Aaron Sabolch

Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewings sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.

Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

PURPOSE To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. METHODS AND MATERIALS Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigans Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. RESULTS Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). CONCLUSIONS Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

Adjuvant Therapies and Patient and Tumor Characteristics Associated With Survival of Adult Patients With Adrenocortical Carcinoma

CONTEXT Adrenocortical carcinoma is a rare malignant endocrine neoplasia. Studies regarding outcome and prognostic factors rely on fairly small studies. Here we summarize the experience with patients with a diagnosis of adrenocortical carcinoma from a large tertiary referral center. OBJECTIVE The objective of the study was to identify prognostic factors in patients with adrenocortical carcinoma and evaluate adjuvant treatment strategies. DESIGN Patient data were collected in a retrospective single-center study. Epidemiological, patient, and tumor characteristics were analyzed for prognostic factors regarding overall and recurrence-free survival in Cox regression models (multivariable and univariable). RESULTS Three hundred ninety-one adult patients with the diagnosis of adrenocortical carcinoma were identified. Median overall survival was 35.2 months. Cortisol production [hazard ratio (HR) 1.4, HR 1.5], tumor stage (HR stage 3 of 2.1 and 2.1, HR stage 4 of 4.8), and tumor grade (HR 2.4 and 2.0) were identified as negative prognostic factors (HR for death, HR for recurrence). Mitotane therapy increases recurrence-free survival, an effect that was significantly further improved by adjuvant radiation therapy but did not impact overall survival. Patients with open adrenalectomy had improved overall survival. CONCLUSIONS This study increases the evidence for adverse risk factors (cortisol production, high tumor stage, and high tumor grade) and suggests the following therapy approach: adrenocortical carcinoma patients should be treated with open adrenalectomy. Adjuvant therapy, particularly mitotane therapy in conjunction with radiation, should be considered to delay tumor recurrence.

Gleason pattern 5 is the greatest risk factor for clinical failure and death from prostate cancer after dose-escalated radiation therapy and hormonal ablation.

PURPOSE The division of Gleason score (GS) into three categories (2-6, 7, 8-10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5. METHODS AND MATERIALS Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). RESULTS At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p < 0.002; hazard ratio [HR] 3.4 [1.7-7.1]); CSS (p < 0.0001; HR 12.9 [5.4-31]); and OS (p < 0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS. CONCLUSION The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

Risk factors for local recurrence and metastasis in soft tissue sarcomas of the extremity.

ObjectivesWe reviewed our institutions experience in treating soft tissue sarcomas of the extremity to identify factors associated with local recurrence, metastasis, and overall survival, to identify patients who may benefit from intensification of therapy. MethodsA retrospective analysis was performed for patients who underwent both limb-sparing surgery and external beam radiotherapy for extremity sarcoma. Those who had gross residual disease or who presented with recurrent or metastatic disease were excluded. The Kaplan-Meier product limit and multivariate Cox regression were used to estimate local failure-free probability, distant failure-free probability, and overall survival along with associations with patient, tumor, and treatment characteristics. ResultsOne hundred eighty-eight patients were included in the analysis. Twenty-five (13%) and 46 (24%) experienced local and distant recurrence, respectively. Patients with high/intermediate-grade tumors [hazard ratio (HR)=5.63, 95% confidence interval (CI): 1.27-24.89, P=0.023] or with multifocally positive margins (HR=4.27, 95% CI: 1.20-15.24, P=0.026) were more likely to fail locally. Those with a preceding local recurrence (HR=8.58, 95% CI: 3.87-19.04, P<0.0001), high/intermediate-grade tumors (HR=5.68, 95% CI: 1.28-25.25, P=0.023), or no secondary reexcision (HR=2.5, 95% CI: 1.09-5.74, P=0.031) were more likely to develop metastasis. Patients with local recurrence (HR=3.6, 95% CI: 1.77-7.29, P<0.001), metastasis (HR=16.0, 95% CI: 7.93-32.31, P<0.0001), or without secondary reexcision (HR=3.2, 95% CI: 1.27-8.09, P=0.014) had decreased overall survival. ConclusionsPatients whose tumor grade or margin status put them at high risk for local failure should be considered for intensification of therapy. Those with a local recurrence should be considered for increased surveillance or systemic therapy, as local failure is associated with subsequent metastasis and decreased survival.

Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

PURPOSE Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. METHODS AND MATERIALS We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. RESULTS From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. CONCLUSIONS Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed.

The Cancer of the Prostate Risk Assessment (CAPRA) in patients treated with external beam radiation therapy: Evaluation and optimization in patients at higher risk of relapse

BACKGROUND The Cancer of the Prostate Risk Assessment (CAPRA) was developed to predict freedom from biochemical failure (FFBF) following radical prostatectomy (RP). Its utility following external beam radiation therapy (EBRT) has not been externally evaluated. METHODS A retrospective study of 612 patients treated with dose-escalated EBRT at the University of Michigan Medical Center. RESULTS Compared to the derivation cohort, EBRT treated patients had higher-risk disease (28% with CAPRA of 6-10 vs. 5%, respectively). A total of 114 patients (19%) had BF with 5-year BF ranging from 7% with CAPRA 0-3 to 35% with CAPRA 7-10. For RT patients the risk of BF at 5-year was similar to 4 surgical cohorts for CAPRA scores 0-2 but lower for all CAPRA scores ≥ 3. The difference favoring RT increased with increasing CAPRA score reaching a 27-50% absolute improved at 5-years for CAPRA scores of 6-10. On multivariate analysis each CAPRA point increased the risk of BF (p<0.0001) while Gleason pattern 5 in the biopsy also increased BF (p=0.01) and long-term androgen deprivation therapy (ADT) significantly reduced the risk of BF (p=0.015). CONCLUSIONS Compared to surgical series the risk of BF was lower with dose-escalated EBRT with the greatest difference at the highest CAPRA scores.

Dose–Effect Relationships for Femoral Fractures After Multimodality Limb-Sparing Therapy of Soft-Tissue Sarcomas of the Proximal Lower Extremity

PURPOSE We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). METHODS AND MATERIALS We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. RESULTS Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. CONCLUSIONS These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients.

Perspectives of Patients With Cancer on the Ethics of Rapid-Learning Health Systems

Purpose To inform the evolving implementation of CancerLinQ and other rapid-learning systems for oncology care, we sought to evaluate perspectives of patients with cancer regarding ethical issues. Methods Using the GfK Group online research panel, representative of the US population, we surveyed 875 patients with cancer; 621 (71%) responded. We evaluated perceptions of appropriateness (scored from 1 to 10; 10, very appropriate) using scenarios and compared responses by age, race, and education. We constructed a scaled measure of comfort with secondary use of deidentified medical information and evaluated its correlates in a multivariable model. Results Of the sample, 9% were black and 9% Hispanic; 38% had completed high school or less, and 59% were age ≥ 65 years. Perceptions of appropriateness were highest when consent was obtained and university researchers used data to publish a research study (weighted mean appropriateness, 8.47) and lowest when consent was not obtained and a pharmaceutical company used data for marketing (weighted mean appropriateness, 2.7). Most respondents (72%) thought secondary use of data for research was very important, although those with lower education were less likely to endorse this (62% v 78%; P < .001). Overall, 35% believed it was necessary to obtain consent each time such research was to be performed; this proportion was higher among blacks/Hispanics than others (48% v 33%; P = .02). Comfort with the use of deidentified information from medical records varied by scenario and overall was associated with distrust in the health care system. Conclusion Perceptions of patients with cancer regarding secondary data use depend on the user and the specific use of the data, while also frequently differing by patient sociodemographic factors. Such information is critical to inform ongoing efforts to implement oncology learning systems.

Patient Perspectives on the Ethical Implementation of a Rapid Learning System for Oncology Care

INTRODUCTION A rapid learning system (RLS) of health care harnesses data generated from routine patient care to create a virtuous cycle of data collection and analysis for quality improvement and research. The success of such systems depends on understanding patient perspectives regarding the ethical issues that arise from the ongoing implementation of this transformative concept. METHODS An interview guide was designed to evaluate patient perspectives to inform the ethical implementation of an oncology RLS. A purposively selected, diverse sample of 32 patients with cancer was recruited from two institutions to participate in semistructured, in-depth interviews for formal qualitative analysis. RESULTS The extent to which respondents expressed discomfort with more permissive system features (less formal notification/consent, broader uses/users, inclusion of sensitive data) reflected their trust, which in turn seemed to vary by sociodemographic features. It was also influenced by their familiarity with technology and their attitudes and beliefs regarding privacy and the use of electronic medical records more generally. Distrust of insurers and the pharmaceutical industry led subjects to desire greater oversight and restriction of these potential users of the system. Subjects were most comfortable when doctors were the primary users, engaged patients directly in the notification and consent discussion, and oversaw the system. CONCLUSION Those actively developing RLSs should recognize the critical importance of trust and the key role that doctors will need to play in order for such systems to be successful and to ensure that their implementation is ethically palatable to the patients whose data are being included.