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Background Breast conserving surgery (BCS) followed by whole breast irradiation with a tumor bed boost is a common approach for locoregional treatment of patients with breast cancer. While tumor bed boost improves local control, it is also associated with increased risk of fibrosis and fat necrosis. Oncoplastic reconstruction is being increasingly employed to improve cosmesis and symmetry with the contralateral breast following partial mastectomy. The extensive rearrangement of breast tissue during oncoplastic reconstruction has the potential to increase tumor bed volume, thereby increasing the volume of breast receiving a higher dose of radiation. In this study, we aimed to elucidate the current rise in use of oncoplastic reconstruction following breast-conserving surgery in patients with breast cancer and its impact on the volume of tumor bed as contoured by attending radiation oncologists at the time of radiation treatment planning. Methods A retrospective chart review of 331 women, who underwent breast conserving surgery at our institution between Jan 2020 and March 2021 for treatment of breast cancer was conducted. Patient demographics and tumor characteristics, including clinical and pathological staging, tumor receptor status, and tumor histology were recorded. Treatment-related information such as type of oncoplastic reconstruction where applicable, receipt of systemic therapy, dose and fractionation of radiation therapy, treatment technique and volume of tumor bed defined at the time of radiation treatment planning were collected. Results The median age of the cohort was 61, and 54.7% of patients received oncoplastic reconstruction. A plastic surgeon was involved in reconstruction in 22.8% of patients. Complex tissue advancement closure was the most common oncoplastic reconstruction employed in this cohort. A two-tailed T-test assuming unequal variances demonstrated that oncoplastic reconstruction was associated with a contoured tumor bed that was on average almost 10 mL larger (35.5 vs. 26.6 mL, p < 0.02). Conclusion Over half of patients receiving breast conserving surgery at our institution underwent oncoplastic reconstruction. The rate of oncoplastic reconstruction in this cohort was significantly higher than historic rates reported in the literature, likely reflecting an exponential growth in adoption of this approach in the United States. Use of oncoplastic reconstruction was associated with larger tumor bed volume at the time of radiation treatment. Although tumor bed boost improves local control, it also increases risk of fibrosis and fat necrosis. Therefore, further studies are needed to determine if larger volume of tumor bed irradiated in patients receiving oncoplastic reconstruction is associated with decline in long term cosmetic outcomes due to fibrosis and fat necrosis. Increased multi-disciplinary communication and collaboration between surgical oncologists, reconstructive surgeons and radiation oncologists is necessary to address the competing interests between breast reconstruction and irradiation following breast conserving surgery in patients undergoing breast conserving surgery for treatment of breast cancer. Citation Format: Brian Ko-Hung Lue, Ev Kakadiaris, Prasanna Alluri, M.D. Radiation oncology treatment planning in breast cancer patients undergoing lumpectomy with and without oncoplastic reconstruction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-13.

Active breathing coordinator (ABC)-assisted deep inspiration breath hold (DIBH) is an important organ sparing radiation therapy (RT) technique for left-sided breast cancer patients. Patients with advanced breast cancer undergoing chest wall and regional nodal irradiation often require a field matching technique. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in DIBH/ABC use has not been previously reported.To report the accuracy, feasibility, and safety of field matching with ABC/DIBH for patients receiving breast/chest wall irradiation with nodal irradiation using a three-field technique.From December 2012 to May 2018, breast cancer patients undergoing ABC/DIBH-based RT at a single institution were reviewed. For each fraction, the amount of overlap/gap between the supraclavicular and the tangential field were measured and recorded. Patient characteristics, including acute and delayed skin toxicities, were analyzed.A total of 202 patients utilized ABC/DIBH and 4973 fractions had gap/overlap measurements available for analysis. The average gap/overlap measured at junction was 0.28 mm ± 0.99 mm. A total of 72% of fractions had no measurable gap/overlap (0 mm), while 5.6% had an overlap and 22.7% a gap. There was no significant trend for worsening or improvement of gap/overlap measurements with increasing fraction number per patient. OSLD measurements were compared to the planned dose. The median dose 1 cm above the junction was 106% ± 7% of planned dose (range 94%-116%). One centimeter below the junction, the median dose was 114% ± 11% of planned dose (range 95%-131%). At the junction, the median dose was 106% ± 16.3% of planned dose (range 86%-131%). Acute skin toxicity was similar to historically reported values (grade 3, 5.4%, grade 4, 0%).ABC-assisted DIBH is a safe and technically feasible method of delivering RT in the setting of complex matching field technique for breast and regional nodal treatments.

Describe an early-adopting institution's experience with online adaptive radiation for stereotactic partial breast irradiation.Retrospective review of 22 women treated between May 2021 and March 2022 with adaptive stereotactic partial breast irradiation. A total of 106 of 110 fractions were evaluated for dosimetric changes in target coverage and organ-at-risk (OAR) dose. Patient set up with stereotactic wooden frame and adapted per fraction. Treatment and planning times were collected prospectively by radiation therapists.Scheduled PTVAdaptive stereotactic breast irradiation resulted in improved target coverage with equivalent dosing to OARs in an efficient and tolerated treatment time. Improved target coverage allowed for decreased PTV margins compared to prior trial protocols that may improve acute and late toxicities.

Accurate and efficient delineation of the clinical target volume (CTV) is of utmost significance in post-operative breast cancer radiotherapy. However, CTV delineation is challenging as the exact extent of microscopic disease encompassed by CTV is not visualizable in radiological images and remains uncertain. We proposed to mimic physicians’ contouring practice for CTV segmentation in stereotactic partial breast irradiation (S-PBI) where CTV is derived from tumor bed volume (TBV) via a margin expansion followed by correcting the extensions for anatomical barriers of tumor invasion (e.g. skin, chest wall). We proposed a deep-learning model, where CT images and the corresponding TBV masks formed a multi-channel input for a 3D U-Net based architecture. The design guided the model to encode the location-related image features and directed the network to focus on TBV to initiate CTV segmentation. Gradient weighted class activation map (Grad-CAM) visualizations of the model predictions revealed that the extension rules and geometric/anatomical boundaries were learnt during model training to assist the network to limit the expansion to a certain distance from the chest wall and the skin. We retrospectively collected 175 prone CT images from 35 post-operative breast cancer patients who received 5-fraction partial breast irradiation regimen on GammaPod. The 35 patients were randomly split into training (25), validation (5) and test (5) sets. Our model achieved mean (standard deviation) of 0.94 (±0.02), 2.46 (±0.5) mm, and 0.53 (±0.14) mm for Dice similarity coefficient, 95th percentile Hausdorff distance, and average symmetric surface distance respectively on the test set. The results are promising for improving the efficiency and accuracy of CTV delineation during on-line treatment planning procedure.

Pre-operative endocrine therapy use in post-menopausal women with localized, ER-positive breast cancer affords comparable rates of response and breast preservation, but lower toxicity relative to chemotherapy. Pre-operative endocrine therapy exerts selective pressure on cancer cells and promote evolution and/or enrichment of pathogenic alternations such as ESR1 mutations and other cellular adaptations. How such endocrine therapy-induced adaptations alter response to radiation therapy remains poorly defined. In this study, we show that diverse mechanisms that confer endocrine therapy resistance also drive radiation resistance by reprogramming of DNA repair pathways. We also show that BRD4, a member of bromodomain and extraterminal domain (BET) family of proteins, mediates such DNA repair reprogramming. BRD4 also plays a key role in trascriptional reprogramming in ER-positive breast cancer cells that confers endocrine therapy resistance. Thus, OTX015, a BET inhibitor with a favorable safety profile in early stage clinical trials, reverses both endocrine therapy resistance and radiation resistance in ER-positive breast cancer cells and tumors. Our findings are also consistent with reports that tamoxifen-resistant breast cancer cells are resistant to DNA damaging chemotherapeutic agents such as adriamycin and cisplatin. Overall, our findings suggest that endocrine therapy resistance in the pre-operative setting serves as a biomarker for reduced response to adjuvant radiation therapy, and that pharmacological BET inhibition reverses radiation resistance in such patients. The increasing use of “window of opportunity” studies to assess response to endocrine therapy in the pre-operative setting will further facilitate personalization of radiation treatments in these patients based on their response to endocrine therapy. Thus, we provides a therapeutic rationale for personalization of radiation treatments in breast cancer patients based on their response to endocrine therapy. We also provide a molecularly targeted approach for reversing radiation resistance in such patients. Thus, our study provides a framework for advancing Precision Radiation Oncology in breast cancer patients. Citation Format: SM Nashir Udden, Asal Rahimi, Dong W. Nathan Kim, Prasanna Alluri. Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-Positive Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-08.

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021.

Background: Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation, which is a common treatment for malignancies like lung cancer. There is currently no standardized program for follow-up of RIHD in cancer survivors. Therefore, there is an acute need for developing detection of RIHD at a stage that offers potential for early intervention and reversibility. The gold standard for detection of global cardiac dysfunction is echocardiography. However, this current paradigm detects cardiac changes in metrics such as Left Ventricular Ejection Fraction (LVEF), which are relatively late manifestations in the pathology of cardiotoxicity, decreasing the possibility of reversing such damage. We sought to assess radiation-induced changes significantly earlier than the current standard of care by measuring the efficiency of the tricarboxylic acid cycle in cardiac mitochondria; we hypothesized that radiation leads to impaired mitochondrial function, causing increased conversion of pyruvate to lactate in the cytosol and decreased conversion in the mitochondria. In order to non-invasively measure this impairment, we utilized Magnetic Resonance Spectroscopy (MRS) to track the fate of hyperpolarized (HP) C-13 pyruvate. Methods: Sprague-Dawley rats underwent baseline and post treatment echocardiography and HP C-13 pyruvate MRS at multiple timepoints. Half of the animals underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions, a paradigm similar to a common dose given to lung cancer patients. Results: In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac function (determined by bicarbonate-to-lactate ratio in myocardial mitochondria) compared to pre-radiation baseline (p=0.02, one-tailed paired t-test) as early as 1 week post treatment. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (p=0.95). Comparatively, no significant changes in LVEF or global longitudinal strain were observed in either the cardiac irradiation or control group of rats until 2 months post treatment. Conclusion: Radiation-induced myocardial mitochondrial dysfunction is an early event that can be characterized and detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation prior to onset of echocardiographic changes. For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. This technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually. Citation Format: Jayesh Sharma, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, Jaemo Park, Craig Malloy, Vlad Zaha, Prasanna Alluri. Early in vivo detection of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3659.

Background Radiation therapy is a critical component in the multi-disciplinary care of many breast cancer patients, but traditionally, has necessitated daily treatment visits over several weeks. Accelerated partial breast irradiation (APBI) in appropriately selected patients affords clinical outcomes that rival those achieved with conventionally fractionated whole-breast radiation. In addition to exposing a smaller volume of breast to radiation, APBI also allows reduction in total number of radiation treatment fractions to 1-10. This regimen thus stands to particularly benefit minorities such as Black American patients, who suffer disproportionately from high rates of economic burden in the form of absence from work, lost wages, and transportation costs related to prolonged cancer treatments. Yet, Black Americans have been traditionally underrepresented in clinical trials, threatening the generalizability of new treatments like APBI. In this study, we evaluated the racial makeup of clinical trials evaluating ABPI and the inclusion of Black Americans in these studies. Methods We retrospectively reviewed all published manuscripts involving accelerated partial breast irradiation therapy and analyzed the demographics of their study populations. Studies reported from centers outside the United States were excluded. When race reporting was not available in the published results, this information, where available, was obtained through the NIH Clinical trials registry. Results A total of 130 APBI trials were identified by PubMed search. Out of these, 80 studies were based in the United States. A total of 20 studies investigating APBI provided demographics data, comprising 1735 total patients. Of these, 1488 patients were White (85.7%), 124 were Black (7.1%), 67 were Hispanic (3.9%), and 46 were Asian (2.7%), and 10 patients were classified as multiple or unknown (0.6%). This percentage is lower than the 2019 US Census estimate of 13.4% Black Americans. We compared these results to two APBI trials conducted at our institution investigating 5-fraction and single fraction APBI regimens. Out of a total of 104 patients treated, 17 patients (16.3%) were Black. The higher proportion of Black Americans in our trials is likely due to a unique partnership between Parkland Hospital, a county Hospital that serves a high proportion of minority patients, and UT Southwestern Medical Center, which provides access to technologically sophisticated treatments such as APBI. Conclusion Despite APBI being uniquely positioned to provide increased benefits to racial minorities, Black Americans are underrepresented in clinical trials evaluating APBI, mirroring the broader national trend in all clinical trials. Based on our institutional experience, partnership between academic medical centers, which often have access to novel treatment regimens and county hospitals, which serve a large proportion of minority patients, is needed to reduce racial disparities in clinical trial participation and to eventually narrow and eliminate the racial health disparity gap. Citation Format: Ev Kakadiaris, Brian K Lue, Sherry Gu, Jonathan C. Tyes, Prasanna Alluri. Cancer disparities and African American representation in clinical trials involving Accelerated Partial Breast Irradiation Therapy [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-214.

Postmastectomy radiotherapy (PMRT) is an integral component of the multimodal treatment of invasive breast cancer in patients with sufficient risk of harboring a reservoir of locoregional disease despite mastectomy and systemic therapy. Microscopic residual disease in the chest wall and/or regional lymph nodes, if left untreated, may seed or reseed distant metastases after initial clearance of distant disease by highly effective contemporary systemic therapies. In addition, occult disease may also serve as a source of locoregional recurrence, which is often highly morbid to the patient in the postmastectomy setting. Therefore, the goal of PMRT is to eliminate residual occult locoregional disease and reduce the risk of both locoregional and distant recurrences. This chapter focuses on the role of PMRT in the treatment of patients with invasive breast cancer and the evidence regarding the impact of PMRT on locoregional control and overall survival. It begins by reviewing the evidence from randomized trials, followed by a discussion of how best to generalize from these trials and select patients appropriately for treatment, especially among those with N1 and N0 disease, for whom treatment is more controversial. It then turns to special considerations, including axillary management postmastectomy in patients with limited volume node-positive disease treated without axillary node dissection, the role of PMRT in patients who were treated with neoadjuvant chemotherapy, implications of differences in tumor biologic subtype, and the optimal integration of PMRT and breast reconstruction.

Additional file 1: Figure S1. (A) MCF-7 or (B) T-47D cells were stimulated with E2 (10-8M) for 3 days in the presence or absence of 1 μM of ERX-11 or cisplatin or paclitaxel or gemcitabine or in combination and the cell viability was measured by Cell Titre-Glo Luminescent assay. Figure S2. ZR-75, T-47D, MCF-7/TamR, ZR-75-ESR1-MT-Y537S and ZR-75-ESR1-MT-D538G cells were stimulated with E2 (10-8M) for 7 days in the presence or absence of ERX-11 (0.5μM) or palbociclib (0.5μM) or in combination with indicated concentrations of ERX-11 and the cell viability was measured by MTT assay. Figure S3. Equal number of ZR-75, ZR-75-ESR1-MT-Y537S and ZR-75-ESR1-MT-D538G cells were plated and treated with ERX-11 (500nM) or palbociclib (50 nM) or abemaciclib (50nM) or ribociclib (50nM) or combination and clonogenic (survival) assays were performed after 14 days. Figure S4. (A) Parental MCF-7 or ribociclib resistant MCF-7/RR cells were stimulated with E2 (10-8M) for 5 days in the presence or absence of ERX-11 (1, 5, 10 μM) or ribociclib (1 μM) or in combination and the cell viability was measured by Cell Titer-Glo Luminescent assay. (B) MCF-7 or (C) MCF-7/RR cells were treated with E2 (10-8M) for 5 days in the presence or absence of ERX-11 (1, 2, 5 μM) or ICI (0.2, 0.4, 1 μM). Figure S10. Schematic representation of model for mechanisms of ERX-11+palbociclib therapy.

Additional file 1: Figure S1. (A) MCF-7 or (B) T-47D cells were stimulated with E2 (10-8M) for 3 days in the presence or absence of 1 μM of ERX-11 or cisplatin or paclitaxel or gemcitabine or in combination and the cell viability was measured by Cell Titre-Glo Luminescent assay. Figure S2. ZR-75, T-47D, MCF-7/TamR, ZR-75-ESR1-MT-Y537S and ZR-75-ESR1-MT-D538G cells were stimulated with E2 (10-8M) for 7 days in the presence or absence of ERX-11 (0.5μM) or palbociclib (0.5μM) or in combination with indicated concentrations of ERX-11 and the cell viability was measured by MTT assay. Figure S3. Equal number of ZR-75, ZR-75-ESR1-MT-Y537S and ZR-75-ESR1-MT-D538G cells were plated and treated with ERX-11 (500nM) or palbociclib (50 nM) or abemaciclib (50nM) or ribociclib (50nM) or combination and clonogenic (survival) assays were performed after 14 days. Figure S4. (A) Parental MCF-7 or ribociclib resistant MCF-7/RR cells were stimulated with E2 (10-8M) for 5 days in the presence or absence of ERX-11 (1, 5, 10 μM) or ribociclib (1 μM) or in combination and the cell viability was measured by Cell Titer-Glo Luminescent assay. (B) MCF-7 or (C) MCF-7/RR cells were treated with E2 (10-8M) for 5 days in the presence or absence of ERX-11 (1, 2, 5 μM) or ICI (0.2, 0.4, 1 μM). Figure S10. Schematic representation of model for mechanisms of ERX-11+palbociclib therapy.