Adjuvant and salvage radiotherapy after neoadjuvant therapy and radical prostatectomy for high-risk localized prostate cancer.

BACKGROUND: We sought to describe patterns of delivery of adjuvant (aRT) and salvage RT (sRT) in patients who underwent RP after receiving neoadjuvant androgen receptor pathway inhibitor (ARPI) before radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC). METHODS: Two hundred eighteen patients treated on phase 2 neoadjuvant trials between 2006 and 2018 at two academic centers were evaluated. aRT and sRT were defined as receipt of RT with a PSA of ≤0.1 or >0.1 ng/mL, respectively. Primary outcomes were biochemical recurrence (BCR), defined as time from aRT/sRT to a PSA rising to >0.1 ng/mL, and metastasis-free survival (MFS) after RT. RESULTS: Twenty-three (11%) and 55 (25%) patients received aRT and sRT respectively. Median PSA at start of aRT and sRT was 0.01 and 0.16 ng/mL, and median duration from RP to RT was 5 and 14 months, respectively. All aRT patients had NCCN high-risk disease, 30% were pN1 and 43% had positive surgical margins; 52% had prostate bed RT. Fifty-one percent of sRT patients had biopsy Gleason 9-10, 29% were pT2 and 9% had positive surgical margins; 63% had RT to the prostate bed/pelvis. At a median follow-up of 5.3 and 3.0 years after aRT and sRT, 3-year freedom from BCR was 55% and 47%, and 3-year MFS was 56% and 53%, respectively. CONCLUSIONS: aRT was infrequently used in patients who received neoadjuvant ARPI before RP for HRLPC. Outcomes of aRT and sRT were similar but generally poor. Studies evaluating intensified systemic therapy approaches with postoperative RT in this high-risk population are needed.

Distinct Profiles of DNA Repair Activity Define Favorable-risk Prostate Cancer Subtypes With Divergent Outcome.

INTRODUCTION: Understanding if divergent molecular profiles of DNA damage and repair (DDR) pathway activity, a biomarker of disease progression, exist in prostate tumors with favorable-risk features is an unmet need, which this study aim to unearth. MATERIALS AND METHODS: This was a multicenter registry genome-wide expression profiling study of prospectively collected radical prostatectomy (RP) tumor samples from 2014 to 2016. DDR activity was calculated from average expression of 372 DDR genes. Consensus hierarchical clustering was used to arrive at a robust clustering solution based on DDR gene expression patterns. Genome-wide differential expression between clusters was performed, and outcomes were evaluated across expression patterns. RESULTS: Of 5239 patients from the prospective registry, 376 had favorable-risk disease (Grade group [GG] 1 to 2, PSA prior to RP <10ng/ml, pT2 or less). DDR activity score was correlated with prognostic genomic signatures that predict for metastatic risk (r = 0.37, P < 2e-16) and high grade groups (P < .001). High DDR activity (top-quartile) was observed in 28% of patients with favorable-risk disease. In favorable-risk disease, 3 distinct clusters with varied DDR activity emerged with consensus clustering. Cluster I (compared with cluster II-III and GG3-GG5 disease) had the highest expression of all DDR sub-pathways, MYC, PAPR1, AR, and AR activity (P < .001 for all). Furthermore, cluster I was associated with poorer metastasis-free survival (MFS) and Overall survival (OS) compared with other clusters (MFS; HR: 2.43, 95%CI, [1.22-4.83], P = .01; OS; HR: 2.77, 95%CI, [1.18-6.5], P = .01). CONCLUSIONS: Cluster I is a novel subgroup of favorable-risk disease with high DDR activity, AR activity, PARP1 and chr8q/MYC expression, and poorer MFS and OS.

Accuracy of Pathologic Diagnosis in Patients With Lymphoma and Survival: A Prospective Analysis From Botswana.

PURPOSE: With intense HIV epidemics, southern African countries have a high burden of classic Hodgkin lymphoma (CHL) and non-Hodgkin lymphoma (NHL). However, suboptimal access to pathology resources limits subtype classification. We sought to assess the diagnostic accuracy of specimens classified as lymphoma and to determine association between discordant pathologic diagnosis and overall survival. METHODS: Seventy patients with CHL or NHL and treated at three Botswana hospitals from 2010 to 2016 were analyzed. Local pathologic assessment relied primarily on morphology. All cases underwent secondary US hematopathology review, which is considered gold standard. RESULTS: The median follow-up was 58 months. The overall reclassification rate was 20 of 70 cases (29%). All 20 CHL cases were correctly classified in Botswana, and mixed cellularity was the most common subtype, diagnosed in 11 (55%) cases. Of 47 confirmed NHL cases, diffuse large B-cell lymphoma was the final US diagnosis in 28 cases (60%), another aggressive B-cell NHL in nine (19%), an indolent B-cell NHL in six (13%), and T-cell NHL in four (9%). Common types of diagnostic discordance included NHL subtype reclassification (11 of 20, 55%) and CHL reclassified as NHL (7 of 20, 35%). Concordant versus discordant diagnosis after secondary review was associated with improved 5-year overall survival (60.1% v 26.3%, P = .0066). Discordant diagnosis was independently associated with increased risk of death (adjusted hazard ratio 2.733; 95% CI, 1.102 to 6.775; P = .0300) even after stratifying results by CHL versus NHL. CONCLUSION: In this single prospective cohort, discordant pathologic diagnosis was associated with a nearly three-fold increased risk of death. Limited access to relatively basic diagnostic techniques impairs treatment decisions and leads to poor patient outcomes in low-resource countries.

Novel genomic signature predictive of response to immune checkpoint blockade: A pan-cancer analysis from project Genomics Evidence Neo-plasia Information Exchange (GENIE).

BACKGROUND: High tumor mutation burden (TMB) and total mutation count (TMC) can be predictive of better response to immune checkpoint blockade (ICB). Nevertheless, TMB and TMC are limited by variation across cancers and inconsistent definitions due to different profiling methods (targeted vs whole genome sequencing). Our objective was to identify genomic alterations (GAs) associated with ICB response and builds a novel genomic signature predictive of ICB response, independent of TMB/TMC. METHODS: This was a pan-cancer next generation sequencing (NGS)-association study using January 2014-May 2016 data from AACR Project Genomics Evidence Neo-plasia Information Exchange (GENIE). Participants included 6619 patients with metastatic or un-resectable cancer across 9 cancer types (including 1572 ICB-treated patients). GA data was collected using next-generation sequencing (NGS) assays and downloaded from cbioportal.org. Predictive analyses for ICB response were performed to develop the signature (ImmGA). RESULTS: GAs in 16 genes were associated with improved OS in ICB-treated patients (p < 0.005). 13 GAs were associated with an OS benefit in ICB-treated patients (Pinteraction < 0.05); these genes composed the ImmGA signature. High ImmGA score (≥2 alterations out of 13 predictive GAs) was associated with better OS in ICB-treated patients (AHR:0.67, 95%CI [0.6-0.75], p = 1.4e-12), even after accounting for TMC (Pinteraction = 8e-16). High ImmGA was associated with better OS in ICB-treated patients across most cancers and across different ICB treatment modalities. CONCLUSION: A novel signature predictive of ICB response (ImmGA) was developed from 13 GAs. Further investigation of the utility of ImmGA for treatment and trial selection is warranted.

Patterns of Palliative Radiotherapy Utilization for Patients With Metastatic Breast Cancer in Harare, Zimbabwe.

PURPOSE: In sub-Saharan Africa, radiotherapy (RT) utilization and delivery patterns have not been extensively studied in patients with metastatic breast cancer. METHODS: A retrospective cohort study of female patients with metastatic breast cancer seen at Parirenyatwa Radiotherapy Centre in Zimbabwe from 2014 to 2018 was conducted. Demographics, pathology, staging, and treatment data were abstracted through chart review. Fisher's exact test and chi-squared test of independence were used to compare proportions, and independent two-sample t-tests were used to compare means. RESULTS: Of 351 patients with breast cancer, 152 (43%) had metastatic disease, median age 51 years (interquartile range: 43-61 years). Of those with metastatic disease, 30 patients (20%) received radiation to various metastatic sites: 16 spine; three nonspine bone metastases; six whole brain; and five chest wall or supraclavicular. Patients who received radiation were younger (46 v 52 years; P = .019), but did not differ significantly by performance status than those who did not. The most common dose prescription was 30 Gy in 10 fractions (33%). Five (17%) patients had treatment interruption and two (7%) had treatment noncompletion. Province of origin and clinical tumor stage were significant predictors of RT receipt (P = .002; and P = .018, respectively). CONCLUSION: A minority of patients with metastatic breast cancer received RT (20%), and these were likely to be younger, with advanced tumor stage, and resided in provinces where RT is available. Conventional courses were generally prescribed. There is a need to strongly consider palliative RT as an option for patients with metastatic breast cancer and use of hypofractionated courses (e.g. 8 Gy in one fraction) may support this goal.

Utilization and predictors of postmastectomy radiation receipt in an Oncology Center in Zimbabwe.

PURPOSE: Few sub-Saharan African studies have ascertained utilization for postmastectomy radiation (PMRT) for breast cancer, the second most common cancer among African women. We estimated PMRT utilization and identified predictors of PMRT receipt in Zimbabwe. METHODS: Retrospective patient cohort included non-metastatic breast cancer patients treated from 2014 to 2019. PMRT eligibility was assigned per NCCN guidelines. Patients receiving chemotherapy for non-metastatic disease were also included. The primary endpoint was receipt of PMRT, defined as chest wall with/without regional nodal radiation. Predictors of receiving PMRT were identified using logistic regression. Model performance was evaluated using the c statistic and Hosmer-Lemeshow test for goodness-of-fit. RESULTS: 201 women with localized disease and median follow-up of 11.4 months (IQR 3.3-17.9) were analyzed. PMRT was indicated in 177 women and utilized in 59(33.3%). Insurance coverage, clinical nodal involvement, higher grade, positive margins, and hormone therapy receipt were associated with higher odds of PMRT receipt. In adjusted models, no hormone therapy (aOR 0.12, 95% CI 0.043, 0.35) and missing grade (aOR 0.07, 95% CI 0.01, 0.38) were associated with lower odds of PMRT receipt. The resulting c statistic was 0.84, with Hosmer-Lemeshow p-value of 0.93 indicating good model fit. CONCLUSION: PMRT was utilized in 33% of those meeting NCCN criteria. Missing grade and no endocrine therapy receipt were associated with reduced likelihood of PMRT utilization. In addition to practice adjustments such as increasing hypofractionation and increasing patient access to standard oncologic testing at diagnosis could increase postmastectomy utilization.

Breast cancer in Zimbabwe: patterns of care and correlates of adherence in a national referral hospital radiotherapy center cohort from 2014 to 2018.

BACKGROUND: Breast cancer is the second most common cancer among women in Zimbabwe. Patients face socioeconomic barriers to accessing oncology care, including radiotherapy. We sought to understand patterns of care and adherence for women with breast cancer in sub-Saharan Africa (SSA) with radiotherapy access. METHODS: A retrospective cohort was created for women with breast cancer evaluated at the Parirenyatwa Hospital Radiotherapy and Oncology Center (RTC) from 2014 to 2018. Clinical data were collected to define patterns of care. Non-adherence was modeled as a binary outcome with different criteria for patients with localized versus metastatic disease. RESULTS: In total, 351 women presented with breast cancer with median age 51 at diagnosis (IQR: 43-61). Receptor status was missing for 71% (248). 199 (57%) had non-metastatic disease, and 152 (43%) had metastases. Of women with localized disease, 34% received post-mastectomy radiation. Of women with metastatic disease, 9.7% received radiotherapy. Metastatic disease and missing HIV status were associated with increased odds of study-defined non-adherence (aOR: 1.85, 95% CI: 1.05, 3.28; aOR: 2.13, 95% CI: 1.11, 4.05), while availability of ER/PR status was associated with lower odds of non-adherence (aOR: 0.18, 95% CI: 0.09, 0.36). CONCLUSIONS: Radiotherapy is likely underutilized for women with breast cancer, even in a setting with public sector availability. Exploring patient-level factors that influence adherence to care may provide clinicians with better tools to support adherence and improve survival. Greater investment is needed in multidisciplinary, multimodality care for breast cancer in SSA.

Development and Validation of a Novel TP53 Mutation Signature That Predicts Risk of Metastasis in Primary Prostate Cancer.

INTRODUCTION: Prostate tumors with TP53 gene mutations are molecularly heterogenous, and the presence of TP53 gene mutations has been linked to inferior outcomes. We developed an RNA-based gene signature that detects underlying TP53 gene mutations and identifies wild-type prostate tumors that are analogous to TP53-mutant tumors. MATERIALS AND METHODS: Using genomic expression profiles from The Cancer Genome Atlas, we developed a mutation signature score to predict prostatic tumors with a molecular fingerprint similar to tumors with TP53 mutations. Area under the receiver operating characteristic curve assessed model accuracy in predicting TP53 mutations, and Cox regression models measured association between the signature and progression-free survival and metastasis-free survival (MFS). RESULTS: The TP53 signature score achieved an area under the receiver operating characteristic curve of 0.84 in the training and 0.82 in the validation cohorts for predicting an underlying mutation. In three retrospective cohorts, a high score was prognostic for poor 5-year MFS: 46% versus 81% (hazard ratio [HR], 3.05; P < .0001; Johns Hopkins University cohort), 64% versus 83% (HR, 2.77; P < .0001; Mayo Clinic cohort), and 71% versus 97% (HR, 6.8; P = .0001; Brigham and Women's Hospital cohort). The signature also identified TP53 wild-type tumors molecularly analogous to TP53 mutant tumors, wherein high signature score correlated with worse 5-year MFS (50% vs. 82%; HR, 3.05; P < .0001). CONCLUSIONS: This novel mutational signature predicted tumors with TP53 mutations, identified TP53 wild-type tumors analogous to mutant tumors, and was independently associated with poor MFS. This signature can therefore be used to strengthen existing clinical risk-stratification tools.

Prostate cancer-specific mortality burden by risk group among men with localized disease: Implications for research and clinical trial priorities.

OBJECTIVE: To estimate contemporary population-based patterns of the relative burden of prostate cancer-specific mortality (PCSM) attributable to each N0M0 prostate cancer risk-group, that may guide prioritization in research, trial design, and clinical practice. METHODS: We categorized 2004-2015 Surveillance, Epidemiology, and End Results database patients by risk group (low, favorable intermediate, unfavorable intermediate, high, and very highrisk). Using the Fine-Gray method, we calculated the relative burden of 10-year PCSM attributable to each risk group. RESULTS: Among N = 337 162 men (6.8-year median follow-up; median age 65 years), the relative proportion of low-, favorable intermediate-, unfavorable intermediate-, high-, and very high-risk diagnoses were 29.9% (N = 100 969), 31.1% (N = 104 696), 17.9% (N = 60 360), 18.1% (N = 61 023), and 3.0% (N = 10 114). Within 10 years of diagnosis, among patients who died of prostate cancer (N = 15 064), 5.0% (N = 746) had low-risk, 13.7% (N = 2060) had favorable intermediate-risk, 16.1% (N = 2429) had unfavorable intermediate-risk, 47.8% (N = 7196) had high-risk, and 17.5% (N = 2633) had very high-risk disease at diagnosis. Patients aged 65 and older accounted for 51.9% of all diagnoses and 72.3% of 10-year PCSM. Although black patients accounted for 15.0% of low-risk diagnoses, they accounted for 20.6% of 10-year PCSM. White patients accounted for 80.3% of low-risk diagnoses and 75.7% of 10-year PCSM. CONCLUSION: Although high-risk and very high-risk disease account for one-fifth of diagnoses, they account for two-thirds of 10-year PCSM. Older patients and black patients with low-risk disease accounted for a disproportionately large proportion of deaths. These findings support targeting research toward high-risk disease and ensuring adequate representation of older and black men in clinical trials.

Genomic and clinical characterization of stromal infiltration markers in prostate cancer.

BACKGROUND: The progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer. METHODS: Genome-wide expression profiles of formalin-fixed, paraffin-embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis-free survival (MFS). RESULTS: Stromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment-Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37-4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction  = .02). CONCLUSIONS: Expression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.

Are Staging Computed Tomography (CT) Scans of the Chest Necessary in Pancreatic Adenocarcinoma?

BACKGROUND: There is no consensus on the use of chest imaging in pancreatic ductal adenocarcinoma (PDAC) patients. Among PDAC patients, we examined the use of chest computed tomography (CT) over time and determined whether the use of chest CT led to a survival difference or change in management via identification of indeterminate lung nodules (ILNs). METHODS: Retrospective clinical data was collected for patients diagnosed with PDAC from 1998 to 2014. We examined the proportion of patients undergoing staging chest CT scan and those who had ILN, defined as ≥ 1 well-defined, noncalcified lung nodule(s) ≤ 1 cm in diameter. We determined time to overall survival (OS) using multivariate Cox regression. We also assessed changes in management of PDAC patients who later developed lung metastasis only. RESULTS: Of the 2710 patients diagnosed with PDAC, 632 (23%) had greater than one chest CT. Of those patients, 451 (71%) patients had ILNs, whereas 181 (29%) had no ILNs. There was no difference in median overall survival in patients without ILNs (16.4 [13.6, 19.0] months) versus those with ILN (14.8 [13.6, 15.8] months, P = 0.18). Examining patients who developed isolated lung metastases (3.3%), we found that staging chest CTs did not lead to changes in management of the primary abdominal tumor. CONCLUSIONS: Survival did not differ for PDAC patients with ILNs identified on staging chest CTs compared with those without ILNs. Furthermore, ILN identification did not lead to changes in management of the primary abdominal tumor, questioning the utility of staging chest CTs for PDAC patients.

Use of frailty to predict survival in elderly patients with early stage non-small-cell lung cancer treated with stereotactic body radiation therapy.

OBJECTIVES: Frailty has been shown to increase morbidity and mortality independent of age, but studies are lacking in radiation oncology. This study evaluates a modified frailty index (mFI) in predicting overall survival (OS) and non-cancer death for Stage I/II [N0M0] Non-Small-Cell Lung Cancer (NSCLC) patients treated with Stereotactic Body Radiation Therapy (SBRT). MATERIALS AND METHODS: Medical records for all patients with Stage I/II NSCLC treated at our institution with SBRT from 2009 to 2014 were reviewed. A validated mFI score, consisting of 11 variables was calculated, classifying patients as non-frail (0-1) or frail (≥2). Primary endpoint (OS) was analyzed using Kaplan-Meier method and log-rank. Secondary endpoint, non-cancer death, was analyzed using Fine-Gray's method, with death from lung cancer as a competing risk. RESULTS: Patient cohort consisted of 38 (27.3%) non-frail and 101 (72.7%) frail [median total mFI score 3.0 (range 0-7)]. Median age and pack-year history was 74 and 46years, respectively. Median follow-up among survivors was 38.5months (range 4.0-74.1months). Frailty was associated with a lower 3-year OS (37.3% vs. 74.7%; p=0.003) and 3-year cumulative incidence of non-cancer death (36.7% vs. 12.5%; p=0.02). Frailty remained significant in the multivariate model [OS HR for mFI ≥2: 2.25 (1.14-4.44); p=0.02]. CONCLUSION: Frailty is associated with lower OS in older patients with early stage NSCLC treated with SBRT, yet frail patients survived a median 2.5years, and were more likely to die of causes unrelated to the primary lung cancer, suggesting SBRT should be considered even in older patients deemed unfit for surgery.