Genomic spectrum of actionable alterations in serial cell free DNA (cfDNA) analysis of patients with metastatic breast cancer.

We aimed to study the incidence and genomic spectrum of actionable alterations (AA) detected in serial cfDNA collections from patients with metastatic breast cancer (MBC). Patients with MBC who underwent plasma-based cfDNA testing (Guardant360®) between 2015 and 2021 at an academic institution were included. For patients with serial draws, new pathogenic alterations in each draw were classified as actionable alterations (AA) if they met ESCAT I or II criteria of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). A total of 344 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) MBC, 95 patients with triple-negative (TN) MBC and 42 patients with HER2-positive (HER2 + ) MBC had a baseline (BL) cfDNA draw. Of these, 139 HR+/HER2-, 33 TN and 13 HER2+ patients underwent subsequent cfDNA draws. In the HR+/HER2- cohort, the proportion of patients with new AA decreased from 63% at BL to 27-33% in the 2nd-4th draws (p < 0.0001). While some of the new AA in subsequent draws from patients with HR+/HER2- MBC were new actionable variants in the same genes that were known to be altered in previous draws, 10-24% of patients had new AA in previously unaltered genes. The incidence of new AA also decreased with subsequent draws in the TN and HER2+ cohorts (TN: 25% to 0-9%, HER2 + : 38% to 14-15%). While the incidence of new AA in serial cfDNA decreased with subsequent draws across all MBC subtypes, new alterations with a potential impact on treatment selection continued to emerge, particularly for patients with HR+/HER2- MBC.

The Right Dose: Results of a Patient Advocate-Led Survey of Individuals With Metastatic Breast Cancer Regarding Treatment-Related Side Effects and Views About Dosage Assessment to Optimize Quality of Life.

PURPOSE: Although patients with metastatic breast cancer (MBC) have been living longer with the advent of more effective treatments such as targeted therapy and immunotherapy, the disease remains incurable, and most patients will undergo therapy indefinitely. When beginning therapy, patients are typically prescribed dose often based upon the maximum tolerated dose identified in phase I clinical trials. However, patients' perspectives about tolerability and willingness to discuss individualized dosing of drugs upon initiation of a new regimen and throughout the course of treatment have not been comprehensively evaluated. METHODS: Patient advocates and medical oncologists from the Patient-Centered Dosing Initiative (PCDI) developed a survey to ascertain the prevalence and severity of MBC patients' treatment-related side effects, the level of patient-physician communication, mitigation strategies, perception about the relative efficacy of higher versus lower doses, and willingness to discuss alternative dosing. The PCDI distributed the anonymous confidential online survey in August 2020 to individuals with self-reported MBC. RESULTS: One thousand and two hundred twenty-one patients with MBC completed the survey. 86.1% (n = 1,051) reported experiencing at least one significant treatment-related side effect, and of these, 20.3% (n = 213) visited the emergency room/hospital and 43.2% (n = 454) missed at least one treatment. Nearly all patients with side effects (97.6%, n = 1,026) informed their doctor and 81.7% (n = 838) received assistance. Of the 556 patients given a dose reduction for side-effect mitigation, 82.6% (n = 459) reported relief. Notably, majority of patients (53.3%, n = 651) do not believe that higher dose is always more effective than lower dose, and 92.3% (n = 1,127) would be willing to discuss flexible dosing options with their physicians based upon personal characteristics to optimize quality of life. CONCLUSION: Given that the majority of patients with MBC experienced at least one substantial treatment-related side effect and most patients given a dose reduction reported improvement, innovative dosage-related strategies are warranted to sustain and improve patients' well-being. Patient-physician discussions in which the patient's unique attributes and circumstances are assessed upon initiation of new treatment and throughout the course of therapy may facilitate the identification of the most favorable dose for each patient, and the majority of patients would be receptive to this approach.

Clinical Outcomes of De Novo Versus Relapsed Early Metastatic Testicular Seminoma Treated With Contemporary Radiation Therapy.

PURPOSE: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions. METHODS AND MATERIALS: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field. RESULTS: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively). CONCLUSIONS: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation.

Portal Vein or Superior Mesenteric Vein Thrombosis with Dose-Escalated Radiation for Borderline or Locally Advanced Pancreatic Cancer.

PURPOSE: Portal vein and superior mesenteric vein thrombosis (PVT/SMVT) are potentially morbid complications of radiation dose-escalated local therapy for pancreatic cancer. We retrospectively reviewed records for patients treated with and without intraoperative radiation (IORT) to identify risk factors for PVT/SMVT. METHODS: Ninety-six patients with locally advanced or borderline resectable pancreatic adenocarcinoma received neoadjuvant therapy followed by surgical exploration from 2009 to 2014. Patients at risk for close or positive surgical margins received IORT boost to a biologically effective dose (BED10) > 100. Prognostic factors for PVT/SMVT were evaluated using competing risks regression. RESULTS: Median follow-up was 79 months for surviving patients. Fifty-six patients (58%) received IORT. Twenty-nine patients (30%) developed PVT/SMVT at a median time of 18 months. On univariate competing risks regression, operative blood loss and venous repair with a vascular interposition graft, but not IORT dose escalation or diabetes history, were significantly associated with PVT/SMVT. The development of thrombosis in the absence of recurrence was significantly associated with a longstanding diabetes history, post-neoadjuvant treatment CA19-9, and operative blood loss. All 4 patients who underwent both IORT and vascular repair with a graft developed PVT/SMVT. PVT/SMVT in the absence of recurrence is not associated with significantly worsened overall survival but led to frequent medical interventions. CONCLUSIONS: Approximately 30% of patients who underwent neoadjuvant chemoradiation for PDAC developed PVT/SMVT a median of 18 months following surgery. This was significantly associated with venous reconstruction with vascular grafts, but not with escalating radiation dose. PVT/SMVT in the absence of recurrence was associated with significant morbidity.

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression.

PURPOSE: For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression. METHODS: We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[-] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture. RESULTS: In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(-) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 (P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells. CONCLUSION: For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(-) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2- MBC.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Surgery and proton radiation therapy for pediatric base of skull chordomas: Long-term clinical outcomes for 204 patients.

BACKGROUND: Data on clinical outcomes for base of skull (BOS) chordomas in the pediatric population is limited. We report patient outcomes after surgery and proton radiotherapy (PRT). METHODS: Pediatric patients with BOS chordomas were treated with PRT or combined proton/photon approach (proton-based; for most, 80% proton/20% photon) at the Massachusetts General Hospital from 1981 to 2021. Endpoints of interest were overall survival (OS), disease-specific survival, progression-free survival (PFS), freedom from local recurrence (LC), and freedom from distant failure (DC). RESULTS: Of 204 patients, median age at diagnosis was 11.1 years (range, 1-21). Chordoma location included 59% upper and/or middle clivus, 36% lower clivus, 4% craniocervical junction, and 1% nasal cavity. Fifteen (7%) received pre-RT chemotherapy. Forty-seven (23%) received PRT, and 157 (77%) received comboRT. Median total dose was 76.7 Gy (RBE) (range, 59.3-83.3). At a median follow-up of 10 years (interquartile range, 5-16 years), 56 recurred. Median OS and PFS were 26 and 25 years, with 5-, 10-, and 20-year OS and PFS rates of 84% and 74%, 78% and 69%, and 64% and 64%, respectively. Multivariable actuarial analyses showed poorly differentiated subtype, radiographical progression prior to RT, larger treatment volume, and lower clivus location to be prognostic factors for worse OS, PFS, and LC. RT was well tolerated at a median follow-up of 9 years (interquartile range, 4-16 years). Side effects included 166 patients (80%) with mild/moderate acute toxicities, 24 (12%) patients with late toxicities, and 4 (2%) who developed secondary radiation-related malignancies. CONCLUSION: This is the largest cohort of BOS chordomas in the literature, pediatric and/or adult. High-dose PRT following surgical resection is effective with low rates of late toxicity.

Utilizing cell-free DNA to predict risk of developing brain metastases in patients with metastatic breast cancer.

We compared cell-free DNA (cfDNA) results at MBC diagnosis in patients who developed brain metastases (BM) vs those without (non-BM) to understand genomic predictors of BM. Patients with cfDNA testing at MBC diagnosis (Guardant360®, 73 gene next generation sequencing) were identified. Clinical and genomic features of BM and non-BM were compared (Pearson's/Wilcoxon rank sum tests). Eighteen of 86 patients (21%) with cfDNA at MBC diagnosis developed BM. Comparing BM vs non-BM, a higher prevalence of BRCA2 (22% vs 4.4%, p = 0.01), APC (11% vs 0%, p = 0.005), CDKN2A (11% vs 1.5%, p = 0.05), and SMAD4 (11% vs 1.5%, p = 0.05) was observed. Seven of 18 BM had ≥1 of the following 4 mutations in baseline cfDNA: APC, BRCA2, CDKN2A or SMAD4 vs 5/68 non-BM (p = 0.001). Absence of this genomic pattern had a high negative predictive value (85%) and specificity (93%) in excluding BM development. Baseline genomic profile varies in MBC that develops BM.

Proton FLASH effects on mouse skin at different oxygen tensions.

Objective. Irradiation at FLASH dose rates (>40 Gy s-1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration.Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2elliptical field at a dose rate of ∼130 Gy s-1. The conventional dose rate was ∼0.4 Gy s-1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time.Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response.Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

Racial and ethnic disparities in a real-world precision oncology data registry.

Biorepositories enable precision oncology research by sharing clinically annotated genomic data, but it remains unknown whether these data registries reflect the true distribution of cancers in racial and ethnic minorities. Our analysis of Project Genomics Evidence Neoplasia Information Exchange (GENIE), a real-world cancer data registry designed to accelerate precision oncology discovery, indicates that minorities do not have sufficient representation, which may impact the validity of studies directly comparing mutational profiles between racial/ethnic groups and limit generalizability of biomarker discoveries to all populations.

Effects of Proton Craniospinal Radiation on Vertebral Body Growth Retardation in Children.

PURPOSE: It is of great interest to physicians and patients/patients' families to be able to predict the amount of growth decrement after craniospinal irradiation (CSI). Little data exist on the effect of proton CSI. Our aim was to determine the effect of proton CSI on vertebral body (VB) growth retardation, and to identify factors associated with growth delay. METHODS AND MATERIALS: We performed a retrospective outcome data analysis of 80 patients <16 years old with central nervous system tumors who received proton radiation therapy (PRT) at the Massachusetts General Hospital between 2002 and 2010 with available spinal magnetic resonance imaging. Forty-eight patients received CSI, and 32 patients with brain tumors who received focal cranial irradiation served as controls. VB height was measured midline using sagittal T1-weighted contrast or noncontrast enhanced magnetic resonance imaging of the spine. Measurements were repeated at multiple levels (C3, C3-C4, T4, T4-T5, C3-T6, T4-T7, L3, L1-L5) on available scans for the duration of follow-up. Data were fitted using a mixed-effects multivariable regression model, including follow-up time, CSI dose, age at CSI, and pretreatment VB percentile as parameters. RESULTS: Median follow-up was 69.6 months for patients treated with proton CSI and 52.9 months for the control group. There was a significant association of CSI dose, follow-up time, age at treatment, and pretreatment VB percentile with VB growth retardation. Growth retardation was shown to be independent of gender or growth hormone deficiency. CONCLUSIONS: Although the current practice of PRT CSI delivery allows for sparing of the organs anterior to the spine, the vertebral column receives radiation therapy because of its close proximity to the targeted spinal canal. In growing children, the whole VB has generally been included so that growth impairment is even across the VB. We present a quantitative model predicting the growth retardation of patients treated with PRT CSI based on age at treatment, CSI dose, follow-up time, and pretreatment growth percentile.

Demographic Trends Among American Society for Radiation Oncology Clinical Practice Guideline Task Force Participants From 2010 to 2022.

PURPOSE: The American Society for Radiation Oncology (ASTRO) has produced evidence-based clinical practice guidelines since 2009. It is unknown whether task force members for these guidelines are representative of the diversity of the radiation oncology field, particularly in comparison to the ASTRO membership demographics. We sought to characterize the demographic composition of all task force members to date. METHODS: The author list for ASTRO-led published guidelines from 2010 to 2022 was assessed. Main practice location/institution was extracted from the guideline publication. Self-identified gender and race/ethnicity were obtained from the ASTRO membership database. Years of experience were measured as the number of years post-board certification at time of guideline development. For United States (US)-based physicians, gender was confirmed with the National Provider Identifier database. Proportions of task force members overall and by individual guideline were described by gender, underrepresented in medicine (URM) status, geography (US vs international), US region (if US based), years of experience (separated into ≤5 years including residents, 6-12 years, and >12 years), and type of practice. Proportions for gender, URM, and geography were compared with ASTRO membership demographics. RESULTS: Between 2010 and 2022, there were 25 guideline task forces, with a total of 366 participants: 233 men, 126 women, and 7 unknown gender. There were more men than women serving on most individual task force topics, with 28% of all task forces having >80% composition of men. Of those with self-identified race/ethnicity, 9/204 (4.4%) were URM, which was lower in proportion to URM self-identified ASTRO members (336/3277, 10.3%; P = .007). Most participants were based in the US (n = 323, 88.3%), had >12 years of experience (n = 141, 38.5%), and were from academic institutions (n = 302, 82.5%). Community practitioners were less likely to be women or URM. CONCLUSIONS: Improved data collection and more intentional efforts are needed to ensure that the diversity of guidelines task forces is representative of ASTRO membership and the specialty.

Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience.

BACKGROUND: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. METHODS: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). CONCLUSIONS: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

Association of the USPSTF Grade D Recommendation Against Prostate-Specific Antigen Screening With Prostate Cancer-Specific Mortality.

Importance: The 2012 US Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen (PSA) screening for all men has been controversial, with data documenting a shift to a higher stage of disease at diagnosis. The association between the Grade D recommendation and prostate cancer-specific mortality (PCSM) among contemporary cohorts, however, is unclear. Objective: To evaluate PCSM rates between 1999 and 2019, comparing trends in rates before and after the change in the 2012 USPSTF screening guideline to assess its association with PCSM. Exposure: The 2012 USPSTF Grade D recommendation against PSA screening for all men. Design, Setting, and Participants: This cross-sectional study used Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research maintained by the National Center for Health Statistics to collect data on cause of death for all individuals who died of prostate cancer in the US from 1999 to 2019. Analysis was performed from January to August 2021. Main Outcomes and Measures: Trends in PCSM rates were calculated from 1999 to 2012 and from 2014 to 2019, with a washout year of 2013, using linear regression, with year and binary indicator of pre-2013 and post-2013 status as interaction terms. Trends were further analyzed by age, race and ethnicity, urbanization category, and US Census region. Other measures included diagnosis of localized or metastatic prostate cancer and overall cancer mortality. Results: A total of 618 095 patients died of prostate cancer in the US from 1999 to 2019. Age-adjusted PCSM decreased linearly at a rate of -0.273 per 100 000 population per year from 1999 to 2012 and stalled at a rate of -0.009 per 100 000 per year from 2014 to 2019 (P < .001). This finding was significant among men aged 60 years or older, especially among men aged 60 to 69 years, men aged 80 years or older, and among Black men. Men aged 60 to 64 years had a decreasing, age-adjusted PCSM rate of -0.0088 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0014 per 100 000 per year. Men aged 65 to 69 years had a decreasing, age-adjusted PCSM rate of -0.024 per 100 000 population per year prior to 2013 followed by an increasing rate of 0.0011 per 100 000 population per year. Men aged 80 years or older had the largest absolute difference between rates before and after 2013 compared with all other age groups, with a difference of 0.06 for men aged 80 to 84 years and 0.07 for men 85 aged years or older. Black men had a decreasing, age-adjusted PCSM rate of -0.700 per 100 000 population per year prior to 2013 followed by a flattened rate of -0.091 per 100 000 population per year. Changes were observed across races and ethnicities, urbanization categories, and US Census regions and were accompanied by increased diagnoses of metastatic disease, which are inconsistent with mortality trends across all malignant neoplasms. Conclusions and Relevance: This cross-sectional study using comprehensive PCSM data through 2019 demonstrated decreasing PCSM rates that flattened or increased after the 2012 USPSTF Grade D recommendation, suggesting that decreased PSA screening may be a factor associated with this change. This change was seen across ages, races and ethnicities, urbanization categories, and US Census regions. The updated 2018 USPSTF guideline supporting shared decision-making may reverse these trends in the coming years.

Effect of Mismatch Repair Status on Outcome of Early-Stage Grade 1 to 2 Endometrial Cancer Treated With Vaginal Brachytherapy.

OBJECTIVES: The objective of this study was to determine if deficiency of mismatch repair (dMMR) proteins in patients with early-stage favorable endometrial cancer treated with vaginal brachytherapy (VB) is associated with increased recurrence. MATERIALS AND METHODS: A multi-institutional retrospective cohort study of 141 patients with stage I to II grade 1 and 2 endometrioid adenocarcinoma treated with surgery and adjuvant VB was performed to compare recurrence risk in dMMR (n=41) versus MMR-preserved (pMMR) (n=100). Additional clinical and pathologic risk factors were also collected. Univariate analysis and multivariable analysis Cox regression analysis was performed to identify factors associated with any recurrence. Kaplan-Meier method and log rank test were used to compare recurrence free survival and overall survival (OS). RESULTS: Median follow up was 42 months. Forty-one patients (29%) were dMMR. There were 7 recurrences (17%) in dMMR versus 4 recurrences (4%) in pMMR (P=0.009). On univariate analysis of any recurrence, both dMMR (hazard ratio: 5.3, P=0.008) and stage (hazard ratio: 3.8, P=0.05) were statistically significantly associated with time to first recurrence. The 5-year recurrence free survival was 90% (95% CI: 73%-96%) in pMMR versus 61.0% (95% CI: 19%-86%) in dMMR (P=0.003). Five-year OS was 96% (95% CI: 76%-99%) in pMMR versus 86% (95% CI: 62%-95%) in dMMR (P=0.03). CONCLUSIONS: MMR deficiency in stage I to II grade 1 to 2 endometrial cancer patients treated with adjuvant VB alone was associated with statistically significant increased risk for any recurrence and worse OS. MMR status may be an important prognosticator in this cohort of patients warranting adjuvant treatment intensification in the clinical trial setting.

Diversity Trends by Sex and Underrepresented in Medicine Status Among US Radiation and Medical Oncology Faculty Over 5 Decades.

IMPORTANCE: It remains unclear how the historical exclusion of women and racial and ethnic minority groups from medical training, and therefore the oncologic subspecialties, has contributed to rates of faculty diversity among oncology departments over time. Oncologic faculty diversity is an important initiative to help improve care and address health disparities for an increasingly diverse US population with cancer. OBJECTIVES: To report trends in academic faculty representation by sex and by race and ethnicity for radiation oncology (RO) and medical oncology (MO) departments and to describe comparisons with the general US population, medical students, RO and MO trainees, clinical department chairs, and faculty in other departments. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis used data from the Association of American Medical Colleges to analyze trends by sex and by race and ethnicity among full-time US faculty in RO and MO departments from 1970 through 2019. Data were analyzed between October 2020 and April 2021. MAIN OUTCOMES AND MEASURES: Proportions of women and individuals from underrepresented in medicine (URM) racial and ethnic groups (Black, Hispanic, and Indigenous individuals) were calculated among RO and MO academic departments; trends were analyzed over 5 decades. These proportions were compared with cohorts already described. In addition, proportions of women and URM individuals were calculated by faculty rank among RO and MO departments. RESULTS: In 1970, there were 119 total faculty in RO (10 women [8.4%] and 2 URM [1.7%]) and 87 total faculty in MO (11 women [12.6%] and 7 URM [8.0%]). In 2019, there were 2115 total faculty in RO (615 women [29.1%] and 108 URM [5.1%]) and 819 total faculty in MO (312 women [38.1%] and 47 URM [5.7%]). Total faculty numbers increased over time in both RO and MO. Faculty representation of URM women proportionally increased by 0.1% per decade in both RO (95% CI, 0.005%-0.110%; P <. 001 for trend) and MO (95% CI, -0.03% to 0.16%; P = .06 for trend) compared with non-URM women faculty, which increased by 0.4% (95% CI, 0.25%-0.80%) per decade in RO and 0.7% (95% CI, 0.47%-0.87%) per decade in MO (P < .001 for trend for both). Faculty representation of URM men did not significantly change for RO (0.03% per decade [95% CI, -0.008% to 0.065%]; P = .09 for trend) or MO (0.003% per decade [95% CI, -0.13% to 0.14%]; P = .94 for trend). Representation of both women and URM individuals among both specialties was lower than their representation in the US population in both 2009 and 2019. Across all cohorts studied, RO faculty had the lowest URM representation in 2019 at 5.1%. At every rank in 2019, the number of total URM faculty represented among both MO and RO remained low (MO: instructor, 2 of 44 [5%]; assistant professor, 18 of 274 [7%]; associate professor, 13 of 177 [7%]; full professor, 13 of 276 [5%]; and RO: instructor, 9 of 147 [6%]; assistant professor, 57 of 927 [6%]; associate professor, 20 of 510 [4%]; full professor, 18 of 452 [4%]). CONCLUSIONS AND RELEVANCE: This cross-sectional study suggests that RO and MO academic faculty have increased the representation of women over time, while URM representation has lagged. The URM trends over time need further investigation to inform strategies to improve URM representation in RO and MO.

Dosimetric Comparison of Proton Versus Photon Radiosurgery for Treatment of Pituitary Adenoma.

PURPOSE: To compare the dosimetric differences in stereotactic radiosurgery between use of passively scattered protons (PSRS) versus photons (XSRS) for pituitary adenomas. METHODS AND MATERIALS: Nine patients with pituitary adenomas were selected among patients receiving single-fraction proton stereotactic radiosurgery (PSRS) between 2016 and 2017. These cases were replanned with XSRS using volumetric-modulated arc therapy with 2.5 mm and 5 mm multileaf collimators (2.5XSRS and 5XSRS, respectively). PSRS was planned with a dedicated single scattering stereotactic proton unit delivered via 3 equally or unequally weighted isocentric fields. XSRS plans were created with optimization to spare organs at risk. Plans were generated using the original total treatment dose delivered in 1 fraction. RESULTS: Plans were evaluated for target volume dosimetry and estimated clinical toxicity. There was no significant difference in clinical target volume V100%, V95%, V90% or homogeneity index between treatment modalities. PSRS offered lower maximum dose (Dmax) to organs at risk and equivalent uniform dose (EUD) compared with 5XSRS and 2.5XSRS, respectively, for critical structures including optic nerve (right, Dmax 4.18, 5.32, 5.41; EUD 3.35, 4.08, 4.20) and hypothalamus (Dmax 1.71, 3.94, 3.77; EUD 0.94, 2.47, 2.39; P < .05 for PSRS vs 5XSRS and 2.5XSRS). The projected risk of secondary tumors in excess of baseline was lowest for PSRS plans (PSRS 5.28, 5XSRS 12.93, 2.5XSRS 12.66 cases per 10,000 patient-years; P = .008 for PSRS vs 5XSRS, PSRS vs 2.5XSRS, and P = .77 for 5XSRS vs 2.5XSRS). CONCLUSIONS: We demonstrate that neither modality has empirically superior dosimetry and identify potential clinical advantages as well as limitations of each technique. PSRS, 5XSRS and 2.5XSRS demonstrate comparable target volume dosimetry for pituitary adenoma. PSRS compared with XSRS modalities offers modestly decreased maximum dose and EUD to critical proximal structures and decreases risk of radiation-induced secondary tumors by more than half.

Racial and Ethnic Disparities Among Participants in Precision Oncology Clinical Studies.

Importance: Precision oncology is revolutionizing cancer care, allowing for personalized treatments to improve outcomes. Cancer research has benefitted from well-designed studies incorporating precision medicine objectives, but it is unclear if these studies are representative of the diverse cancer population. Objective: To evaluate racial and ethnic representation in breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives in the Clinicaltrials.gov registry and compare with the incidence of these cancer types in racial and ethnic minority groups in the US population. Design, Setting, and Participants: This cross-sectional study identified US-based breast, prostate, lung, and colorectal cancer studies incorporating precision oncology objectives for reporting of race and ethnicity. The Surveillance, Epidemiology, and End Results and US Census databases were used to determine cancer incidence by race and ethnicity, linked with cancer type and median year of enrollment for each trial. Data were collected and analyzed between December 2020 and April 2021. Main Outcomes and Measures: The expected number of participants per study by each racial and ethnic group was calculated based on the corresponding US-based proportion. Under- and overrepresentation was defined as the ratio of the actual number of enrolled cases to the expected number of cases for each trial by cancer type. Ratios above 1 indicated overrepresentation while a ratio below 1 indicated underrepresentation. Random-effects meta-analysis of representation ratios of individual trials was performed to weigh each individual study. Results: Of 93 studies encompassing 5867 enrollees with race and ethnicity data; 4826 participants (82.3%) were non-Hispanic White, 587 (10.0%) were Black, and 238 (4.1%) were Asian. Per observed-to-expected ratios, White participants were overrepresented in all studies, with a ratio of 1.35 (95% CI, 1.30-1.37), as well as Asian participants, with a ratio of 1.46 (95% CI, 1.28-1.66), while Black participants (ratio, 0.49; 95% CI, 0.45-0.54), Hispanic participants (ratio, 0.24; 95% CI, 0.20-0.28), and American Indian and Alaskan Native participants (ratio, 0.43; 95% CI, 0.24-0.78) were underrepresented. By individual cancer site, White participants were consistently overrepresented in all studies, while Black and Hispanic participants were underrepresented. Conclusions and Relevance: This analysis found that precision oncology studies for breast, lung, prostate, and colorectal cancers vastly underrepresent racial and ethnic minority populations relative to their cancer incidence in the US population. It is imperative to increase diversity among enrollees so that all individuals may benefit from cancer research breakthroughs and personalized treatments.

Outcome and Toxicity of Proton Therapy for Vestibular Schwannoma: A Cohort Study.

OBJECTIVE: To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. STUDY DESIGN: Retrospective chart review and volumetric MRI-analyses. SETTING: Tertiary referral center. PATIENTS: Vestibular schwannoma patients treated with protons between 2003 and 2018. INTERVENTION: Proton radiotherapy. MAIN OUTCOME MEASURES: Tumor control was defined as not requiring salvage treatment. Progressive hearing loss was defined as a decrease in maximum speech discrimination score below the 95% critical difference in reference to the pretreatment score. Hearing assessment includes contralateral hearing and duration of follow-up. Dizziness and/or unsteadiness and facial and trigeminal nerve function were scored. Patients who had surgery prior to proton radiotherapy were separately assessed. RESULTS: Of 221 included patients, 136 received single fraction and 85 fractionated proton radiotherapy. Actuarial 5-year local control rate was 96% (95% CI 90-98%). The median radiological follow-up was 4.5 years. Progressive postirradiation speech discrimination score loss occurred in 42% of patients with audiometric follow-up within a year. Facial paresis was found in 5% (usually mild), severe dizziness in 5%, and trigeminal neuralgia in 5% of patients receiving protons as primary treatment. CONCLUSIONS: Proton radiotherapy achieves high tumor control with modest side effects aside from hearing loss in vestibular schwannoma patients. Limited and heterogeneous outcome reporting hamper comparisons to the literature. Potential sequelae of radiation therapy impacting vestibular function, cognitive function, and quality of life warrant further evaluation. Subgroups that benefit most from proton radiotherapy should be identified to optimize allocation and counterbalance its costs.