Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer

Purpose To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). Methods and Materials In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. Results The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], –0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, –0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. Conclusions With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease

Racial Disparities in Patients with Stage IIIC Endometrial Cancer

Purpose/Objective(s): To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma (EC). Materials/Methods: A retrospective multi-institutional cohort study was conducted across 13 Northern American academic centers and included patients with stage IIIC endometrial carcinoma (EC) who received both chemotherapy and radiation in an adjuvant setting. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. Propensity score matching was used to estimate the effect of race on survival outcomes. Statistical analyses were conducted using statistical software. Results: A total of 90 Black and 568 non-Black patients (83%) were identified with a median age at diagnosis of 62 (Interquartile Range (IQR) 55-70). Median follow-up was 45.3 months (IQR 24-71 months). Black patients were significantly older (p\u3c0.0001), had significantly more non-endometrioid histology (p\u3c0.0001), grade 3 tumors (p\u3c0.0001) and were more likely to have \u3e1 positive paraaortic lymph nodes (PALN) compared to non-black patients. The presence of lymphovascular space invasion (LVSI), depth of myometrial involvement, number of total nodes involved, adnexal and cervical involvement and stage were not correlated with race (all p\u3e0.1). As for treatment type, chemoradiotherapy sequencing approach was not correlated with race and no difference in number of chemotherapy cycles between Black and non-Black patients (p=0.32) was observed. Black patients were more often treated with external beam radiation therapy (EBRT) (43.3% and 24%, respectively) while a higher proportion of non-black patients received both EBRT and vaginal cuff brachytherapy (VBT) (65% vs. 38 %) (P\u3c0.0001) despite similar cervical involvement. The 5-year estimated OS and RFS rates were 45% and 47% compared to 77% and 68% for Black patients vs. non-black patients, respectively (p\u3c0.001). After propensity score matching, the 2 groups were well balanced for most of the covariates (age, histology, stage, grade, number of positive PALN, adnexal and cervical involvement) except for depth of myometrial invasion and radiation type. The estimated hazard ratios (HRs) of Black vs. non-Black patients were 1.613 (95% CI = (1.01, 2.575), p-value = 0.045) for OS and 1.487 (95% CI = (0.906, 2.440), p-value = 0.116) for RFS, indicating that Black patients have significantly worse OS. RFS differences did not reach statistical significance. Conclusion: Compared to non-Black patients, Black patients have higher rates of non-endometrioid histology, grade 3 tumors and number of PALNs. After propensity score matching, Black patients had worse OS but no statistically significant difference in RFS. Racial disparities could be mitigated by better access to care, equitable inclusion on randomized trials, and identification of genomic/molecular differences to better tailor adjuvant treatment

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs

Trends in Receipt of Shorter Regimens of Radiation Therapy and Treatment Noncompletion Disparities Among Breast and Prostate Cancer Patients in the United States

Although racial and sociodemographic disparities exist in the rates of treatment noncompletion for patients receiving breast and prostate radiotherapy, shorter regimens may be associated with lower rates of treatment noncompletion. We assessed predictors of treatment noncompletion and racial disparities in access to shorter regimens for patients with prostate cancer (PCa) and breast cancer (BCa). Using the 2004-2017 National Cancer Database, men with localized PCa were defined as receiving conventional fractionation if they received 180cGY/fraction (noncompletion: < 41 fractions) or 200cGY/fraction (noncompletion: < 37 fractions). Stereotactic body radiotherapy (SBRT) was defined as five to eight fractions of 600-800cGY/fraction (non-completion: < 5 fractions). Women with non-metastatic BCa who received surgery with radiotherapy were included. Patients receiving 180cGY or 200cGY/fraction were defined as receiving conventional fractionation (noncompletion: < 25 fractions); patients receiving 266cGY, 267cGY, or 270cGY per fraction (noncompletion: < 15 fractions) were defined as receiving hypofractionated regimens. Multivariable logistic regressions assessed predictors of treatment noncompletion and racial disparities in access to shorter regimens. 166,436 men with complete data met inclusion criteria (median age 70 years [IQR 64–75]; 19.6% low-risk, 47.3% intermediate-risk; 33.1% high-risk; 17.5% Black; 82.5% white). Black men had higher rates of treatment noncompletion compared with white men (13.5% vs. 12.3%, OR 1.07, 95% CI 1.03-1.12, P < 0.001). SBRT was associated with lower odds of treatment non-completion compared with conventional EBRT (SBRT 1.3% vs. EBRT 13.2%; OR 0.08, 95% CI 0.07-0.1, P < 0.001). Although use of SBRT increased from 0.07% in 2004 to 13.03% in 2017, Black patients were less likely to receive SBRT (5.3% vs. 6.1%, OR 0.77, 95% CI 0.71-0.83, P < 0.001). 306,846 women met inclusion criteria (median age 61 years [IQR 52–69]; 17.4% in situ; 43.0% stage 1; 26.5% stage 2; 13.2% stage 3; 12.3% were Black and 87.7% were white). Treatment noncompletion did not differ significantly for Black (2.8%) vs. White (2.0%) women. Women who received hypofractionated EBRT had lower rates of treatment noncompletion compared to women who received conventional regimens (1.0% vs. 2.3%; OR 0.39, 95% CI 0.35-0.44, P < 0.001). Although rates of hypofractionated EBRT for breast cancer significantly increased from 0.8% in 2004 to 35.6% in 2017, Black patients were significantly less likely to receive hypofractionated EBRT (10.4% vs. 15.3%, OR 0.78, 95% CI 0.75-0.81, P < 0.001). Although shorter treatment regimens of radiation therapy were associated with lower rates of treatment noncompletion, disparities persisted in receipt of shorter regimens. Our findings underscore the need to identify barriers to treatment completion and racial bias and inequities in access to treatment regimens that are more likely to be completed