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Historically, radiotherapy fractionation for early-stage breast cancer primarily consisted of 1.8-2 Gy per fraction given once daily to a total dose of 45-66 Gy over 5-7 weeks for whole breast treatment. Partial breast treatment employed larger dose per fraction (3.4-3.85 Gy) in 10 fractions given twice daily over 1 week. Radiobiologically, breast cancer is increasingly appreciated as a low alpha-beta ratio malignancy that is best treated with larger dose per fraction. Over the past 10 years, there have been increasing data from multiple large randomized clinical trials that support the use of shorter treatment courses: first hypofractionated regimens consisting of 15-20 treatments, and more recently, ultra-hypofractionated regimens as short as 5 treatments. Simultaneously, data from modern partial breast irradiation (PBI) trials support once daily treatment regimens ranging from 1-5 treatments. Shorter treatment courses represent less treatment burden on patients, reduced financial impact, and potentially improved access to care for patients with transportation and/or socioeconomic barriers. Here we review the evolution of whole and partial breast treatment regimens for early-stage breast cancer.

Objectives: The machine learning (ML)-based automated treatment planning tool has been developed and evaluated for whole breast radiotherapy. This study implemented the tool in clinic and compared plan quality and planning efficiency with the manual treatment process for whole breast radiotherapy using irregular surface compensator technique. Methods: This study involved two phases. The 1st phase was to evaluate and the 2nd phase was to implement in the clinic. In the 1st phase, thirty whole breast or chest wall cases were planned by using the irregular surface compensator technique with fluence maps manually and iteratively edited to achieve uniform dose distribution to the target by planners. Patients were treated with these manual plans after physician’s approval. The evaluation phase thus compared our in-house ML-based automated treatment planning tool implemented in Eclipse Scripting Application Programming Interface (ESAPI) to these manual plans. The ML-based planning tool generated the fluence maps with the same beam parameters such as beam energy, gantry angle, collimator angle, and aperture shape as manual plans. Breast or chest wall clinical target volume (CTV) coverage based on the percentage CTV volume receiving 95% of the prescribed dose (V95%) and high-dose volume based on V105% were compared to evaluate the plan quality as well as the planning efficiency. Two-tailed Wilcoxon Signed-Rank test was performed to test the null hypothesis that the two planning schemes yield equivalent plan quality. In the 2nd phase, the planners used the automated planning tool for fourteen plans (twelve patients) followed by manual fluence modification as needed. Physicians reviewed and approved the plans, and patients were treated. Results: For the 1st phase, the mean planning time was 110.2 min with standard deviation (SD) of 62.8 min for the manual planning with the range from 25 to 270 min, and 6.4 min with SD of 2.1 min for the automated planning with the range from 4 to 12 min (p For the 2nd phase, the mean planning time was 16.4 min (SD: 9.1 min) and the mean time for additional manual editing was 12.7 min (SD: 12.5 min). The mean total treatment planning time was 29.1 min (SD: 14.8 min).). CTV mean V95% was 97.2% (SD: 4.2%) and mean V105% was 8.2 % (SD: 3.6%). The manual post modifications were added by the planners with intention to improve the target coverage or to reduce high doses, yet, the difference between the plans without and without the manual post modification was negligible. Conclusion: The ML-based automated treatment planning tool through Varian ESAPI has been successfully implemented for clinical use going through two phases of study. Abiding to the same plan quality as manual process, the automated tool significantly reduced the planning time as the ML-based tool automate the iterative fluence editing process. Citation Format: Sua Yoo, Yang Sheng, Rachel Blitzblau, Suzanne Catalano, Jay Morrison, Leigh O'Neill, Fangfang Yin, Q. Jackie Wu. Clinical implementation of the machine learning-based automated treatment planning tool for whole breast radiotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-10.

Complications from breast reconstruction may delay postmastectomy radiation therapy and impact breast cancer outcomes. The authors hypothesized that immediate breast reconstruction may be associated with delays in the initiation of radiation, but that this delay would not significantly impact overall patient survival.Using the National Cancer Database, the authors identified women with breast cancer who underwent mastectomy and received postmastectomy radiation therapy. Delayed radiation was defined as treatment initiated 6 months or more after surgery in patients who received adjuvant chemotherapy or 12 weeks or more after surgery in patients who received neoadjuvant or no chemotherapy.Women undergoing breast reconstruction had an increased time to postmastectomy radiation therapy, 154 days versus 132 days (p0.001), and were more likely to experience a delay in initiating radiation (OR, 1.25; 95 percent CI, 1.188 to 1.314). Other factors associated with delayed radiation included increased Charlson/Deyo scores, neoadjuvant chemotherapy, nonprivate insurance, and black race. Cox proportional hazards models revealed no evidence of a reduced adjusted overall survival in the immediate breast reconstruction group (hazard ratio, 0.836; 95 percent CI, 0.802 to 0.871; p0.001). Restricted cubic spline analysis identified the threshold number of days at which the start of radiation began to impact survival at 169 days (95 percent CI, 160 to 190 days), 75 days (95 percent CI, 42 to 90 days), and 71 days (95 percent CI, 41 to 90 days) in patients undergoing adjuvant, neoadjuvant, and no chemotherapy, respectively.Immediate breast reconstruction is associated with a modest delay in initiating postmastectomy radiation therapy but does not impact overall survival.Therapeutic, III.

Purpose: The machine learning–based automated treatment planning (MLAP) tool has been developed and evaluated for breast radiation therapy planning at our institution. We implemented MLAP for patient treatment and assessed our clinical experience for its performance. Methods and Materials: A total of 102 patients of breast or chest wall treatment plans were prospectively evaluated with institutional review board approval. A human planner executed MLAP to create an auto-plan via automation of fluence maps generation. If judged necessary, a planner further fine-tuned the fluence maps to reach a final plan. Planners recorded the time required for auto-planning and manual modification. Target (ie, breast or chest wall and nodes) coverage and dose homogeneity were compared between the auto-plan and final plan. Results: Cases without nodes (n = 71) showed negligible (

Immunotherapy using immune checkpoint blockade has revolutionized the treatment of many types of cancer. Radiation therapy (RT)—particularly when delivered at high doses using newer techniques—may be capable of generating systemic antitumor effects when combined with immunotherapy in breast cancer. These systemic effects might be due to the local immune-priming effects of RT resulting in the expansion and circulation of effector immune cells to distant sites. Although this concept merits further exploration, several challenges need to be overcome. One is an understanding of how the heterogeneity of breast cancers may relate to tumor immunogenicity. Another concerns the need to develop knowledge and expertise in delivery, sequencing, and timing of RT with immunotherapy. Clinical trials addressing these issues are under way. We here review and discuss the particular opportunities and issues regarding this topic, including the design of informative clinical and translational studies.

PURPOSE: To evaluate the mammographic sequelae of preoperative accelerated partial breast irradiation (APBI) delivered via either stereotactic radiosurgery or a conventionally fractionated regimen. METHODS AND MATERIALS: This multicenter, retrospective study evaluated surveillance mammograms from patients enrolled in 2 prospective, preoperative APBI clinical trials. At 1 site, 31 patients with cT1N0 invasive carcinomas or low- or intermediate-grade ductal carcinoma in situ (

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

Introduction The purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery. Methods and materials The American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. Results For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized. Conclusions WBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.

The aim of this study was to determine whether hospital volume was associated with mortality in breast cancer, and what thresholds of case volume impacted survival.Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery.All adults (18 to 90 years) with stages 0-III unilateral breast cancer diagnosed from 2004 to 2012 were identified from the American College of Surgeons National Cancer Data Base (NCDB). A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital volume and overall survival, after adjusting for measured covariates. Intergroup comparisons of patient and treatment characteristics were conducted with X and analysis of variance (ANOVA). The log-rank test was used to test survival differences between groups. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) associated with each volume group.One million sixty-four thousand two hundred and fifty-one patients met inclusion criteria. The median age of the sample was 60 (interquartile range 50 to 70). Hospitals were categorized into 3 groups using restricted cubic spline analysis: low-volume (148 cases/year), moderate-volume (148 to 298 cases/year), and high-volume (298 cases/year). Treatment at high volume centers was associated with an 11% reduction in overall mortality for all patients (HR 0.89); those with stage 0-I, ER+/PR+ or ER+/PR- breast cancers derived the greatest benefit.Treatment at high volume centers is associated with improved survival for breast cancer patients regardless of stage. High case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment.

Purpose/objective(s) Telehealth (TH) for radiation oncology services has emerged as a new modality for care delivery and will likely persist beyond the COVID pandemic. Data regarding radiation oncology provider satisfaction of TH are limited and essential to the sustainable adoption of this tool. Materials/methods An anonymous electronic survey assessing TH experience was distributed in 11/2020 to all clinical radiation oncology physicians and APPs at a single large NCI-designated institution, including affiliate clinics. Those who utilized TH (phone or video) were invited to participate. The provider survey was designed using the technology-acceptance model (TAM), a validated method to predict use and acceptance of technology tools. Survey items included 4 assessing provider role, 1 regarding TH utilization, 26 assessing TH experience on a 5-point Likert scale, and 1 free response assessing current barriers to TH. Percent satisfaction is reported as the percentage of top 2 positive or affirmative responses on the Likert scale as a proportion of all responses. Results 19 of 34 radiation oncology providers (56%) completed the survey, including 15 attending physicians and 4 APPs. Providers specialized in central nervous system (n = 3), head and neck (n = 2), gastrointestinal (n = 1), breast (n = 2), genitourinary (n = 4), gynecological (n = 2), sarcoma (n = 1), and general oncology (n = 4). Providers reported having 1-10 (n = 5), 11-15 (n = 7), or > 20 years (n = 7) in practice. Providers utilized TH for on-treatment visits (53%), follow-ups (86%), and consults (79%). 56% of providers enjoyed experimenting with new technology and 61% felt that technological advances improved care for patients. Regarding aspects of the TH clinical encounter: providers had high satisfaction with ability to document the visit (89%), obtaining patient history (83%), and ease of discussing radiation treatment decisions (71%). There was lower satisfaction with ability to create rapport (33%), ease of obtaining consent for radiation (33%), and ease of evaluating physical exam findings (19%). Regarding workflow: 39% felt that TH was compatible with existing oncology clinical workflow, 39% felt TH gave them greater control over work, 33% providers felt that TH improved their job efficiency, and 28% felt TH made them more productive. Regarding ease of TH use: 44% felt that interacting with TH services was frustrating and 39% felt that TH services did not require much training. 24% felt the TH adequately replaced face to face visits. Providers identified the following barriers to TH implementation: lack of MA/RN/APP support, interruptions to TH visits by treatment/simulation clinical duties, lack of dedicated TH template, and burden of navigating the electronic medical record. Conclusion Radiation oncology providers at our institution expressed mixed satisfaction to incorporating TH into their practice. Current strategies to address barriers, including implementation of a telehealth care coordinator, are underway.

Introduction: Breast cancer treatment costs are rising, and identification of high-value oncology treatment strategies is increasingly needed. We sought to determine the potential cost savings associated with an evidence-based radiation treatment (RT) approach among women with early-stage breast cancer treated in the United States. Patients and Methods: Using the National Cancer Database, we identified women with T1-T2 N0 invasive breast cancers treated with lumpectomy during 2011. Adjuvant RT regimens were categorized as conventionally fractionated whole-breast irradiation, hypofractionated whole-breast irradiation, and omission of RT. National RT patterns were determined, and RT costs were estimated using the Medicare Physician Fee Schedule. Results: Within the 43,247 patient cohort, 64% (n = 27,697) received conventional RT, 13.3% (n = 5,724) received hypofractionated RT, 1.1% (n = 477) received accelerated partial-breast irradiation, and 21.6% (n = 9,349) received no RT. Among patients who were eligible for shorter RT or omission of RT, 57% underwent treatment with longer, more costly regimens. Estimated RT expenditures of the national cohort approximated $420.2 million during 2011, compared with $256.2 million had women been treated with the least expensive regimens for which they were safely eligible. This demonstrated a potential annual savings of $164.0 million, a 39% reduction in associated treatment costs. Conclusion: Among women with early-stage breast cancer after lumpectomy, use of an evidence-based approach illustrates an example of high-value care within oncology. Identification of high-value cancer treatment strategies is critically important to maintaining excellence in cancer care while reducing health care expenditures.

Breast cancer patients with overall poor health are at a greater risk of both complications during treatment and mortality from competing causes. We sought to determine the association of pre-existing comorbidities on treatment-related complications and overall survival. We identified women ages 40–90 years old from our institutional registry with stage I–II invasive breast cancer from 2005 to 2014. Recursive partitioning was used to stratify women based on pre-existing comorbidities as low, moderate, or high risk of treatment-associated complications. Cox proportional hazards model was constructed to estimate the association of risk with overall survival. 2077 women were studied. Mean age was 60 (IQR 51–68). Over half (54%) had ≥ 1 comorbid condition, and 29% experienced at least one adverse medical event within 1 year of diagnosis. Risk categories included low (no comorbidities or hypertension), moderate (combinations of comorbidities excluding congestive heart failure), and high (congestive heart failure in isolation or in combination with other conditions). High-risk women had a lower 10-year OS compared to moderate- or low-risk women (89% vs 90% vs 96%, log-rank p

1579 Background: Telehealth (TH) utilization for patients at our cancer institute increased in 2020 in response to the COVID-19 pandemic, however oncology-specific TH patient satisfaction is unknown. Methods: Monthly TH utilization at a single large NCI-designated institute from 3/1/2020-11/30/2020 was reviewed. Utilization was calculated as chargeable TH visits (new video, established video, phone) as a proportion of all consult/follow up visits. Patient satisfaction surveys for oncology TH visits for MD/PA/NP providers were reviewed from 4/1/2020-11/30/2020. Surveys were sent after every TH visit, unless the patient had a prior visit in the past 3 months. Percent (%) top box score (TBS) was defined as proportion of responses in the highest possible response category (i.e. very good). % TBS was reported for 14 survey items in 4 domains: technology, access, care provider (CP), and overall assessment. Satisfaction was assessed over time and according to patient factors: generation, gender, insurance type, employment status, and clinic site. The Cochrane-Armitage trend test was used to compare proportions of TBS responses across monthly time points. Results: TH comprised 21% (22,055/103,461) of all encounters in the study period. TH use increased from 9% in 3/2020 to a peak of 47% in 4/2020. In 11/2020, TH use was 18%. 28.0% (2,286/8,173) of TH patient surveys were returned. Multiple patient satisfaction metrics were improved over time (Table). Patients had higher satisfaction with phone compared to video visits with regards to technology (86% vs 76%) and access (80% vs 72%). Millennials (born 1981-1995) had higher satisfaction with access to TH (87%) compared to Gen X (1965-1980) (77%), Baby Boomer (1946-1964) (74%), and Silent Generation (1928-1945) (72%), however all generations had similar levels of satisfaction with technology (range 77-80%). Disabled patients had higher overall satisfaction of TH (82%) versus those working full time or retired (71%). Patients with commercial insurance had worse overall satisfaction of TH compared to other insurance types (65% vs 72%). Patients with encounters in genitourinary, thoracic, and endocrine oncology clinics had the highest levels of overall satisfaction (75%) compared to other clinics (69%). There were no observed differences in TH satisfaction according to gender. Conclusions: TH cancer patient satisfaction is high and has improved over time, however satisfaction differs by patient demographics. Further data are needed to best select patients appropriate for TH.[Table: see text]

Effective local control is associated with improved overall survival, particularly for women with early-stage cancers. No other local therapy is typically offered to women with T1-2 N0 breast cancer after mastectomy, although in select women the 5-year local recurrence rate can be as high as 20%. Therefore, accurately predicting the women who are at highest risk for recurrence after mastectomy will identify those who might benefit from more aggressive adjuvant treatment. A systematic search was conducted identifying risk factors associated with locoregional recurrence, including age, menopausal status, receptor status, lymphovascular invasion (LVI), margin status, use of systemic therapy, size, grade, and genomic classifer score. Although associations varied among studies, the risk factors most consistently identified were age ≤ 40 years, LVI, positive/close margin, and larger tumor size. In women with multiple high risk factors, risk of local recurrence was as high as 20% at 10 years. Additional multicenter studies are needed to investigate risk factors for locoregional recurrence after mastectomy without radiotherapy in T1-2N0 breast cancer. Consideration of additional adjuvant local therapy might be warranted in a subset of women at high risk of local recurrence.

Although surgical management of the axilla for breast cancer continues to evolve, axillary lymphadenectomy remains the standard of care for women with advanced nodal disease. We sought to evaluate national patterns of care in axillary surgery, and its association with overall survival (OS) among women with N2–3 invasive breast cancer. Women (18–90 years) with clinical N2–3 invasive breast cancer who underwent axillary surgery were identified from the National Cancer Data Base (NCDB) from 2004 to 2013. Axillary surgery was categorized as sentinel lymph node biopsy (SLNB, 1–5 nodes) or axillary lymph node dissection (ALND, ≥ 10 nodes). Patient and treatment characteristics, trends over time, and overall survival (OS) were compared by surgical treatment. Overall, 22,156 patients were identified. At diagnosis, 68.5% had cN2 and 31.5% had cN3 disease. Treatment included: lumpectomy (27%), mastectomy (73%), adjuvant chemotherapy (53.4%), neoadjuvant chemotherapy (NAC) (39.7%), radiation (74%), and endocrine therapy (54.4%). In total, 9.9% (n = 2190) underwent SLNB and 90.1% (n = 19,966) underwent ALND. Receipt of SLNB was associated with private insurance, grade 3 disease, invasive ductal cancer, NAC, and lumpectomy (all p

OBJECTIVE: We evaluated patterns of surgical care and their association with overall survival among a contemporary cohort of women with stage IV breast cancer. BACKGROUND: Surgical resection of the primary tumor remains controversial among women with stage IV breast cancer. METHODS: Women diagnosed with clinical stage IV breast cancer from 2003 to 2012 were identified from the American College of Surgeons National Cancer Database. Those with intact primary tumors who were alive 12 months after diagnosis were categorized by treatment sequence: (1) surgery before systemic therapy, (2) systemic therapy before surgery, and (3) systemic therapy alone. Multivariate logistic regression was used to estimate the association of treatment sequence with surgery type. Overall survival was estimated using multivariate Cox proportional hazards models. RESULTS: Among 24,015 women, 56.2% (13,505) underwent systemic therapy alone and 43.8% (10,510) underwent surgical resection. Rates of surgery decreased slightly over time (43.1% in 2003 to 41.9% in 2011). Treatment with systemic therapy before surgery was associated with larger tumor size (median 4.5 vs 3.1 cm, P < 0.001) and receipt of mastectomy (81.4% vs 52.2%, P < 0.001) when compared to those who underwent surgery first. Receipt of surgery, whether before or after systemic therapy (Hazard Ratio, 0.68; 95% confidence interval, 0.62–0.73; Hazard Ratio, 0.56; 95% confidence interval, 0.52–0.61; P < 0.001), was independently associated with improved adjusted overall survival when compared to systemic therapy alone. CONCLUSIONS: Surgical resection of the primary tumor occurs in almost half of women with stage IV breast cancer alive 1 year after diagnosis, and is increasingly occurring after systemic therapy. Coordinated multidisciplinary care remains highly relevant in the setting of metastatic breast cancer, where surgical decisions should be made on an individual basis and may affect survival in select women.

Purpose To evaluate locoregional recurrence (LRR) after mastectomy and impact of postmastectomy radiation (PMRT) by breast cancer subtype. Methods and Materials Between 2000 and 2009, 5673 patients with stage I to III breast carcinoma underwent mastectomy and nodal evaluation; 30% received PMRT. Isolated LRR (iLRR) and LRR were compared across groups defined by biological subtype and receipt of trastuzumab: luminal A (estrogen [ER]/progesterone [PR]+, HER2−, low/intermediate grade), luminal B (ER/PR+, HER2−, high grade), HER2 with trastuzumab, HER2 without trastuzumab, and triple negative (TN; ER−, PR−, HER2−). LRR hazard ratios (HR) were estimated with multivariable Fine and Gray models. The effect of PMRT on LRR was evaluated with Fine and Gray models stratified by propensity for PMRT. Results With a median follow-up time of 50.1 months, there were 19 iLRR and 109 LRR events. HER2 patients with trastuzumab had no iLRR and only a single LRR. Compared with luminal A patients, TN patients had significantly greater adjusted risk of iLRR (HR 14.10; 95% CI 2.97%-66.90%), with a similar trend among luminal B (HR 4.94; 95% CI 0.94%-25.82%) and HER2 patients without trastuzumab (HR 4.41; 95% CI 0.61%-32.11%). Although PMRT reduced LRR, the effect of PMRT varied by subgroup, with the greatest and smallest effects seen among luminal A (HR 0.17; 95% CI 0.05%-0.62%) and TN patients (HR 0.59; 95% CI 0.25%-1.35%), respectively. Conclusions TN patients had the highest risk of LRR and the least benefit from PMRT; these patients may benefit from alternative treatment strategies. In contrast, in the era of HER2-directed therapy, the role of local therapy may need to be reassessed among HER2 patients.

Purpose Diffusion of accelerated partial breast irradiation into clinical practice is limited by the need for specialized equipment and training. The accessible external beam technique yields unacceptable complication rates, likely from large postoperative target volumes. We designed a phase 1 trial evaluating preoperative radiation therapy to the intact tumor using widely available technology. Methods and materials Patients received 15, 18, or 21 Gy in a single fraction to the breast tumor plus margin. Magnetic resonance imaging (MRI) was used in conjunction with standard computed tomography (CT)-based planning to identify contrast enhancing tumor. Skin markers and an intratumor biopsy marker were used for verification during treatment. Results MRI imaging was critical for target delineation because not all breast tumors were reliably identified on CT scan. Breast shape differences were consistently seen between CT and MRI but did not impede image registration or tumor identification. Target volumes were markedly smaller than historical postoperative volumes, and normal tissue constraints were easily met. A biopsy marker within the breast proved sufficient for setup localization. Conclusions This single fraction linear accelerator–based partial breast irradiation approach can be easily incorporated at most treatment centers. In vivo targeting may improve accuracy and can reduce the dose to normal tissues.

Radiation therapy is associated with acute treatment-related complications that can lead to decreased quality of life (QOL). Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes, and acute radiation therapy toxicities.Women receiving curative breast radiation therapy were enrolled. Each patient completed an exercise behavior/QOL survey before or during the first week of treatment and again during the last week of treatment. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Measurements to evaluate upper extremity lymphedema and shoulder range of motion were completed. Skin toxicity was assessed weekly. Patient-reported outcomes were measured using standardized questionnaires.Forty-five patients were enrolled. Mean patient age was 54 (range, 28-73) years. Mean METs in the exercise cohort (≥9 METs/wk) was 21 per week (range, 11-38, n = 14); 3 per week (range, 0-8, n = 25) in the nonexercise cohort (9 METs/wk). Women in the exercise cohort showed improvements in treatment-induced quality of life and fatigue (not significant) despite more extensive surgical, medical, and radiation treatment. No differences in treatment-related toxicities, pain, or sleep scores were noted. Lymphedema was mild (3 cm) in the entire patient cohort.The vast majority of current exercise oncology literature implicates physical activity as an independent predictor of QOL in cancer patients. Our study noted similar trends, but they were not statistically significant. This may be due to our finding that patient-reported outcomes with radiation therapy are relatively high compared with other treatment modalities and remain stable throughout treatment. Thus, it may be that radiation therapy has a limited impact on QOL in breast cancer patients. Exercise may be best used as a targeted therapy in patients at high risk for poor QOL or radiation-related toxicities at baseline.

Purpose/Objectives: RT is associated with acute treatment-related complications that can lead to poor quality of life (QOL) and fatigue. Exercise has been shown in other cancer treatment settings to improve negative outcomes. We conducted a prospective pilot study to explore the association between exercise, patient-reported outcomes (PROs), and radiation therapy (RT) toxicities. Materials/Methods: Patients with surgically excised ductal carcinoma in situ or invasive breast carcinoma receiving curative radiation were enrolled. Each patient completed an exercise behavior/QOL survey at two time points: before the patient’s 5th fraction of radiation and during the last week of treatment. Limb girth measurements to evaluate lymphedema and assessment of shoulder range of motion (ROM) were completed on all patients at the same two time points. Skin toxicity was assessed weekly throughout radiotherapy. Exercise behavior was quantified with the Godin Leisure Time Exercise Questionnaire (metabolic equivalent [MET] hours per week). Patients with >7 METs/week were designated the exercise cohort (n=10) and those with Results: Median patient age was 56 (range 28-70) years. Median MET in the exercise cohort was 12.9/week (range 7.5-35.0, n=10); 0.0/week in the non-exercise cohort (range 0-5.8, n=10). Women in the exercise cohort experienced significant improvement in depression scores over the course of treatment as compared to those who did not exercise (p=0.013). Those in the exercise cohort also reported less fatigue on the FACT-Fatigue subscale at treatment completion (exercise: 133.0; non-exercise: 121.0) (p=0.6). In addition, only 30% of exercisers suffered from grade 2 dermatitis compared to 70% of non-exercisers (p=0.2), despite a similar body mass index (26.4 exercise cohort versus 28.1 non-exercise). Exercisers also had greater ROM in the affected (91.7 vs. 85.2%, p=0.1) and contralateral shoulder (95 vs. 90%, p=0.048) at treatment completion. No differences in pain or sleep scores were noted and lymphedema was mild ( Conclusion: The vast majority of current exercise oncology literature indicates that physical activity is an independent predictor of quality of life metrics in cancer patients. Our study notes a trend towards improved outcomes with increased exercise during radiation therapy, suggesting that accrual of additional patients to our pilot study is worthwhile. Ultimately, a concurrent exercise intervention may improve quality of life and reduce acute toxicity in patients undergoing breast radiation treatment. Citation Format: Ritu Arya, Lee W Jones, Rachel C Blitzblau, Manisha Palta, Lisa Massa, Gloria Broadwater, Janet K Horton. The association between exercise behavior and patient-reported outcomes in women with early breast cancer receiving locoregional radiation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-12-07.

BACKGROUND: Breast cancer treatment contributes the greatest proportion of cancer-related health care spending in the United States. Locoregional therapy comprises a significant share of these costs. We hypothesized that among eligible women with early-stage breast cancer treated with lumpectomy, evidence-based utilization of hypofractionated whole breast radiation or omission of radiotherapy could substantially reduce cancer-related treatment costs. METHODS: Using the National Cancer Data Base which captures approximately 70% of all newly diagnosed cancers in the United States, we identified 43,247 women with clinically node-negative, T1-T2 invasive breast cancers treated with lumpectomy during 2011. Women with DCIS, those treated with mastectomy, accelerated partial breast irradiation (APBI), or unknown or questionable radiation regimens were excluded. Adjuvant radiation was categorized into the following regimens: conventionally fractionated whole breast irradiation therapy (CF-WBI) [25-40 fractions, 45-66 Gy], hypofractionated whole-breast irradiation (HF-WBI) [15-24 fractions, 40-58 Gy), and lumpectomy without radiation (no RT). Women were considered eligible for no RT if ≥70 years with T1N0, ER+ breast cancers, and for HF-WBI if ≥50 years, with T1-T2 N0 invasive breast cancer. Treatment costs were calculated using Medicare Physician Fee Schedule payment information for 2011, and based on average current procedural codes billed per regimen. Costs per patient were estimated as follows: CF-WBI $13,358.37, HF-WBI $8,327.98, and lumpectomy without RT $0. Actual treatment costs were compared to evidence-based, reduced-cost radiation regimens for which patients were potentially eligible. RESULTS: Median patient age was 63 years (range 19-90). Median tumor size was 1.2 cm. Of the total study cohort, 84.5% was eligible for HF-WBI, and 22.3% for no RT. Among the 36,562 (84.5%) patients eligible for treatment with HF-WBI, 28,383 (77.6%) received radiation therapy. Of these, 22,653 (79.8%) received CF-WBI, 5,289 (18.6%) received HF-WBI, and 441 (1.6%) received accelerated partial breast irradiation (APBI). Among 9,651 women ≥70 years with ER+ tumors eligible for no-RT, 4,245 (44.0%) received CF-WBI, 1,768 (18.3%) received HF-WBI, 153 (1.6%) received APBI, and 3,485 (36.1%) received no RT. 26% of women received the least expensive evidence-based radiation regimen for which they were eligible, while 67% of patients were treated with more costly radiation regimens. Estimated costs of actual treatment were $420.2 million during 2011, compared to $256.2 million had women been treated with the least expensive radiation regimen for which they were eligible. This translates into an annual cost savings of $164.0 million, a 39% reduction in costs. CONCLUSIONS: Utilization of evidence-based adjuvant radiation following lumpectomy is associated with reductions in cancer-related costs in the locoregional treatment of early-stage breast cancer. Although treatment decisions should not be driven by health care costs alone, consideration of hypofractionated regimens or omission of radiotherapy for patients that fit evidence-based eligibility criteria could translate into dramatic reductions in annual health care spending. Citation Format: Rachel A Greenup, Rachel Blitzblau, Kevin Houck, Janet Horton, Lynn Howie, Manisha Palta, Aimee Mackey, Randy Scheri, Julie A Sosa, Alphonse G Taghian, Jeffrey Peppercorn, Barbara L Smith, E Shelley Hwang. Adjuvant radiation after lumpectomy: A cost comparison of treatment patterns in 43,247 women from the National Cancer Data Base [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-10-02.

Background: In June 2013, our health system transitioned to an electronic medical record (EMR) which included collecting patient quality of life data at each clinic visit. We used the NCCN distress thermometer (DT), a short, simple to use, self-report measure which uses a 10-point scale from 0 (no distress) to 10 (extreme distress) as well as an associated problem checklist which queries the source(s) of their distress. Among our breast cancer clinic population, we studied the severity and sources of distress as well as whether the DT score was associated with stage at diagnosis and time interval since diagnosis. Methods: Between October 1, 2013 and April 30, 2014, starting 3 months after implementation of a comprehensive EMR, all patients seen at our tertiary breast cancer clinic were asked to complete the DT survey at each clinic visit. DT data were collected and entered into the EMR at point of care. The DT tool was correlated with demographic and tumor information from our prospectively curated electronic datamart. Results: We collected 7276 DT surveys from 3267 unique patients over seven months. Median age of the cohort was 60 years; 73% were white and 21% were black. Among those with available staging data and a diagnosis of breast cancer, stage distribution was 10% stage 0, 34% stage I, 37% stage II, 15% stage III and 4% stage IV. The median reported distress score was 1.0 (range 0-10) with score distribution shown in Figure 1. The most commonly reported source of stress was fatigue (8.0%) followed by pain (6.8%). For new patient appointments the most commonly reported sources were worry (9.5%) followed by nervousness (8.0%). There was no significant correlation between overall distress score and stage at diagnosis. Among patients who were seen more than once during the study interval, the DT score changed for 33.7% of patients. The lowest distress scores were reported among women >3 years from initial diagnosis. Conclusions: The transition to an integrated EMR system has allowed collection of analyzable patient reported data to inform medical and psychosocial intervention. Structured data collection at point of care allows for efficient identification of and management for the major sources of distress among patients during breast cancer treatment and survivorship. Citation Format: Shelley Hwang, Steve Power, Ilona Stashko, Rachel Blitzblau, Rachel Greenup, Janet Horton, Kellly Westbrook, Kimberly Blackwell, Heather Sperling, Jeffrey Peppercorn, Gretchen Kimmick, Kelly Marcom. The distress screening tool: Initial experience with electronically curated patient reported measures [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-11.

Background: Large randomized controlled trials have shown that hypofractionated whole breast irradiation (HF-WBI) is not inferior to or more toxic than conventionally fractionated whole breast irradiation (CF-WBI) for the treatment of early-stage breast cancer. Royal Marsden data were published in 2006 (10-yr), the Ontario trial was reported in 2002 (5-yr) and 2010 (10-yr), and the UK START trials were published in 2006 (5-yr) and 2013 (10-yr). We utilized the National Cancer Data Base (NCDB) to evaluate patterns of radiotherapy fractionation for early-stage, node-negative breast cancer in the U.S. We hypothesized that HF-WBI use would increase over time in response to emerging data supporting its use in this population. Methods: We conducted a retrospective, population-based cohort study of women >18 years diagnosed with T1-2N0 invasive breast carcinoma and treated with breast-conserving surgery between 2004 and 2011. Radiotherapy was categorized as accelerated partial breast irradiation (APBI; 38-40 Gy/1-10 fractions), HF-WBI (40-56 Gy/15-24 fractions) or CF-WBI (50-66 Gy/25-40 fractions). Patients treated with alternate fractionation were excluded. Patterns of breast radiotherapy fractionation were compared using the chi-square test. Multivariable logistic regression was performed for patients diagnosed in 2011, the year with the highest levels of HF-WBI utilization. Results: 217,789 patients in the NCDB met inclusion criteria. HF-WBI use increased over time, rising from 2.1% among eligible patients in 2004 to 15.1% in 2011, while APBI use remained low at 30 years. Table 1 shows frequency of HF-WBI use over time by center type. On multivariate analysis of patients diagnosed in 2011, the following factors were associated with higher use of HF-WBI: treatment at an academic center, older patient age, hormone receptor positivity, pT1 tumor size, and rural residence (Table 2). Table 1: % HF-WBI use Community Cancer CenterComprehensive Community Cancer CenterAcademic Center20040.9%1.7%3.8%20051.6%2.1%3.8%20061.2%2.0%4.6%20071.5%2.8%7.1%20082.9%5.3%10.8%20093.9%8.5%14.7%20105.8%10.7%16.4%20119.6%13.9%20.5% Table 2. Multivariate analysis, year 2011 (n=5568) OR95% CIAcademic Center vs. Community Cancer Center3.062.324.02Academic Center vs. Comprehensive Community Cancer Center1.781.532.08Patient age, 50-90 vs. 18-492.371.863.01T2 vs. T10.540.460.63HER2+ vs. Hormone Receptor +/HER2-0.750.590.97ER-/PR-/HER2- vs. Hormone Receptor +/HER2-0.660.520.84Rural vs. urban2.681.694.24 Conclusions: Utilization of HF-WBI in the US is rising, but remains low overall despite level I evidence showing its non-inferiority to CF-WBI. Given the advantages of HF-WBI in terms of patient convenience and potential healthcare system costs, further research is indicated to explore disparities in HF-WBI utilization in the US and to guide education of breast cancer providers. Citation Format: Yvonne M Mowery, Rachel A Greenup, Kevin Houck, Manisha Palta, Janet K Horton, Eun-Sil S Hwang, Julie A Sosa, Rachel C Blitzblau. Low utilization of hypofractionated radiotherapy for the treatment of early-stage breast cancer in the US [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-10.

The purpose of this study was to compare dosimetric parameters of treatment plans among four techniques for preoperative single‐fraction partial breast radiotherapy in order to select an optimal treatment technique. The techniques evaluated were noncoplanar 3D conformal radiation therapy (3D CRT), noncoplanar intensity‐modulated radiation therapy (IMRTNC), coplanar IMRT (IMRTCO), and volumetric‐modulated arc therapy (VMAT). The planning CT scans of 16 patients in the prone position were used in this study, with the single‐fraction prescription doses of 15 Gy for the first eight patients and 18 Gy for the remaining eight patients. Six (6) MV photon beams were designed to avoid the heart and contralateral breast. Optimization for IMRT and VMAT was performed to reduce the dose to the skin and normal breast. All plans were normalized such that 100% of the prescribed dose covered greater than 95% of the clinical target volume (CTV) consisting of gross tumor volume (GTV) plus 1.5 cm margin. Mean homogeneity index (HI) was the lowest (1.05±0.02) for 3D CRT and the highest (1.11±0.04) for VMAT. Mean conformity index (CI) was the lowest (1.42±0.32) for IMRTNC and the highest (1.60±0.32) for VMAT. Mean of the maximum point dose to skin was the lowest (73.7±11.5%) for IMRTNC and the highest (86.5±6.68%) for 3D CRT. IMRTCO showed very similar HI, CI, and maximum skin dose to IMRTNC (differences

BACKGROUND The Cancer and Leukemia Group B (CALGB) 9343 randomized phase 3 trial established lumpectomy and adjuvant therapy with tamoxifen alone, rather than both radiotherapy and tamoxifen, as a reasonable treatment course for women aged >70 years with clinical stage I (AJCC 7th edition), estrogen receptor-positive breast cancer. An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry was undertaken to assess practice patterns before and after the publication of this landmark study. METHODS The SEER database from 2000 to 2009 was used to identify 40,583 women aged ≥70 years who were treated with breast-conserving surgery for clinical stage I, estrogen receptor-positive and/or progesterone receptor-positive breast cancer. The percentage of patients receiving radiotherapy and the type of radiotherapy delivered was assessed over time. Administration of radiotherapy was further assessed across age groups; SEER cohort; and tumor size, grade, and laterality. RESULTS Approximately 68.6% of patients treated between 2000 and 2004 compared with 61.7% of patients who were treated between 2005 and 2009 received some form of adjuvant radiotherapy (P < .001). Coinciding with a decline in the use of external beam radiotherapy, there was an increase in the use of implant radiotherapy from 1.4% between 2000 and 2004 to 6.2% between 2005 to 2009 (P < .001). There were significant reductions in the frequency of radiotherapy delivery over time across age groups, tumor size, and tumor grade and regardless of laterality (P < .001 for all). CONCLUSIONS Randomized phase 3 data support the omission of adjuvant radiotherapy in elderly women with early-stage breast cancer. Analysis of practice patterns before and after the publication of these data indicates a significant decline in radiotherapy use; however, nearly two-thirds of women continue to receive adjuvant radiotherapy. Cancer 2015;121:188–93. © 2014 American Cancer Society.

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of omitting axillary lymph node dissection (ALND) for early-stage breast cancer patients with limited nodal disease undergoing lumpectomy. We examined the extent of axillary surgery among women eligible for Z0011 based on patient age and tumor subtype. Patients with cT1–2, cN0 breast cancers and one or two positive nodes diagnosed from 2009 to 2014 and treated with lumpectomy were identified in the National Cancer Data Base. Sentinel lymph node biopsy (SLNB) was defined as the removal of 1–5 nodes and ALND as the removal of 10 nodes or more. Tumor subtype was categorized as luminal, human epidermal growth factor 2-positive (HER2+), or triple-negative. Logistic regression was used to estimate the odds of receiving SLNB alone versus ALND. The inclusion criteria were met by 28,631 patients (21,029 SLNB-alone and 7602 ALND patients). Patients 70 years of age or older were more likely to undergo SLNB alone than ALND (27.0% vs 20.1%; p

Purpose: To develop an automated optimization program to generate optimal beam settings for whole-breast radiation therapy driven by clinically oriented goals. Materials and Methods: Forty patients were retrospectively included in this study. Each patient’s planning images, contoured structures of planning target volumes, organs-at-risk, and breast wires were used to optimize for patient-specific–beam settings. Two beam geometries were available tangential beams only and tangential plus supraclavicular beams. Beam parameters included isocenter position, gantry, collimator, couch angles, and multileaf collimator shape. A geometry-based goal function was defined to determine such beam parameters to minimize out-of-field target volume and in-field ipsilateral lung volume. For each geometry, the weighting in the goal function was trained with 10 plans and tested on 10 additional plans. For each query patient, the optimal beam setting was searched for different gantry-isocenter pairs. Optimal fluence maps were generated by an in-house automatic fluence optimization program for target coverage and homogeneous dose distribution, and dose calculation was performed in Eclipse. Automatically generated plans were compared with manually generated plans for target coverage and lung and heart sparing. Results: The program successfully produced a set of beam parameters for every patient. Beam optimization time ranged from 10 to 120 s. The automatic plans had overall comparable plan quality to manually generated plans. For all testing cases, the mean target V95% was 91.0% for the automatic plans and 88.5% for manually generated plans. The mean ipsilateral lung V20Gy was lower for the automatic plans (15.2% vs 17.9%). The heart mean dose, maximum dose of the body, and conformity index were all comparable. Conclusion: We developed an automated goal-driven beam setting optimization program for whole-breast radiation therapy. It provides clinically relevant solutions based on previous clinical practice as well as patient specific anatomy on a substantially faster time frame.

Purpose/Objectives(s): Women with biologically favorable early stage breast cancer are increasingly treated with accelerated partial breast techniques. However, many alternative techniques require costly specialized equipment not routinely available in most radiation oncology facilities. In addition, suboptimal cosmetic outcomes have been reported with the external beam technique, possibly related to large post-operative treatment volumes. To address these issues, we designed a phase I dose-escalation protocol to determine the maximally tolerated dose (MTD) of a single radiosurgery treatment delivered preoperatively to the intact tumor plus a small margin. Materials/Methods: Women aged 55 or older with clinically node negative, ER and/or PR+, HER2-, T1 invasive carcinomas were enrolled (n = 26). Patients with low/intermediate grade in situ disease Tumor tissue was obtained from diagnostic and lumpectomy specimens. Immunohistochemistry (IHC) for Fas was performed on paraffin-embedded samples before and after radiation. A histoscore was created using the average membrane and cytoplasmic staining intensity multiplied by the percentage of positive cells. Results: Thirty-two women were treated, 8 each at the 15, 18, and 21Gy dose levels with an additional expansion cohort at the final 21Gy dose level. The maximally tolerated dose was not reached. Three patients required post-operative conventional radiation due to high-risk tumor features (ex. larger primary, nodal involvement). At a median follow-up of 6.8 months, primarily mild toxicities (grade 1-2 dermatitis, fibrosis, and pain) were noted. At 6 months (n = 20), all reported cosmetic outcomes are excellent or good. At 12 months (n = 10), 80% are excellent or good. Both patients with a fair/poor cosmetic outcome received radiosurgery plus post-operative conventional treatment; one experienced grade 3 breast atrophy. There have been no local or distant recurrences to date. Post-treatment MRIs were obtained in 20/32 patients, with early indicators of decreased cell density and increased vascular permeability. Sixteen patients had evaluable paired IHC and six demonstrated significant Fas up-regulation after radiation. The mean combined post-treatment histoscore was about twice as high as the mean pre-treatment score. Conclusion: Preoperative stereotactic radiotherapy to the intact breast tumor can be delivered with widely available clinical tools in a convenient single fraction, and provides a unique opportunity to study breast cancer radiation response. 21Gy did not yield dose-limiting toxicity and will be utilized for future studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-04.

Classic randomized trials documented the benefit of postmastectomy radiotherapy in women with node-positive or locally advanced breast cancer. Modern advances in surgical therapy, systemic therapy, and radiotherapy, however, along with an improved understanding of cancer biology, have called into question previously assumed recurrence risks and treatment benefits. This article explores the impact of tumor biology and genomic medicine on utilization of postmastectomy radiotherapy and how treatment decision making is moving beyond TNM-based predictors.

Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3′ untranslated region (3′UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the 3′UTR of BRCA1 and haplotypes containing these functional polymorphisms may be associated with breast cancer risk. We sequenced the BRCA1 3′UTR from breast cancer patients to identify miRNA disrupting polymorphisms. We further evaluated haplotypes of this region including the identified 3′UTR variants in a large population of controls and breast cancer patients (n = 221) with known breast cancer subtypes and ethnicities. We identified three 3′UTR variants in BRCA1 that are polymorphic in breast cancer populations, and haplotype analysis including these variants revealed that breast cancer patients harbor five rare haplotypes not generally found among controls (9.50% for breast cancer chromosomes, 0.11% for control chromosomes, p = 0.0001). Three of these rare haplotypes contain the rs8176318 BRCA1 3′UTR functional variant. These haplotypes are not biomarkers for BRCA1 coding mutations, as they are found rarely in BRCA1 mutant breast cancer patients (1/129 patients = 0.78%). These rare BRCA1 haplotypes and 3′UTR SNPs may represent new genetic markers of breast cancer risk.

Identification of people or populations at risk for developing cancer is a key to improved screening programs and earlier detection, with the hope of a commensurate reduction in cancer mortalities. Genetic alterations that change gene expression levels have long been investigated for association with development of cancer. Misregulation of genes through altered interactions is another potential mechanism of oncogenesis. Gene regulation by microRNAs (miRNAs) is a relatively new area of study, and a growing body of evidence suggests that alterations in this process may be associated with increased cancer risk. This can occur through alterations in miRNA levels, interactions with targets, or perhaps more complicated combinations of the two. Here we review the current data for association between single nucleotide polymorphisms (SNPs) in miRNA binding sites and specific cancers. This growing body of literature suggests that these SNPs have a potential role as biomarkers for cancer risk.

Ovarian cancer (OC) is the single most deadly form of women's cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from nonselected OC patients in three independent cohorts, two independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. Our results indicate that the KRAS-variant is associated with more than 25% of nonselected OC cases. Further, we found that it is a marker for a significant increased risk of developing OC, as confirmed by two independent case-control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities. Cancer Res; 70(16); 6509–15. ©2010 AACR.

Muscular dystrophy patients often show cognitive impairment, in addition to muscle degeneration caused by dystrophin gene defects. The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Dystrophin regulates the stability of selected GABA(A) receptor subtypes and alpha3-containing nicotinic acetylcholine receptors (nAChRs) at a subset of central GABAergic and peripheral sympathetic nicotinic neuron synapses. Similarly, utrophin, the autosomal homologue of dystrophin, is not required for clustering but indirectly stabilizes muscle-type nAChRs at the neuromuscular junction. We examined dystrophin and utrophin expression and localization in the avian parasympathetic ciliary ganglion (CG) to determine whether these proteins play a general role at neuronal nicotinic synapses. We have determined that full-length utrophin and dystrophin and the short dystrophin isoform Dp116 are the major isoforms expressed in the CG based on immunoblotting and immunolabeling. Unexpectedly, the cytoskeletal proteins were not detected at nicotinic synapses or in CG neurons. They are expressed in myelinating and non-myelinating Schwann cells. Further, utrophin expression developmentally precedes that of dystrophin. The proteins show partially overlapping distributions, but also differential accumulation along the surface membrane of Schwann cells adjacent to neuronal somata versus axonal processes. Our findings are consistent with reports that dystrophin protein family members function in the maintenance of cell-cell interactions and myelination by anchoring the Schwann cell surface membrane to the basal lamina. In contrast, our results differ from those in skeletal muscle and a subset of sympathetic neurons where utrophin and dystrophin localize at nicotinic synapses.

Purpose Primary CD30+ cutaneous lymphoproliferative disease (PCLPD) is a spectrum of indolent cutaneous T-cell lymphomas. The primary intention of the analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database was to report epidemiologic information and overall survival of patients with PCLPD. Methods We investigated the SEER database from 1973 to 2004 and performed univariable and multivariable survival analysis. Results A total of 268 cases of PCLPD were recorded from 1973 to 2004. Median age at diagnosis was 61 years (range, 5 to 98 years). Among cases, 58% were male, and 42% female. Race distribution was 87% white, 7% black, and 4% Asian/Pacific Islander. A total of 157 patients had primary, localized PCLPD. For the total population (N = 268), overall survival at 3 years was 81% (95% CI, 74% to 87%). Population-matched relative survival at 3 years was 87% (SE, 3.6%). Disease-specific survival at 5 years was 92% (95% CI, 86% to 95%). Head and neck skin site predicted for inferior overall survival in patients with primary, localized PCLPD on univariable analysis (hazard ratio [HR] = 4.4; P = .008; 95% CI, 1.5 to 13.2), and was suggestive of decreased overall survival on multivariate analysis (HR = 3.0; P = .06; 95% CI, 0.95 to 9.7). Conclusion Localized PCLPDs are rare diseases with an excellent overall survival and occur more frequently in whites and in men. Head and neck skin primary site may be associated with poorer survival. Conclusions regarding subsets demonstrating association with survival should be taken with caution, given the small number of deaths analyzed.

Purpose Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods and Materials Women aged ≥55 years with clinically node-negative, estrogen receptor–positive, and/or progesterone receptor–positive HER2−, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. Results No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.

This study aims to (a) prospectively determine if multiple dwell (multidwell) position dose delivery can decrease skin dose and resultant toxicity over single-dwell balloon-catheter partial breast irradiation and (b) evaluate whether specific skin parameters could be safely used instead of skin–balloon distance alone for predicting toxicity and treatment eligibility. A single-arm phase II study using a Simon two-stage design was performed on 28 women with stage 0–II breast cancer. All patients were treated with multidwell position balloon-catheter brachytherapy. The primary endpoint was ≥ grade 2 skin toxicity. Initial entry required a balloon–skin distance of ≥7 mm. Based on the toxicity in the first 16 patients, additional patients were treated irrespective of skin–balloon distance as long as the D max to 1 mm skin thickness was

Purpose: To enable near-real-time (

Individual cholinoceptive neurons express high levels of different neuronal nicotinic acetylcholine receptor (nAChR) subtypes, and target them to the appropriate synaptic regions for proper function. This review focuses on the intercellular and intracellular processes that regulate nAChR expression in vertebrate peripheral nervous system (PNS) and central nervous system (CNS) neurons. Specifically, we discuss the cellular and molecular mechanisms that govern the induction and maintenance of nAChR expression-innervation, target tissue interactions, soluble factors, and activity. We define the regulatory principles of interneuronal nicotinic synapse differentiation that have emerged from these studies. We also discuss the molecular players that target nAChRs to the surface membrane and the interneuronal synapse.