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Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo. Mol Cancer Ther; 15(11); 2598–608. ©2016 AACR.

Scratch assay using HDQ-P1 cells. Top vehicle, bottom (1b) (50 μM) over a 10h time frame.

Supplementary Materials and Methods; Table S1 and Figures S1 through S5; Supplementary Movies S1 through S3 Legends - Supplementary Materials and Methods: Description of velocity determination, conditions for immunostaining and sources and application of the antibodies used in the study are provided. Supplementary Tables: The table provides information on the race and age of the de-identified patients from which samples were obtained and used for Figure 2. Supplementary Figures: The supplementary figures demonstrate the kinase specificity of (1b) on a large panel of human kinases (Figure S1), the efficacy of (1b) to inhibit proliferation (Figure S2) and motility (Figure S3) of various TNBC cell lines, the effect of RSK1 or RSK2 silencing on MDA-MB-231 metastasis (Figure S4) and demonstrate that the HDQ-P1 model preferentially targets to the viscera (Figure S5).

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER+) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies.Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER+ breast cancer susceptible to endocrine-based therapies. Cancer Res; 78(8); 2014–25. ©2018 AACR.

Patient histopathological information

Supplementary Figures and Legends 1-6: Supplementary Figure 1 - RSK2 in ER+ breast cancer, Supplementary Figure 2-Analysis of RSK2 gene signature, Supplementary Figure 3-Anti-estrogen regulation of RSK2 nuclear accumulation, Supplementary Figure 4- Mapping the region responsible for RSK2 nuclear accumulation, Supplementary Figure 5-Characterization of RSK2 nuclear accumulation, Supplementary Figure 6-Analysis of NLS-RSK mouse model. Supplementary Table Legends 1-4: Supplementary Table 1-Patient histopathological information, Supplementary Table 2-Differentially expressed gene in RSK2-KO cells, Supplementary Table 3-Analysis of ER+ and ER- clustering of invasive ductal carcinoma samples using different gene sets, Supplementary Table 4-Small molecule inhibitors screened for inhibition of RSK2 nuclear localization. Supplementary Experimental Procedures. Resource Table. Supplementary References.

Purpose Intraoperative radiation therapy (IORT), a form of accelerated partial breast irradiation (APBI), is an appealing alternative to postoperative whole breast irradiation for early-stage breast cancer. The purpose of this study was to examine the toxicity and cosmetic outcomes of patients treated with a novel form of breast IORT (precision breast IORT; PB-IORT), that delivers a targeted, higher dose of radiation than conventional IORT. Methods and Materials The first 204 patients treated with PB-IORT in a Phase II clinical trial (NCT02400658) with 12 months of followup were included. Trial inclusion criteria were age ≥45 years, invasive or in situ breast cancer, tumor size ≤3 cm, and node negative. Toxicity and cosmetic scoring were performed at 6 and 12 months. Results 98 patients (48%; 95% CI, 41–55%) experienced toxicity. Seven Grade 3 toxicities occurred (3.4%; 95% CI, 1.4–6.9%). Most patients (95%) had excellent or good cosmetic outcomes (95% CI, 91–98%) at 12 months. Most patients (94%) had little or no pigmentation change (95% CI, 90–97%), 88% little to no size change (95% CI, 82–92%), and 87% experienced minimal shape change (95% CI, 82–92%). Conclusions Overall, Grade 3+ toxicity was rare and cosmetic outcomes were excellent. Severe toxicity with PB-IORT is similar to that reported in the TARGIT trial (3.3% rate of major toxicity) but lower than APBI (NSABP-39, 10.1% Grade 3/4 toxicities). We propose that the toxicity of PB-IORT compared with TARGIT and NSABP-39 is related to the radiation dose and delivery schedule. PB-IORT offers low-toxicity and good cosmetic outcomes when compared with other forms of APBI.

INTRODUCTION. The opioid epidemic in the United States is a public health crisis. Breast surgeons are obligated to provide good pain control for their patients after surgery but also must minimize administration of narcotics to prevent a surgical episode of care from becoming a patient’s gateway into opioid dependence. METHODS. A survey to ascertain pain management practice patterns after breast surgery was performed. A review of currently available literature that was specific to breast surgery was performed to create recommendations regarding pain management strategies. RESULTS. A total of 609 surgeons completed the survey and demonstrated significant variations in pain management practices, specifically within regards to utilization of regional anesthesia (e.g., nerve blocks), and quantity of prescribed narcotics. There is excellent data to guide the use of local and regional anesthesia. There are, however, fewer studies to guide narcotic recommendations; thus, these recommendations were guided by prevailing practice patterns. CONCLUSIONS. Pain management practices after breast surgery have significant variation and represent an opportunity to improve patient safety and quality of care. Multimodality approaches in conjunction with standardized quantities of narcotics are recommended.

Objective Breast fibroadenomas (FAs) are common, benign, and often bothersome. Current management includes observation or surgical excision. This study evaluated the safety and feasibility of ultrasound-guided high-intensity focused ultrasound ablation for the treatment of FAs. Methods Twenty women with a palpable, biopsy-confirmed FA were enrolled in a prospective trial, and they underwent treatment utilizing an ultrasound-guided high-intensity focused ultrasound ablation device. Tumors were greater than 1 cm in diameter, with volumes of 0.3–10 cc. Safety, treatment experience, toxicity, cosmesis, and change in tumor size on palpation and ultrasound measurement were obtained before and after treatment at 3, 6, and 12 months. Results All of the 20 patients completed therapy. Pretreatment mean tumor volume was 1.8 cc (standard deviation = 1.23, range 0.57–5.7). Half of the patients reported a painful mass before treatment. All adverse events were well tolerated and transient, with the most common being mild pain, reported by 15 of 20 patients during treatment, and 14 of 20 at the day-7 postprocedure follow-up. Mean pain score during treatment was 16, and at day 7, it was 12.2, on a scale from 0 to 100 (100 = worst pain). Mean patient satisfaction was 4.4 on a scale of 1–5 (5 = most satisfied). Mean likelihood of recommending treatment was 4.7 (5 = most likely). At the 12-month postprocedure follow-up, the mean reduction in volume of the FA was 65.5% on ultrasound; the mass was no longer palpable in 80% of the patients; no patients reported pain; and cosmesis was rated as excellent in all patients. Conclusion Ultrasound-guided high-intensity focused ultrasound ablation appears to be effective, safe, and well tolerated for the treatment of FAs. A larger multicenter clinical trial is currently under way.

Breast cancer treatment has evolved through continuous integration of technological advances and changes in our understanding of tumor biology. Radical mastectomy was the best operation for the technology and beliefs of its time. Advances in technology, the acknowledgement that care is best delivered through a multi-modal approach, and continued investigation have resulted in less disfiguring procedures. Ablative therapy for the treatment of breast cancer is the natural continuation of this trend. Data from breast cancer ablation trials utilizing various energy forms have been favorable and have led to the development of ongoing multi-center treat and observe studies. This paper examines the current status of cryoablation, laser ablation, and focused ultrasound ablation for the treatment of breast cancers. The advantages and shortcomings of each technique are considered and the challenges to be met in order for ablative therapy to become a mainstream clinical treatment of breast cancer are discussed.

Intraoperative radiation therapy (IORT) involves the application of high dose radiation (HDR) to adjacent tissue following surgical resection of a tumor. Recently, it was shown that X-ray CT provides clinically useful image guidance to better verify the presence of air voids, or adjacency to skin or bone, that determine optimal, and safe, dosing. As a lower cost, safer and real-time alternative, we assembled a prototype ultrasound device to provide real-time intraoperative image guidance, viewed from within the minimally invasive HDR applicator, as a substitute for X-ray CT. Sequences of offset 2D image planes were interpolated to a 3D grid image data set. Imaging resolution was spatially variant (approximately 0.5 mm axial, 2 mm azimuth). We successfully conducted a single human patient study, involving a breast cancer resection, in an intraoperative setting. Despite a number of practical challenges relating to the dimensions and materials of the components employed, the prototype device worked satisfactorily. Air voids were readily evident in the reconstructed images. In addition to breast cancer, the method has applicability in other cancers involving tumor resection - e.g. prostate cancer.

Purpose We evaluated the use of ultrasound imaging within a brachytherapy applicator as a method for applicator positioning, evaluation, and treatment planning in a series of in vitro, cadaver, and human studies. Methods and Materials We evaluated the performance of a prototype system comprising a small ultrasound imaging catheter inserted within the lumen of a balloon brachytherapy catheter. We tested the device in an ultrasound phantom, in human breast tissue, and in an endoscopic ultrasound catheter in cadaveric breast tissue. We evaluated the visualization of adjacent tissue to consider future development of a similar system for use in brachytherapy and intraoperative radiation therapy. Results Based on the ultrasound images obtained in an ultrasound phantom, cadaveric breast, and human participants, we observed that an ultrasound imaging catheter placed within the lumen of a brachytherapy applicator can effectively image adjacent tissue, ribs, and air voids, with appropriate quality to support clinical use. We observed high correlation in clinically useful information detected on ultrasound and comparative CT, with ultrasound spatial resolution near 1 mm (spatially variant). Conclusions The findings from our pilot work suggest that real-time ultrasound imaging, operated from within the applicator, is a promising technique for image guidance and treatment planning during brachytherapy and intraoperative radiation therapy. Further expansion of this technology for clinical use will require development of a cohesive system of components to suit specific clinical applications.

Opioid overdose accounted for more than 47,000 deaths in the United States in 2018. The risk of new persistent opioid use following breast cancer surgery is significant, with up to 10% of patients continuing to fill opioid prescriptions one year after surgery. Over prescription of opioids is far too common. A recent study suggested that up to 80% of patients receiving a prescription for opioids post-operatively do not need them (either do not fill the prescription or do not use the medication). In order to address this important issue, The American Society of Breast Surgeons empaneled an inter-disciplinary committee to develop a consensus statement on pain control for patients undergoing breast surgery. Representatives were nominated by the American College of Surgeons, the Society of Surgical Oncology, The American Society of Plastic Surgeons, and The American Society of Anesthesiologists. A broad literature review followed by a more focused review was performed by the inter-disciplinary panel which was comprised of 14 experts in the fields of breast surgery, anesthesiology, plastic surgery, rehabilitation medicine, and addiction medicine. Through a process of multiple revisions, a consensus was developed, resulting in the outline for decreased opioid use in patients undergoing breast surgery presented in this manuscript. The final document was reviewed and approved by the Board of Directors of the American Society of Breast Surgeons.

Background Nearly half of the patients with breast cancer experience clinically significant mental distress within the first year of receiving their cancer diagnosis. There is an urgent need to identify scalable and cost-efficient ways of delivering empirically supported mental health interventions to patients with breast cancer. Objective The aim of this study was to evaluate the feasibility of in-clinic recruitment for a mobile phone app study and to evaluate the usability and preliminary impact of a suite of mental health apps (IntelliCare) with phone coaching on psychosocial distress symptoms in patients recently diagnosed with breast cancer. Methods This pilot study adopted a within-subject, 7-week pre-post study design. A total of 40 patients with breast cancer were recruited at a US National Cancer Institute–designated clinical cancer center. Self-reported distress (Patient Health Questionnaire-4) and mood symptoms (Patient-Reported Outcomes Measurement Information System depression and anxiety scales) were assessed at baseline and postintervention. App usability was assessed at postintervention. Results The minimum recruitment threshold was met. There was a significant decrease in general distress symptoms, as well as symptoms of depression and anxiety, from baseline to postintervention. Overall, participants reported high levels of ease of app use and learning. Scores for app usefulness and satisfaction were reinforced by some qualitative feedback suggesting that tailoring the apps more for patients with breast cancer could enhance engagement. Conclusions There is a dire need for scalable, supportive interventions in cancer. The results from this study inform how scalable mobile phone–delivered programs with additional phone support can be used to support patients with breast cancer. International Registered Report Identifier (IRRID) RR2-10.2196/11452

BACKGROUND Completion of prescribed neoadjuvant chemotherapy for breast cancer is paramount to patients obtaining full benefit from the treatment; however, factors affecting neoadjuvant chemotherapy completion are not known. We hypothesized that race is a predictor of completion of neoadjuvant chemotherapy in patients with breast cancer. METHODS All patients with breast cancer treated with neoadjuvant chemotherapy 2009-2016 at a single institution were stratified by completion of neoadjuvant chemotherapy and by race. Univariate analysis and multivariable logistic regression were used to identify patient and tumor characteristics that affected the rate of neoadjuvant chemotherapy completion. RESULTS A total of 92 (74%) of 124 patients completed their prescribed neoadjuvant chemotherapy. On univariate analysis, white patients were more likely to complete neoadjuvant chemotherapy than non-white patients (76% vs 50%, P = .006). Non-white patients were more likely to have government insurance and larger prechemotherapy tumors (both, P < .05), but these factors were not associated with rates of neoadjuvant chemotherapy completion. After controlling for age, insurance status, tumor size, and estrogen receptor status, whites remained associated with completion of neoadjuvant chemotherapy (OR 3.65, P = .014). CONCLUSION At our institution, white patients with breast cancer were more likely than non-white patients to complete neoadjuvant chemotherapy. Further investigation into the underlying factors impacting this disparity is needed.

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER+) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies. Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER+ breast cancer susceptible to endocrine-based therapies. Cancer Res; 78(8); 2014–25. ©2018 AACR.

Background Breast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial. Methods A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, −A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays. Results Twelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series. Conclusions Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination. Trial registration ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960 Electronic supplementary material The online version of this article (10.1186/s40425-017-0295-5) contains supplementary material, which is available to authorized users.

Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo. Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo. Mol Cancer Ther; 15(11); 2598–608. ©2016 AACR.

Existing intraoperative radiation therapy (IORT) techniques are criticized for the lack of image guided treatment planning and energy deposition with, at times, poor resultant dosimetry and low radiation dose. We pioneered a novel method of IORT that incorporates customized, computed tomography (CT)-based treatment planning and high-dose-rate (HDR) brachytherapy to overcome these drawbacks: CT-HDR-IORT.A phase 1 study was conducted to demonstrate the feasibility and safety of CT-HDR-IORT. Eligibility criteria included age ≥50 years, invasive or in situ breast cancer, tumor size3 cm, and N0 disease. Patients were eligible before or within 30 days of breast-conserving surgery (BCS). BCS was performed, and a multilumen balloon catheter was placed. CT images were obtained, a customized HDR brachytherapy plan was created, and a dose of 12.5 Gy was delivered to 1-cm depth from the balloon surface. The catheter was removed, and the skin was closed. The primary endpoints were feasibility and acute toxicity. Feasibility was defined as IORT treatment interval (time from CT acquisition until IORT completion) ≤90 minutes. The secondary endpoints included dosimetry, cosmetic outcome, quality of life, and late toxicity.Twenty-eight patients were enrolled. The 6-month follow-up assessments were completed by 93% of enrollees. The median IORT treatment interval was 67.2 minutes (range, 50-108 minutes). The treatment met feasibility criteria in 26 women (93%). The dosimetric goals were met in 22 patients (79%). There were no Radiation Therapy Oncology Group grade 3+ toxicities; 6 patients (21%) experienced grade 2 events. Most patients (93%) had good/excellent cosmetic outcomes at the last follow-up visit.CT-HDR-IORT is feasible and safe. This promising approach for a conformal, image-based, higher-dose breast IORT is being evaluated in a phase 2 trial.

Purpose A multidisciplinary team at our institution developed a novel method of intraoperative breast radiation therapy (precision breast intraoperative radiation therapy [PB-IORT]) that uses high-dose-rate brachytherapy with CT on-rails imaging to deliver high-dose, customized radiotherapy to patients with early-stage breast cancer. This report summarizes our program's experience developing and implementing PB-IORT. Methods and Materials Literature on PB-IORT was reviewed including published articles and abstracts. To evaluate case volume, all patients with a breast cancer diagnosis who underwent breast surgery or breast radiation (2010–2017) at our academic institution were identified. Patients were stratified into pre-IORT and post-IORT eras with initiation of our PB-IORT program in October 2013. Overall trends in surgical and radiation therapy volume in each era were analyzed by linear regression. Travel distance for all surgical patients was calculated using Google Maps (Alphabet Inc.) and then compared between IORT and non-IORT patients. Results Data from a PB-IORT Phase 1 trial found that the primary endpoints were met and that PB-IORT is feasible and safe. The direct health system's delivery costs for PB-IORT exceed those of 16-fraction whole-breast irradiation when accounting for consumable supplies (multilumen balloon applicator = $2,750 per patient). There was a significant increase in yearly growth of breast cancer surgical volume with PB-IORT. Conclusions Accrual rates for the ongoing Phase II trial have been quicker than expected in an area where more research is needed. The rapid accrual indicates patient interest and demand for this treatment and that it is very feasible to get more data from randomized trials.

BACKGROUND Obesity and breast density are associated with breast cancer in postmenopausal women. Bariatric surgery effectively treats morbid obesity, with sustainable weight loss and reductions in cancer incidence. We evaluated changes in qualitative and quantitative density; hypothesizing breast density would increase following bariatric surgery. METHODS Women undergoing bariatric surgery from 1990 to 2015 were identified, excluding patients without a mammogram performed both before and after surgery. Changes in body mass index (BMI), time between mammograms and surgery, and American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) scores were assessed. VolparaDensity™ automated software calculated volumetric breast density (VBD), fibroglandular volume (FGV), and total breast volume for the 82 women with digital data available. Differences between pre- and postsurgery values were assessed. RESULTS One hundred eighty women were included. Median age at surgery was 50.0 years, with 8.8 months between presurgery mammogram and surgery and 62.3 months between surgery and postsurgery mammogram. Median BMI significantly decreased over the study period (46.0 vs 35.4 kg/m2 ; P

BACKGROUND Over one-third of cancer patients experience clinically significant mental distress, and distress in caregivers can exceed that of the cancer patients for whom they care. There is an urgent need to identify scalable and cost-efficient ways of delivering mental health interventions to cancer patients and their loved ones. OBJECTIVE The aim of this study is to describe the protocol to pilot a mobile app–based mental health intervention in breast cancer patients and caregivers. METHODS The IntelliCare mental health apps are grounded in evidence-based research in psychology. They have not been examined in cancer populations. This pilot study will adopt a within-subject, pre-post study design to inform a potential phase III randomized controlled trial. A target sample of 50 individuals (with roughly equal numbers of patients and caregivers) at least 18 years of age and fluent in English will be recruited at a US National Cancer Institute designated clinical cancer center. Consent will be obtained in writing and a mobile phone will be provided if needed. Self-report surveys assessing mental health outcomes will be administered at a baseline session and after a 7-week intervention. Before using the apps, participants will receive a 30-min coaching call to explain their purpose and function. A 10-min coaching call 3 weeks later will check on user progress and address questions or barriers to use. Self-report and semistructured interviews with participants at the end of the study period will focus on user experience and suggestions for improving the apps and coaching in future studies. RESULTS This study is ongoing, and recruitment will be completed by the end of 2018. CONCLUSIONS Results from this study will inform how scalable mobile phone-delivered programs can be used to support breast cancer patients and their loved ones. CLINICALTRIAL ClinicalTrials.gov NCT03488745; https://clinicaltrials.gov/ct2/show/NCT03488745 INTERNATIONAL REGISTERED REPOR DERR1-10.2196/11452

Historically, through the conduct of prospective clinical trials, breast cancer surgeons have performed less radical breast and axillary surgeries with no survival decrement to our patients. Currently, other opportunities exist for the treating breast surgeon to do less. Possibilities include active surveillance for ductal carcinoma in situ, ablative therapy for small primary breast cancers, selective omission of a sentinel node biopsy, and selective elimination of breast surgery after neoadjuvant systemic therapy. Breast surgeons must be leaders in the development and testing of effective therapy with the least intervention possible.

Introduction Intraoperative radiation therapy (IORT) is an alternative to whole breast radiation following breast conserving surgery. Conventional breast IORT is limited by lack of cross-sectional imaging. In response, our institution developed Precision Breast IORT (PB-IORT) which utilizes intraoperative computed tomography (CT) images for confirmation of brachytherapy applicator placement and for treatment planning. The purpose of this study was to determine the utility of CT imaging in PB-IORT in the first 103 patients treated in two prospective clinical trials. Methods We retrospectively reviewed the first 103 patients treated with PB-IORT. All patients underwent breast surgery and placement of a multi-lumen brachytherapy applicator. Patients had a CT scan followed by high-dose-rate (HDR) brachytherapy. Endpoints were the number of patients having more than one CT during PB-IORT and the number of treatment plans having image-based modifications. Results After initial CT scan, 27 patients (26.2%) had findings prompting surgical applicator adjustment. One patient underwent an additional scan to localize a biopsy clip and aid in excision to negative margin. Eighty-one patients (78.6%) had dosimetry modifications based on CT findings with 36 plans (35.0%) adjusted to protect the skin or chest wall and 45 plans (43.7%) to protect both the skin and chest wall. Conclusions Computed tomography findings prompted treatment alterations in the majority of patients treated with PB-IORT to enhance tissue conformity and to sculpt the radiation dose away from normal tissues. CT imaging is unique to PB-IORT. These findings suggest the potential clinical superiority of PB-IORT given its allowance for patient-specific alterations.

Purpose Intraoperative radiation therapy (IORT) is an increasingly popular approach to breast conserving therapy in the treatment of early-stage breast cancer. A drawback to IORT compared with postoperative adjuvant radiation therapy is that it is not performed using image guidance. Our aim was to report on how our institution's unique IORT workflow integrates CT image guidance and how these CT images were used intraoperatively to change applicator positioning. Methods and Materials We retrospectively reviewed the first 29 patients who participated in a prospective clinical trial of breast IORT at our institution. All patients underwent lumpectomy, multicatheter balloon placement, intraoperative CT scan, and high-dose-rate brachytherapy treatment delivery to 12.5 Gy to 1 cm from the balloon surface. This report focuses on the intraoperative CT findings that led to clinical changes, followed by repeat CT for IORT treatment planning. Results After initial intraoperative CT, 7 patients underwent an additional intraoperative CT scan (24.1%). In 6 patients, the initial intraoperative CT scan identified large air cavities and/or poor tissue conformity. This defect could be improved in all patients with adjustment of the balloon applicator before planning and delivering IORT. Intraoperative CT scan was used in one patient to localize a biopsy clip and aided in excision to negative margin. Conclusions In our study, intraoperative CT identifies actionable findings in breast IORT, including residual tumor or errors in applicator positioning, in almost 25% of patients. Clinical results of the described trial will serve to further validate this image-guided approach to IORT.

Glenda G. Callender, MD, Brian J. Kaplan, MD, Richard L. White, MD, David R. Brenin, MD, Anees B. Chagpar, MD, MSc, MA, MPH, MBA, Kimberly M. Dalal, MD, Marissa Howard-McNatt, MD, James Howe, MD, Joseph Kim, MD, Scott H. Kurtzman, MD, John C. Mansour, MD, Elizabeth A. Mittendorf, MD, PhD, John H. Stewart IV, MD, Larissa K. F. Temple, MD, Patti Stella, BA, CCMEP, Charmaine Cummings, PhD, RN, CCMEP, Sandra L. Wong, MD, MS, and V. Suzanne Klimberg, MD

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to anti-estrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of ER+ breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N-terminus to activate a pro-neoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Anti-estrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to anti-estrogen therapies.

Paraneoplastic cerebellar degeneration (PCD) is a rare anti-Yo mediated paraneoplastic syndromes rarely that is infrequently associated with breast cancer. We present a case of a 52-year-old female presenting with diplopia, gait instability, dysarthria, dysphagia, nystagmus, and, most notably, new onset paroxysmal episodes of uncontrollable crying concerning for pseudobulbar affect (PBA). Serologic testing showed anti-Yo antibodies. The patient was found to have stage IIIA breast cancer as the inciting cause of the paraneoplastic syndrome. The patient was treated with neoadjuvant chemotherapy, modified radical mastectomy, adjuvant Herceptin, and pertuzumab. She was given IVIG for paraneoplastic syndrome, antidepressants, and dextromethorphan-quinidine (Nuedexta), the first FDA-approved therapy for PBA. With multimodality therapy, she demonstrated significant improvement in neurologic and mood symptoms associated with PCD and PBA.

Purpose At our institution, the availability of a shielded procedure room with in-room CT-on-rails imaging allows for the exploration of a high-dose-rate (HDR) brachytherapy approach for breast intraoperative radiation therapy (IORT). We hypothesize that HDR brachytherapy will permit a higher prescription dose without increasing toxicity. In this study, we compare the dosimetry of intraoperative HDR brachytherapy, using multilumen balloon applicator, to IORT with a 50 kV source and then select a prescription dose for a subsequent clinical trial. Methods and Materials The CT scans of 14 patients who had previously received multilumen balloon-based breast brachytherapy were replanned to a standard prescription to the target volume. The same 14 cases were planned to the specifications of a 50 kV x-ray system. Uniform volume optimization and prescription doses were used to permit direct comparisons. All plans were evaluated for the dose homogeneity index, tumor coverage, and dose to normal tissues, including skin, ribs, and heart (for left breast plans). Results The HDR brachytherapy plans were superior to 50 kV superficial photon plans for IORT in all dosimetric parameters except for the heart and rib dosimetric parameters. Prescription dose of 12.5 Gy to the planning target volume for evaluation yielded a dose to 95 percent of the balloon surface of 19.7 Gy. Conclusions Image-guided HDR intraoperative brachytherapy with a multilumen balloon applicator provides superior target volume coverage compared with 50 kV photons, while maintaining doses within tolerance limits for normal tissues. An ongoing prospective clinical trial will evaluate the safety and feasibility of this technique.

National guidelines recommend one dose of perioperative antibiotics for breast surgery and discourage postoperative continuation. However, reported skin and soft tissue infection (SSI) rates after mastectomy range from 1-26 %, higher than expected for clean cases. Utility of routine or selective postoperative antibiotic use for duration of drain presence following mastectomy remains uncertain.This study included all female patients who underwent mastectomy without reconstruction at our institution between 2005 and 2012. SSI was defined using CDC criteria or clinical diagnosis of cellulitis. Information on risk factors for infection (age, body mass index [BMI], smoking status, diabetes, steroid use), prior breast cancer treatment, drain duration, and antibiotic use was abstracted from medical records. Multivariable logistic regression was used to assess the association between postoperative antibiotic use and the occurrence of SSI, adjusting for concurrent risk factors.Among 480 patients undergoing mastectomy without reconstruction, 425 had sufficient documentation for analysis. Of these, 268 were prescribed antibiotics (63 %) at hospital discharge. An overall SSI rate of 7.3 % was observed, with 14 % of patients without postoperative antibiotics developing SSI compared with 3.4 % with antibiotics (p 0.0001). Factors independently associated with SSI were smoking and advancing age. Diabetes, steroid use, BMI, prior breast surgery, neoadjuvant chemotherapy, prior radiation, concomitant axillary surgery, and drain duration were not associated with increased SSI rates.SSI rates among patients who did and did not receive postoperative antibiotics after mastectomy were significantly different, particularly among smokers and women of advanced age. These patient subgroups may warrant special consideration for postoperative antibiotics.

The original version of this article unfortunately contained a mistake in the article title. The captured title was “Local-Regional Evaluation and Therapy (D Euhus, Section Editor)” instead of “Ablative Treatment of Breast Cancer; Are We There Yet?”

Appropriate utilization of treatment is a goal for all patients undergoing cancer treatment. Proper treatment maximizes benefit and limits exposure to unnecessary measures. This report describes findings of the feasibility and acceptability of implementing a short, clinic-based decision aid and presents an in-depth clinical profile of the participants.This descriptive study used a prospective, quantitative approach to obtain the feasibility and acceptability of a decision aid (DecisionKEYS for Balancing Choices) for use in clinical settings. It combined results of trials of patients with three different common malignancies. All groups used the same decision aid series. Participants included 80 patients with solid tumors (22 with newly diagnosed breast cancer, 19 with advanced prostate cancer, and 39 with advanced lung cancer) and their 80 supporters as well as their physicians and nurses, for a total of 160 participants and 10 health professionals.The decision aid was highly acceptable to patient and supporter participants in all diagnostic groups. It was feasible for use in clinic settings; the overall value was rated highly. Of six physicians, all found the interactive format with the help of the nurse as feasible and acceptable. Nurses also rated the decision aid favorably.This intervention provides the opportunity to enhance decision making about cancer treatment and warrants further study including larger and more diverse groups. Strengths of the study included a theoretical grounding, feasibility testing of a practical clinic-based intervention, and summative evaluation of acceptability of the intervention by patient and supporter pairs. Further research also is needed to test the effectiveness of the decision aid in diverse clinical settings and to determine if this intervention can decrease overall costs.

TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.

Objective This study was conducted to evaluate a computer-imaging program called HAAIR (Help with Adjustment to Alopecia by Image Recovery) that was developed to provide educational support and reduce distress in women with hair loss following chemotherapy.

The task of breaking bad news, whether news of need for biopsy or a new breast cancer diagnosis, is increasingly performed by breast imaging radiologists. Most radiologists have little exposure to didactic teaching or modeling for learning methods of breaking bad news. Understanding barriers for communicating bad news and general improvements in communication, such as avoiding jargon and active listening, are initial steps in learning this important task. Bad news should be communicated to a patient in a supportive environment and directly in simple, but not blunt, terms. The amount of news delivered at any one time must be judged by a patient's response. It may be preferable to deliver bad news in smaller portions to allow time for a patient to cope. The use of a "warning shot," particularly at the time of diagnostic imaging, can be helpful to alert patients to forthcoming bad news. Common patient responses to bad news include shock, disbelief, denial, fear, anger, and guilt. An empathetic response from a physician demonstrates support. In breast imaging, providing a patient with perspective about her risk for breast cancer or the characteristics of the cancer if early may instill hope without giving false reassurance. Establishing a plan, typically an appointment with a breast surgeon in the setting of breast cancer, allows a patient to have a sense of control over her disease. Offering additional support also demonstrates empathy. The task of delivering bad news is an important task that, if done well, improves patients' ability to cope with their disease.

Fibroadenomas are common, benign lesions of the breast. A minority of fibroadenomas will disappear without treatment, but most increase in size or remain unchanged. Current management of patients with fibroadenomas in the United States varies on a case by case basis and includes observation or surgical excision. Many patients find their fibroadenoma bothersome, and opt for surgical excision. The objectives of this study are to evaluate the safety and feasibility of Ultrasound guided High Intensity Focused Ultrasound (USgHIFU) delivered by the Echopulse device (Theraclion, Paris) for treatment of breast fibroadenomas. General patient safety, cosmetic outcome, tumor response, patient experience, physician/operator experience, and device performance will be assessed.

Background One of the modalities of treatment for breast cancer surgery pain is opioids, and opioids are associated with adverse effects such as itching and postoperative nausea and vomiting (PONV). Intravenous (IV) lidocaine has been shown to reduce opioid consumption and to improve overall postoperative outcomes in abdominal surgery. In this study, we tested the effect of intraoperative IV lidocaine infusion on the quality of postoperative recovery after breast cancer surgery. Methods Seventy-one patients undergoing breast cancer surgery were randomly assigned to receive either placebo (group P; n = 34) or IV lidocaine (group L; n = 37, bolus 1.5 mg/kg at induction, then infusion at 2 mg/kg/h, stopped 2 hours after the end of surgery) in a prospective double-blind design. Intraoperative and postoperative morphine consumption was calculated. Postoperative pain scores, PONV, and fatigue were assessed at 2, 24, and 48 hours after surgery. Duration of postoperative hospital stay was recorded. Results Demographics were the same between the groups. There was no statistically significant difference in intraoperative or postoperative morphine consumption (P = 0.188 and P = 0.758) between groups. Overall pain scores either at rest or activity (P = 0.348 and P = 0.810, respectively), PONV (P = 0.350), fatigue (P = 0.758), or duration of postoperative hospital stay (P = 0.218) were not statistically different. Conclusions Our findings did not show a significant effect of IV lidocaine during breast cancer surgery on opioid consumption, pain score, PONV, or fatigue, indicating that the benefit of this approach does not generalize across all types of surgery.

Occult breast cancer presenting with axillary metastases is an unusual presentation and can be a diagnostic and therapeutic challenge. A comprehensive work-up, including mammogram, sonogram, magnetic resonance imaging, and even pathologic examination of the mastectomy specimen may not disclose the primary tumor in up to one third of patients. Traditionally, occult breast cancer is treated with total mastectomy and axillary dissection, but accumulating data suggest that primary breast irradiation following axillary dissection may provide an equivalent survival with the advantage of breast conservation. Occult breast cancer patients are eligible for adjuvant chemotherapy and radiation as stage II/ III node-positive patients would be treated. Overall, the prognosis for occult breast cancer is equivalent to or slightly better than staged counterparts with detectable primary breast tumors.

Background: The current AJCC protocol for breast cancer staging does not include additional tumor found at the time of re-excision in the calculation of tumor size. We hypothesize that the AJCC protocol may result in understaging and undertreatment of breast cancer patients who have additional tumor found at re-excision. Methods: In a retrospective chart review of breast cancer patients, patients with tumor present at re-excision for positive margins were placed in group 1 (n=72); patients with no tumor present at re-excision, or who underwent a single, negative margin procedure were placed in group 2 (n=147). Results: Patients in group 1 had a higher risk of nodal metastases when compared to patients in group 2. Mean tumor size did not differ significantly between the subgroups. Positive re-excision was strongly associated with lymph node metastases on multivariate analysis after correction for age, grade, stage, and lymphatic invasion (odds ratio=3.13, 95% CI=1.58 6.18,P=.0011). Conclusions: Current AJCC guidelines may result in undertreatment of breast cancer patients with positive re-excisions. The presence of additional tumor at the time of re-excision should be considered when determining the need for systemic therapy, and may be relevant in determining T stage.

More women with breast cancer who either have already had radiation therapy or will be getting radiation therapy as part of their treatment protocol are now seeking implant-based breast reconstruction. The literature on the success of this type of reconstruction in the setting of radiation injury is mixed.A single reconstructive surgeon's experience over a 10-year period with implant-based, two-stage breast reconstruction was retrospectively examined. A total of 267 breasts in 194 patients were included in the study and divided into three groups. Reconstruction was performed for breasts that had no radiation exposure (n = 218), radiation exposure before mastectomy/reconstruction (n = 32), or radiation exposure after mastectomy and first-stage reconstruction but before completion of the second stage of reconstruction (n = 17). Age, follow-up time, history (of diabetes, smoking, and chemotherapy), body mass index, and expander volume were recorded. Logistical regression analysis was performed for major reoperative complications following the reconstruction.Radiation exposure before reconstruction resulted in a 43.8 percent complication rate, during reconstruction had a 41.2 percent complication rate, and no radiation exposure had a 13.8 percent complication rate. The most common complication in both radiation groups was wound dehiscence, but there were also a significant number of patients who had failure of expansion. In addition, smoking significantly influenced the occurrence of complications.Radiation therapy for the treatment of breast cancer significantly increased the incidence of major, reoperative complications in implant-based, two-stage breast reconstruction. Despite this high rate, however, in the present study, 80 percent of patients with major complications went on to complete their breast reconstructions with either implants or autogenous tissue.Risk, II.

Whereas guidelines supporting breast MRI in high-risk screening exist, guidelines for MRI use in newly diagnosed breast cancer are lacking. We, therefore, conducted a study of breast surgeons to determine practice beliefs surrounding MRI use in newly diagnosed breast cancer. A survey sent to 2,274 American Society of Breast Surgeons members in December 2010 queried routine MRI use (defined as >75 % of time) in specific clinical scenarios. Analyses were performed by respondent practice setting, practice volume, and practice specialization. Descriptive statistics and subgroup analysis using a χ2 and logistic regression were used. Responses from 1,012 surgeons (45.5 % response rate) were eligible for analysis. Respondents represented diverse practice settings (20 % academic, 72 % private practice) and volume (≤50 new breast cancer patients, 36 %; 51–100, 26 %; 101–200, 25 %; >200, 13 %). Also, 41 % of surgeons indicated routine MRI use for newly diagnosed patients, with higher rates of use among surgeons from high-volume practices, high specialization, and private practice. Greater consensus in routine MRI use was seen in the setting of extreme mammographic density (87.9 %), strong family history of breast cancer (73.4 %), and invasive lobular carcinoma (69.4 %). Responses were increasingly discordant in setting of pursuing breast conservation (47.4 %), invasive ductal carcinoma (41.8 %), and ductal carcinoma in situ (37.2 %). Personal experience was the most commonly cited influence on MRI use. Divergent responses in MRI use in newly diagnosed breast cancer reflect clinical uncertainty and variable practice beliefs among breast surgeons. Such diverging practice patterns highlight areas where clinical research and guidelines may be most helpful.

Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model.

Advances in technology and changes in our understanding of tumor biology have allowed breast cancer treatment to evolve toward less disfiguring procedures. Noninvasive ablative therapy is a natural continuation of this trend. The following paper presents the concepts underpinning focused ultrasound ablation therapy for the treatment of breast cancer and reviews the investigative experience to date in the evaluation of this promising technique.

This study was conducted to evaluate a computer program named Help with Adjustment to Alopecia by Image Recovery (HAAIR) that was developed to provide educational support and reduce distress in women with hair loss following chemotherapy.Forty-five women who had been diagnosed with cancer and anticipated alopecia following treatment were randomly assigned to either the Imagining group (IG) or Standardized Care group (SCG). Patients in the IG used a computer-imaging program that created the patient's image on a screen to simulate baldness and use of wigs whereas patients in the SCG were directed to a resource room at the Cancer Center established for women with chemotherapy-related alopecia. Assessment data using the Brief Symptom Inventory, Importance of Hair Questionnaire, and the Brief Cope were completed at baseline (T1), before chemotherapy and hair loss, following hair loss (T2), and 3 months follow-up (T3).All women were able to successfully use the touch screen computerized-imaging program and reported that using the computer was a positive, helpful experience, thus establishing acceptability and usability. Women in both the IG and the SCG group showed significantly lower hair loss distress scores at T2 after hair loss than at T1 with T3 distress scores increasing in the SCG and decreasing in the IG. Those with avoidance coping reported more distress.This evaluation demonstrates that the HAAIR program is a patient-endorsed educational and supportive complement to care for women facing chemotherapy-related alopecia.

Background Breast cancer treatment beliefs in areas of scientific uncertainty may contribute to widely variable practices. We sought to better describe surgeons' beliefs and to identify the relative importance of different information sources on surgeons' decision-making. Methods A total of 2,188 American College of Surgeons (ACoS) members were surveyed on their treatment beliefs in 4 controversial areas and on the perceived influence of various information sources on their decision-making. Responses were analyzed by sex, practice type, oncology training, professional society membership, and breast cancer patient volume. Results Nine hundred twenty-three responses were received, with 459 eligible for analysis. Responses diverged most regarding significance of positive sentinel lymph node biopsy (SNLB) and role of post-lumpectomy radiation for low-risk ductal carcinoma-in-situ (DCIS). Overall, expert opinion ranked as the most influential information source. Conclusions Axillary dissection after positive SLNB and post-lumpectomy radiation in low-risk DCIS denoted areas of greater uncertainty. Breast cancer opinion leaders have substantial influence when standard practice is uncertain.