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Lumpectomy and breast radiotherapy (RT) achieve good longterm control of disease in patients diagnosed with ductal carcinoma in situ (DCIS). In the combined analysis of NSABP B-17/B-24 DCIS trials, these treatments were shown to reduce invasive ipsilateral breast tumor recurrences by 52% compared to lumpectomy alone. RT has been consistently used as an adjuvant to surgery and therefore, little is known of its activity on intact/untreated DCIS. Elucidating the effectiveness of radiation therapy may help optimize the treatment of DCIS and avoid over-treatment.Trial Design The objective of the ongoing phase 2 pilot trial is to evaluate the ablative and treatment effects of neoadjuvant RT (neoRT) on DCIS. Patients diagnosed with DCIS on core needle biopsy are randomized to upfront lumpectomy (Arm 1) followed by partial breast irradiation (PBI) or neoRT PBI followed by delayed surgical excision (Arm 2). Arm 1 serves as a reference group for pathological-radiological correlations as well as to ascertain the rate of upstaging to invasive cancer. The neoRT regimen consists of 6 Gy daily x 5 (consecutive or non-consecutive days) to the intact tumor with a 0.5 cm margin. Surgical excision is delayed 12-16 weeks, allowing for the ablative effects of neoRT to occur. Specific Aims •To determine if neoRT can completely ablate 30% of DCIS cases•To determine if DCIS subtypes exhibit differential sensitivity to neoRT•To evaluate microscopic treatment effects; wound complication rates; post-RT breast imaging changes; and invasive carcinoma rate.Eligibility Women 18 years of age or older diagnosed with DCIS by core needle biopsy and intending to receive breast conserving surgery are eligible. Tumors must be ≤4 cm, discovered as mammographic microcalcifications and/or MRI non-mass enhancement measuring with evidence of residual imaging abnormality after diagnostic needle biopsy. Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10%. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoadjuvant PBI. Accrual 10 (open 2019) Contact wapnir@stanford.edu. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027.McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Carol Marquez, Kimberly Stone, Kimberly Allison, Wendy DeMartini, Catherine Salem, Jacqueline Tsai, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-09-01.

A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) Breast radiotherapy (RT) for DCIS has been studied only in the adjuvant setting, following lumpectomy surgery. Adjuvant RT reduced invasive recurrences by 52% in the combined analysis of the two largest DCIS trials NSABP B-17/B-24, and reduced recurrences even for low or intermediate grade DCIS in the RTOG 9804 trial (recurrence 0.9% with RT versus 6.7% without RT). The mechanism of action is hypothesized to be elimination of occult disease and/or inhibition of neoplastic transformation in normal breast tissue. Trial Design To understand the ablative effects of RT on pure DCIS, we are conducting a prospective randomized trial comparing histopathological findings of surgical excision (Arm 1) to neoadjuvant partial breast irradiation (neoRT) followed by delayed surgical excision (Arm 2) for patients with core needle biopsy proven DCIS. Arm 1 will provide a reference group for upstaging to invasive cancer, molecular markers and pathological-radiological correlations. Arm 2 participants will receive 6 Gy daily x 5 to the intact tumor with a 0.5 cm margin of normal tissue. Surgical excision will be delayed 12-16 weeks to allow for the radioablative effects to occur and radiation-induced inflammation to subside. Specific Aims To determine if neoRT can completely ablate at least 30% of pure DCISTo determine if DCIS subtypes exhibit differential sensitivity to neoRTTo determine the radiation-induced treatment effects; wound complication rates; radiological Eligibility Women 18 years of age or older with DCIS diagnosed on vacuum assisted core needle biopsy who intend to receive breast conserving surgery are eligible, excluding those with a prior history of ipsilateral breast cancer. The imaging abnormality must be mammographic microcalcifications and/or MRI non-mass enhancement measuring Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10% in the reference group. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoRT. Accrual Opened to accrual June 1, 2019 Contact wapnir@stanford.edu Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Wendy DeMartini, Kimberly Allison, Kimberly Stone, Frederick Dirbas, Carol Marquez, Debra Ikeda, Sunita Pal, Jacqueline Tsai, Rachel Yang, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-04.

Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-12.

Patient-derived orthotopic xenograft (PDOX) models have been verified as a useful method for studying human cancers in mice. Previous studies on the extent of metastases in these models have been limited by the necessity of welfare euthanasia (primary tumors reaching threshold size), at which point metastases may only be micrometers in diameter, few in number, and solely identified by step-sectioning of formalin-fixed paraffin-embedded tissue. These small micro-metastases are less suitable for many downstream molecular analyses than macro-metastases. Resection of the primary tumor by survival surgery has been proven to allow further time for metastases to grow. Although PDOX models of triple-negative breast cancer (TNBC) shed circulating tumor cells (CTCs) into the bloodstream and metastasize, similar to human TNBC, little data has been collected in these TNBC PDOX models regarding the association between CTC characteristics and distant metastasis following excision of the primary tumor xenograft. This study assembles a timeline of PDOX tumor shedding and metastatic tumor progression before and after tumor excision surgery. We report the ability to use tumorectomies to increase the lifespan of TNBC PDOX models with the potential to obtain larger metastases. CTC clusters and CTCs expressing a mesenchymal marker (vimentin) were associated with metastatic burden in lung and liver. The data collected through these experiments will guide the further use of PDOX models in studying metastatic TNBC.

TPS1109 Background: PALB2 (Partner and Localizer of BRCA2) plays a critical role in the maintenance of genomic integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. Our recently reported phase II clinical trial (Gruber, et al. JCO 2019) showed that talazoparib monotherapy was associated with single agent activity in germline PALB2 (gPALB2) mutation-associated advanced breast cancers. Of 5 patients with a germline PALB2 mutation, all 5 had reduction in target lesions > 20% with 3 of 5 achieving a RECIST 1.1 response. All patients had visceral metastases and were heavily pretreated; one response occurred in a patient with 8 prior lines of therapy for metastatic breast cancer. Clinical activity of the PARP inhibitor olaparib was also demonstrated in breast cancer patients with gPALB2 mutations in the Olaparib Expanded trial (TBCRC 048). Thus, we believe there is significant value in generating additional PARP inhibitor monotherapy data in subjects with advanced PALB2 mutation-associated breast cancer. We propose this phase II trial to better estimate the rate of RECIST 1.1 objective response in this patient population. Methods: This is a single-arm, two-stage, non-randomized study to assess the objective response rate (ORR) of talazoparib monotherapy in patients with PALB2 mutation-associated advanced breast cancer. Eligible subjects will be adults with inoperable locally advanced or metastatic breast cancer with a germline or somatic PALB2 mutation with 0-3 prior therapies for advanced disease. Eligible patients must have a deleterious or suspected deleterious mutation in PALB2 on a CLIA approved commercial germline or next generation sequencing tumor assay. Study treatment is talazoparib 1 mg PO daily. In stage 1, ORR will be assessed after 15 patients; if at least 2 responses are observed then an additional 15 patients will be enrolled; if less than 2 responses are observed the study will be terminated. The primary objective is to evaluate whether talazoparib monotherapy can induce a 30% ORR in subjects with advanced breast cancer associated with a PALB2 mutation. Response will be assessed by RECIST 1.1. Secondary objectives include safety, PFS, clinical benefit rate, and patient-reported quality-of-life. Exploratory endpoints will assess for the presence of PALB2 loss-of-heterozygosity, biallelic mutations, correlation of ctDNA profile with treatment response and the correlation of germline versus somatic mutations with response rate. This trial is currently activated and enrolling at Stanford Cancer Center and it is expected that 4 additional sites will be added. Conclusion: This trial will evaluate gPALB2 as a biomarker for PARP inhibitor monotherapy in advanced or metastatic HER2- breast cancer. Clinical trial information: pending .

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy regimens than TNBC patients whose tumors are HR non-deficient. We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to better estimate the pCR rates amongst HR deficient and HR non-deficient tumors. Methods: Patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00148694/NCT00580333 (N=50), NCT01372579 (N=26), TBCRC 008 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Logistic regression models were used to adjust for study effects. The addition of data from the TNBC platinum-treated arm of GeparSixto (n=101) to this pooled analysis will be available at the time of presentation bringing the total sample size to 267. Results: pCR was achieved in 51 patients (31%) and 104 patients (63%) were HR deficient (31 with high HRD score and tBRCA mutation, 67 with high HRD score only, and 6 with tBRCA mutation only). Patients with HR deficient tumors were more likely to achieve a pCR than those with HR non-deficient tumors: 44% vs. 8% (p Likelihood of pCR adjusting for studyModel #Predictor VariablePopulation (n)Adjusted Odds RatioLower 95% CIUpper 95% CIP Value1HR DeficiancyAll (166)12.54.237.3 Conclusion: HR deficiency status is a robust predictor of pCR across different neoadjuvant platinum-based regimens. This pooled analysis suggests that HRD can be used to identify TNBC patients with a high probability of obtaining pCR with a platinum-based neoadjuvant chemotherapy regimen. Citation Format: Telli ML, McMillan A, Ford JM, Richardson AL, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar W, Stearns V, Connolly RM, Loibl S, Elkin EP, Timms K, Hartman A-R, von Minckwitz G. Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-12.

211 Background: Patient reported outcomes (PROs) allow for systematic and more continuous capture of the patient experience. PROs have been associated with improved symptom management and quality of life in patients with advanced cancer; however how to do this in a real world setting is not thoroughly described. We sought to provide a description of the implementation and feasibility of a digital PRO application in patients with advanced cancer at one academic center. Methods: This is an ongoing randomized trial, comparing digital PRO intervention vs standard of care, in advanced cancer patients from three oncology groups (thoracic, gastrointestinal, genitourinary). Prior to trial initiation, a lead in period to test workflows was conducted, as well as key stakeholder interviews to optimize engagement with the platform. Clinical team members (e.g. nurses, advanced practice providers) were critical to the workflows developed, thus operational leadership buy-in was required. We were unable to integrate our PRO platform with our digital EHR. Regular sponsor meetings addressed technical concerns and patient/provider feedback. Processes were tailored for each disease group to handle varying degrees of symptoms (mild, moderate and severe). Patient and clinician satisfaction and qualitative feedback was collected. We defined feasibility as > 70% questionnaire completion on the platform. Results: There are 64 patients on the intervention arm and 64 on the control arm. Of eligible patients, 93% (128/138) enrolled in the study. During the study period, 447 digital symptom questionnaires were sent by the platform, of which 333 were completed (74%). The majority of clinicians (82%, n = 18) and patients (85%, n = 64) felt neutral or positive when asked if the tool was easy to use. Approximately half of clinicians (45%, n = 10) and patients (46%, n = 36) would probably or definitely recommend the platform. Conclusions: Web-based PRO reporting for patients with advanced cancer is feasible. Clinicians and patients found the platform both acceptable and easy to use. Future directions include integration with our EHR, expansion across disease groups and other centers, and creation of workflows that are integrated into routine clinical practice.

3006 Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 g PALB2, 1 g CHEK2/g FANCA/sPTEN) and 3 additional pts (g PALB2, s ATR, s PTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (g CHEK2 testicular, g ATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.

Several studies have demonstrated substantial variability among individual radiation oncologists in defining target volumes using computed tomography (CT). The objective of this study was to determine the impact of combined positron emission tomography and computed tomography (PET/CT) on inter-observer variability of target volume delineation in rectal cancer. We also compared the relative concordance of two PET imaging tracers, 18F-fluorodeoxyglucose (FDG) and 18F-fluorodeoxythymidine (FLT), against conventional computed tomography (CT). Six consecutive patients with locally advanced rectal cancer were enrolled onto an institutional protocol involving preoperative chemoradiotherapy and correlative studies including FDG- and FLT-PET scans acquired in the treatment position. Using these image data sets, four radiation oncologists independently delineated primary and nodal gross tumor volumes (GTVp and GTVn) for a hypothetical boost treatment. Contours were first defined based on CT alone with observers blinded to the PET images, then based on combined PET/CT. An inter-observer similarity index (SI), ranging from a value of 0 for complete disagreement to 1 for complete agreement of contoured voxels, was calculated for each set of volumes. For primary gross tumor volume (GTVp), the difference in estimated SI between CT and FDG was modest (CT SI = 0.77 vs. FDG SI = 0.81), but statistically significant (p = 0.013). The SI difference between CT and FLT for GTVp was also slight (FLT SI = 0.80) and marginally non-significant (p < 0.082). For nodal gross tumor volume, (GTVn), SI was significantly lower for CT based volumes with an estimated SI of 0.22 compared to an estimated SI of 0.70 for FDG-PET/CT (p < 0.0001) and an estimated SI of 0.70 for FLT-PET/CT (p < 0.0001). Boost target volumes in rectal cancer based on combined PET/CT results in lower inter-observer variability compared with CT alone, particularly for nodal disease. The use of FDG and FLT did not appear to be different from this perspective.

BACKGROUND. Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population. METHODS. In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981–2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed. RESULTS. Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage IE or IIE. Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%. CONCLUSIONS. DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease. Cancer 2007. © 2007 American Cancer Society.

Amplification of MYCN occurs commonly in neuroblastoma. We report that phosphatidylinositol 3-kinase (PI3K) inhibition in murine neuroblastoma (driven by a tyrosine hydroxylase-MYCN transgene) led to decreased tumor mass and decreased levels of Mycn protein without affecting levels of MYCN mRNA. Consistent with these observations, PI3K inhibition in MYCN-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis. To clarify the importance of Mycn as a target of broad-spectrum PI3K inhibitors, we transduced wild-type N-myc and N-myc mutants lacking glycogen synthase kinase 3β phosphorylation sites into human neuroblastoma cells with no endogenous expression of myc. In contrast to wild-type N-myc, the phosphorylation-defective mutant proteins were stabilized and were resistant to the antiproliferative effects of PI3K inhibition. Our results show the importance of Mycn as a therapeutic target in established tumors in vivo, offer a mechanistic rationale to test PI3K inhibitors in MYCN-amplified neuroblastoma, and represent a therapeutic approach applicable to a broad range of cancers in which transcription factors are stabilized through a PI3K-dependent mechanism. (Cancer Res 2006; 66(16): 8139-46)

We compare survival estimates for population-based glioma cases by using two diagnostic coding schemes, (1) the International Classification of Diseases, Oncology, second edition (ICD-O-2) as reported by the Surveillance, Epidemiology, and End Results (SEER) program and (2) central neuropathology review diagnosis based on the World Health Organization II classification. In addition, among review categories, we estimate survival in relation to several patient demographic and treatment factors. Eligible cases included adults residing in the San Francisco Bay SEER Area with newly diagnosed, histologically confirmed glioma during the years 1991-1994 and 1997-1999. The study group included participating subjects for whom subsequent central neuropathology review confirmed glioma. We determined treatments, vital status, and other factors by using registry, interview, medical record, and active follow-up data. Survival differences between anaplastic astrocytoma (AA) and astrocytoma were apparent from review diagnoses (median months of survival for AA, 13.0 [95% CI, 9.9-19.5], and astrocytoma, 101.3 [95% CI lower limit, 42.1; upper limit not yet reached]), but not with ICD-O-2 diagnoses reported by SEER (median months of survival for AA, 16.6 [95% CI, 12.0-20.7], and astrocytoma, not otherwise specified, 17.2 [95% CI, 10.6-71.6]). This finding emphasizes the need for improvements in coding for nonglioblastoma astrocytomas to provide better population survival estimates. When review diagnosis was used, younger age and resection (vs. biopsy) were statistically significant for all histology groups analyzed by multivariable Cox proportional hazard models. Additional statistically significant variables were as follows: among 517 glioblastoma patients, radiation treatment and being married; among 105 AA patients, inclusion of chemotherapy in the initial treatment; and among 106 patients with nonanaplastic oligodendroglial tumors, college education. Further consideration of impact of marital status, education, and other social factors in glioma survival may be warranted.

ERCC2 and ERCC1 are important in DNA nucleotide excision repair and lie on chromosome 19q13.3 near a putative glioma suppressor region. We genotyped constitutive variants ERCC1 C8092A and ERCC2 K751Q and R156R in approximately 450 adults with glioma and 500 controls from two independent population-based series, uniformly reviewed patients’ tumors to determine histopathologic category, and determined a variety of tumor markers among astrocytic tumors. Odds ratios (ORs) for glioblastoma for those carrying two ERCC1 A alleles versus none or one were 1.67 in series 1 and 1.64 in series 2, which yielded a combined OR of 1.67 (95% CI, 0.93–3.02; P = 0.09), adjusted for age, gender, ethnicity, and series. Odds ratios for the ERCC2 variants were not consistently elevated or reduced for the two series in all cases versus controls. However, among whites, for those with ERCC2 K751Q genotype QQ versus QK/KK, the OR for nonglioblastoma histologies versus controls was 1.82 (95% CI, 0.97–3.44; P = 0.06). Also, among whites, glioma patients were significantly more likely than controls to be homozygous for variants in both ERCC1 C8092A and ERCC2 K751Q (OR, 3.2; 95% CI, 1.1–9.3). Given the numbers of comparisons made, these findings could be due to chance. However, the results might warrant clarification in additional series in conjunction with the nearby putative glioma suppressor genes (GLTSCR1 and GLTSCR2)

We and others have reported previously that adults with glioma are 1.5- to 4-fold less likely than controls to report a variety of allergic conditions. The consistent nature of this relationship calls for a biological explanation so that preventative or therapeutic modalities can be explored. We enrolled 403 newly diagnosed adult glioma cases in the San Francisco Bay Area over a 3-year period using a population-based cancer registry and 402 age/gender/ethnicity frequency-matched controls identified via random digit dialing. We assessed total, food-specific, and respiratory-specific IgE in available case (n = 228) and control (n = 289) serum samples. IgE levels were associated with gender, age, smoking status, and ethnicity among cases and/or controls. Among the cases, IgE levels were not associated with aspects of glioma therapy including radiation, chemotherapy, or tumor resection. Total IgE levels were lower in cases than controls: age/gender/ethnicity/education/smoking-adjusted odds ratio (OR) for elevated versus normal total IgE was 0.37 [95% confidence interval (CI), 0.22–0.64]. For the food panel, OR was 0.12 (95% CI, 0.04–0.41). For the respiratory panel, OR was 0.76 (95% CI, 0.52–1.1). Among respiratory allergies, late age of onset (>12 years) but not IgE levels defined a group with strong associations with risk (OR, 0.50; 95% CI, 0.33–0.75). These results corroborate and strengthen our findings of an inverse association between allergic reactions and glioma by showing a relationship with a biomarker for allergy and cancer for the first time. Furthermore, the results indicate a complex relationship between allergic disease and glioma risk that varies by allergen and allergic pathology.

We examined CYP1A1 T6235C (M1) and A4889G (M2) polymorphisms in San Francisco Bay Area African Americans and Latinos who were newly diagnosed with primary lung cancer from September 1998 to November 2002 and in age-gender-ethnicity frequency-matched controls. Owing mainly to rapid mortality of cases, overall percentages of cases genotyped were 26% and 32% for Latinos and African Americans, respectively. CYP1A1 variants were genotyped for Latinos (104 cases, 278 controls) and African Americans (226 cases, 551 controls). M1 and M2 frequencies in controls were 0.23 and 0.02 for African Americans and 0.38 and 0.29 for Latinos. In Latinos, the overall inverse odds ratio (OR) of 0.51 (95% CI = 0.32-0.81) for M1 variant genotype resulted from an inverse interaction with smoking. Nonsmokers with M1 genotype had a slight elevated OR (1.5; 0.59-3.7), but those with less than 30 or 30 or more pack-year history had 0.20 (0.06-0.70) and 0.21 (0.06-0.81) times (about 1/5) the odds expected if smoking and genotype were independent lung cancer risk factors. African Americans had interactions of similar magnitude that were not statistically significant. Results for M2 were very similar. Inverse interactions of CYP1A1 variants and smoking-associated lung cancer risk in Latinos might be causal, due to undetected bias or confounding, or represent a unique linkage disequilibrium between a new lung cancer locus and CYP1A1 in this highly admixed population.

PURPOSE: To develop a pretreatment prognostic model for survival of patients with progressive metastatic prostate cancer after castration using parameters that are measured during routine clinical management. PATIENTS AND METHODS: Pretreatment clinical and biochemical determinants from 409 patients enrolled onto 19 consecutive therapeutic protocols from June 1989 through January 2000 were evaluated. The factors selected were age, Karnofsky performance status (KPS), hemoglobin (HGB), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALK), and albumin. These factors were combined in an accelerated failure time regression model to produce a nomogram to predict median, 1-year, and 2-year survival. The nomogram was validated internally and externally using data from a multicenter randomized trial of suramin plus hydrocortisone versus hydrocortisone alone. RESULTS: The median survival of the entire group was 15.8 months (range, 0.9 to 77.8 months); 87% have died. In multivariable analysis, KPS, HGB, ALK, albumin, and LDH were significantly associated with survival (P < .05), whereas age and PSA were not. All seven factors were included in the nomogram. When applied to the external validation data set, the nomogram achieved a concordance index of 0.67. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSION: A nomogram derived from pretreatment parameters that are measured on a routine basis was constructed. It can be used to predict the median, 1-year, and 2-year survival of patients with progressive castrate metastatic disease with reasonable accuracy. The information is useful to assess prognosis, guide treatment selection, and design clinical trials.

Background Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Methods Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. Results Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2–7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5–37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6–5.2), and the median OS was 10.7 months (95% CI 3.9–NR). Conclusions Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.

PURPOSE: Validated end points are lacking for clinical trials in hormone-refractory prostate cancer (HRPC). Controversy remains regarding the utility of a posttreatment decline of prostate-specific antigen (PSA). The purpose of this study was to determine whether posttreatment declines in PSA were associated with clinical measures of improvement in a randomized phase III trial of suramin plus hydrocortisone versus placebo plus hydrocortisone. PATIENTS AND METHODS: A total of 460 HRPC patients were randomized to receive suramin plus hydrocortisone (n = 229) or placebo plus hydrocortisone (n = 231). All patients had symptomatic, metastatic HRPC requiring opioid analgesics. Clinical end points evaluated included overall survival, objective progression-free survival (OPFS), and time to pain progression (TTPP). An evaluation of overall survival, OPFS, and TTPP as a function of a PSA decline of ≥ 50%, lasting at least 28 days, was undertaken by using a landmark analysis at 6, 9, and 12 weeks. A multivariate analysis of the impact of PSA decline was performed on these clinical end points. RESULTS: A decline in PSA of ≥ 50% lasting ≥ 28 days was significantly associated with a prolonged median overall survival, OPFS, and TTPP, both in the entire group and the suramin plus hydrocortisone group at all three landmarks in both univariate and multivariate analysis. CONCLUSION: In this prospective, randomized trial of suramin plus hydrocortisone versus placebo plus hydrocortisone, a posttherapy decline in PSA of ≥ 50%, lasting 28 days, was associated with prolonged median overall survival, improved median progression-free survival, and median TTPP. This analysis suggests that a posttreatment decline in PSA may be a reasonable intermediate end point in HRPC trials and calls into question the clinical utility of preclinical assays evaluating the in vitro effect of given agents on PSA secretion.

p14(ARF) is a putative tumor suppressor gene thought to modify the levels of p53. CpG sites within the 5'-flanking region and exon 1beta of p14(ARF) are targets of aberrant methylation and transcriptional silencing in human colorectal cancer (CRC). Here we have developed methylation-specific polymerase chain reaction (MSPCR) methods to detect methylation of CpG sites in p14(ARF) in CRC cell lines and primary CRC tumors, and correlated p14(ARF) mRNA expression with methylation in CRC cell lines using competitive quantitative reverse transcription-polymerase chain reaction methods. Ten CRC cell lines were studied; three (DLD-1, HCT15 and SW48) showed extensive methylation and six (Colo320, SW480, HT29, Caco2, SW837 and WiDr) were unmethylated; the other cell line, LoVo, showed partial methylation that affected exon 1beta but not the immediate upstream CpG sites. p14(ARF) mRNA was expressed at extremely low levels in fully methylated cell lines and at 10(4)- to 10(5)-fold higher levels in unmethylated cell lines. p14(ARF) expression in the partially methylated LoVo cell line was intermediate. Treatment of LoVo cells with 2 microM 5-aza-2'-deoxycytidine for 72 h was associated with marked (100-fold) induction of mRNA levels. Of 119 primary CRCs, 18% contained p14(ARF) methylation, although partial methylation was the most common pattern observed (in 67% of methylated tumors). Methylation of p14(ARF) was often accompanied by p16(INK4a) methylation; however, 50% of p14(ARF) methylated tumors contained unmethylated p16(INK4a). Methylation at p14(ARF) was associated with female gender, greater age, proximal anatomic location and poor differentiation, but not stage at diagnosis. A two-step MSPCR method for assaying p14(ARF) methylation in human tumors is described.

Relatively rare squamous cell carcinomas of the tongue in young patients may be associated with different etiologic factors and pathogenetic mechanisms than carcinomas from the same site in older patients. Alterations in cell cycle proteins likely contribute to the biologic behavior of these neoplasms. The purpose of this investigation was to evaluate cell cycle proteins (p53, p21, Rb, MDM2) in lateral tongue cancers from patients at the two ends of the age spectrum. All available archived lateral tongue carcinomas from patients35 years (n = 36, 23 males and 13 females) were sectioned, immunohistochemically stained, and evaluated. Protein expression was scored as percent positive nuclei. An equal number of sequentially accessioned lateral tongue specimens from patients75 years (23 males and 13 females) were stained and compared. Positive p53 staining was seen in 18/36 of the35-year group versus 24/36 of the75-year group (p = 0.149). Increased p21 staining (both percent of positive cells and intensity) was evident in 25/32 of the35-year group versus 24/32 of the75-year group (p = 1.0). Increased p21 expression was seen in both p53-positive and -negative cases in both age groups. Rb protein was increased in 16/29 of the35-year group versus 17/26 of the75-year group (p = 0.58). Fourteen cases (4/35 vs 10/36, p = 0.135) showed positive MDM2 staining; MDM2-positive cases were also p53 positive in 4/4 younger and 8/10 older patients. We conclude that p53, p21, Rb, and MDM2 are over-expressed in lateral tongue cancers, and that immunohistochemical profiles are heterogeneous. A p53-independent pathway of p21 induction is supported by the results; p53 suppression may be associated with MDM2 protein expression in a subset of cancers. Significant differences in the expression of p53, p21, Rb, and MDM2 proteins are not evident in lateral tongue carcinomas from patients35 years as compared to patients75 years.

Primary therapy for Hodgkin lymphoma (HL) is curative in ˜ 85% of patients [1]. Randomized phase III and single arm phase II trials have established high dose chemotherapy and autologous hematopoie...

Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges. Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of ∼10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2). Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 T alleles were 66, 57, and 59 years in group 1 and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of T alleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03). Conclusions: Although limited by a relatively small sample size, this pilot study, using well-characterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.

BACKGROUND Approximately 30% of fine-needle aspiration (FNA) biopsies of thyroid nodules are indeterminate, nondiagnostic, or suspicious. The purpose of the current study was to determine the accuracy of novel candidate diagnostic markers to distinguish benign from malignant thyroid neoplasms, and to predict the extent of disease. METHODS A real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assay of 6 novel candidate diagnostic and extent of disease marker genes (extracellular matrix protein 1 [ECM1]; transmembrane protease, serine 4 [TMPRSS4]; angiopoietin 2 [ANGPT2]; TIMP metallopeptidase inhibitor 1 [TIMP1]; ephrin-B2 [EFNB2], and epidermal growth factor receptor [EGFR]) was used in 126 thyroid tissues. To evaluate the performance of the scoring model for the diagnostic markers in combination, the area under the receiver operating characteristic (ROC) curve (AUC) was determined. RESULTS The levels of ECM1, TMPRSS4, ANGPT2, and TIMP1 mRNA expression were found to be independent diagnostic markers of malignant thyroid neoplasms. The AUC for the 4 diagnostic genes in combination was 0.993 with a sensitivity of 100%, a specificity of 94.6%, a positive predictive value of 96.5%, and a negative predictive value of 100%. In 31 thyroid nodule FNA biopsy samples, the scoring model had a sensitivity of 91.0%, a specificity of 95.0%, a positive predictive value of 92.9%, and a negative predictive value of 92.3%. The multigene assay correctly classified 93% of tumors into the correct risk group (low-risk vs. high-risk) with a sensitivity of 78.9% (true positive in high-risk tumors), specificity of 92% (true negative in low-risk tumors), positive predictive value of 87.5%, and negative predictive value of 92%. In 11 malignant thyroid nodule FNA samples, the extent of disease scoring model correctly identified 3 of 4 high-risk differentiated thyroid cancers and 7 of 7 low-risk differentiated thyroid cancers. CONCLUSIONS This novel multigene assay is an excellent diagnostic and extent of disease marker for differentiated thyroid cancer and would be a helpful adjunct to FNA biopsy of thyroid nodules. Cancer 2006. © 2006 American Cancer Society.

The causes of most adult gliomas are essentially unknown. Previous studies have indicated associations between immune system factors and the incidence of adult glioma, specifically that those individuals with certain allergic conditions may have decreased risk of glioma. We obtained detailed allergy histories for 405 adults newly diagnosed with glioma in the San Francisco Bay Area from 1997-1999 and 402 age-gender-ethnicity frequency-matched population-based controls. Seventy-nine percent of eligible cases or their proxies and 74% of eligible controls completed in-person interviews about allergies, age at onset, frequency, duration and severity. Overall, cases were less likely than controls to report any allergy (72% vs. 85%; odds ratio [OR] = 0.5 [0.3-0.7]); for self-reported cases (n = 269), OR = 0.7 (0.4-0.97) and for proxy-reported cases, OR = 0.3 (0.2-0.5). Pollen, dairy and nut allergies were significantly less common in cases than controls and most other allergens had odds ratios of less than one. There were no apparent trends with numbers of symptoms, route of exposure of allergen or reported severity of allergy, but there was a significant dose-response with increasing numbers of allergens (p < 0.0001 for linear trend among all cases vs. controls and p = 0.02 among self-reported cases only vs. controls). Although our work displays strong and consistent associations, future efforts must attempt to establish whether an immune system typified by proclivity to allergies, or an immunologic consequence of the allergies themselves, might be capable of preventing nascent brain tumors. The dominance of humoral immunity in the central nervous system is consistent with either of these models. Alternatively, common genetic or environmental causes for allergies and gliomagenesis may mediate or confound these observed inverse risks for allergies and gliomas, or other explanations may exist. Future work might reveal an important role for immunologic factors in gliomagenesis and potential preventative and/or therapeutic modalities.

Expression of cell cycle regulatory proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of the cell cycle may be altered in the development of oral squamous cell carcinoma. Archived paraffin-embedded specimens (n = 90) from 25 patients with recurrent or persistent lesions were evaluated in immunohistochemically stained sections for cell cycle regulatory proteins p53, Rb, Cyclin D1, p27, and p21. The cell cycle was also evaluated by expression of nuclear protein Ki 67. Sections were graded semiquantitatively using a 0-3 + scale to indicate the percentage of positively stained cells. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty-three of 90 specimens showed positive p53 expression, 11 of which were dysplasias. Eighty-nine of 90 specimens, from all stages of disease, showed positive Rb expression. Twenty-three of 90 specimens showed positive Cyclin D1 expression, typically in the later stages (carcinoma) of a patient's disease. Eighty-four of 90 specimens showed positive p21 expression; while 55 of 90 specimens were positive for p27. In control mucosa, p27 was highly expressed, while Rb and p21 proteins were expressed at relatively low levels; p53 and Cyclin D1 proteins were largely absent. Generally, staining of p53, Rb, p21, and Ki 67 increased with time in serial biopsies, while p27 showed decreased staining with disease progression. These data show that cell cycle regulatory proteins are altered in both premalignant and malignant disease, and that protein phenotypes are heterogeneous. P53 expression is seen early, and Cyclin D1 expression is seen late in the development of oral premalignant and malignant disease. Expression of p53, Rb, p21 and Ki67 increased, while p27 decreased, with disease progression.

Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paraffin-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a significantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease.

PURPOSE The goals of this study were to define the efficacy and toxicity of doxorubicin and dose-escalated cyclophosphamide (Cy) along with granulocyte colony-stimulating factor (G-CSF) in the treatment of hormone-refractory prostate cancer (HRPC), to determine the maximal-tolerated dose (MTD) of Cy in this regimen, and to evaluate the impact of prior pelvic irradiation (XRT) on MTD and toxicity. PATIENTS AND METHODS Thirty-five patients were treated every 21 days with fixed-dose doxorubicin (40 mg/m2) and Cy 800 to 2,000 mg/m2 (in a cohort dose-escalation schema) along with G-CSF. RESULTS Five of 15 patients (33%) with measurable disease obtained an objective response. Sixteen of 35 patients (46%) had a greater than 50% decrease in prostate-specific antigen (PSA) level (95% confidence interval [CI], 28.8% to 63.4%). Ten of 35 patients (28.6%) had a greater than 75% decrease in PSA level. The median survival time was 11 months. The median survival duration of patients with a greater than 50% decrease in PSA level was 23 months, versus a median survival time of 7 months in patients without a PSA response (P = .02). Although 33% of cycles were associated with grade 4 neutropenia, febrile neutropenia occurred in only 7.8% of all cycles. Thrombocytopenia and anemia were rare. Nonhematologic toxicity was minimal. Patients who had received prior pelvic XRT had a lower Cy MTD, but their hematologic toxicity was not appreciably different. CONCLUSION This is a well-tolerated, active regimen for the treatment of HRPC. Toxicity was not different in patients with prior pelvic XRT, although these patients had a lower MTD.

8060 Background: ENKL is a rare and aggressive subtype of peripheral T-cell lymphoma. Due to its geographic predilection there is a paucity of data on clinical experiences from non-Asian countries. The purpose of this study was to analyze characteristics and outcomes of patients (pts) with ENKL identified from major academic centers in NA. Methods: Pts with newly diagnosed CD56+ ENKL were retrospectively identified. Analyses included disease characteristics, ethnicity, therapy, and outcomes. Results: 115 pts (63.5% Caucasian, 20% Asian, 16.5% other) were identified across 10 centers diagnosed between 5/1990-5/2011 (Era 1: pre-2000, n=16; Era 2: 2000-2005, n=45; Era 3: post-2005, n=54). Median age was 52 years (19-88). 75 (65%) had stage I/II disease and were treated with combined modality therapy (CMT) n=48, chemotherapy (CT) n=14 or radiotherapy (RT) n=14. 40 pts had stage III/IV disease and were treated with CT (n=23), CMT (n=12) or RT (n=5). CT regimens used alone or in CMT were either anthracycline-based (n=68) or other (n=29). 63% of stage I/II pts and 40% with stage III/IV achieved complete remission (CR). 30 pts underwent a stem cell transplant (SCT); 14 in first CR and 16 at progression/relapse (autologous, n=21; allogeneic, n=9). Pts with stage I/II disease had a better progression-free survival (PFS) and overall survival (OS) compared with stage III/IV (12 vs 5.2 months (p=0.003) and 41.5 vs 8.9 months (p

5556 Background: NPC is traditionally treated with chemoradiation followed by chemotherapy. Ongoing trials are exploring neoadjuvant chemotherapy in NPC. Hypoxic head and neck cancers are known to be less sensitive to radiation. It is unknown if reversal of hypoxia prior to radiation results in better tumor control with radiation or if hypoxia is merely a marker of inherent radiation resistance. Data in other cancer settings suggest that both chemotherapy and bevacizumab might reduce tumor hypoxia. F-18 misonidazole (FMISO) is a hypoxia detection agent based upon misonidazole’s covalent binding to cellular macromolecules when reduced. Tumor/blood pool ratios of FMISO can be used to assess for relative tumoral hypoxia. Methods: Patients with locoregionally advanced or oligometastatic NPC were enrolled on an IRB approved clinical trial of a single dose of bevacizumab, followed by 3 cycles of therapy with concurrent cisplatin, docetaxel, 5-fluorouracil and bevacizumab (TPFB), followed by chemoradiation with ...

This report examines lung cancer mortality among a cohort of white underground uranium miners in the Colorado plateau and is based on mortality follow-up through December 31, 1977. The analytic methods represent a miner's annual age-specific lung cancer mortality rate as the (unspecified) rate among nonsmoking men born at the same time and with no mining history, multiplied by the relative risk factor R. This factor depends on the miner's total exposures to radon daughters [in working level months (WLM) and to cigarettes (in packs), accumulated from start of exposure until 10 years before his current age. Among those examined, the relative risk function giving the highest likelihood of the data was R = (1 + 0.31 X 10(-2) WLM)(1 + 0.51 X 10(-3) packs). This multiplicative function specifies that ratios of mortality rates for miners versus nonminers with similar age and smoking characteristics do not depend on smoking status. By contrast, differences between miners' and nonminers' mortality rates are substantially higher for smokers than for nonsmokers. The data rejected (P = .01) several additive functions for R that specify relative risk as a sum of components due to radiation and to cigarette smoking. Cumulative exposures to both radiation and cigarettes gave better fits to the data than did average annual exposure rates. Age at start of underground mining had no effect on risk, after controlling for age at lung cancer death, year of birth, and cumulative radiation and smoking exposures.