Citations

8583 Background: Patient QOL assessment requires balancing the detail provided by multi-item assessments with the reduced burden of single-item assessments. We investigated the psychometric properties of single-item LASA assessments used in 3 North Central Cancer Treatment Group (NCCTG) phase II trials for patients with newly diagnosed high-grade gliomas. Methods: Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS), and Functional Assessment for Cancer Therapy (FACT; overall, physical, emotional). Association of LASA measures with SDS, POMS, and FACT domains and with ECOG performance score (PS) and MMSE was assessed with Spearman’s correlation. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT. Cox regression modeled the association of baseline QOL and survival. Results: 205 patients completed the QOL assessments across 3 time points. LASA mean scores ranged from 60–78; SDS, POMS, and FACT ranged from 68–81. No significant changes across time for overall and emotional scores were observed. FACT physical decreased over time (p<0.001) as did LASA physical (p=0.08). LASA scales were strongly associated with corresponding scales on SDS, POMS, and FACT (0.44<rho<0.65; p<0.001). LASA was negatively associated with PS and positively with MMSE. Baseline scores for overall FACT (p=0.005) and LASA physical (p=0.015) were associated with better survival. Conclusions: The single-item LASA assessments have comparable psychometric properties as longer assessments for the same constructs. Correlations with PS and MMSE were as expected (convergent/concurrent validity). The discriminant validity and prognostic ability of LASA items were similar to the multi-item instruments. Collectively, the data suggest that the single item LASA scales are valid for assessing QOL in patients with newly diagnosed high grade gliomas and are an appropriate alternative when a shorter instrument is warranted. No significant financial relationships to disclose.

Objective To evaluate patient‐reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression‐free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death‐ligand 1 (PD‐L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks ( n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks ( n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6‐week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2‐point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue‐related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

TPS11077 Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018. (References: Oldham, R. K., Reid, W. K., Preisler, H. D., and Barnett, D. (1998) Cancer Biother. Radiopharm. 13, 71-80; Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., Oldham, R. K., Caluag, Z., Frye, R. A., Steinberg, S. M., Fojo, T., Bates, S. E. (2012) The Oncologist 17 (4) 512-e523; Robey, R. W., Shukla, S., Finely, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., Bates, S. E., (2008) Biochemical Pharmacology 75, 6, 1302-1312). Clinical trial information: NCT03002805.

1037 Background: Folate receptor alpha (FRA the product of the FOLR1 gene) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense expression of FRA in breast tumors and poor prognosis, yet little is known about FOLR1/FRA expression across clinically relevant breast cancer subtypes. Methods: 131 breast cancer tumors including 4 benign, 33 ER+, 26 HER2+, and 68 triple negative (TN) were constructed into tissue microarrays (TMAs). FRA expression was analyzed by immunohistochemistry (IHC) using a high affinity FRA antibody. Tumor membrane staining intensity was scored by a pathologist as negative (0), weak (1+), moderate (2+) and strong (3+). The percent of cells within each tissue core stained at each intensity was recorded to calculate an H-score. The H-score is a weighted score that captured both the proportion of positive staining and intensity for each tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 (100% membrane staining at 3+). H-scores for each patient sample were averaged over 3 TMA cores. The mean H-scores for each tumor subtype and the percentage of 3+ staining in >30% of tumor cells were compared by a Mann-Whitney test. The distribution of FOLR1 mRNA was completed using a TCGA RNA-seq dataset from 691 breast tumors classified as ER+, HER2+ and TN. FOLR1 levels of TN versus ER+ and HER2+ were compared by a Mann-Whitney test. Results: The mean H-score for the benign tumors was 0, ER+ (13.31), HER2+ (39.36), TN (119.02). The median H-score for the benign tumors was 0, ER+ (0), HER2+ (7.5), TN (127.5). The TN tumors mean and median H scores were significantly higher than benign, ER+ or HER2+ (p<0.001). The largest percentage of 3+ staining in >30% of tumor cells was observed in TN tumors (36.7%) and lowest in ER+ tumors (0%) (p<0.001). TN tumors had significantly higher levels of FOLR1 mRNA compared to ER+ and HER2+ subtypes (p<0.0001). Conclusions: Our data indicate that expression of FRA is highly prevalent in TN tumors and is supported by FOLR1 mRNA levels. Anti-FRA therapy may represent an important therapeutic intervention in TNBC who to this point have no active targeted treatment options.

520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg<10.7, equiv 10.7 to <11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]

6015 Background: Comorbidity increases with age. We evaluated how comorbidity was associated with toxicity and clinical outcomes among older women with BC who received adjuvant chemotherapy. Methods: Cancer and Leukemia Group B (CALGB 49907) enrolled 633 women ≥65 years with early stage BC and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women on the Quality of Life companion study completed a pre-treatment health survey (Older American Resources and Services Questionnaire, physical health subscale). The survey evaluates 14 conditions and the degree to which each interferes with daily activities (rated from 1 “not at all” to 3 “a great deal”). Comorbidity was analyzed as follows: 1) total number 2) comorbidity burden score (summed conditions multiplied by interference rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall survival (OS). Contingency table methods were used to evaluate the association between comorbidity and toxicity. Cox proportional hazards models were used to evaluate TTR and survival outcomes. Results: Among 329 women [median age 71 years (range 65-89), 86% white, 98% ECOG performance score 0-1, 75% stage 1-2] the median number of comorbidities was 2 (0-10), median comorbidity burden score was 3 (0-25), and most common conditions were arthritis (58%) and hypertension (54%). Few patients had diabetes (17%), heart disease (16%), and pulmonary disease (9%). No comorbidity measure was associated with toxicity or TTR. With a median follow-up of 5.4 years, increasing comorbidity was associated with shorter OS. For each additional comorbid condition the hazard of death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for age, tumor size, treatment, node status and receptor status. Comorbidity burden score was similarly associated with OS (HR 1.08 [95% CI; 1.03-1.14]), while no specific condition was independently associated. Conclusions: Among older women with good functional status, comorbidity was not associated with toxicity or BC relapse. However, comorbidity burden was associated with shorter OS.

522 Background: In the adjuvant setting, patients with HER2 breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy in patients with HER2+ metastatic breast cancer. It remained unclear from those studies, however, whether the HER2-specific immunity played a role and if antibody immunity was associated with improved disease free survival in the adjuvant setting. In the present study, we addressed these questions by analyzing sera samples from a subset of patients enrolled in the NCCTG adjuvant trial, N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831 (22 Arm A; 14 Arm B, and 14 Arm C). Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and presented as an index (>0.2 was considered a positive response). Results: Prior to therapy, across all three arms, N9831 patients had similar mean HER2 IgG levels (0.19 units in Arm A, 0.14 in Arm B, and 0.23 in Arm C, P=0.85). Following treatment, the mean levels of antibodies increased in Arm B to 0.35 units and in Arm C to 0.56 units and were higher (p<0.001) than in Arm A where levels did not increase. The proportion of patients who demonstrated antibody immunity increased by 9% in Arm A, 50% in Arm B and 28% in Arm C (P=0.026). Although the event rate was low in this cohort, Cox modeling suggested that larger increases in antibodies were associated with improved disease free survival (HR=0.23; p=0.04). Conclusions: These results show that the increased antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant and results from the inclusion of trastuzumab. The findings may have important implications for improving treatment outcomes in patients treated with trastuzumab.

521 Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an age-matched group (N=56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (≥ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (±0.6 sem), 6.2 (±2.7) and 2.7 (±0.7) fold, respectively (p<0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.

7008 Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) is recommended for diagnosis and staging of known or suspected NSCLC. Meta-analyses examining the accuracy of FDG-PET to diagnose lung cancer demonstrated high sensitivity 94% and specificity 83% but were performed in select centers. The purpose of this study is to evaluate the accuracy of FDG-PET to diagnose NSCLC and examine enrolling site differences in the national prospective ACOSOG Z4031 trial. Methods: 1,074 patients with clinical stage I (cT1-2N0M0) known or suspected NSCLC were enrolled between 2004 and 2006 in the Z4031 study and underwent surgical resection. The final diagnosis was determined by pathological examination. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: not avid and not cancerous (SUV=0), low avidity and likely not cancerous (SUV>0 and <2.5), avid and probably cancerous (SUV>2.5 and <5) and highly avid and likely cancerous (SUV>5). Sensitivity analysis of FDG-PET diagnostic accuracy was performed for varying levels of avidity and by preoperative lesion size. Differences in accuracy by enrolling site were examined. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 682 participants. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% CI: 79-85), and specificity was 31% (95% CI: 23-40). Positive and negative predictive values were 85% and 26%, respectively and accuracy improved with lesion size. There were 80 false positive scans and 69% were granulomas. False negative scans occurred in 101 patients (11were ≤10mm) with adenocarcinoma, squamous, bronchoalveolar cell and neuroendocrine tumors responsible for 64%, 12%, 10% and 8% of false negative results, respectively. Specificity did not differ between the 8 sites with >25 patients (p=0.74). Conclusions: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared to published studies. Reasons for poor test performance should be explored.

4565 Background: The efficient delivery of adjuvant therapy after radical prostatectomy (RP) in patients with prostate cancer is limited by the lack of biomarkers, beyond clinicopathologic factors, that are able to assess the risk of clinically significant disease progression. Previously, routine FFPE patient specimens from the Mayo Clinic Radical Prostatectomy Registry with long term follow-up were selected to develop a genomic classifier (GC) to predict clinical progression. Here, we present the validation of a GC in a cohort of patients at high risk of disease progression. Methods: A case-cohort study of high-risk RP patients from the Mayo Clinic (N=219) was used to validate the genomic classifier (GC) for predicting clinical progression (defined by positive bone or CT scan post-RP). Its performance was compared to a multivariable clinical classifier (CC) and a genomic-clinical classifier (GCC) which combines GC with established clinicopathologic variables. Concordance index, Cox modeling and decision curve analysis were used to compare the different models. Results: GC and GCC were predictive of clinical progression in the high-risk cohort with c-indices of 0.79 and 0.82, respectively, compared to the clinical classifier (0.70). Multivariable survival analysis showed that the majority of prognostic information of GCC came from the GC with a minor contribution from Gleason score. Decision curve analysis showed that GCC had a higher overall net benefit compared to CC over a wide range of ‘decision-to-treat’ thresholds for the risk of progression. Conclusions: In this high-risk cohort, GC and GCC classifiers showed improved performance over CC in prediction of clinical progression. GC is an independent prognostic factor in this cohort and captures the majority of prognostic information. GC and GCC’s prognostic performance and their usefulness in guiding decision-making in the adjuvant setting after RP need further testing in studies of additional prostate cancer risk groups.