Citations

Abstract Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

Respiratory motion is traditionally assessed using tumor motion magnitude. In proton therapy, respiratory motion causes density variations along the beam path that result in uncertainties of proton range. This work has investigated the use of water‐equivalent thickness (WET) to quantitatively assess the effects of respiratory motion on calculated dose in passively scattered proton therapy (PSPT). A cohort of 29 locally advanced non‐small cell lung cancer patients treated with 87 PSPT treatment fields were selected for analysis. The variation in WET (ΔWET) along each field was calculated between exhale and inhale phases of the simulation four‐dimensional computed tomography. The change in calculated dose (ΔDose) between full‐inhale and full‐exhale phase was quantified for each field using dose differences, 3D gamma analysis, and differential area under the curve (ΔAUC) analysis. Pearson correlation coefficients were calculated between ΔDose and ΔWET. Three PSPT plans were redesigned using field angles to minimize variations in ΔWET and compared to the original plans. The median ΔWET over 87 treatment fields ranged from 1‐9 mm, while the ΔWET 95th percentile value ranged up to 42 mm. The ΔWET was significantly correlated to the ΔDose for all metrics analyzed. The patient plans that were redesigned using ΔWET analysis to select field angles were more robust to the effects of respiratory motion, as ΔAUC values were reduced by more than 60% in all three cases. The tumor motion magnitude alone does not capture the potential dosimetric error due to respiratory motion because the proton range is sensitive to the motion of all patient anatomy. The use of ΔWET has been demonstrated to identify situations where respiratory motion can impact the calculated dose. Angular analysis of ΔWET may be capable of designing radiotherapy plans that are more robust to the effects of respiratory motion.PACS number(s): 87.55.‐x

The objective of this study was to evaluate and understand the systematic error between the planned three‐dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single‐field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II‐III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time‐weighted average CT, as well as the four‐dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose‐volume histogram (DVH) and voxel‐based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel‐based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single‐field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient‐specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.PACS number: 87.55.D

42 Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.

326 Background: Review initial outcomes for patients enrolled on the University of Florida Proton Therapy Institute PC01 protocol for patients with unresectable pancreatic cancer. Methods: The protocol received Institutional Review Board (IRB) approval in 7/2007. The first patient was enrolled in 4/2010. The accrual target was 66 patients to test if the Serious Adverse Event (SAE) ratecould be reduced from 15% (expected) to less than 5%. Protocol therapy consisted of proton therapy to a planning target volume (PTV) dose of 59.4 Cobalt Gray Equivalent (CGE) at 1.8CGE per fraction with concomitant oral Capecitabine (1000mg PO BID 5 days/week on radiation treatment days). Only gross disease was targeted. Results: 12 patients were enrolled. 1 patient died of a gunshot wound 5 days after starting treatment so only 11 patients are reported. Median follow up from start of treatment: 13 months (range 2 to 21 months). Median age: 68 (range 51 to 86) years. Gender: Males 5, Females 6. Race/Ethnicity: 9 White, 2 Hispanic. Overall survival: 90% at 6 months and 60% at 12 months. Freedom from progression: 80% at 6 months and 53% at one year. Local control: 100% at 6 months and 86% at 12 months. Freedom from metastasis: 80% at 6 months and 67% at 12 months.No patient experienced any grade 3 or greater toxicity during treatment or the follow up period. Grade 2 toxicity was limited to a single patient experiencing grade 2 fatigue. Median weight loss over the course of treatment was 1.7 (range: loss of 5.7 to gain of 4.9) Kg. 4 patients were deemed to have had an adequate radiographic response to radiotherapy so as to justify surgical exploration. Conclusions: Proton therapy to 59.4 CGE with concomitant Capecitabine was well tolerated with no grade 2 or greater gastrointestinal toxicities. 4 of 11 patients achieved a radiographic response allowing for attempted surgical resection. The study was closed to accrual on 9/1/2013 due to recognition that slow accrual made achievement of the primary study endpoint unlikely. At the same time, the lack of any meaningful gastrointestinal toxicity suggests significant opportunities for treatment intensification when proton therapy is used in this setting. Clinical trial information: NCT00685763.

7 Background: Improved prognostic biomarkers are needed for localized prostate cancer. We undertook an unbiased large-scale analysis of genes associated with metastatic progression and validated the prognostic ability of the top candidate gene. Methods: Prostate cancer samples from prostatectomy patients were analyzed for gene expression using a clinical-grade, high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci and assessed in a CLIA-certified laboratory. Nomination of prognostic candidate genes was performed on a discovery cohort (n=545) and validated on 3 independent cohorts (n=463). Multivariate analyses were performed for the primary endpoint of metastasis. The top prostate-specific gene was further evaluated in 208 additional tumor samples with a novel RNA in-situ hybridization (ISH) assay and in urine samples from 230 patients using PCR. Results: Of all known genes, the long noncoding RNA SChLAP1 ranked first for elevated expression in patients with metastatic progression by receiver-operator-curve analyses. Validation in three independent cohorts confirmed the prognostic value of SChLAP1. On multivariate modeling, SChLAP1 expression independently predicted metastasis within 10 years (odds ratio (OR) = 2.45, 95% confidence interval (CI) 1.70 – 3.53), death within 10 years (OR = 1.93, 95% CI 1.31 – 2.85), and biochemical recurrence within 5 years (OR = 1.76, 95% CI 1.28 – 2.41) with ORs comparable to Gleason score. Evaluation of SChLAP1 expression by RNA ISH confirmed a significant association with disease recurrence (OR = 1.99, 95% CI 1.06 – 3.73). Evaluation of urine SChLAP1 levels demonstrated increased expression in patients at higher risk for disease progression. Conclusions: We perform the largest high-throughput, unbiased study of prostate cancer prognostic biomarkers to date and discover SChLAP1 as a top gene predictive of metastatic progression. We validate SChLAP1 extensively with a clinical-grade assay. We show feasibility of a RNA ISH assay and a non-invasive urine test for SChLAP1. Our results, spanning 1,446 patients from 6 independent patient cohorts, suggest that SChLAP1 represents a very promising biomarker for aggressive clinical course.

259 Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma. Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle. Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending. Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. [Table: see text]

271 Background: MEDI-573 is a dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin receptor-A (IR-A) signaling pathways, which play a role in breast and other epithelial cancers. By sparing IR-B and its hybrid receptors, MEDI-573 is expected to achieve antitumor activity without perturbing glucose homeostasis. Methods: In a 3 + 3 dose-escalation trial ( NCT00816361 ), patients with advanced solid tumors, KPS ≥ 60, received MEDI-573 as a weekly 1-hr IV infusion at 0.5, 1.5, 5, 10, or 15 mg/kg every 21 days. Objectives included determination of MTD, safety profile, pharmacokinetics (PK), pharmacodynamics, and tumor response. In a separate biomarker study, mRNA expression of IR-A and IR-B was compared in HR+/HER- breast cancers. Results: Patients included 13M/12F (17 evaluable for efficacy at data cutoff); median age 59 yrs (range 37-78). No DLTs, drug-related SAEs, or significant toxicity patterns were reported. Forty-five AEs were considered treatment-related (% of patients): decreased appetite (28%), fatigue (24%), nausea (20%), diarrhea (16%), and anemia (12%). Hyperglycemia occurred in 2 patients, 1 with evidence of prestudy insulin resistance. No other significant changes in plasma glucose levels occurred. MEDI-573 had dose-proportionality, with AUC of 415 ± 165, 597 ± 298, and 1940 ± 904 d*μg/mL at 5, 10, and 15 mg/kg, respectively. Suppression of free IGF-1 and -2 was fully achieved at doses ≥ 5 mg/kg. Stable disease spanning ≥ 12 wks (range 12-36+) was seen in 6/17 patients. No antidrug antibodies were reported. In a study to identify breast cancer subsets that are dependent on IGF signaling, the IR-A:IR-B ratio was significantly higher in HR+/HER2- breast cancer than matched adjacent normal tissues and in proliferative luminal B than in luminal A breast cancer. Conclusions: MEDI-573 showed acceptable safety and favorable PK profiles without significant changes in glucose levels. The IR-A:IR-B ratio supports a biomarker approach for MEDI-573 patient stratification. A biomarker-rich phase Ib/II study of MEDI-573 with an aromatase inhibitor in patients with advanced HR+/HER2- breast cancer opens in 2011.