Management of bone disease with concurrent chimeric antigen receptor T-cell therapy for multiple myeloma.

In the intricate landscape of multiple myeloma, a hematologic malignancy of plasma cells, bone disease presents a pivotal and often debilitating complication. The emergence of Chimeric Antigen Receptor T-cell (CAR-T) therapy has marked a pivotal shift in the therapeutic landscape, offering novel avenues for the management of MM, particularly for those with relapsed or refractory disease. This innovative treatment modality not only targets malignant cells with precision but also influences the bone microenvironment, presenting both challenges and opportunities in patient care. In this comprehensive review, we aim to examine the multifaceted aspects of bone disease in patients with multiple myeloma and concurrent CAR-T therapy, highlighting its clinical ramifications and the latest advancements in diagnostic modalities and therapeutic interventions. The article aims to synthesize current understanding of the interplay between myeloma cells, CAR-T cells, and the bone microenvironment in the context of current treatment strategies in this challenging and unique patient population.

Feasibility and Toxicity of Full-Body Volumetric Modulated Arc Therapy Technique for High-Dose Total Body Irradiation.

Introduction: High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ arcs to the inferior-most portion of the body that can be simulated in a head-first position and use 2D planning for the inferior body which can result in heterogeneous doses. Here, we describe our institution's unique protocol for delivering high-dose TBI entirely with VMAT and retrospectively compare dosimetric outcomes with helical tomotherapy (HT) plans. Additionally, we describe our method of oropharyngeal mucosal sparing that was implemented after fatal mucositis occurred in two patients. Methods: Thirty-one patients were simulated and treated in head-first (HFS) and feet-first (FFS) orientations. Patients were treated with VMAT (n = 26) or HT (n = 5). In VMAT plans, to synchronize doses between the orientations, images were deformably registered and the HFS dose was transferred to the FFS plan and used as a background dose when optimizing plans. Six to eight isocenters with two arcs per isocenter were generated. HT was delivered with an established technique. Patients were treated to 13.2 Gy over eight twice daily fractions. Dosimetric outcomes and toxicities were retrospectively compared. Results: Prescription dose and organ at risk (OAR) constraints were met for all patients. Lower lung doses were achieved with VMAT relative to HT plans (7.4 vs 7.7 Gy, P = .009). Statistically significant improvement in mucositis was not achieved after adopting a mucosal-sparing technique, however lower doses to the oropharyngeal mucosal were achieved (6.9 vs 14.1 Gy, P = .009), and no further mucositis-related deaths occurred. Conclusions: This full-body VMAT method of TBI achieves dose goals, eliminates risk of heterogenous doses within the femur, and demonstrates that selective OAR sparing with the purpose of reducing TBI-related morbidity and mortality is possible at any institution with a VMAT-capable linear accelerator.

Neoadjuvant Simultaneous Integrated Boost Radiation Therapy Improves Clinical Outcomes for Retroperitoneal Sarcoma.

PURPOSE: Neoadjuvant radiation therapy (RT) with standard techniques (ST) offers a modest benefit in retroperitoneal sarcoma (RPS). As the high-risk region (HRR) at risk for a positive surgical margin and recurrence is posterior and away from radiosensitive organs at risk, using a simultaneous integrated boost (SIB) allows targeted dose escalation to the HRR while sparing these organs. We hypothesized that neoadjuvant SIB RT can improve disease control compared with ST, without increasing toxicity. METHODS AND MATERIALS: We retrospectively identified patients with resectable nonmetastatic RPS from 2000 to 2021 who received neoadjuvant RT of 180 to 200 cGy/fraction to standard volumes. SIB patients received 205 to 230 cGy/fraction to the appropriate HRR. Clinical endpoints included abdominopelvic control (APC), recurrence-free survival (RFS), overall survival (OS), and acute toxicity. RESULTS: With a median follow-up of 57 months (95% confidence interval [CI], 50-64), there were 103 patients with RPS who received either ST (n = 69) or SIB (n = 34) RT. Median standard volume dose was 5000 cGy (ST) and 4500 cGy (SIB), with a median HRR SIB dose of 5750 cGy. Liposarcomas (79% vs 53%; P = .004) and cT4 tumors (59% vs 19%; P < .001) were more common in the SIB cohort, without a significant difference in the rate of resection (82% vs 81%; P = .88) or R1 margin (53.5% vs 50%; P = .36); there were no R2 resections. SIB was associated with a significant improvement in 5-year APC (96% vs 70%; P = .046) and RFS (60.2% vs 36.3%; P = .036), with a nonsignificant OS difference (90.1% vs 67.5%; P = .164). On multivariable analysis, SIB remained a predictor for APC (hazard ratio, 0.07; 95% CI, 0.01-0.74; P = .027) and RFS (hazard ratio, 0.036; 95% CI, 0.13-0.98; P = .045). SIB showed no significant detriment in toxicity, albeit with a lower rate of overall grade 3 acute toxicity (3% vs 22%; P = .023) compared with ST. CONCLUSIONS: In RPS, dose escalation with neoadjuvant SIB RT may be independently associated with improved APC and RFS, without a detriment in toxicity, compared with ST. With the addition of standard RT having only a modest benefit compared with surgery alone, our study suggests that future prospective studies evaluating for the benefit of SIB RT should be considered.

Radiation therapy prior to CAR T-cell therapy in lymphoma: impact on patient outcomes.

INTRODUCTION: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with refractory or recurrent (R/R) diffuse large B-cell lymphomas (DLBCL). Nonetheless, most patients ultimately progress. The use of bridging or salvage radiotherapy (RT) in combination with CAR T-cell therapy has been proposed as potential strategies to improve patient outcomes, but consensus is currently lacking as to which, if either, approach is effective. AREAS COVERED: We reviewed the immunologic and molecular mechanisms of resistance and the current retrospective data on patterns-of-failure, clinical risk factors, and treatment outcomes in patients undergoing CAR T-cell therapy, with and without bridging or salvage RT. EXPERT OPINION: We believe that current basic and clinical evidence supports the use of comprehensive, ablative bridging irradiation (CABI), as opposed to low-dose bridging or salvage radiotherapy, as a promising strategy to improve CAR T-cell therapy outcomes in patients with R/R DLBCL. This potential benefit is likely greatest in patients with high tumor burden and/or localized disease, who are both at elevated risk of local recurrence and can often be safely and comprehensively treated with ablative radiation doses (EQD2 > 39 Gy). Hypothesis-driven clinical trials are needed prospectively assess the impact of radiation on outcomes in patients undergoing CAR T-cell therapy.

The presentation of brain metastases in melanoma, non-small cell lung cancer, and breast cancer and potential implications for screening brain MRIs.

PURPOSE: This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. METHODS: Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. RESULTS: A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006). CONCLUSION: Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.

Patterns and Predictors of Failure in Recurrent or Refractory Large B-Cell Lymphomas After Chimeric Antigen Receptor T-Cell Therapy.

PURPOSE: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies. METHODS AND MATERIALS: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression. RESULTS: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02). CONCLUSIONS: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases.

BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

Outcomes and the Role of Primary Histology Following LINAC-based Stereotactic Radiation for Sarcoma Brain Metastases.

OBJECTIVES: The brain is a rare site for sarcoma metastases. Sarcoma's radioresistance also makes standard whole-brain radiotherapy less appealing. We hypothesize that stereotactic radiation techniques (stereotactic radiosurgery [SRS]/stereotactic fractionated radiotherapy [FSRT]) may provide effective local control. MATERIALS AND METHODS: This single-institution retrospective analysis evaluated our experience with linear acceleator-based SRS/FSRT for sarcoma brain metastases. Time to event analysis was estimated via Kaplan-Meier. Univariable/multivariable Cox regression analyses followed to assess the impact of patient and disease characteristics on outcomes. RESULTS: Between 2003 and 2018, 24 patients were treated with 34 courses of SRS/FSRT to 58 discrete lesions. The median age at first treatment was 57 years (range: 25 to 87 y). Majority of patients had concurrent lung metastases (n=21; 88%), diagnosed spindle cell sarcoma (n=15; 25%) or leiomyosarcoma (n=12; 21%) histology, and were treated with either SRS (n=43; median dose=19 Gy, range: 15 to 24 Gy) or FSRT (n=17; 3/5 fractions, median dose=25 Gy, range: 25 to 35 Gy). With a median follow-up after brain metastasis of 7.3 months, the 6 month/12 month local control, distant brain control, and overall survival of 89%/89%, 59%/34%, and 50%/38%, respectively. All local failures were of primary spindle cell histology (P<0.001), which was associated with poorer distant control (hazard ratio=25.8, 95% confidence interval: 3.1-536.4; P=0.003) on univariable analysis, and OS (hazard ratio=7.1, 95% confidence interval: 2.0-26.1; P=0.003) on multivariable analysis. CONCLUSIONS: This is the largest patient cohort with sarcoma brain metastases treated with SRS/FSRT, it provides durable local control, despite a reputation for radioresistance. Further prospective evidence is required to determine the impact of primary histology on control and survival following brain metastasis diagnosis.

Management of brain metastases in breast cancer: a review of current practices and emerging treatments.

PURPOSE: Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. CONCLUSIONS: BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.

Using the Radiosensitivity Index (RSI) to Predict Pelvic Failure in Endometrial Cancer Treated With Adjuvant Radiation Therapy.

PURPOSE: Variability exists in the adjuvant treatment for endometrial cancer (EC) based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multigene expression index that estimates tumor radiosensitivity. We evaluate RSI as a genomic predictor for pelvic failure (PF) in EC patients treated with adjuvant radiation therapy (RT). METHODS AND MATERIALS: Using our institutional tissue biorepository, we identified EC patients treated between January 1999 and April 2011 with primarily endometrioid histology (n = 176; 86%) who received various adjuvant therapies. The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined using the previously identified cutpoint where RSI ≥ 0.375 denotes radioresistance (RR) and RSI < 0.375 describes radiosensitivity. RESULTS: A total of 204 patients were identified, of which 83 (41%) were treated with adjuvant RT. Median follow-up was 38.5 months. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n = 181; 88%). In patients treated with radiation, RR tumors were more likely to experience PF (3-year pelvic control 84% vs 100%; P = .02) with worse PF-free survival (PFFS) (3-year PFFS 65% vs 89%; P = .04). Furthermore, in the patients who did not receive RT, there was no difference in PF (P = .87) or PFFS (P = .57) between the RR/radiosensitive tumors. On multivariable analysis, factors that continued to predict for PF included the RR phenotype (hazard ratio [HR], 12.2; P = .003), lymph node involvement (HR, 4.4; P = .02), and serosal or adnexal involvement (HR, 5.3; P = .01). CONCLUSIONS: On multivariable analysis, RSI was found to be a significant predictor of PF in patients treated with adjuvant RT. We propose using RSI to predict which patients are at higher risk for failing in the pelvis and may be candidates for treatment escalation in the adjuvant setting.

Novel Dose Escalation Approaches for Stereotactic Body Radiotherapy to Adrenal Oligometastases: A Single-Institution Experience.

OBJECTIVES: The role of local disease control in the oligometastatic setting is evolving. Stereotactic body radiation therapy (SBRT) is a noninvasive treatment option for oligometastases; however, using ablative radiation doses for adrenal metastases raises concern given the proximity to radiosensitive organs. Novel treatment techniques may allow for selective dose escalation to improve local control (LC) while minimizing dose to nearby critical structures. MATERIALS AND METHODS: We retrospectively reviewed patients with adrenal oligometastases treated with SBRT from 2013 to 2018. LC, disease-free survival, and overall survival were estimated using Kaplan-Meier methods. Predictors of outcomes were evaluated by log-rank and Cox proportional hazard analyses. RESULTS: We identified 45 adrenal oligometastases in 41 patients treated with SBRT. The median age at treatment was 67 years (range, 40 to 80). The most common primary histologies were non-small cell lung cancer (51%), renal cell carcinoma (24%), and small cell lung cancer (10%). The median prescription dose was 50 Gy (range, 25 to 60 Gy), with 30 (67%) lesions receiving ≥50 Gy and 14 (31%) receiving 60 Gy. In total, 26 (58%) lesions received a simultaneous-integrated boost. Of the 42 treatment simulations, 26 (62%) were supine, 5 (12%) prone, and 11 (26%) in the left lateral decubitus position. At a median follow-up of 10.5 months, there were 3 local failures with a 12-month LC rate of 96%. CONCLUSIONS: Adrenal SBRT for oligometastatic disease is a feasible, noninvasive option with excellent LC and minimal toxicity. Lesions in close proximity to radiosensitive organs may benefit from dynamic patient positioning and selective simultaneous-integrated boost techniques to allow for dose escalation, while also limiting toxicity risks.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Utilizing the genomically adjusted radiation dose (GARD) to personalize adjuvant radiotherapy in triple negative breast cancer management.

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.

Breast leptomeningeal disease: a review of current practices and updates on management.

PURPOSE: Leptomeningeal disease (LMD) is an advanced metastatic disease presentation portending a poor prognosis with minimal treatment options. The advent and widespread use of new systemic therapies for metastatic breast cancer has improved systemic disease control and extended survival; however, as patients live longer, the rates of breast cancer LMD are increasing. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of breast cancer LMD. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, intrathecal, surgical, and radiotherapy treatment modalities), and treatment response evaluation specific to breast cancer patients. Furthermore, we discuss the controversies within this unique clinical setting and identify potential clinical opportunities to improve upon the diagnosis, treatment, and treatment response evaluation in the management of breast LMD. CONCLUSIONS: We recognize the shortcomings in our current understanding of the disease and explore the future role of genomic/molecular disease characterization, technological innovations, and ongoing clinical trials attempting to improve the prognosis for this advanced disease state.