage II-III breast cancer treated with adjuvant RNI from 2013 to 2018, excluding those with BCRL preradiation. We defined BCRL as difference in arm circumference between the ipsilateral and contralateral limb >2.5 cm at any 1 encounter or ≥2 cm on ≥2 visits. All patients suspected of having BCRL at routine follow-up visits were referred to physical therapy for confirmation. The ALTJ was retrospectively contoured and dose metrics were collected. Cox proportional hazards regression models were used to test the association between clinical and dosimetric parameters with the development of BCRL., Results: The study population included 378 patients with a median age of 53 years, median body mass index of 28.4 kg/m 2 , and median of 18 axillary nodes removed; 71% underwent mastectomy. Median follow-up was 70 months (interquartile range, 55-89.7 months). BCRL developed in 101 patients at a median of 18.9 months (interquartile range, 9.9-32.4 months), with a corresponding 5-year cumulative incidence BCRL of 25.8%. On multivariate analysis, none of the ALTJ metrics were associated with BCRL risk. Only increasing age, increasing body mass index, and increasing number of nodes were associated with a higher risk of developing BCRL. The 6-year locoregional recurrence rate was 3.2%, the axillary recurrence rate was 1.7%, and the isolated axillary recurrence rate was 0%., Conclusions: The ALTJ is not validated as a critical OAR for reducing BCRL risk. Until such an OAR is discovered, the axillary PTV should not be modified or dose reduced in efforts to reduce BCRL., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many patients with non-metastatic breast cancer benefit from adjuvant radiation therapy after lumpectomy or mastectomy on the basis of many randomized trials. However, there are many patients that have such low risks of recurrence after surgery that de-intensification of therapy by either reducing the treatment volume or omitting radiation altogether may be appropriate options. On the other hand, dose intensification may be necessary for more aggressive breast cancers. Until recently, these treatment decisions were based solely on clinicopathologic factors. Here, we review the current literature on the role of genomic assays as prognostic and/or predictive biomarkers to help guide adjuvant radiation therapy decision-making.

The breast cosmetic outcome after breast conserving therapy is essential for evaluating breast treatment and determining patient's remedy selection. This prompts the need of objective and efficient methods for breast cosmesis evaluations. However, current evaluation methods rely on ratings from a small group of physicians or semi-automated pipelines, making the processes time-consuming and their results inconsistent. To solve the problem, in this study, we proposed: 1. a fully-automatic Machine Learning Breast Cosmetic evaluation algorithm leveraging the state-of-the-art Deep Learning algorithms for breast detection and contour annotation, 2. a novel set of Breast Cosmesis features, 3. a new Breast Cosmetic dataset consisting 3k+ images from three clinical trials with human annotations on both breast components and their cosmesis scores. We show our fully-automatic framework can achieve comparable performance to state-of-the-art without the need of human inputs, leading to a more objective, low-cost and scalable solution for breast cosmetic evaluation in breast cancer treatment.

Purpose: To derive a prescriptive sex-specific fetal growth standard and assess clinical management and outcomes according to sex-specific growth status., Materials and Methods: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b), a prospective observational study of 10,038 nulliparas from eight U.S. centers who underwent ultrasounds at 14-20 and 22-29 weeks with outcomes ascertained after delivery. From these, we selected a nested cohort of lower risk participants (excluded those with chronic hypertension, pre-gestational diabetes, suspected aneuploidy, and preterm delivery) to derive a sex-specific equation for expected fetal growth using fetal weights by ultrasound and at birth. We compared the male-female discrepancy in the rate of weight <10th (small for gestational age [SGA]) and >90th (large for gestational age [LGA]) percentiles between the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we then assessed outcomes and clinical management according to sex-specific SGA and LGA status., Results: Overall, 7280 infants in the lower risk nested cohort were used to derive a sex-specific equation with fetal sex included as an equation intercept. The sex-neutral standard diagnosed SGA more often in female newborns (21% vs. 13%, p  < .001) and LGA more often in male newborns (5% vs. 3%, p  < .001). The sex-specific standard resolved these disparities (SGA: 9% vs. 10%, p  = .23; LGA: 13% vs. 13%, p  = .58). To approximate an unselected population, 1059 participants initially excluded for risk factors for abnormal growth were then included for our secondary objective ( N  = 8339). In this unselected cohort, 39% (95% CI 37.0-42.0%) of the 1498 newborns classified as SGA by the sex-neutral standard were reclassified as appropriate for gestational age (AGA) by the sex-specific standard. These reclassified newborns were more likely to be delivered for growth restriction despite having lower risk of morbidity (females) or comparable risk of morbidity (males) compared to newborns considered AGA by both methods. Of the 6485 newborns considered AGA by the sex-neutral standard, 737 (11.4%, 95% CI 10.6-12.2%) were reclassified as LGA by the sex-specific standard. These reclassified newborns had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. None were reclassified from LGA to AGA by the sex-specific standard., Conclusion: The Hadlock sex-neutral standard generates sex disparities in SGA and LGA at birth. Our sex-specific standard resolves these disparities and has the potential to improve accuracy of growth pathology risk stratification.

During the γ-radiation sterilization process, the levels of radiation exposure to a medical device must be carefully monitored to achieve the required sterilization without causing deleterious effects on its intended physical and chemical properties. To address this issue, here we have demonstrated the development of an all-printed disposable low-cost sensor that exploits the change in electrical impedance of a semi-interpenetrating polymer network (SIPN) composed of poly(vinyl alcohol) (PVA) and poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) as a functional polymer composite for radiation sterilization monitoring applications. Specifically, the PEDOT:PSS acts as the electrically conductive medium, while the PVA provides the ductility and stability of the printed sensors. During irradiation exposure, chain scission and cross-linking events occur concurrently in the PEDOT:PSS and PVA polymer chains, respectively. The concurrent scissoring of the PEDOT polymer and cross-linking of the PVA polymer network leads to the formation of a stable SIPN with reduced electrical conductivity, which was verified through FTIR, Raman, and TGA analysis. Systematic studies of different ratios of PEDOT:PSS and PVA mixtures were tested to identify the optimal ratio that provided the highest radiation sensitivity and stability performance. The results showed that PEDOT:PSS/PVA composites with 10 wt % PVA produced sensors with relative impedance changes of 30% after 25 kGy and up to 370% after 53 kGy (which are two of the most commonly used radiation exposure levels for sterilization applications). This composition showed high electrical impedance stability with less than ±5% change over 18 days after irradiation exposure. These findings demonstrate the feasibility of utilizing a printing technology for scalable manufacturing of low-cost, flexible radiation sensors for more effective monitoring of radiation sterilization processes.

The Breast Cancer Weight Loss (BWEL) trial is a randomized controlled trial designed to determine whether weight loss after a breast cancer diagnosis can reduce the risk of cancer recurrence in women with overweight or obesity. The BWEL trial will compare the efficacy of a telephone-based weight-loss intervention plus health education materials versus health education materials alone on invasive disease-free survival in 3,181 women with stage II or III breast cancer and BMI > 27 kg/m 2 . This report provides a detailed description of the goals and methods of the lifestyle intervention and the evidence supporting the intervention used in the BWEL trial. The intervention's primary goal for participants is to achieve and maintain a weight loss ≥ 10% of baseline weight through increased physical activity and caloric restriction. The evidence supporting the diet, physical activity, and behavioral components of this telephone-based weight-loss intervention, as well as strategies to promote participant engagement and retention, is described. The intervention is provided through 42 sessions delivered by trained health coaches over a 2-year period. If the BWEL lifestyle intervention is successful in improving cancer outcomes, then weight loss will be incorporated into the care of thousands of breast cancer patients., (© 2021 The Obesity Society (TOS).)

Purpose: To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here., Patients and Methods: Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs)., Results: A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( P = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( P = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( P = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; P = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; P = .0047) were associated with reduced IBR., Conclusion: RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy., Competing Interests: Beryl McCormickStock and Other Ownership Interests: Varian Medical Systems Henry M. KuererLeadership: American Society of Breast Surgeons, ASCOHonoraria: Genomic HealthConsulting or Advisory Role: Targeted Medical Education Inc, Genomic Health InternationalSpeakers' Bureau: PERPatents, Royalties, Other Intellectual Property: NEJM Group, McGraw-Hill Publishing Eileen RakovitchHonoraria: AstraZenecaResearch Funding: Genomic Health International Barbara L. SmithPatents, Royalties, Other Intellectual Property: Royalty as textbook editor Judith O. HopkinsConsulting or Advisory Role: AIM Specialty Health Lori J. PierceStock and Other Ownership Interests: PFS GenomicsPatents, Royalties, Other Intellectual Property: UpToDate, PFS GenomicsUncompensated Relationships: Bristol Myers Squibb, Exact SciencesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1250431/summary Kenneth N. M. SumidaEmployment: Hawaii Oncology Inc Danny VespriniHonoraria: MerckConsulting or Advisory Role: AstraZeneca Canada Julia R. WhiteResearch Funding: Intraop MedicalNo other potential conflicts of interest were reported.

Purpose: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed., Methods: We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point., Results: Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low., Conclusion: We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes., Competing Interests: Sara M. TolaneyConsulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Celldex, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, AbbVie, Silverback Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, CertaraResearch Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Immunomedics, Odonate Therapeutics, Sanofi, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, Celldex Elizabeth Garrett-MayerConsulting or Advisory Role: Deciphera, Tyme Julia WhiteResearch Funding: Intraop Medical Judith M. BlissResearch Funding: AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Pfizer, Roche, GlaxoSmithKline/Novartis, Lilly, Janssen-Cilag, Clovis OncologyTravel, Accommodations, Expenses: Pfizer Eileen RakovitchHonoraria: AstraZenecaResearch Funding: Genomic Health International Patricia A. SpearsConsulting or Advisory Role: Pfizer Elizabeth FrankHonoraria: AstraZenecaTravel, Accommodations, Expenses: Roche Nadine M. TungResearch Funding: AstraZeneca Anthony D. EliasStock and Other Ownership Interests: AbbVie, Merck, Gilead Sciences, Allergan, Pfizer, Abbott Laboratories, Amgen, Bristol Myers Squibb, United Health Group, Align Oncology, Illumina, Exact Sciences, Lilly, Agilent, Cigna, Alexion Pharmaceuticals, BiogenerixConsulting or Advisory Role: Ayala PharmaceuticalsResearch Funding: Medivation, Astellas Pharma, Genentech, Deciphera, Xencor, Infinity Pharmaceuticals, Karyopharm Therapeutics, TopAlliance BioSciences Inc, Fosun Orinove, BioAtlaUncompensated Relationships: Seiyax David CameronConsulting or Advisory Role: Lilly, Novartis, Research Triangle Institute Health Solutions, Daiichi Sankyo, Prima BioMed, Merck Sharp & Dohme, Zymeworks, Eisai, Puma Biotechnology, Pfizer, Oncolytics, Roche, Samsung Bioepis, Seattle Genetics, Synthon, Clarity PharmaceuticalsResearch Funding: Roche, Novartis, AstraZenecaTravel, Accommodations, Expenses: Novartis Neelima DenduluriEmployment: AstraZenecaResearch Funding: Amgen, Novartis, Genentech, Lilly, Pfizer, Daiichi Sankyo, ImmunomedicsTravel, Accommodations, Expenses: Seattle Genetics Angelo DiLeoHonoraria: Roche, Novartis, Pfizer, AstraZeneca, Eisai, Lilly, Celgene, AmgenConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Lilly, Celgene, Puma Biotechnology, Ipsen, Genentech, Amgen, Seattle Genetics, Genomic Health, Athenex, Daiichi SankyoTravel, Accommodations, Expenses: Roche, Pfizer, Celgene, Novartis Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, ZymeworksResearch Funding: Genentech, AstraZenecaOther Relationship: InfiniteMDNo other potential conflicts of interest were reported.

Purpose: Accrual to clinical trials that challenge well-established treatment paradigms represents a unique challenge. Physician opinions on investigation of a novel approach to breast cancer treatment, in which patients with complete response to neoadjuvant chemotherapy are offered omission of lumpectomy, are unknown. NRG-CC006 sought to describe physician attitudes toward a novel approach to breast cancer treatment., Methods: We recruited 18 participants in the fields of surgery, medical oncology, and radiation oncology to participate in the semi-structured telephone interviews. Main outcomes are qualitative themes associated with omission of surgery., Results: Of 18 interview participants, specialty and gender were evenly represented across surgery, medical oncology, and radiation oncology. Qualitative themes included general attitudes toward treatment de-escalation, stakeholder considerations, and trial/protocol considerations. The vast majority of participants expressed interest in investigation of omission of surgery, with all participants endorsing need for further investigation into treatment de-escalation. Stakeholder considerations in opening such a trial emphasized need for multidisciplinary involvement and, particularly, the unique role of surgeons as gatekeepers in breast cancer treatment. Finally, participants endorsed a need for further foundational studies to develop ways to predict complete pathologic response to chemotherapy without surgical intervention., Conclusions: Physicians expressed interest in investigating a novel approach to breast cancer treatment that would omit surgery in complete responders to neoadjuvant chemotherapy. Multidisciplinary input, and specifically surgeon engagement, will be key to the success of future investigations. Ongoing work to develop approaches to predict pathologic complete response accurately is needed to achieve the promise of this idea. ClinTrials #: BR005: NCT03188393 June 13, 2017.

Importance: Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases., Objective: To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other., Design, Setting, and Participants: This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non-small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019., Interventions: The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP)., Main Outcomes and Measures: The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated., Results: A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non-small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients., Conclusions and Relevance: This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002)., Trial Registration: ClinicalTrials.gov Identifier: NCT02206334.

In the modern era, highly effective anti-HER2 therapy is associated with low local-regional recurrence (LRR) rates for early-stage HER2+ breast cancer raising the question of whether local therapy de-escalation by radiation omission is possible in patients with small-node negative tumors treated with lumpectomy. To evaluate existing data on radiation omission, we used the National Cancer Database (NCDB) to test the hypothesis that RT omission results in equivalent overall survival (OS) in stage 1 (T1N0) HER2+ breast cancer. We excluded patients that received neoadjuvant systemic therapy. We stratified the cohort by receipt of adjuvant radiation. We identified 6897 patients (6388 RT; 509 no RT). Patients that did not receive radiation tended to be ≥70 years-old (odds ratio [OR] = 3.69, 95% CI: 3.02-4.51, p < 0.0001), to have ≥1 comorbidity (OR = 1.33, 95% CI: 1.06-1.68, p = 0.0154), to be Hispanic (OR = 1.49, 95% CI: 1.00-2.22, p = 0.049), and to live in lower income areas (OR = 1.32, 95% CI: 1.07-1.64, p = 0.0266). Radiation omission was associated with a 3.67-fold (95% CI: 2.23-6.02, p < 0.0001) increased risk of death. While other selection biases that influence radiation omission likely persist, these data should give caution to radiation omission in T1N0 HER2+ breast cancer.

Background/purpose: Shoulder/arm morbidity is a late complication of breast cancer treatment with surgery and regional nodal irradiation (RNI). We set to analyze the impact of radiation technique [intensity modulated radiation therapy (IMRT) or 3D conformal radiation therapy (3DCRT)] on radiation dose to the shoulder with a hypothesis that IMRT use results in smaller volume of shoulder receiving radiation. We explored the relationship of treatment technique on long-term patient-reported outcomes using the quick disabilities of the arm, shoulder, and hand (q-DASH) questionnaire., Materials/methods: We identified patients treated with adjuvant RNI (50 Gy/25 fractions) from 2013 to 2018. We retrospectively contoured the shoulder organ-at-risk (OAR) from 2 cm above the ipsilateral supraclavicular (SCL) planning target volume (PTV) to the inferior SCL PTV slice and calculated the absolute volume of shoulder OAR receiving 5-50 Gy (V5-V50). We identified patients that completed a q-DASH questionnaire ≥6 months from the end of RNI., Results: We included 410 RNI patients: 54% stage III, 72% mastectomy, 35% treated with IMRT. IMRT resulted in significant reductions in the shoulder OAR volume receiving 20-50 Gy vs. 3DCRT. In total, 82 patients completed the q-DASH. The mean (SD) q-DASH=25.4 (19.1) and tended to be lower with IMRT vs. 3DCRT: 19.6 (16.4) vs. 27.8 (19.8), p=0.078., Conclusion: We found that IMRT reduces radiation dose to the shoulder and is associated with a trend toward reduced q-DASH scores ≥6 months post-RNI in a subset of our cohort. These results support prospective evaluation of IMRT as a technique to reduce shoulder morbidity in breast cancer patients receiving RNI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bazan, DiCostanzo, Hock, Jhawar, Kuhn, Lindsey, Tedrick, Healy, Beyer and White.)

Background/purpose: Rates of acute esophagitis in breast cancer patients undergoing regional nodal irradiation (RNI) are under-reported. We set to identify esophageal dose-volume constraints associated with grade 2 esophagitis (G2E). We hypothesized that the G2E rate was higher with intensity modulated radiation therapy (IMRT) vs. 3D conformal radiation therapy (3DCRT)., Materials/methods: We identified patients that received RNI (50 Gy/25 fractions) from 1/2013 to 6/2019. We retrospectively contoured the esophagus in a consistent manner and recorded esophageal mean dose, max dose, and V10-V50. Our primary endpoint was the G2E rate. Receiver operating characteristics curves analysis (e.g., Youden's J statistic) were used to determine the cutpoints for the dosimetric parameters which were then tested in logistic regression models., Results: We identified 531 patients (50% left-sided; 41% IMRT; 16.2% G2E). G2E was significantly higher in IMRT vs. 3DCRT patients (23.6% vs. 10.9%, p < 0.0001). All esophageal dosimetric parameters were significantly associated with G2E after adjusting for age and laterality. The cutpoints for esophageal mean dose, V10 and V20 were 11 Gy, 30%, and 15%, respectively. The associations between the dichotomized dose-volume parameters and G2E were OR = 3.82 (95% CI 2.28-6.40, p < 0.0001) for esophageal mean dose, OR = 5.37 (95% CI 3.01-9.58, p < 0.0001) for esophageal V10, and OR = 3.23 (95% CI 1.93-5.41, p < 0.0001) for esophageal V20., Conclusion: In patients receiving RNI with modern techniques, we found that G2E occurs in >15%, and more frequently with IMRT. These data strongly support the routine contouring of the esophagus in RNI planning, and our constraints should be incorporated in future prospective protocols of RNI., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Clinical trials support adjuvant regional nodal irradiation (RNI) after breast-conserving surgery or mastectomy for patients with lymph node-positive breast cancer. Advanced treatment planning techniques (eg, intensity modulated radiation therapy [IMRT]) can reduce dose to organs at risk (OARs) in this situation. However, uncertainty persists about when IMRT is clinically indicated (vs 3-dimensional conformal radiation therapy [3DCRT]) for RNI. We hypothesized that an adaptive treatment planning algorithm (TPA) for IMRT adoption would allow OAR constraints for RNI to be met when 3DCRT could not without significantly changing toxicity and locoregional recurrence (LRR) patterns., Methods and Materials: Since 2013, all RNI patients also underwent an adaptive TPA that began with 3DCRT and then changed to IMRT when OAR constraints (mean heart dose ≤500 cGy; ipsilateral lung V20 ≤35%) could not be met. Patients received 2 Gy/d to the prospectively contoured target volumes (including internal mammary nodes). We retrospectively evaluated the dosimetry and clinical outcomes of the treatment groups (IMRT vs 3DCRT). The primary endpoint was the cumulative incidence of LRR as the site of first recurrence, and we specifically address patterns of failure based on dose to the posterior supraclavicular nodal region (SCL-post)., Results: Two hundred forty patients (60% stage III; mean 4.0 + nodes) underwent an adaptive-TPA for RNI after mastectomy (74%) or breast-conserving surgery (26%), resulting in 168 patients treated with 3DCRT and 72 patients treated with IMRT. There were 7 LRRs (2 IMRT, 5 3DCRT) resulting in 4-year LRR of 2.8% for IMRT versus 1.8% for 3DCRT (P = .99). Three patients (2 IMRT, 1 3DCRT) had SCL nodal failures (1 in the SCL-post)., Conclusions: An adaptive TPA for use of IMRT when 3DCRT does not meet critical OAR constraints resulted in rare high-grade toxicity and no difference in failure patterns between patients treated with IMRT and 3DCRT. These data should provide reassurance that IMRT maintains the therapeutic ratio by preserving cancer control outcomes without excess toxicity when 3DCRT fails to meet OAR constraints., (Copyright © 2020 Elsevier Inc. All rights reserved.)

While provision of in-stream habitat complexity remains common practice in efforts to restore streams, the evidence of positive effects on in-stream communities is inconsistent. In streams of urban catchments, where both reach-scale habitat manipulation and catchment-scale actions to ameliorate the disturbance regime of urban stormwater runoff are common management responses, clearer understanding of the effects of habitat complexity under different degrees of urban impact are needed. We experimentally assessed the effect of increased surface complexity in wood, the dominant hard substrate in our 18 study reaches on 14 small streams, on in-stream macroinvertebrate assemblages across a range of urban impact. Increased surface complexity increased abundance of most taxa, but this effect was less pronounced in urban streams, partly because of the reduced species pool tolerant of urban stormwater impacts, and partly because of a lesser response of some species to increased complexity in more urban streams. Collectively these taxon-specific effects resulted in small, uncertain increases in taxon richness with increased complexity in rural streams, and no change in richness of the less diverse assemblages of urban streams. Increased abundances suggest increased availability of refugia or resources with increased surface complexity, while the reduced effect of complexity in urban streams suggests that any refuge or resource provided by greater surface complexity is less effective in more disturbed environments receiving urban stormwater runoff. The reduced abundance of sensitive taxa in more urban streams, and the resultant reduced richness, confirms that urban stormwater runoff acts as a strong environmental filter, limiting the species pool available for community assembly. Restoration of habitat complexity in streams without catchment-scale drivers of degradation is likely to have positive benefits to in-stream biotic assemblages, but the efficacy of such approaches in catchments subject to urban stormwater runoff will be greatly diminished. In such cases, restoration activities should first be aimed at controlling the larger-scale problem., (© 2020 by the Ecological Society of America.)

Background: Breast conserving surgery (BCS) and adjuvant hormonal therapy (HT) without radiation therapy (RT) is an acceptable approach for older women with early stage, estrogen receptor (ER) positive breast cancer. Toxicity and compliance remain issues with HT. Adjuvant RT alone may have better compliance, but its efficacy in the absence of HT is unclear. We aim to assess patterns of adjuvant therapy and survival outcomes among older women with early stage, ER positive (ER+) breast cancer., Methods: The National Cancer Data Base (NCDB) was used to identify 130,194 women age ≥65 years with invasive ER+, node negative breast cancer diagnosed between 2004 and 2015. All patients underwent BCS. Kaplan-Meier survival curves were used to examine overall survival (OS). The association between adjuvant therapy and OS was assessed in multivariable Cox proportional hazards regression models., Results: Unadjusted 5/10-year OS rates were 90.0%/64.3% for HT and RT, 84.2%/54.9% for RT alone, 78.7%/44.5% for HT alone, and 71.6%/38.0% for no treatment; p<0.001 for all. Compared to HT alone, the 10-year multivariable hazard ratio (HR) for death for RT alone was 0.86 (95% CI 0.82-0.91). In propensity-matched patients who received RT alone or HT alone (n=21,326), RT alone had significantly better survival at 5 (HR adj : 0.84) and 10 (HR adj : 0.87) years., Conclusions: Older women with early stage ER+ breast cancer who undergo BCS and receive both HT and RT have the best survival, while RT as single-modality therapy had higher rates of OS at 5 and 10 years compared to HT alone., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose/objectives: Node-positive breast cancer patients often receive chemotherapy and regional nodal irradiation. The cardiotoxic effects of these treatments, however, may offset some of the survival benefit. Cardiac magnetic resonance (CMR) is an emerging modality to assess cardiac injury. This is a pilot trial assessing cardiac damage using CMR in patients who received anthracycline-based chemotherapy and three-dimensional conformal radiotherapy (3DCRT) regional nodal irradiation using heart constraints., Materials and Methods: Node-positive breast cancer patients (2000-2008) treated with anthracycline-based chemotherapy and 3DCRT regional nodal irradiation (including the internal mammary chain nodes) with heart ventricular constraints (V25 < 10%) were invited to participate. Cardiac tissues were contoured and analyzed separately for whole heart (pericardium) and for combined ventricles and left atrium (myocardium). CMR obtained ventricular function/dimensions, late gadolinium enhancement (LGE), global longitudinal strain (GLS), and extracellular volume fraction (ECV) as measures of cardiac injury and/or early fibrosis. CMR parameters were correlated with dose-volume constraints using Spearman correlations., Results: Fifteen left-sided and five right-sided patients underwent CMR. Median diagnosis age was 50 (32-77). No patients had baseline cardiac disease before regional nodal irradiation. Median time after 3DCRT was 8.3 years (5.2-14.4). Median left-sided mean heart dose (MHD) was 4.8 Gy (1.1-11.2) and V25 was 5.7% (0-12%). Median left ventricular ejection fraction (LVEF) was 63%. No abnormal LGE was observed. No correlations were seen between whole heart doses and LVEF, LV mass, GLS, or LV dimensions. Increasing ECV did not correlate with increased heart or ventricular doses. However, correlations between higher LV mass and ventricular mean dose, V10, and V25 were seen., Conclusion: At a median follow-up of 8.3 years, this cohort of node-positive breast cancer patients who received anthracycline-based chemotherapy and regional nodal irradiation had no clinically abnormal CMR findings. However, correlations between ventricular mean dose, V10, and V25 and LV mass were seen. Larger corroborating studies that include advanced techniques for measuring regional heart mechanics are warranted., (Copyright © 2020 Bergom, Rubenstein, Wilson, Welsh, Ibrahim, Prior, Schottstaedt, Eastwood, Zhang, Currey, Puckett, Strande, Bradley and White.)

Many are interested in how to safely ramp up elective surgeries after national, state, and voluntary shutdowns of operating rooms to minimize the spread of COVID-19 infections to patients and providers. We conducted an analysis of diverse perspectives from stakeholders regarding how to trade off risks and benefits to patients, healthcare providers, and the local community. Our findings indicate that there are a large number of different categories of stakeholders impacted by the post-pandemic decisions to reschedule delayed treatments and surgeries. For a delayed surgery, the primary stakeholders are the surgeon with expertise about the clinical benefits of undergoing an operation and the patient's willingness to tolerate uncertainty and the increased risk of infection. For decisions about how much capacity in the operating rooms and in the inpatient setting after the surgery, the primary considerations are minimizing staff infections, preventing patients from getting COVID-19 during operations and during post-surgical recovery at the hospital, conserving critical resources such as PPE, and meeting the needs of hospital staff for quality of life, such as child care needs and avoiding infecting members of their household. The timing and selection of elective surgery cases has an impact on the ability of hospitals to steward finances, which in turns affects decisions about maintaining employment of staff when operating rooms and inpatient rooms are not being used.

Purpose: To investigate patterns of failure in institutional credentialing submissions to NRG/RTOG 1005 with the aim of improving the quality and consistency for future breast cancer protocols., Methods and Materials: NRG/RTOG 1005 allowed the submission of 3-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and simultaneous integrated boost (SIB) breast plans. Credentialing required institutions to pass a 2-step quality assurance (QA) process: (1) benchmark, requiring institutions to create a plan with no unacceptable deviations and ≤1 acceptable variation among the dose volume (DV) criteria, and (2) rapid review, requiring each institution's first protocol submission to have no unacceptable deviations among the DV criteria or contours. Overall rates, number of resubmissions, and reasons for resubmission were analyzed for each QA step., Results: In total, 352 institutions participated in benchmark QA and 280 patients enrolled had rapid review QA. Benchmark initial failure rates were similar for 3DCRT (18%), IMRT (17%), and SIB (18%) plans. For 3DCRT and IMRT benchmark plans, ipsilateral lung most frequently failed the DV criteria, and SIB DV failures were seen most frequently for the heart. Rapid review contour initial failures (35%) were due to target rather than organs at risk. For 29% of the rapid review initial failures, the planning target volume boost eval volume was deemed an unacceptable deviation., Conclusions: The review of the benchmark and rapid review QA submissions indicates that acceptable variations or unacceptable deviations for the ipsilateral lung and heart dose constraints were the most commonly observed cause of benchmark QA failure, and unacceptable deviations in target contouring, rather than normal structure contouring, were the most common cause of rapid review QA failure. These findings suggest that a rigorous QA process is necessary for high quality and homogeneity in radiation therapy in multi-institutional trials of breast cancer to ensure that the benefits of radiation therapy far outweigh the risks., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising <0.1% of all breast carcinomas. Here we present a case of thyroid transcription factor-1 (TTF-1) positive SCCB that recurred within 3 years of diagnosis in the lung and lymph nodes. Given the small number of cases, no clear guidelines exist on the appropriate management of patients with these aggressive tumors. We present a case study and review the current literature to highlight the knowledge gaps and needs of patients with these rare tumors. A 50-year-old premenopausal woman with no family history, presented with a palpable right breast mass. Biopsy was consistent with primary SCCB that was poorly differentiated, positive for synaptophysin and chromogranin and TTF-1 and presence of ductal carcinoma in situ component showing neuroendocrine differentiation. Imaging with PET, CT, and MRI brain excluded any other sites of primary disease. She underwent a right lumpectomy with axillary lymph node dissection and was treated with adjuvant cisplatin-based chemotherapy and concurrent radiation therapy. Thirty-four months later, routine scans showed a new right lower-lobe lung nodule and an enlarged sub-carinal node that was proven to be poorly differentiated neuroendocrine cancer. This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Primary SCCB is an extremely rare, aggressive form of breast cancer that is molecularly and histologically similar to SCLC. However, a review of the literature highlights recent mutational analyses that show important differences between these two cancer types, including an increase in PIK3CA mutations in primary SCCB. Further studies, including genomic analyses are needed to better define this malignancy and to develop a standard treatment., (Copyright © 2020 Boutrid, Kassem, Tozbikian, Morgan, White, Shah, Vandeusen, Sardesai, Williams, Stover, Lustberg, Wesolowski, Pudavalli, Williams, Konda, Fortier, Carbone, Ramaswamy and Cherian.)

Background: Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms., Methods: Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively., Results: Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed., Conclusions: ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

The centrosome linker serves to hold the duplicated centrosomes together until they separate in late G2/early mitosis. Precisely how the linker is assembled remains an open question. In this study, we identify Cep44 as a novel component of the linker in human cells. Cep44 localizes to the proximal end of centrioles, including mother and daughter centrioles, and its ablation leads to loss of centrosome cohesion. Cep44 does not impinge on the stability of C-Nap1 (also known as CEP250), LRRC45 or Cep215 (also known as CDK5RAP2), and vice versa, and these proteins are independently recruited to the centrosome. Rather, Cep44 associates with rootletin and regulates its stability and localization to the centrosome. Our findings reveal a role of the previously uncharacterized protein Cep44 for centrosome cohesion and linker assembly., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Importance: Mastectomy is standard for recurrence of breast cancer after breast conservation therapy with whole breast irradiation. The emergence of partial breast irradiation led to consideration of its application for reirradiation after a second lumpectomy for treatment of recurrence of breast cancer in the ipsilateral breast., Objectives: To assess the effectiveness and adverse effects of partial breast reirradiation after a second lumpectomy and whether the treatment is an acceptable alternative to mastectomy., Design, Setting, and Participants: The NRG Oncology/Radiation Therapy Oncology Group 1014 trial is a phase 2, single-arm, prospective clinical trial of 3-dimensional, conformal, external beam partial breast reirradiation after a second lumpectomy for recurrence of breast cancer in the ipsilateral breast after previous whole breast irradiation. The study opened on June 4, 2010, and closed June 18, 2013. Median follow-up was 5.5 years. This analysis used all data received at NRG Oncology through November 18, 2018. Eligible patients experienced a recurrence of breast tumor that was less than 3 cm and unifocal in the ipsilateral breast more than 1 year after breast-conserving therapy with whole breast irradiation and who had undergone excision with negative margins., Interventions: Adjuvant partial breast reirradiation, 1.5 Gy twice daily for 30 treatments during 15 days (45 Gy), using a 3-dimensional conformal technique., Main Outcomes and Measures: The main outcomes of the present study were the predefined secondary study objectives of recurrence of breast cancer in the ipsilateral breast, late adverse events (>1 year after treatment), mastectomy incidence, distant metastasis-free survival, overall survival, and circulating tumor cell incidence., Results: A total of 65 women were enrolled, with 58 evaluable for analysis (mean [SD] age, 65.12 [9.95] years; 48 [83%] white). Of the recurrences of breast cancer in the ipsilateral breast, 23 (40%) were noninvasive and 35 (60%) were invasive. In all 58 patients, 53 (91%) had tumors 2 cm or smaller. All tumors were clinically node negative. A total of 44 patients (76%) tested positive for estrogen receptor, 33 (57%) for progesterone receptor, and 10 (17%) for ERBB2 (formerly HER2 or HER2/neu) overexpression. Four patients had breast cancer recurrence, with a 5-year cumulative incidence of 5% (95% CI, 1%-13%). Seven patients underwent ipsilateral mastectomies for a 5-year cumulative incidence of 10% (95% CI, 4%-20%). Both distant metastasis-free survival and overall survival rates were 95% (95% CI, 85%-98%). Four patients (7%) had grade 3 and none had grade 4 or higher late treatment adverse events., Conclusions and Relevance: For patients experiencing recurrence of breast cancer in the ipsilateral breast after lumpectomy and whole breast irradiation, a second breast conservation was achievable in 90%, with a low risk of re-recurrence of cancer in the ipsilateral breast using adjuvant partial breast reirradiation. This finding suggests that this treatment approach is an effective alternative to mastectomy.

Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation., Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181., Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5-11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94-1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7-5·7) in the APBI group versus 3·9% (3·1-5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group., Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women., Funding: National Cancer Institute, US Department of Health and Human Services., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Antibodies blocking programmed death 1 (anti-PD-1) or its ligand (anti-PD-L1) are associated with modest response rates as monotherapy in metastatic breast cancer, but are generally well tolerated and capable of generating dramatic and durable benefit in a minority of patients. Anti-PD-1/L1 antibodies are also safe when administered in combination with a variety of systemic therapies (chemotherapy, targeted therapies), as well as with radiotherapy. We summarize preclinical, translational, and preliminary clinical data in support of combination approaches with anti-PD-1/L1 in metastatic breast cancer, focusing on potential mechanisms of synergy, and considerations for clinical practice and future investigation., Competing Interests: Competing interestsD.B.P.: Research support: BMS, Merck, Brooklyn ImmunoTherapeutics. Speakers Bureau: Genentech, Novartis. Scientific Advisory Board: BMS, Merck, Syndax, Nektar, Puma, Nanostring H.B.: Receives research support from Merck and serves on the Advisory Board for Merck. S.P.: No COI or disclosures Gatti-Mays: No COI or disclosures. A.T.: Research support (to institution): Syndax, Genentech; Stockholder: Bristol-Myers Squibb, Gilead Sciences, Johnson and Johnson, Pfizer; Consultant (DSMB) BeyondSpring Pharmaceuticals (managed by Watermark Research Partners), H.M.A.: Consulting: Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Immunomedics, Pfizer, Genentech, Bristol-Myers Squibb, Genomic Health. Research Funding: Bristol-Myers Squibb, ZIOPHARM Oncology, Lilly, Merck; Travel expenses: Merck, Spectrum Pharmaceuticals, Lilly, Amgen, Puma Biotechnology, Immunomedics, Genentech, Pfizer. Expert panel: Lilly. J.M.B.: Receives research support from Genentech/Roche, Bristol Myers Squibb, and Incyte Corporation, has received consulting/expert witness fees from Novartis, and is an inventor on provisional patents regarding immunotherapy targets and biomarkers in cancer. S.R.G.: No COIs or disclosures. R.N.: Advisory Board: AstraZeneca, Athenex, Celgene, Daiichi Sankyo, Inc, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma, Syndax. DSMB:G1 Therapeutics Research Funding: AstraZeneca, Celgene, Corcept. Therapeutics, Genentech/Roche, Immunomedics, Merck, Odonate Therapeutics, Pfizer, Seattle Genetics, J.L.G.: National Cancer Institutes has several Cooperative Research and Development Agreements (CRADAs) with various biotech and pharma agencies involved in immunotherapy. Kalinsky: Consulting: Biotheranostics, Eli-Lilly, Pfizer, Amgen, Novartis, Eisai, AstraZeneca, Odonate Therapeutics, Ipsen, Genentech. Speakers’ bureau: Eli-Lilly. Institutional support: Incyte, Genentech, Eli-Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zeno Pharmaceuticals, CytomX Therapeutics. Spouse: employment at Array Biopharma. J.W.: None. J.L.: Research support: Novartis, Medivation/Pfizer, Genentech, GSK, EMD-Serono, AstraZeneca, Medimmune. Speaker’s Bureau: MedLearning, Physician’s Education Resource, Prime Oncology, Medscape. Honoraria: Uptodate; Advisory committee: AstraZeneca, Pfizer (both uncompensated). Review panels: NCCN, ASCO, NIH PDQ. S.J.C.: Astellas (spouse), RefleXion (Consulting). M.-Y.P.: No COIs or disclosures. B.V.: Research funding: Merck, Phamacyclics, Acerta Pharma; Equity: Select Immunogenomics. D.W.C.: Honoraria (non-accredited CME) Pfizer, and Novartis. Consulting or advisory role: Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Agendia, Puma Biotechnology and Dynamo Therapeutics. Research funding (to instituton): Merck, Roche/Genentech, GlaxoSmithKline, and Pfizer. M.L.D.: COI: grants from Epithany, Celgene, EMD Serono, Pfizer, Seattle Genetics, Silverback Therapeutics, Janssen. Stockholder in Epithany. Vendor-sponsored travel: Eli-Lilly, Novartis, Genentech, Ipsen and Amgen. J.A.S.: Receives research support: Deciphera, Inc., Prescient Therapeutics; Paid consultant: Astra Zeneca, Pfizer; Pharmaceutical sponsored research: Genentech. Mittendorf: serves on advisory boards for Merck, SELLAS Lifesciences, AstraZeneca/MedImmune, TapImmune, and Peregrine Pharmaceuticals, and received institutional research funding from Genentech, Astra Zeneca/MedImmune, and SELLAS Lifesciences. S.A.: Advisory Board: BMS, Merck, Genentech (all uncompensated), research funding to institution: Genentech, Merck, Amgen, Novartis, BMS, Celgene., (© The Author(s) 2019.)

Purpose: Although the wind, rain, and flooding of Hurricane Maria in Puerto Rico abated shortly after its landfall on September 20, 2017, the disruption of the electrical, communications, transportation, and medical infrastructure of the island was unprecedented in scope and caused lasting harm for many months afterward. A compilation of recommendations from radiation oncologists who were in Puerto Rico during the disaster, and from a panel of American Society for Radiation Oncology (ASTRO) cancer experts was created., Methods and Materials: Radiation oncologists throughout Puerto Rico collaborated and improvised to continue treating patients in the immediate aftermath of the storm and as routine clinical operations were restored gradually. Empirical lessons from the experience of radiation therapy administration in this profoundly altered context of limited resources, impaired communication, and inadequate transportation were organized into a recommended template, applicable to any radiation oncology practice. ASTRO disease-site experts provided evidence-guidelines for mitigating the impact of a 2- to 3-week interruption in radiation therapy., Results: Practical measures to mitigate the medical impact of a disaster are summarized within the framework of "Prepare, Communicate, Operate, Compensate." Specific measures include the development of an emergency operations plan tailored to specific circumstances, prospective coordination with other radiation oncology clinics before a disaster, ongoing communications with emergency management organizations, and routine practice of alternate methods to disseminate information among providers and patients., Conclusions: These recommendations serve as a starting point to assist any radiation oncology practice in becoming more resiliently prepared for a local or regional disruption from any cause. Disease-site experts provide evidence-based guidelines on how to mitigate the impact of a 2- to 3-week interruption in radiation therapy for lung, head and neck, uterine cervix, breast, and prostate cancers through altered fractionation or dose escalation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: There is tremendous interest in using immunotherapy to treat breast cancer, as evidenced by the more than 290 clinical trials ongoing at the time of this narrative review. The objective of this review is to describe the current status of immunotherapy in breast cancer, highlighting its potential in both early-stage and metastatic disease., Observations: After searching ClinicalTrials.gov on April 24, 2018, and PubMed up to June 30, 2018, to identify breast cancer immunotherapy trials, we found that immune checkpoint blockade (ICB) is the most investigated form of immunotherapy in breast cancer. Use of ICB as monotherapy has achieved objective responses in patients with breast cancer, with higher rates seen when administered in earlier lines of therapy. For responding patients, those responses are durable. More recent data suggest clinical efficacy when ICB is given in combination with chemotherapy. Ongoing studies are evaluating combination strategies pairing ICB with additional chemotherapeutic agents, targeted therapy, vaccines, and local ablative therapies to enhance response. To date, robust predictive biomarkers for response to ICB have not been established., Conclusions and Relevance: It is anticipated that combination therapy strategies will be the way forward for immunotherapy in breast cancer, with an improved understanding of tumor, microenvironment, and host factors informing treatment combination decisions. Thoughtful study design incorporating appropriate end points and correlative studies will be critical in identifying optimal strategies for enhancing the immune response against breast tumors.

Purpose: Lumpectomy (L) and breast radiotherapy (RT) results in equivalent outcomes in comparison to mastectomy (M) for early-stage breast cancer (BC) based on randomized controlled trials (RCT). Since 2004, RCT support that L without RT yields equivalent survival and acceptable local-regional outcomes in women ≥70-years old with T1N0 hormone-sensitive (ER+) BC on endocrine therapy. Based on this, we hypothesized that M rates should decrease substantially after 2004 in this low-risk elderly population. Methods: We used the Surveillance Epidemiology and End Results registry data to conduct this study. We included women with T1N0 ER+ BC from 2000 to 2014. We compared M rates in women diagnosed from 2000 to 2004 vs. 2005-2012 using the Chi-Square test. Logistic regression analyses was performed to examine demographic/clinical factors associated with mastectomy. Results: 67,506 women met the study criteria. In elderly Stage I ER+ BC, the M rate decreased by 6.3%: 29.0% before 2004 to 22.7% after 2004 ( p < 0.0001). M rates remained higher in elderly non-Hispanic black (NHB, 27.1%, p < 0.0001), non-Hispanic Asian-Pacific-Islander (NHAPI, 30.1%, p < 0.0001), and Hispanics (24.4%, p = 0.0004) vs. non-Hispanic White (NHW, 21.5%). Treatment in the modern cohort was associated with decreased odds of mastectomy (OR = 0.71, 95% CI 0.68-0.74, p < 0.0001) while NH-API race was associated with the highest increased odds of mastectomy (OR = 1.65, 95% 1.53-1.78, p < 0.0001). In the modern cohort specifically (2005-2014), Hispanic women (OR = 1.12, p = 0.014), NHB women (OR = 1.21, p < 0.0001), and NHAPI women (OR = 1.73, p < 0.0001) all had higher odds of undergoing mastectomy relative to NHW women after adjusting for all other patient and tumor related factors. Conclusions: In elderly patients with stage I, ER+ BC, M rates have decreased modestly since 2004. These trends are driven mostly be decreases in the M rate in NHW women, but M rates remain ~25% in Hispanic, NHB, and NHAPI women. Further research is needed to identify why M, which is associated with higher cost and morbidity than L alone, has not changed substantially in elderly, low-risk BC.

A digital filter based on non-negative matrix factorization (NMF) enables blind deconvolution of temporal information from large data sets, simultaneously recovering both photon arrival times and the instrument impulse response function (IRF). In general, the measured digital signals produced by modern analytical instrumentation are convolved by the corresponding IRFs, which can complicate quantitative analyses. Common examples include photon counting (PC), chromatography, super resolution imaging, fluorescence imaging, and mass spectrometry. Scintillation counting, in particular, provides a signal-to-noise advantage in measurements of low intensity signals, but has a limited dynamic range due to pulse overlap. This limitation can complicate the interpretation of data by masking temporal and amplitude information on the underlying detected signal. Typical methods for deconvolution of the photon events require advanced knowledge of the IRF, which is not generally trivial to obtain. In this work, a sliding window approach was developed to perform NMF one pixel at a time on short segments of large (e.g., 25 million point) data sets. Using random initial guesses for the IRF, the NMF filter simultaneously recovered both the deconvolved photon arrival times and the IRF. Applying the NMF filter to the analysis of triboluminescence (TL) data traces of active pharmaceutical ingredients enabled discrimination between different hypothesized physical origins of the signal.

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates., Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively., Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results., Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality., Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided., Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other)., Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death.

Background: Angiogenic factors have been implicated in the pathogenesis of preeclampsia. This pilot study explored the association between antenatal blood pressure levels and angiogenic biomarkers (sFlt1 and PlGF) among women with chronic hypertension (cHTN)., Methods: Blood samples were collected from women with cHTN (with/without superimposed preeclampsia) within 96 h prior to delivery. Subjects were stratified by mean outpatient BP as controlled (cBP < 140/90) or uncontrolled (uBP ≥ 140/90). Descriptive statistics were generated and assessed as appropriate. Logistic regression was employed to assess for adverse pregnancy outcomes between groups., Results: Data from seventy-eight women were analyzed, of which 58 (74.4%) were African American. Fifty-six (71.8%) had cBP and 22 (28.2%) had uBP. Use of antepartum outpatient antihypertensive medications was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01). Compared to women with cBP, women with uBP had higher levels of pre-delivery sFlt1 and sFlt1/PlGF ratio (sFlt: 4218.5 vs. 3056.0 pg/ml, p = 0.046; sFlt/PlGF: 62.5 vs. 25.0, p = 0.04). Additionally, more uBP patients had superimposed preeclampsia with severe features (54.6% vs. 25.0%; p = 0.01) and preterm delivery (defined as a gestational age <35 weeks (40.9% vs. 10.7%; p = 0.002)) than cBP patients. In the multivariable model, women with uBP had greater odds of preterm delivery (OR 6.78; p = 0.01), superimposed preeclampsia (OR 3.20; p = 0.03) and preeclampsia with severe features (OR 3.27; p = 0.04) than women with cBP., Conclusion: In women with cHTN, elevated antepartum BP is associated with worsened outcomes and may be associated with abnormal angiogenic profile at delivery. Larger studies are needed to confirm these findings., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)