Citations

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.

11 Background: Currently there are no serum markers of response to AA. We performed a proteome based analysis of serum from prostate cancer patients, followed by mapping of candidate markers to networks based on known molecular interactions in Ingenuity Knowledge Base (IKB). Methods: Isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) was performed in serum of 3 non-localized prostate cancer cohorts. The first cohort included 15 paired untreated hormone-sensitive “pre AA” and 3-month “post AA” specimens; the second included 10 “early AA failure” (median failure time: 11 months) and the third included 10 “late AA failure” specimens (median failure time: 95 months). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post AA proteomes and (ii) post AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. To facilitate biological interpretation of multiple candidates identified in the comparisons, IPA was used. Candidate markers implicated in IPA networks with statistical significance were pursued in a second, independent patient cohort for association with time to AA failure using univariate Cox regression analysis. Results: Median PSA for pre/post AA first cohort were 3.15 and 0.29 ng/ml. Median PSA for the second and third cohorts were 27.3 and 4.3 ng/ml. Between post AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. Network enrichment analysis of the 47 proteins by IPA identified four interaction networks (p<0.01), one of which highlighted a role for 17-β-estradiol (E1). Gas chromatography used for measuring 3-month post AA initiation serum E1, estrone (E2) and testosterone levels (N=38) detected high E1, E2 levels associated with longer time to AA failure (P=0.07 for E1; P=0.08 for E2) in the independent cohort. Conclusions: A global proteomic analysis identified post AA initiation serum E1, E2 levels as potential response markers, which needs validation.

347 Background: 9,704 was the first phase 3 pancreatic cancer trial to validate the prognostic value of postresection CA19-9 for overall survival (OS), with values > 90/180 associated with worse OS. All pts received adjuvant gemcitabine or 5-FU and chemo-radiotherapy (RT). This analysis evaluates patterns of disease failure. Methods: SMS was negative, positive, or unknown. CA19-9 was analyzed at cut points 90, 180 and continuously. LRF and DF were estimated by cumulative incidence and Gray’s test compared. Cox hazard models were used for multivariate analyses (MVA) and included treatment, tumor site, size and nodal status. To adjust for multiple comparisons a p-value < 0.01 is statistically significant and 0.01 to < 0.05 a trend. Results: 538 pts accrued, with 451 eligible and analyzable for SMS and 385 for CA19-9. For CA19-9, 132 (34%) were Lewis Antigen negative (no CA19-9 expression), 200 (52%) < 90 and 220 (57%) < 180. 188 (42%) had negative margins, 152 (34%) positive and 111 (25%) unknown (i.e., no margin comment in path report; shown to have outcomes similar to negative margin pts). Pts with CA19-9 ≥ 180 were more likely to have tumors ≥ 3 cm and pts with positive SMS more likely to have KPS 60 - 80, T3/T4, or N1 disease. On univariate analysis (UVA) CA19-9 cut at 90 was associated with significant increases in both LRF (trend) and DF; in the gemcitabine arm this was seen in DF, not in LRF; in the 5-FU arm it was seen in both. Results were similar at the 180 cut point and continuously. SMS on UVA was not associated with increase in LRF/DF; see Table. On MVA, CA19-9 > 90 was significantly associated with LRF and DF; positive SMS showed only a trend for DF. Conclusions: Postresection CA19-9 has significant association with both LRF and DF not seen with SMS. These findings support continued use of RT in trials and consideration of dose intensification among pts with elevated postresection CA19-9. Grants: NCI U10, CA21661, CA37422, CA180868, CA180822. Clinical trial information: 0000000. [Table: see text]

225 Background: Recent guidelines promote simultaneous palliative care with active treatment for advanced/metastatic cancers, including interventions addressing all quality of life (QOL) domains. Dignity Therapy (DT) is an intervention demonstrating promising outcomes at end of life. It has not been offered earlier to cancer patients nor paired with a Life Plan (LP) intervention. The purpose of this phase I/II feasibility study was to determine the feasibility, acceptability and selected patient-reported outcomes (PROs) of the Dignity Therapy/Life Plan intervention and pilot study methods in advanced pancreatic cancer patients pursuing chemotherapy. Methods: DT is a brief psychotherapeutic intervention consisting a focused life review/values clarification delivered during 3 outpatient oncology clinic visits. Interviews were audiotaped, transcribed, and edited to produce a Generativity Document, which the patient can later share with family. Life Plan is a type of “bucket list”, where patients document future hopes/dreams. Feasibility was evaluated, distress measured with the Distress Thermometer (0-10 scale) and QOL measured with the Linear Analogue Self Assessment (LASA, 0-10 scale). Baseline scores of distress and QOL were compared with scores after the intervention, 4-6 weeks later (Time 2 [T2]). Results: Ten pancreatic adenocarcinoma patients enrolled, mean age 63. Two-thirds of those recruited enrolled; 90% completed all study procedures. Two-thirds were satisfied/very satisfied with DT/LP, and 78% found study participation worthwhile, DT/LP timing to be just right and would recommend DT/LP to others. QOL improved (baseline mean = 7.0; T2 = 7.25). Distress scores improved (Baseline mean = 6.13; T2 = 5.63). Conclusions: Distress and QOL modestly improved from baseline to T2. Baseline scores were collected before patients had begun any chemotherapy, therefore any improvements while undertaking aggressive chemotherapy are noteworthy. Participants felt the intervention was acceptable and better than they had expected. Conducting DT/LP in an outpatient oncology setting for newly diagnosed pancreatic cancer patients is both feasible and acceptable. Outcomes are encouraging for future larger scale trials. Clinical trial information: NCT02132325.

202 Background: Posttraumatic stress disorder (PTSD) is associated with morbidity and mortality in affected populations. Cancer survivors experience PTSD at a rate higher than the general population, with young age and female gender identified as risk factors. While young women with breast cancer experience greater psychosocial distress in general following diagnosis (dx), little is known about PTSD in this population. Methods: Women dx’d with Stage I-III breast cancer at age ≤ 40 were surveyed as a part of a multi-site cohort study. Demographic, treatment, psychosocial characteristics (including self-reported psychiatric conditions and use of psychiatric medications prior to dx), anxiety and depression (Hospital Anxiety and Depression Scale), fear of recurrence (Lasry Scale), and social support (Medical Outcomes Study) were assessed within 1 year after dx. PTSD was measured at 30 months post-dx using the PTSD Checklist – Civilian Version; a score ≥ 50 was considered positive for PTSD. Univariable and stepwise multivariable logistic regression were used to evaluate factors associated with PTSD. Results: 572 women were eligible for this analysis; median age at dx was 37 (range: 17-40); 87% had Stage I or II cancer. 37/572 women (6.5%) met criteria for PTSD at 30 months. Lower educational attainment, less financial comfort, less social support, stage 2 (vs. 1) disease, receipt of chemotherapy, fear of recurrence, anxiety and depression, and psychiatric comorbidities were associated (p ≤ 0.05) with PTSD in univariable analyses. Chemotherapy (OR = 3.48, 95% CI = 1.09-11.06), anxiety by HADS (OR = 20.29, 95% CI = 7.83-52.53), and psychiatric comorbidities (OR = 4.22, 95% CI = 1.40-12.74) were associated with increased likelihood of PTSD, whereas college education (OR = 0.25, 95% CI = 0.10-0.59) and greater social support (OR = 0.41, 95% CI = 0.17-0.99) appeared to be protective in multivariable analyses. Conclusions: PTSD affects a minority of young breast cancer survivors, with the prevalence in our cohort similar to that seen in other breast cancer populations. Early identification of those at risk for developing PTSD is essential for the adequate treatment of affected women and for the improvement of health outcomes and quality of life in cancer survivors.

175 Background: Inactivity is common in breast cancer survivors and has been linked to poor outcomes. Few trials have tested physical activity (PA) interventions in young women with breast cancer, who may face unique PA barriers due to demands of jobs and young families. Methods: Young and Strong was a cluster-randomized study evaluating the effect of education interventions for young breast cancer survivors.Sites were randomized 1:1 to a young women’s intervention (YWI), focused on fertility and other issues facing young women, or to a physical activity intervention (PAI). At PAI sites, providers were instructed to discuss PA with patients, and participants were given materials to encourage PA. PA was measured with the modified Godin Leisure Score Index at baseline, and 3, 6, and 12 months. Medical records were reviewed to assess provider attention to PA. Changes in weekly min of PA were compared between the PAI and YWI groups using general estimating equations to evaluate clustered binary and Gaussian data. Results: 467 patients enrolled between 7/12 -12/13 across 54 sites. Median age at dx was 40yrs (range 22-45). At baseline, participants were moderately active. PA increased in both groups over time (Table); there was no significant difference in PA between groups at any time (all p > 0.1). Provider attention to PA was documented in 74% of participants on PAI and 61% on YWI (p = 0.15), and correlated with PA at 12 months (median 100 min/wk of PA in participants with provider attention to PA vs. 60 min/wk in those without, p = 0.016). Participants who reported reading all or most the PAI materials reported higher levels of PA vs. those who read less (78% vs. 64%, p = 0.05) Conclusions: Young breast cancer survivors assigned to a PA intervention did not increase PA more than those assigned to an intervention focused on young women’s issues. However, the higher levels of PA among women who engaged with the PAI materials and those whose oncology providers addressed PA suggests the importance of enhancing patient and provider engagement with healthy lifestyle information and recommendations. Clinical trial information: NCT01647607. [Table: see text]

33 Background: Pathologic complete response (pCR) is an important prognostic indicator and surrogate endpoint, particularly for patients with hormone receptor-negative breast cancer. Previous studies have suggested differential response to pre-operative therapy by age and body mass index (BMI), though no association has been seen by race. We assessed associations of age at diagnosis, BMI and race with pCR accounting for breast cancer subtype. Methods: Women enrolled in four clinical trials of neoadjuvant chemotherapy (CALGB 40601 and 40603; ACOSOG Z1031 and Z1041) were eligible for this analysis. Age, race, and BMI were abstracted from patient records at baseline. Tumor subtype was assessed using immunohistochemical staining and/or fluorescence in situ hybridization. Logistic regression models were used to determine the association of race/ethnicity and age at diagnosis with pCR, the absence of residual invasive disease in the breast after neoadjuvant chemotherapy, adjusting for subtype (HER2+, ER+/ HER2-, triple negative), age, study arm, lymph node status, tumor size, and tumor grade. Results: 1,146 women with a mean age of 51.5 years were included. 156 (13.6%) were of black race. 590 (51.5%) of tumors were HER2+, 169 (14.7%) were ER+/HER2- and 387 (33.8%) were triple negative. In multivariate analyses controlling for tumor characteristics and other factors, black race (OR: 1.07, 95% CI: 0.67-1.70), age (OR: 0.99, 95% CI: 0.97-1.00) and BMI (OR: 0.99, 95% CI: 0.96-1.01) were not significant predictors of pCR. Similar associations we observed when stratified by subtype, and we found no interaction between age and black race (p=0.06), black race and BMI (p=0.54) or age and BMI (p=0.73). Conclusions: After accounting for tumor characteristics, we observed no differences in pCR rates according to race, age or BMI.

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.

PURPOSE: The purpose of this study was to determine whether the presence of HER-2/neu gene amplification and/or overexpression in benign breast disease was associated with an increased risk of subsequent breast cancer. PATIENTS AND METHODS: We conducted a nested case-control study of a cohort of women who were diagnosed with benign breast disease at the Mayo Clinic and who were subsequently observed for the development of breast cancer. Patients who developed breast cancer formed the case group, and a matched sample from the remaining cohort served as controls. Benign tissue samples from 137 cases and 156 controls and malignant tissues from 99 cases provided DNA or tissue for evaluation of HER-2/neu amplification and protein overexpression. RESULTS: Among the controls, seven benign tissues (4.5%) demonstrated low-level HER-2/neu amplification, whereas 13 benign (9.5%) and 18 malignant (18%) tissue specimens from cases exhibited amplification. HER-2/neu amplification in benign breast biopsies was associated with an increased risk of breast cancer (odds ratio [OR] = 2.2; 95% confidence interval [CI], 0.9 to 5.8); this association approached statistical significance. The risks for breast cancer associated with benign breast histopathologic diagnoses were OR = 1.1 (95% CI, 0.6 to 1.9) for lesions exhibiting proliferation without atypia and OR = 1.5 (95% CI, 0.4 to 5.6) for the diagnosis of atypical ductal hyperplasia. For women having both HER-2/neu amplification and a proliferative histopathologic diagnosis (either typical or atypical), the risk of breast cancer was more than seven-fold (OR = 7.2; 95% CI, 0.9 to 60.8). Overexpression of the HER-2/neu protein product, defined as membrane staining in 10% or more of epithelial cells, was found in 30% of the breast tumors but was not detected in any of the benign breast tissues. Case patients who had HER-2/neu gene amplification in their malignant tumor were more likely to have had HER-2/neu amplification in their prior benign biopsy (P = .06, Fisher’s exact test). CONCLUSION: Women with benign breast biopsies demonstrating both HER-2/neu amplification and a proliferative histopathologic diagnosis may be at substantially increased risk for subsequent breast cancer.