Plasmonic nano-aperture label-free imaging of single small extracellular vesicles for cancer detection.

BACKGROUND: Small extracellular vesicle (sEV) analysis can potentially improve cancer detection and diagnostics. However, this potential has been constrained by insufficient sensitivity, dynamic range, and the need for complex labeling. METHODS: In this study, we demonstrate the combination of PANORAMA and fluorescence imaging for single sEV analysis. The co-acquisition of PANORAMA and fluorescence images enables label-free visualization, enumeration, size determination, and enables detection of cargo microRNAs (miRs). RESULTS: An increased sEV count is observed in human plasma samples from patients with cancer, regardless of cancer type. The cargo miR-21 provides molecular specificity within the same sEV population at the single unit level, which pinpoints the sEVs subset of cancer origin. Using cancer cells-implanted animals, cancer-specific sEVs from 20 µl of plasma can be detected before tumors were palpable. The level plateaus between 5-15 absolute sEV count (ASC) per µl with tumors ≥8 mm3. In healthy human individuals (N = 106), the levels are on average 1.5 ASC/µl (+/- 0.95) without miR-21 expression. However, for stage I-III cancer patients (N = 205), nearly all (204 out of 205) have levels exceeding 3.5 ASC/µl with an average of 12.2 ASC/µl (±9.6), and a variable proportion of miR-21 labeling among different tumor types with 100% cancer specificity. Using a threshold of 3.5 ASC/µl to test a separate sample set in a blinded fashion yields accurate classification of healthy individuals from cancer patients. CONCLUSIONS: Our techniques and findings can impact the understanding of cancer biology and the development of new cancer detection and diagnostic technologies.

Small extracellular vesicles (sEVs) are tiny particles derived from cells that can be detected in bodily fluids such as blood. Detecting sEVs and analyzing their contents may potentially help us to diagnose disease, for example by observing differences in sEV numbers or contents in the blood of patients with cancer versus healthy people. Here, we combine two imaging methods ­ our previously developed method PANORAMA and imaging of fluorescence emitted by sEVs­to visualize and count sEVs, determine their size, and analyze their cargo. We observe differences in sEV numbers and cargo in samples taken from healthy people versus people with cancer and are able to differentiate these two populations based on our analysis of sEVs. With further testing, our approach may be a useful tool for cancer diagnosis and provide insights into the biology of cancer and sEVs.

Neoadjuvant radioimmunotherapy synergy in triple-negative breast cancer: Is microenvironment-guided patient selection on the horizon?

Neoadjuvant chemotherapy plus immunotherapy for triple-negative breast cancer (TNBC) is associated with improved but incomplete response. In this issue of Cancer Cell, Shiao et al. characterize longitudinal biopsies from a window of opportunity study with single-cell RNA sequencing (scRNA-seq) and spatial proteomic profiling and elucidate synergy between radiotherapy (RT) and pembrolizumab.

Partial breast irradiation for patients with early-stage invasive breast cancer or ductal carcinoma in situ: an ASTRO clinical practice guideline

This guideline provides evidence-based recommendations on appropriate indications and techniques for partial breast irradiation (PBI) for patients with early-stage invasive breast cancer and ductal carcinoma in situ. ASTRO convened a task force to address 4 key questions focused on the appropriate indications and techniques for PBI as an alternative to whole breast irradiation (WBI) to result in similar rates of ipsilateral breast recurrence (IBR) and toxicity outcomes. Also addressed were aspects related to the technical delivery of PBI, including dose-fractionation regimens, target volumes, and treatment parameters for different PBI techniques. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. PBI delivered using 3-dimensional conformal radiation therapy, intensity modulated radiation therapy, multicatheter brachytherapy, and single-entry brachytherapy results in similar IBR as WBI with long-term follow-up. Some patient characteristics and tumor features were underrepresented in the randomized controlled trials, making it difficult to fully define IBR risks for patients with these features. Appropriate dose-fractionation regimens, target volume delineation, and treatment planning parameters for delivery of PBI are outlined. Intraoperative radiation therapy alone is associated with a higher IBR rate compared with WBI. A daily or every-other-day external beam PBI regimen is preferred over twice-daily regimens due to late toxicity concerns.

Partial Breast Irradiation for Patients With Early-Stage Invasive Breast Cancer or Ductal Carcinoma In Situ: An ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides evidence-based recommendations on appropriate indications and techniques for partial breast irradiation (PBI) for patients with early-stage invasive breast cancer and ductal carcinoma in situ. METHODS: ASTRO convened a task force to address 4 key questions focused on the appropriate indications and techniques for PBI as an alternative to whole breast irradiation (WBI) to result in similar rates of ipsilateral breast recurrence (IBR) and toxicity outcomes. Also addressed were aspects related to the technical delivery of PBI, including dose-fractionation regimens, target volumes, and treatment parameters for different PBI techniques. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: PBI delivered using 3-dimensional conformal radiation therapy, intensity modulated radiation therapy, multicatheter brachytherapy, and single-entry brachytherapy results in similar IBR as WBI with long-term follow-up. Some patient characteristics and tumor features were underrepresented in the randomized controlled trials, making it difficult to fully define IBR risks for patients with these features. Appropriate dose-fractionation regimens, target volume delineation, and treatment planning parameters for delivery of PBI are outlined. Intraoperative radiation therapy alone is associated with a higher IBR rate compared with WBI. A daily or every-other-day external beam PBI regimen is preferred over twice-daily regimens due to late toxicity concerns. CONCLUSIONS: Based on published data, the ASTRO task force has proposed recommendations to inform best clinical practices on the use of PBI.

Patient Interest in Exploring Nonsurgical Treatment Approaches for Early-Stage Breast Cancer: A Qualitative Study.

PURPOSE: Advances in radiation therapy have enabled the ability to deliver ablative treatments, but there has been limited application of these treatments to early-stage breast cancers with a goal of omitting surgery. The purpose of this study was to explore patient interest in pursuing nonsurgical treatment approaches for their early-stage breast cancer. METHODS AND MATERIALS: We conducted a qualitative study involving interviews with 21 patients with early-stage breast cancer who were eligible for participation in a phase 2 clinical trial offering omission of definitive surgery. Interviews were transcribed and an inductive, thematic analysis was performed by 3 independent reviewers to generate themes and subthemes. RESULTS: Data analysis revealed the following factors that affected patient willingness and desire to explore nonsurgical treatment options: (1) perceptions and feelings about their cancer; (2) current quality of life and the level of support available in their daily life; (3) external conversations focusing on family members' and friends' experiences with cancer and/or cancer treatments; (4) personal health care experiences, including their current breast cancer diagnosis; (5) perceptions and feelings about their physicians; (6) conversations with their physicians about their treatment options; and (7) self-identified desire to direct care decisions. Specifically, patients verbalized fearing surgery and surgical recovery; wanting to preserve their breast(s); the prior negative surgical experiences of friends, family, and themselves; a desire to receive treatment per the latest research; wanting to match the level of treatment with the severity of their cancer; and other comorbidities as reasons for wanting to explore omitting surgery. CONCLUSIONS: Our findings demonstrate an unmet need directed by patient interest to explore nonsurgical options for early-stage, biologically favorable breast cancer. These results may shape conversations around shared decision-making and clinical trial design, and result in more personalized treatment options for women with early-stage breast cancer.

Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer.

PURPOSE: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRF-LI) signals preclinical lymphedema that precedes the development of volumetrically defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). METHODS AND MATERIALS: Patients with breast cancer planned for axillary dissection and RNI prospectively underwent perometry, NIRF-LI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey [LSIDS] and QuickDASH) at baseline, after surgery, and at 6, 12, and 18 months after radiation. Clinical lymphedema was defined as an arm volume increase ≥5% over baseline. Trends over time were assessed using analysis of variance testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. RESULTS: Sixty participants completed at least 2 sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a body mass index >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18 months. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all P < .05). Both dermal backflow and lymphedema were associated with QuickDASH score (P < .05). CONCLUSIONS: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRF-LI use to identify patients for early intervention trials after RNI.

Automated contouring and statistical process control for plan quality in a breast clinical trial.

Background and purpose: Automatic review of breast plan quality for clinical trials is time-consuming and has some unique challenges due to the lack of target contours for some planning techniques. We propose using an auto-contouring model and statistical process control to independently assess planning consistency in retrospective data from a breast radiotherapy clinical trial. Materials and methods: A deep learning auto-contouring model was created and tested quantitatively and qualitatively on 104 post-lumpectomy patients' computed tomography images (nnUNet; train/test: 80/20). The auto-contouring model was then applied to 127 patients enrolled in a clinical trial. Statistical process control was used to assess the consistency of the mean dose to auto-contours between plans and treatment modalities by setting control limits within three standard deviations of the data's mean. Two physicians reviewed plans outside the limits for possible planning inconsistencies. Results: Mean Dice similarity coefficients comparing manual and auto-contours was above 0.7 for breast clinical target volume, supraclavicular and internal mammary nodes. Two radiation oncologists scored 95% of contours as clinically acceptable. The mean dose in the clinical trial plans was more variable for lymph node auto-contours than for breast, with a narrower distribution for volumetric modulated arc therapy than for 3D conformal treatment, requiring distinct control limits. Five plans (5%) were flagged and reviewed by physicians: one required editing, two had clinically acceptable variations in planning, and two had poor auto-contouring. Conclusions: An automated contouring model in a statistical process control framework was appropriate for assessing planning consistency in a breast radiotherapy clinical trial.

Patient-Reported Outcomes of Omission of Breast Surgery Following Neoadjuvant Systemic Therapy: A Nonrandomized Clinical Trial.

Importance: Patients should have an active role in decisions about pursuing or forgoing specific therapies in treatment de-escalation trials. Objective: To evaluate longitudinal patient-reported outcomes (PROs) encompassing decisional comfort and health-related quality of life (HRQOL) among patients who elected to enroll in a clinical trial evaluating radiotherapy alone, without breast surgery, for invasive breast cancers with exceptional response to neoadjuvant systemic therapy (NST). Design, Setting, and Participants: Prospective, single-group, phase 2 clinical trial at 7 US medical centers. Women aged 40 years or older with invasive cT1-2 N0-1 M0 triple-negative or human epidermal growth factor receptor 2 (ERBB2)-positive breast cancer with no pathologic evidence of residual disease following standard NST enrolled from March 6, 2017, to November 9, 2021. Validated PRO measures were administered at baseline and 6, 12, and 36 months post-radiotherapy. Data were analyzed from January to February 2023. Interventions: PRO measures included the Decision Regret Scale (DRS), Functional Assessment of Cancer Therapy-Lymphedema (FACT-B+4), and Breast Cancer Treatment Outcomes Scale (BCTOS). Main Outcomes and Measures: Changes in PRO measure scores and subscores over time. Results: Among 31 patients, the median (IQR) age was 61 (56-66) years, 26 (84%) were White, and 26 (84%) were non-Hispanic. A total of 15 (48%) had triple-negative disease and 16 (52%) had ERBB2-positive disease. Decisional comfort was high at baseline (median [IQR] DRS score 10 [0-25] on a 0-100 scale, with higher scores indicating higher decisional regret) and significantly increased over time (median [IQR] DRS score at 36 months, 0 [0-20]; P < .001). HRQOL was relatively high at baseline (median [IQR] FACT-B composite score 121 [111-134] on a 0-148 scale, with higher scores indicating higher HRQOL) and significantly increased over time (median [IQR] FACT-B score at 36 months, 128 [116-137]; P = .04). Perceived differences between the affected breast and contralateral breast were minimal at baseline (median [IQR] BCTOS score 1.05 [1.00-1.23] on a 1-4 scale, with higher scores indicating greater differences) and increased significantly over time (median [IQR] BCTOS score at 36 months, 1.36 [1.18-1.64]; P < .001). At 36 months postradiotherapy, the cosmetic subscore was 0.45 points higher than baseline (95% CI, 0.16-0.74; P = .001), whereas function, pain, and edema subscores were not significantly different than baseline. Conclusions and Relevance: In this nonrandomized phase 2 clinical trial, analysis of PROs demonstrated an overall positive experience for trial participants, with longitudinal improvements in decisional comfort and overall HRQOL over time and minimal lasting adverse effects of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02945579.

Prospective, early longitudinal assessment of lymphedema-related quality of life among patients with locally advanced breast cancer: The foundation for building a patient-centered screening program.

BACKGROUND: We examined how breast cancer-related lymphedema (BCRL) affects health-related quality of life (HRQOL), productivity, and compliance with therapeutic interventions to guide structuring BCRL screening programs. METHODS: We prospectively followed consecutive breast cancer patients who underwent axillary lymph node dissection (ALND) with arm volume screening and measures assessing patient-reported health-related quality of life (HRQOL) and perceptions of BCRL care. Comparisons by BCRL status were made with Mann-Whitney U, Chi-square, Fisher's exact, or t tests. Trends over time from ALND were assessed with linear mixed-effects models. RESULTS: With a median follow-up of 8 months in 247 patients, 46% self-reported ever having BCRL, a proportion that increased over time. About 73% reported fear of BCRL, which was stable over time. Further in time from ALND, patients were more likely to report that BCRL screening reduced fear. Patient-reported BCRL was associated with higher soft tissue sensation intensity, biobehavioral, and resource concerns, absenteeism, and work/activity impairment. Objectively measured BCRL had fewer associations with outcomes. Most patients reported performing prevention exercises, but compliance decreased over time; patient-reported BCRL was not associated with exercise frequency. Fear of BCRL was positively associated with performing prevention exercises and using compressive garments. CONCLUSIONS: Both incidence and fear of BCRL were high after ALND for breast cancer. Fear was associated with improved therapeutic compliance, but compliance decreased over time. Patient-reported BCRL was more strongly associated with worse HRQOL and productivity than was objective BCRL. Screening programs must support patients' psychological needs and aim to sustain long-term compliance with recommended interventions.

Socioeconomic Barriers to Randomized Clinical Trial Retention in Patients Treated With Adjuvant Radiation for Early-Stage Breast Cancer.

PURPOSE: Socioeconomic barriers contribute to breast cancer clinical trial enrollment disparities. We sought to identify whether socioeconomic disadvantage also is associated with decreased trial retention. METHODS AND MATERIALS: We performed a secondary analysis of 253 (of 287) patients enrolled in a randomized phase 3 trial of conventionally fractionated versus hypofractionated whole-breast irradiation. The outcome of trial retention versus dropout was defined primarily based on whether the patient completed breast cosmesis outcomes assessment at 3-year follow-up, and secondarily, at 5-year follow-up. Associations of retention with severity of socioeconomic disadvantage, quantified by patients' home neighborhood area deprivation index (ADI) rank (1 [least] to 100 [most deprivation]), were tested using the Kruskal-Wallis test and multivariate logistic regression. Associations of retention with patients' use of social resource assistance were analyzed using the χ2 test. RESULTS: In total, 21.7% (n = 55) of patients dropped out by 3 years and 36.7% (n = 92) by 5 years. Median ADI was 36.5 (interquartile range, 22-57) for retained and 46.0 (interquartile range, 29-60) for dropout patients. Dropout was associated with more severe socioeconomic deprivation (ADI ≥45 vs <45) at 3 years (odds ratio, 3.63; 95% confidence interval, 1.62-8.15; P = .002) and 5 years (odds ratio, 2.55; 95% confidence interval, 1.37-4.76; P = .003). While on study, patients who ultimately dropped out were more likely to require resource assistance for practical (transportation, housing, financial) than psychological needs (distress, grief) or advance care planning (P = .03). CONCLUSIONS: In this study, ADI was associated with disparities in clinical trial retention of patients with breast cancer receiving adjuvant radiation treatment. Results suggest that developing multidimensional interventions that extend beyond routine social determinants needs screening are needed, not only to enhance initial clinical trial access and enrollment but also to enable robust long-term retention of socioeconomically disadvantaged patients and improve the validity and generalizability of reported long-term trial clinical and patient-reported outcomes.

Effectiveness Without Efficacy: Cautionary Tale from a Landmark Breast Cancer Randomized Controlled Trial.

Background: "Old" randomized controlled trials established breast conserving therapy (BCT) and total mastectomy (TM) equivalence for treating early breast cancer, whereas recent literature report improved survival with BCT. To reconcile this, we performed a simulation study and re-analyzed B-06 trial data. Methods: We estimated the distributions for overall survival (OS), cumulative incidence functions for breast-cancer-specific death (BCSD) and other causes-specific death (OCSD) by BCT and TM. The restricted mean survival time (RMST) difference and hazard ratio between the two arms were estimated. Given the estimated distributions, we simulated cause-specific death times from each arm, evaluating the power to test treatment difference in OS, BCSD, and OCSD with different sample sizes, follow-up times, and a modified setting by simulating BCT-arm OCSD times from the distribution of patients not receiving radiation. Results: With 200 months follow-up, the average BCT-over-TM gain measured by RMST was 3.7 months for OS and 4.5 months for BCSD. Increasing the trial size to 5,000 per arm, there is a 79.2% chance to detect the OS benefit with RMST and 92.4% for BCSD. A nonproportional increase of OCSD in BCT compared to TM was observed after 144 months, and particularly after 200 months post treatments. When OCSD times of BCT were simulated using patients not receiving radiation, the estimated OS gain increased to 4.4 months, and the power increased to 92.2%. Conclusions: The late excess other-cause-death, likely due to radiation, in the BCT arm and sample size constraints limited the power to report BCT superiority. Given radiation delivered in the era of B-06 trial, BCT and TM remain largely equivalent.

Plasma Cytokines/Chemokines as Predictive Biomarkers for Lymphedema in Breast Cancer Patients.

Breast cancer-related lymphedema (BCRL) occurs in ~ 40% of patients after axillary lymph node dissection (ALND), radiation therapy (RT), or chemotherapy. First-line palliative treatment utilizes compression garments and specialized massage. Reparative microsurgeries have emerged as a second-line treatment, yet both compression and surgical therapy are most effective at early stages of LE development. Identifying patients at the highest risk for BCRL would allow earlier, more effective treatment. Perometric arm volume measurements, near-infrared fluorescent lymphatic imaging (NIRF-LI) data, and blood were collected between 2016 and 2021 for 40 study subjects undergoing treatment for breast cancer. Plasma samples were evaluated using MILLIPLEX human cytokine/chemokine panels at pre-ALND and at 12 months post-RT. A Mann-Whitney t-test showed that G-CSF, GM-CSF, IFN-2α, IL-10, IL-12p40, IL-15, IL-17A, IL-1ß, IL-2, IL-3, IL-6, and MIP-1ß were significantly higher at pre-ALND in those presenting with BCRL at 12 months post-RT. MIP-1ß and IL-6 were significantly higher at pre-ALND in those who developed dermal backflow, but no BCRL, at 12 months post-RT. Plasma IL-15, IL-3, and MIP-1ß were elevated at 12 months after RT in those with clinical BCRL. These findings establish BCRL as a perpetual inflammatory disorder, and suggest the use of plasma cytokine/chemokine levels to predict those at highest risk.

Inclusion of premenopausal women in breast cancer clinical trials.

BACKGROUND: Patients with premenopausal breast cancer (PMBC) have been historically excluded from some clinical trials because of the limitations of using endocrine therapy (ET) in this population. We analyzed breast cancer randomized clinical trials (RCTs) to determine the rates of and factors associated with inclusion of PMBC patients to provide a benchmark for PMBC inclusion in RCTs moving forward. METHODS: Using ClinicalTrials.Gov, we identified breast cancer phase III RCTs and extracted inclusion criteria and patient enrollment information. Multiple binary logistic regression modeling was used to assess trial-related factors that were associated with PMBC patient inclusion. RESULTS: Of 170 breast cancer RCTs identified, 131 (77.1%) included PMBC patients. Sixty-five (38.2%) trials analyzed patients with hormone-receptor-positive (HR+) and HER2-negative (HER2-) breast cancer, of which 31 (47.7%) allowed for enrollment of PMBC patients. Lower rates of PMBC inclusion were seen in trials that studied HR+/HER2-patients (47.7% PMBC inclusion in HR+/HER2-trials vs. 94.3% in non-HR+/HER2-trials, aOR 0.07 [95% CI: 0.02-0.19], p < 0.001) and in trials that randomized or mandated ET (44.4% in ET trials vs. 83.2% in non-ET trials, aOR 0.21 [95% CI: 0.10-0.83], p = 0.02). Trials studying chemotherapy (CT) were associated with inclusion of PMBC patients (100% in CT trials vs. 70.5% in non-CT trials, a OR 14.02 [95% CI: 1.54-127.91], p = 0.01). All surgical and radiation therapy clinical trials allowed for the inclusion of PMBC patients in their eligibility criteria. CONCLUSIONS: Breast cancer clinical trials should carefully select their enrollment criteria and consider inclusion of premenopausal patients when appropriate.

Impact of Medicaid Expansion Under the Affordable Care Act on Receipt of Surgery for Breast Cancer.

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery. Background: Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited. Methods: Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment. Results: Of 624,237 patients diagnosed with invasive breast cancer, 24,728 (4%) patients did not undergo surgical treatment. Overall, no significant differences in rates of omission of surgery over time were seen based on Medicaid expansion status. Significant findings were noted based on patient residential location. In rural areas, Medicaid expansion was associated with lower rates of omission of surgery (adjusted DID -2.47%, 95% confidence interval [CI] -4.01% to -0.94%; P = 0.002). In urban area, rates of omission of surgery increased over time for both groups, but the relative increase was lower in expansion states (adjusted DID -0.72%, 95% CI -1.25% to -0.20%; P = 0.007). In metro areas, changes in rates of surgery over time were comparable across expansion and non-expansion states (adjusted DID -0.08%, 95% CI -0.32% to 0.16%; P = 0.512). Conclusions: Medicaid expansion had no measurable effect on the receipt of surgery for breast cancer in the overall cohort. Medicaid expansion was associated with higher rates of surgery in rural areas, representing the minority of the population.

Targeted Inhibition of DNA-PKcs, ATM, ATR, PARP, and Rad51 Modulate Response to X Rays and Protons.

Small molecule inhibitors are currently in preclinical and clinical development for the treatment of selected cancers, particularly those with existing genetic alterations in DNA repair and DNA damage response (DDR) pathways. Keen interest has also been expressed in combining such agents with other targeted antitumor strategies such as radiotherapy. Radiotherapy exerts its cytotoxic effects primarily through DNA damage-induced cell death; therefore, inhibiting DNA repair and the DDR should lead to additive and/or synergistic radiosensitizing effects. In this study we screened the response to X-ray or proton radiation in cell lines treated with DDR inhibitors (DDRis) targeting ATM, ATR, DNA-PKcs, Rad51, and PARP, with survival metrics established using clonogenic assays. We observed that DDRis generate significant radiosensitization in cancer and primary cells derived from normal tissue. Existing genetic defects in cancer cells appear to be an important consideration when determining the optimal inhibitor to use for synergistic combination with radiation. We also show that while greater radiosensitization can be achieved with protons (9.9 keV/µm) combined with DDRis, the relative biological effectiveness is unchanged or in some cases reduced. Our results indicate that while targeting the DDR can significantly radiosensitize cancer cells to such combinations, normal cells may also be equally or more severely affected, depending on the DDRi used. These data highlight the importance of identifying genetic defects as predictive biomarkers of response for combination treatment.

Prediction of breast cancer-related lymphedema by dermal backflow detected with near-infrared fluorescence lymphatic imaging.

PURPOSE: Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%-10% increase in arm volume, typically measured no earlier than 3-6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL. METHODS: In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4-8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI. RESULTS: By 18 months after RT, 30 of 42 study subjects (71%) developed mild-moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by "dermal backflow" of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL. CONCLUSION: BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes.

An empirical model of proton RBE based on the linear correlation between x-ray and proton radiosensitivity.

BACKGROUND: Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and ß vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE = 1.1. PURPOSE: Here, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters. METHODS AND MATERIALS: We performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x-rays and 1.2, 2.6, or 9.9 keV/µm protons, and combined our measurements with published survival data (n = 397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF% , (the dose required to achieve survival fraction [SF], e.g., D10% ) varied with proton LET, and calculated the Bayesian information criteria associated with different LET-dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six-parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting. RESULTS: Our analyses of the trends in the data show that DSF% is linearly correlated between x-rays and protons, regardless of the choice of the survival level (e.g., D10% , D37% , or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%-30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE-weighted doses than the other empirical models, with RBE-weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE-weighted doses (RBE = 1.1) to the tumor. CONCLUSIONS: We established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams.

Lymphedema in Inflammatory Breast Cancer Patients Following Trimodal Treatment.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a debilitating sequela of breast cancer treatment and is becoming a greater concern in light of improved long-term survival. Inflammatory breast cancer (IBC) is a rare and aggressive malignancy for which systemic therapy, surgery, and radiotherapy remain the standard of care, thereby making IBC patients highly susceptible to developing BCRL. This study evaluated BCRL in IBC following trimodal therapy. METHODS: IBC patients treated from 2016 to 2019 were identified from an institutional database. Patients were excluded if they presented with recurrent disease, underwent bilateral axillary surgery, did not complete trimodal therapy, or were lost to follow-up. Demographic, clinicopathologic factors, oncologic outcomes, and perometer measurements were recorded. BCRL was defined by clinician diagnosis and/or objective perometer measurements when available. Time to development of BCRL and treatment received were captured. RESULTS: Eighty-three patients were included. Median follow-up was 33 months. The incidence of BCRL was 50.6% (n = 42). Mean time to BCRL from surgery was 13 (range 2-24) months. Demographic and clinicopathologic features were similar between patients with and without BCRL with exception of higher proportion receiving delayed reconstruction in the BCRL group (38.1% vs. 14.6%, p = 0.03). Forty patients (95.2%) underwent BCRL treatment, which included physical therapy (n = 39), compression (n = 38), therapeutic lymphovenous bypass (n = 13), and/or vascularized lymph node transfer (n = 12). CONCLUSIONS: IBC patients are at high-risk for BCRL after treatment, impacting 51% of patients in this cohort. Strategies to reduce or prevent BCRL and improve real-time diagnosis should be implemented to better direct early management in this patient population.