Impact of prostate biopsy secondary pathology review on radiotherapy management.

BACKGROUND: The Gleason scoring system is the most widely used method to assess prostate adenocarcinoma pathology however interobserver variability is significant. Gleason score, PSA level, and clinical stage comprise the NCCN risk stratification that guides treatment decision making. Given the importance of an accurate Gleason score and wide interobserver variability, referral centers routinely review outside pathology at the time of consultation. We sought to address the impact a secondary pathology review had on radiation therapy treatment recommendations in men with prostate cancer at our institution. METHODS: We retrospectively collected patient data on 342 patients seen at our institution from January 2012 to December 2018. Clinicopathologic data were used to subdivide patients into risk groups and available treatment options per NCCN criteria. Cases reviewed by our genitourinary pathologist (GUP) were compared with reports from outside pathologists. Inter-rater reliability between pathologists was assessed with weighted Cohen's kappa statistic and agreement of treatment options was determined by McNemar's exact tests. RESULTS: GUP scored more cores positive in 16.47% of cases on secondary review. Primary Gleason score was changed in 12.28% of patients and secondary score in 26.02% of cases. Total Gleason score was different in 29.24% of cases, 19.01% were downgraded and 10.23% upgraded. The weighted kappa statistic was 0.759 (95% confidence interval [CI]: 0.711, 0.807). 18.77% of patients were assigned to a different NCCN risk group following secondary review. The weighted kappa statistic comparing NCCN risk stratification was 0.802 (95% CI: 0.754, 0.850). Secondary review influenced radiation therapy recommendations pertaining to brachytherapy boost and androgen deprivation therapy in men with high risk disease (χ2 = 5.33, p = 0.0386; χ2 = 8.05, p = 0.0072, respectively). Kappa statistic was found to be highest when GUP assessed high-risk disease versus all other categories (κ = 0.823, 95% CI: 0.750, 0.895). CONCLUSIONS: We found nearly one in five men (18.7%) was assigned a different NCCN risk group and thus offered potentially different treatment options after a secondary pathology review at our institution. Given the inherent nature of prostate cancer and lung disease-specific survival associated with modern therapies, our study demonstrates the importance of a secondary pathology review and its potential impact on radiation therapy recommendations.

MRI Response to Pre-operative Stereotactic Ablative Body Radiotherapy (SABR) in Early Stage ER/PR+ HER2- Breast Cancer correlates with Surgical Pathology Tumor Bed Cellularity.

OBJECTIVE: This study evaluates breast MRI response of ER/PR+ HER2- breast tumors to pre-operative SABR with pathologic response correlation. METHODS: Women enrolled in a phase 2 single institution trial of SABR for ER/PR+ HER2- breast cancer were retrospectively evaluated for radiologic-pathologic correlation of tumor response. These patients underwent baseline breast MRI, SABR (28.5 Gy in 3 fractions), follow-up MRI 5 to 6 weeks post-SABR, and lumpectomy. Tumor size and BI-RADS descriptors on pre and post-SABR breast MRIs were compared to determine correlation with surgical specimen % tumor cellularity (%TC). Reported MRI tumor dimensions were used to calculate percent cubic volume remaining (%VR). Partial MRI response was defined as a BI-RADs descriptor change or %VR ≤ 70%, while partial pathologic response (pPR) was defined as %TC ≤ 70%. RESULTS: Nineteen patients completed the trial, and %TC ranged 10% to 80%. For BI-RADS descriptor analysis, 12 of 19 (63%) showed change in lesion or kinetic enhancement descriptors post-SABR. This was associated with lower %TC (29% vs. 47%, P = .042). BI-RADS descriptor change analysis also demonstrated high PPV (100%) and specificity (100%) for predicting pPR to treatment (sensitivity 71%, accuracy 74%), but low NPV (29%). MRI %VR demonstrated strong linear correlation with %TC (R = 0.70, P < .001, Pearson's Correlation) and high accuracy (89%) for predicting pPR (sensitivity 88%, specificity 100%, PPV 100%, and NPV 50%). CONCLUSION: Evaluating breast cancer response on MRI using %VR after pre-operative SABR treatment can help identify patients benefiting the most from neoadjuvant radiation treatment of their ER/PR+ HER2- tumors, a group in which pCR to neoadjuvant therapy is rare.

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.

Quantitative Changes in Intratumoral Habitats on MRI Correlate With Pathologic Response in Early-stage ER/PR+ HER2- Breast Cancer Treated With Preoperative Stereotactic Ablative Body Radiotherapy.

Objective: To quantitatively evaluate intratumoral habitats on dynamic contrast-enhanced (DCE) breast MRI to predict pathologic breast cancer response to stereotactic ablative body radiotherapy (SABR). Methods: Participants underwent SABR treatment (28.5 Gy x3), baseline and post-SABR MRI, and breast-conserving surgery for ER/PR+ HER2- breast cancer. MRI analysis was performed on DCE T1-weighted images. MRI voxels were assigned eight habitats based on high (H) or low (L) maximum enhancement and the sequentially numbered dynamic sequence of maximum enhancement (H1-4, L1-4). MRI response was analyzed by percent tumor volume remaining (%VR = volume post-SABR/volume pre-SABR), and percent habitat makeup (%HM of habitat X = habitat X voxels/total voxels in the segmented volume). These were correlated with percent tumor bed cellularity (%TC) for pathologic response. Results: Sixteen patients completed the trial. The %TC ranged 20%-80%. MRI %VR demonstrated strong correlations with %TC (Pearson R = 0.7-0.89). Pre-SABR tumor %HMs differed significantly from whole breasts (P = 0.005 to <0.00001). Post-SABR %HM of tumor habitat H4 demonstrated the largest change, increasing 13% (P = 0.039). Conversely, combined %HM for H1-3 decreased 17% (P = 0.006). This change correlated with %TC (P < 0.00001) and distinguished pathologic partial responders (≤70 %TC) from nonresponders with 94% accuracy, 93% sensitivity, 100% specificity, 100% positive predictive value, and 67% negative predictive value. Conclusion: In patients undergoing preoperative SABR treatment for ER/PR+ HER2- breast cancer, quantitative MRI habitat analysis of %VR and %HM change correlates with pathologic response.

Genomically Guided Breast Radiation Therapy: A Review of the Current Data and Future Directions.

PURPOSE: To highlight the current evidence and the limitations in data to support a personalized approach in breast oncology radiation therapy management and define steps needed for clinical implementation. METHODS AND MATERIALS: A critical review of the current literature on the use of genomics in breast radiation therapy was undertaken by a group of breast radiation oncologists to discuss current data, future directions, and challenges. RESULTS: A summary of the existing data, ongoing clinical trials, and future directions is provided. The authors note many groups have developed radiation-specific genomic assays, which demonstrate promise in prediction of local control and benefit from radiation therapy; however, prospective validation of their utility is needed. Limitations continue to exist in our understanding of tumor biology and how it can be integrated into clinical practice. CONCLUSIONS: Given the relative ubiquity of breast radiation therapy, the variety of dose and fractionation approaches, and the current data to support a personalized approach, it is our belief that the delivery of breast radiation therapy is uniquely poised for a genomically personalized radiation therapy approach. Prospective clinical trials implementing genomic signatures are needed at this time to advance the field.

The prevalence of luminal B subtype is higher in older postmenopausal women with ER+/HER2- breast cancer and is associated with inferior outcomes.

OBJECTIVES: To establish whether clinicopathologic and genomic characteristics may explain the poor prognosis associated with advanced age in ER+/HER2- breast cancer. MATERIALS AND METHODS: The cohort included 271 consecutive post-menopausal patients with ER+/HER2- invasive breast cancer ages 55 years and older. Patients were categorized as "younger" (ages 55- < 75) and "older" (ages ≥75). The Kaplan-Meier method was used to estimate locoregional recurrence (LRR), recurrence-free interval (RFi), and overall survival (OS). Gene expression of tumor samples was assessed with Affymetrix Rosetta/Merck Human RSTA microarray platform. Differential gene expression analysis of tumor samples was performed using R package Limma. RESULTS: 271 breast cancer patients were identified, including 186 younger and 85 older patients. Older patients had higher rates of Luminal B subtype (53% vs 34%) and lower rates of Luminal A subtype (42% vs 58%, p = 0.02). Older patients were less likely to receive chemotherapy (9% vs 40%, p < 0.001) and hormone therapy (71% vs 89%, p < 0.001). For cases of grade 1-2 disease, older patients had a higher proportion of the luminal B subtype (49% vs. 30%, p = 0.014). Age ≥ 75 predicted for inferior OS (HR = 3.06, p < 0.001). The luminal B subtype predicted for inferior OS (HR = 2.12, p = 0.014), RFi (HR 5.02, p < 0.001), and LRR (HR = 3.12, p = 0.045). There were no significant differences in individual gene expression between the two groups. CONCLUSION: Women with ER+/HER2- breast cancer ≥75 years old had higher rates of the more aggressive luminal B subtype and inferior outcomes. Genomic testing of these patients should be strongly considered, and treatment should be intensified when appropriate.

MR-guided stereotactic body radiation therapy for intracardiac and pericardial metastases.

AIMS: To assess the safety and efficacy of MR-guided stereotactic body radiation therapy (MRgSBRT) for cardiac metastases. MATERIALS/METHODS: This single institution retrospective analysis evaluated our experience with MRgSBRT for cardiac metastases. Response rate was compared between pre-RT and post-RT imaging. Symptomatic changes were also tracked and documented. RESULTS: Between 4/2019 and 3/2020, five patients with cardiac metastases (4 intracardiac and 1 pericardial) were treated with MRgSBRT. Median age at treatment was 73 years (range 64-80) and two patients had pre-existing cardiac disease. Histologies included melanoma and breast adenocarcinoma. Median lesion diameter was 2 cm (range 1.96-5.8 cm). Three patients were symptomatic, one of whom had pulmonary hypertension and RV enlargement. Another patient had an asymptomatic arrythmia. Median PTV prescribed dose was 40 Gy (range 40-50 Gy) and delivered in five fractions on nonconsecutive days. Median PTV volume was 53.4 cc (range 8.7-116.6 cc) and median coverage was 95% (range 84.1-100%). A uniform 3 mm margin was used for real-time gating, allowing a median 7% (range 5-10%) pixel excursion tolerance. Median follow-up was 4.7 months (range 0.9-12.3). Two patients exhibited stable disease, two had a partial response and one exhibited a complete response. All symptomatic patients experienced some relief. There were no acute adverse events, however, one patient without prior cardiac disease developed atrial fibrillation 6 months after treatment. Two patients died of causes unrelated to cardiac MRgSBRT. CONCLUSION: In this largest known series of cardiac metastasis MRgSBRT, real-time image guidance enables safe treatment resulting in good response with improving presenting symptoms without acute adverse events.

Primary vs nodal site PET/CT response as a prognostic marker in oropharyngeal squamous cell carcinoma treated with intensity-modulated radiation therapy.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood. METHODS: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival. RESULTS: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035). CONCLUSION: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS.

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.

Emerging Opportunities for Digital PET/CT to Advance Locoregional Therapy in Head and Neck Cancer.

The purpose of this article is to present the recent imaging advancements enabled by digital photon counting positron emission tomography detector technology and discuss its potential applications in the clinical management of head and neck cancer (HNC) and nodal metastases. 18F-fluorodeoxyglucose positron-emission tomography is a clinically useful biomarker for the detection, targeted biopsy, treatment planning, and therapeutic response assessment of HNC. This article highlights the current state of 18F-fluorodeoxyglucose positron-emission tomography imaging in HNC management as well as the emerging capabilities of the recently introduced digital photon counting positron emission tomography/computed tomography platform for more effective molecular and functional HNC imaging.

Clinical outcomes of breast leptomeningeal disease treated with intrathecal trastuzumab, intrathecal chemotherapy, or whole brain radiation therapy.

PURPOSE: Leptomeningeal disease is a rare presentation of advanced metastatic breast cancer. The purpose of this study was to evaluate craniospinal progression between intrathecal (IT) trastuzumab, IT chemotherapy, and whole brain radiation therapy (WBRT) in leptomeningeal disease. METHODS: A total of 56 patients were identified with breast cancer leptomeningeal disease at our institution treated with IT trastuzumab (n = 18; 32%), single-agent IT chemotherapy (methotrexate n = 14 or thiotepa n = 1; 27%), or WBRT alone (n = 23; 41%). Patients were treated beginning November 2012 and followed until November 2018. RESULTS: Median time from breast cancer diagnosis to development of leptomeningeal disease was 4.3 years. There were no significant differences noted between IT trastuzumab, IT chemotherapy, or WBRT groups in age (p = 0.4), Karnofsky Performance Status (KPS) (p = 0.07), or receipt of systemic therapy at time of leptomeningeal disease treatment (p = 0.47). Median follow-up of patients from leptomeningeal diagnosis was 5 months (range 0.2-81.1 months). Significant differences were noted in Kaplan-Meier (KM) craniospinal progression-free survival (CS-PFS) with 6-month rates of 44%, 18%, and 26% (p = 0.04) between IT trastuzumab, IT chemotherapy, and WBRT, respectively. Craniospinal control > 10 months was achieved in four patients treated with IT trastuzumab. Twelve-month KM OS rates were 54%, 10%, and 19% (p = 0.01) between IT trastuzumab, IT chemotherapy, and WBRT groups, respectively. IT therapy was adequately tolerated with three patients undergoing treatment-related hospitalizations. CONCLUSIONS: In our institutional series, significant differences were noted in CS-PFS and OS by treatment modality. IT trastuzumab should be considered in the management HER2+ breast leptomeningeal disease.

Diabetes mellitus: A significant co-morbidity in the setting of lung cancer?

BACKGROUND: To evaluate the effect of diabetes mellitus (DM) on clinical outcomes in patients managed surgically for non-small cell lung cancer (NSCLC). METHODS: Patients who underwent surgery for pathological I-IIIA NSCLC at Duke University from 1995-2005 were analyzed. Postoperative mortality was defined as any death occurring within 30 days of resection or during the initial hospitalization after surgery. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered a local/regional recurrence (LRR). Survival and LRR rates were estimated using the Kaplan-Meier method and compared using a log rank test. A multivariate regression analysis assessed the association between candidate factors, including DM, and disease recurrence and survival. RESULTS: Of 957 patients, DM was present in 122 (13%). DM was associated with an increased risk of postoperative mortality (7.4% vs. 3.2%, P= 0.04). However, the proportion of patients undergoing sublobar resections, mediastinal lymph node dissection, and receiving adjuvant chemotherapy, was no different among patients with or without DM. Five-year LRR rates were 27% in patients with DM, versus 21% in patients without DM (P= 0.23). Survival at five years was 43% for patients with DM, and 47% for patients without DM (P= 0.10). On multivariate analysis, DM was not independently associated with a higher risk of LRR (hazard ratio [HR] 1.33, P= 0.34), distant recurrence (HR 0.86, P= 0.58), or overall survival (HR 1.08, P= 0.63). CONCLUSIONS: Although a higher risk of postoperative mortality was noted in patients with DM, a detriment in local or distant disease control or overall survival was not observed.

p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.

Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to protect mice from myocardial injury after whole-heart irradiation. Mice with an endothelial cell-specific deletion of p53 succumbed to heart failure after whole-heart irradiation as a result of myocardial necrosis, systolic dysfunction, and cardiac hypertrophy. Moreover, the onset of cardiac dysfunction was preceded by alterations in myocardial vascular permeability and density, which resulted in cardiac ischemia and myocardial hypoxia. Mechanistic studies with primary cardiac endothelial cells irradiated in vitro indicated that p53 signaling caused mitotic arrest and protected cardiac endothelial cells from cell death resulting from abnormal mitosis or mitotic catastrophe. Furthermore, mice lacking the cyclin-dependent kinase inhibitor p21, which is a transcriptional target of p53, were also sensitized to myocardial injury after whole-heart irradiation. Together, our results demonstrate that the p53-p21 axis functions to prevent radiation-induced myocardial injury in mice.