Shelby A. Labe

Low rates of androgen deprivation therapy use with salvage radiation therapy in patients with prostate cancer after radical prostatectomy

OBJECTIVEnThe RTOG 9601 and GETUG-AFU 16 randomized controlled trials demonstrated that the addition of androgen deprivation therapy (ADT) to salvage radiation therapy (SRT) improves progression-free and, for RTOG 9601, overall survival. We examined national trends in the use of ADT with SRT.nnnMATERIALS AND METHODSnOf the 484,009 patients in the National Cancer Database from 2004 to 2012 with localized or locally advanced prostate cancer treated with radical prostatectomy (RP), 4,200 men received SRT (≥6mo after surgery). We used Pearsons chi-squared test to evaluate changes in ADT use, and multiple logistic regression to examine predictors of ADT use.nnnRESULTSnOverall, 32.1% of SRT patients received ADT, which increased after initial results of RTOG 9601 showed an improvement in metastasis-free survival in 2010 (28.5% in 2008/2009 vs. 34.5% in 2011/2012, P = 0.006). Predictors of ADT use include presurgery prostate-specific antigen>20ng/ml vs.<10ng/ml (adjusted odds ratio [AOR] = 1.34, P = 0.002; 36.7% vs. 29.6%); positive vs. negative margins (AOR = 1.29, P = 0.001; 34.9% vs. 27.8%); Gleason 3+4 (AOR = 1.53; 21.3%), Gleason 4+3 (AOR = 2.40; 32.0%), or Gleason 8 to 10 (AOR = 4.49; 49.2%) vs. Gleason 2 to 6 (P≤0.005 for all; 13.2%); and pathologic T3a (AOR = 1.46; 30.9%), T3b (AOR = 2.50; 47.6%), or T4 (AOR = 4.14; 60.9%) vs. T2 (P<0.001 for all; 19.1%). Starting SRT 12 to 23.9 months (AOR = 0.69; 23.2%) or≥24 months (AOR = 0.25; 8.0%) after RP was associated with decreased odds of ADT use vs. starting SRT 6 to 8.9 months after RP (P≤0.002 for both; 35.0%).nnnCONCLUSIONnAlthough less than one-third of SRT patients from the study era received ADT, there is evidence that physicians and patients have begun slowly adopting this practice with the 2010 reporting of a decrease in the cumulative incidence of metastases with the addition of ADT to SRT. Given the newly reported survival benefit of RTOG 9601, additional work will be necessary to identify which patients benefit the most from the use of ADT with SRT to individualize treatment.

National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer

PURPOSEnAndrogen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease.nnnMETHODS AND MATERIALSnUsing the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3xa0+xa03xa0=xa06, prostate-specific antigen level <10xa0ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information.xa0We used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality.nnnRESULTSnOverall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; P<.001; incidence, 14.0% vs 6.0% in 2012); treatment in the South (AOR, 1.51), Midwest (AOR, 1.81), or Northeast (AOR, 1.90) versus West (P<.001); and brachytherapy use versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; P<.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; P<.001); and treatment in the South (AOR, 1.26), Midwest (AOR, 1.52), or Northeast (AOR, 1.28) versus West (P≤.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; P<.001) after adjustment for age and comorbidity.nnnCONCLUSIONSnADT use in low-risk prostate cancer has declined nationally but may remain an issue of concern in certain populations and regions.

Pathologic Outcomes of Gleason 6 Favorable Intermediate-Risk Prostate Cancer Treated With Radical Prostatectomy: Implications for Active Surveillance

&NA; We examined the pathologic outcomes of 2807 men with Gleason 6 favorable intermediate‐risk (FIR) prostate cancer treated with radical prostatectomy; 25.5% of patients with prostate‐specific antigen of 10 to 20 ng/mL and 12.4% with cT2b to T2c stage harbored higher grade or stage disease, suggesting that Gleason 6 FIR patients with cT2b to T2c tumors might generally be reasonable candidates for active surveillance. Background: The safety of active surveillance (AS) for Gleason 6 favorable intermediate‐risk (FIR) prostate cancer is unknown. To provide guidance, we examined the incidence and predictors of upgrading or upstaging for Gleason 6 FIR patients treated with radical prostatectomy. Patients and Methods: We identified 2807 men in the National Cancer Database diagnosed from 2010 to 2012 with Gleason 6 FIR disease (<50% positive biopsy cores [PBC] with either prostate‐specific antigen [PSA] of 10‐20 ng/mL or cT2b‐T2c disease) treated with radical prostatectomy. Logistic regression was used to identify predictors of upgrading (Gleason 3+4 with tertiary Gleason 5 or Gleason ≥4+3) or upstaging (pT3‐4/N1). Results: Fifty‐seven percent of the cohort had PSA of 10 to 20 ng/mL; 25.5% patients with PSA of 10 to 20 ng/mL and 12.4% with cT2b to T2c disease were upgraded or upstaged. In multivariable analysis, predictors of upgrading or upstaging included increasing age (P = .026), PSA (P = .001), and percent PBC (P < .001), and black race versus white (P = .035) for patients with PSA of 10 to 20 ng/mL and increasing PSA (P = .001) and percent PBC (P < .001) for patients with cT2b to T2c disease. Men with PSA of 15.0 to 20.0 ng/mL or 37.5% to 49.9% PBC with PSA of 10 to 20 ng/mL had >30% risk of upgrading or upstaging, whereas cT2b to T2c patients with <12.5% PBC or PSA <5.0 ng/mL had <10% risk. Conclusion: We found that Gleason 6 FIR patients with cT2b to T2c tumors had a low risk of harboring higher grade or stage disease and would be reasonable AS candidates, whereas patients with PSA of 10 to 20 ng/mL had a high risk and might generally be poor AS candidates.

Receipt of definitive therapy in elderly patients with unfavorable-risk prostate cancer

Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10‐year prostate cancer‐specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate‐risk or high‐risk disease.

NF-κB inhibition by dimethylaminoparthenolide radiosensitizes non-small-cell lung carcinoma by blocking DNA double-strand break repair

Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization. Here we demonstrate that inhibition of the canonical NF-κB pathway by dimethylaminoparthenolide (DMAPT) radiosensitizes NSCLC by blocking DNA double-strand break (DSB) repair. NF-κB inhibition results in significant impairment of both homologous recombination (HR) and non-homologous end joining (NHEJ), as well as reductions in ionizing radiation (IR)-induced DNA repair biomarkers. NF-κB inhibition by DMAPT shows preclinical potential for further investigation as a NSCLC radiosensitizer.

Risk of Upgrading and Upstaging Among 10 000 Patients with Gleason 3 + 4 Favorable Intermediate-risk Prostate Cancer

BACKGROUNDnIt is unknown whether active surveillance can be safely offered to patients with Gleason 3+4 favorable intermediate-risk (FIR) prostate cancer.nnnOBJECTIVEnTo examine the incidence and predictors of upgrading and upstaging among patients with Gleason 3+4 FIR disease.nnnDESIGN, SETTING, AND PARTICIPANTSnThe study involved 10 089 patients in the National Cancer Database diagnosed from 2010 to 2012 with Gleason 3+4 disease, prostate-specific antigen (PSA) <10ng/ml, and cT1c-2a prostate cancer with <50% positive biopsy cores (PBCs) who underwent radical prostatectomy.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnLogistic regression was used to examine predictors of upgrading (pathologic Gleason ≥4+3 or tertiary Gleason 5 in a Gleason 7 tumor) or upstaging (pT3-4/N1).nnnRESULTS AND LIMITATIONSnSome 30.3% of Gleason 3+4 FIR patients were upgraded or upstaged. On multivariable analysis, predictors included higher PSA, percentage PBC, age, and cT2a versus cT1c (all p<0.001), but not black race (p=0.895). When stratified into ordinal variables, PSA 8.1-9.9 versus ≤4.0ng/ml (adjusted odds ratio [AOR] 1.93, 38.3% vs 24.4%), PBC 37.5-49.9% versus <12.5% (AOR 1.79, 37.8% vs 25.1%); highest age quartile (≥67 yr) versus lowest (≤55 yr; AOR 1.46, 35.7% vs 24.7%); and cT2a versus cT1c (AOR 1.33, 34.3% vs 29.8%) were associated with a higher risk of upgrading or upstaging (all p<0.001). Men with PBC <12.5% and PSA ≤4.0ng/ml had a 21.7% risk of more advanced disease. This increased to 44.3% for PBC 37.5-49.9% and PSA 8.1-9.9ng/ml. A limitation of the study is its retrospective nature.nnnCONCLUSIONSnApproximately one in three patients with Gleason 3+4 FIR harbored disease of higher grade or stage. Younger patients with low percentage PBC and PSA and cT1c disease have a lower risk and may be candidates for active surveillance. However, widely available clinical information is insufficient for predicting the risk of more advanced disease, and the development and incorporation of additional tools, including magnetic resonance imaging and genomic tests, are necessary.nnnPATIENT SUMMARYnNearly one-third of patients with Gleason 3+4 favorable intermediate-risk prostate cancer harbor disease of higher grade or higher stage than their biopsy and clinical examination suggest. These patients would therefore be poor candidates for active surveillance.

Abstract 4189: Homologous recombination pathway-based biomarkers for treatment of non-small cell lung cancer with PARP inhibitors

Introduction: Clinical trials examining the addition of PARP inhibitors (PARPi) to treatment regimens for non-small cell lung cancer (NSCLC) are underway. Of note, these trials are not biomarker driven, and so any benefit may be obscured due to heterogeneity of tumor responses. The first FDA approved PARPi, olaparib, was approved specifically for ovarian cancer patients with germline mutations in BRCA1 or 2. These patients have tumors that show homologous recombination deficiency (HRD), a DNA damage repair pathway defect that confers synthetic lethality in the setting of PARPi therapy. Whether HRD may serve a biomarker for PARPi sensitivity in NSCLC, however, is unclear. Materials and Methods: Based on prior studies, NSCLC cell lines were classified as 1) HR proficient (A549, NCI-H23, NCI-H460, NCI-H522, NCI-H1299), 2) HR deficient due to early defects in the pathway as evidenced by decreased cisplatin-induced RAD51 focus formation (NCI-H1563, NCI-H1915, NCI-H2087, NCI-H2126) or 3) HR deficient due to late defects in the pathway as evidenced by impaired resolution of ionizing radiation (IR) induced RAD51 and γ-H2AX foci (Calu-1, Calu-6, HCC827, NCI-H520, SK-LU-1). NSCLC cells expressing doxycycline-inducible BRCA1 or 2 shRNA were generated by Tet-pLKO-puro lentiviral transduction. Cell viability assays to determine olaparib IC50 values were performed using CellTiter-Glo and MTS. Gene expression data were extracted from published datasets including CCLE, GSE32665 and TCGA, and expression levels of select genes were assayed by RT-qPCR. Results: BRCA1/2 shRNA knockdown inhibited IR-induced RAD51 focus formation in HR proficient NSCLC cells. This also induced PARPi sensitivity (A549 olaparib IC50 63 µM -> 1.2 µM with BRCA1 and 18 µM -> 3.4 µM with BRCA2 knockdown). Because BRCA alterations are uncommon in NSCLC, however, other HRD biomarkers were explored. There was no statistically significant difference in PARPi sensitivity among cell lines grouped by cisplatin-induced RAD51 focus formation or resolution of IR-induced RAD51 or γ-H2AX foci. BRCA deficient breast and ovarian cancers overexpress POLQ, which drives DNA repair toward non-HR-dependent pathways including alternative end joining. Like these cancers, NSCLC tumors overexpressed POLQ and RAD54L compared to normal lung, p Conclusion: Although certain HRD biomarkers including RAD51 focus formation and impaired resolution did not predict NSCLC olaparib sensitivity, other potential biomarkers, such as BRCA1/2 loss of function and elevated RAD54L expression, may serve as potential HRD-related biomarkers. Citation Format: Peter V. Deraska, Hunter D. Reavis, Shelby Labe, Alan D. D9Andrea, David Kozono. Homologous recombination pathway-based biomarkers for treatment of non-small cell lung cancer with PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4189. doi:10.1158/1538-7445.AM2017-4189