bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes on endorectal MRI during neoadjuvant hormonal therapy for prostate cancer and biochemical outcome in men managed using radiation therapy: A prospective phase II Cancer and Leukemia Group B study
Authors: D’Amico A. V. , Halabi S. , Tempany C. , Vollmer R. , Loffredo M. , Sanford B. , Small E. J.
Published: March 2020

5072

Background: We prospectively determined whether changes in tumor volume (TV) on 1.5 Tesla endorectal magnetic resonance imaging (eMRI) during neoadjuvant androgen suppression therapy (AST) were associated with biochemical outcome after radiation and 6 months of AST. Methods: Between May, 1996 and April, 2001,180 men with T1c-T3c non-metastatic adenocarcinoma of the prostate cancer were registered. Fifteen were found to be ineligible leaving 165 men who had a eMRI TV measurement at baseline and following 2 months of neoadjuvant AST. An eMRI response was defined as > 10% reduction in the volume of all lesions consistent with prostate cancer. In 32 men, the institutional MR radiologist could not completely assess the TV leaving 133 for analysis. A proportional hazards model was used to assess whether a significant association existed between eMRI response and time to prostate-specific antigen (PSA) failure following registration adjusting for PSA level (continuous), Gleason score (8 to 10 or 7 versus 6 or less) and stage (T3 versus T1, 2). PSA failure was defined as 2 consecutive rises of 0.2 above 1.0 ng/ml (PSA fail) and according to the 1997 and the 2006 American Society of Therapeutic Radiology and Oncology (ASTRO) consensus definitions. Results: The median age and PSA level of the study cohort were 70 years and 10.7 ng/ml respectively. An eMRI response was noted in 112 (84%) men and 85, 47, and 47 men experienced PSA failure based on the 1997, 2006 ASTRO consensus and PSA fail definitions respectively. After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a statistically significant association between eMRI defined tumor response and time to PSA failure using the 1997 (p = 0.04) and 2006 (p = 0.009) ASTRO consensus definitions and a near significant association (p = 0.08) using PSA fail. Conclusion: Men lacking a > 10% reduction in the eMRI defined TV during neoadjuvant AST are at increased risk for recurrence following radiation and AST. Therefore, eMRI enables the early documentation of androgen insensitive disease and identifies men for trials evaluating outcome when non-AST based approaches are combined with radiation and AST.

No significant financial relationships to disclose.
Intra vesical gemcitabine (G) single agent as adjuvant chemotherapy in superficial transitional cell carcinoma (TCC) of the bladder: Final results
Authors: Bounedjar A. , Ferhat R. , Smaili F. , Bouzid K.
Published: March 2020

5078

Background: Systemic intravenous G is usually used in advanced bladder carcinoma. A phase I study of intravesical G has shown safety profile in pts refractory to BCG therapy (Dalbani G et al JCO 2002; 20:3193–98). In this study we evaluate the toxicity and the efficacy of intravesical G in patients (pts) with superficial bladder carcinoma. Methods: The study population criteria were: age = 18 years old, histological diagnosis of transitional cell carcinoma (TCC) of bladder (Cis and pT1) confirmed by transurethral resection (TUR), no prior chemotherapy, a performance status (PS) < 2, good bone marrow reserve, adequate renal and liver function and informed consent. Three weeks after a total TUR, pts receive intravesical instillation of 2,000 mg G every wk for 6 wks, than every month for six months. Evaluation is performed 3–4 wks after the last instillation (CT scan and/or US pelvis, urinary cytology and cystoscopy with biopsy). Results: From February 2003 to June 2004, 60 pts (57M/3F) were enrolled in the study (M/F = 57/3). The median age was 59,5 years old (24–84). Nine pts had a carcinoma in situ (Cis) and 51 had pT1 lesions. They received a total of 720 instillations. All pts were evaluable for toxicity and response Toxicity (CTC/NCI scale) is evaluated over the 720 instillations. Non haematological toxicity was grade 1: irritate bladder reaction (4.7%), asthenia (2.9%), nausea and vomiting (1.8%) and hot flashes (2%). Grade 1 haematological toxicity: anaemia (6.8%), leucopenia (4.5%) and thrombocytopenia (0.4%). After a follow-up time of 30 to 48 months, all pts were evaluable for tumor response: 53 patient had a persistant complete remission after TUR. Five patients (8.3%) had a superficial relapse of TCC (one at six months, 2 at 9 months and 2 others at 12 months). Two patients had progressive disease at 18 months and 27 months. Conclusion: Intravesical G is an active and well tolerated treatment even after repeated instillation in pts with superficial TCC carcinoma of the bladder.

No significant financial relationships to disclose.
Chemotherapy for poor prognosis non seminomatous germ cell tumors (NSGCT): Should doses be reduced at first cycle to prevent acute respiratory distress syndrome (ARDS) in patients with multiple lung metastases?
Authors: Fizazi K. , Massard C. , Postel-Vinay S. , Escudier B. , Culine S. , Raynard B. , Blot F. , Antoun S. , Nitenberg G. , Plantade A.
Published: March 2020

5087

Background: Patients with multiple lung metastases from NSGCT and dyspnea at presentation are at high risk of ARDS and death in the first days after chemotherapy induction. This entity has been designated the “choriocarcinoma syndrome” or “very high risk NSGCT”. It is linked to acute intra-alveolar hemorrhage related to early tumor necrosis, which in turn, may be complicated by pulmonary infection promoted by neutropenia. To try to avoid this complication, The policy to manage these patients was changed at Institut Gustave Roussy in 1997. Methods: Data from all patients with lung metastases from NSGCT and dyspnea or a pO2 < 80 and treated between1980–2006 in our institution were collected. Patients were treated in a specialized intensive care unit. From 1980–1997, the first cycle of chemotherapy consisted in a full dose regimen. After 1997, it consisted in a 3-day reduced induction regimen of EP (cisplatin 20 mg/m2/day and etoposide 100 mg/m2/day), with bleomycin and two additional days of EP being postponed to day 15, and the regular BEP regimen being started at day 21. Results: 25 patients with a poor risk NSGCT according to the IGCCCG classification had extensive lung metastases plus either dyspnea at presentation (n=6) or a pO2<80 (n=2), or both criteria (n=17). Median age was 30 years (range 18–49). Median hCG was 200,000 UI (range 11–8,920,000) and 18/25 (72%) patients also had non-pulmonary visceral metastases. During the 1980–1997 period, 13/15 patients (87%) developed ARDS, of whom 10 died, and only 4/15 (27%) patients were long-term survivors. In contrast, during the 1997-2006 period, only 3/10 patients (30%) developed ARDS, of whom 2 died, and 4/10 (40%) survived. Conclusions: Reducing doses of chemotherapy during the first cycle of chemotherapy for poor-prognosis NSGCT with extensive and symptomatic lung metastases seems to prevent the risk of early death due to ARDS and should therefore be recommended.

No significant financial relationships to disclose.
A phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab in patients with metastatic renal cell carcinoma (mRCC)
Authors: Garcia J. A. , Rini B. I. , Mekhail T. , Triozzi P. , Elson P. , Nemec C. , Bukowski R. M.
Published: March 2020

5103

Background: Interleukin-2 and bevacizumab, a VEGF ligand-binding antibody, have each demonstrated antitumor activity in mRCC. Increased VEGF levels can lead to immunosuppression and resistance to immunotherapy through inhibition of dendritic cell (DC) differentiation and increase in immunosuppressive regulatory T cells (Tregs). To further evaluate the clinical and immunomodulatory effect of low-dose IL-2 and bevacizumab in mRCC, a phase II trial was conducted. Methods: Previously untreated good and intermediate risk mRCC pts received 8-week cycles of IL-2 (250,000 U/kg/d SC D1–5 during week 1 and 125,000 U/kg/d SC D1–5 during weeks 2–6, followed by a 2 week break). Bevacizumab 10mg/kg was administered IV every 2 weeks starting on day -14. Eligibility included RECIST-defined measurable disease, clear cell histology, normal organ function, and prior nephrectomy. A Simon 2 stage phase II design was employed to test the hypothesis of a 40% improvement in the 3-month PFS vs. historical IL-2-treated controls. Overall response rate (ORR) and toxicity were recorded. Exploratory endpoints included activation of circulating DC’s, Tregs and VEGF levels. Results: To date 16 of a planned 35 pts are enrolled. Median age is 59 years (range, 44–67); Eight patients have >1 site of metastasis; median treatment duration is 8 weeks (8–32+). Among 11 pts evaluable for response, 1 PR and 3 SD lasting >3 months have been observed. All pts with SD have demonstrated some degree of tumor shrinkage. Seven pts have discontinued therapy (5 PD, 2 withdrew consent). Most common treatment-related toxicity included fatigue, nausea, diarrhea, and fever. When comparing immune correlates at day 56 of therapy vs. baseline, all pts had an increase in the number of Tregs (median increase 1.65, range; 0.76–10.4; p= 0.008). Similarly, all pts had a decline in VEGF levels (median decline 164.38 pg/ml, range; 2.20–393.04 pg/ml; p= 0.008). No differences in DC activation have been observed. Conclusions: The combination of LD IL-2 and bevacizumab produces antitumor activity and moderate toxicity. Preliminary correlative data demonstrates inhibition of VEGF and increase in Tregs without effect on DC activation.

No significant financial relationships to disclose.
Sequential therapy with sorafenib and sunitinib in renal cell carcinoma
Authors: Dham A. , Dudek A. Z.
Published: March 2020

5106

Background: Sunitinib and sorafenib are two small-molecule tyrosine kinase inhibitors (TKI) that have been shown to have antitumor activity in advanced renal cell carcinoma (RCC). However, the optimal sequence of first- and second-line therapies with sunitinib and sorafenib is still unclear. The purpose of this study was to assess whether an objective disease response could be identified in patients after receiving sequential treatment with these two agents. Methods: Patients who had progressed or experienced unacceptable toxicity after first-line therapy with either sunitinib or sorafenib and then subsequently received second-line therapy with the other TKI agent were evaluated for their response to sequential treatment using RECIST criteria. Results: Thirty-seven patients were identified (29 male and 8 female) with a median age of 62 years (range 32–75). Twenty-three patients received sorafenib followed by sunitinib (Group A), and 14 patients received sunitinib followed by sorafenib (Group B). According to Memorial Sloan-Kettering prognostic model, 35% of patients in Group A had favorable risk, 52% had intermediate and 13% had poor risk, whereas 50% of patients in Group B had favorable risk, 43% had intermediate and 7% had poor risk. Three patients (13%) in Group A and two (14%) in Group B switched TKI due to toxicity, while all remaining patients switched due to disease progression. For patients in Group A, median duration of stable disease after starting sunitinib was 32 weeks (range 6–37 weeks)(median follow up 266 days); 9% were not evaluable for response to treatment; 34% had disease progression; and four patients (17%) had an objective partial response of 31%, 36%, 27% and 50%, respectively. For patients in Group B, median duration of stable disease after starting sorafenib was 8 weeks (range 4–10 weeks) (median follow up 179 days); 7% were not evaluable for response to treatment; 50% had disease progression; and one patient (7%) had no evidence of disease after tumor resection. The median duration of disease control in Groups A and B was 42 weeks (range: 10–113 wks) and 30.5 weeks (range: 4–56 wks), respectively. Conclusions: While disease control was observed in both sequences, the duration of response was longer in patients receiving sorafenib followed by sunitinib.

[Table: see text]
Clinical and molecular factors predictive of outcome with first-line sorafenib-based therapy in advanced renal carcinoma (RCC): An analysis of SWOG 0412
Authors: Goldman B. H. , Lara Jr. P. N. , Beer T. M. , Mack P. C. , Drabkin H. A. , Holland W. S. , Crawford E. , Ryan C. W.
Published: March 2020

5108

Background: SWOG 0412 was a phase II study of sorafenib and interferon-a2b (IFN) as first-line therapy for RCC. Response rate was 19%, median PFS was 7 months, and estimated median OS was 17 months (Ryan ASCO 2006). We investigated several potential risk factors among participants in SWOG 0412. Methods: Hemoglobin (hgb), LDH, number of metastatic sites, grade, gender, time from diagnosis to treatment, and MSKCC risk category were analyzed in 62 patients. Von Hipel-Lindau (VHL) gene status was determined by direct sequencing of DNA amplified by PCR methods from archival tumor. Immunohistochemistry for p-MAPK, p-p38, and p- AKT was performed to assess for enhanced signaling through the RAS-RAF and related pathways. Survival differences between subgroups were assessed by the logrank test. Results: Clinical factors associated with improved PFS and OS: favorable MSKCC risk category, time from diagnosis to treatment = 1 year, normal hgb. Fewer metastatic sites was also associated with improved OS but not PFS. No association was found with gender, grade, or LDH. VHL mutations were detected in 4 of 18 (22%) archival tumor specimens. P-p38 was overexpressed in all tumor specimens and p-MAPK was absent in all but one specimen. p-AKT was overexpressed (>20% staining) in 18 (82%) of patients. In this limited subset analysis, none of these tumor markers was found to be significantly predictive of survival. Conclusions: Time from diagnosis, hgb, and MSKCC risk grouping were predictive of PFS and OS in patients receiving sorafenib + IFN. The median PFS of 18 months for favorable MSKCC risk patients is higher than the 8 months expected for first-line patients treated with IFN-based therapy, while the median PFS of 4 months for intermediate and poor risk patients is similar to the expected 5 months (Motzer JCO 2002). This observation is consistent with a hypothesis that the benefit of first-line sorafenib-based therapy may be most profound in or limited to favorable MSKCC risk patients.

[Table: see text]

[Table: see text]
A phase II trial of thalidomide, bevacizumab, and docetaxel in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)
Authors: Ning Y. M. , Arlen P. , Gulley J. , Latham L. , Jones E. , Chen C. , Parnes H. , Wright J. , Figg W. D. , Dahut W. L.
Published: March 2020

5114

Background: Angiogenesis plays a vital role in the progression of prostate cancer. Antiangiogenic agents thalidomide (T) and bevacizumab (Bv) may enhance docetaxel (Doc) activity in metastatic AIPC. However, T and Bv have different antiangiogenic mechanisms. Since tumor angiogenesis is a complex interplay of multiple angiogenic factors, we reasoned that combination of mechanistically different antiangiogenic agents T and Bv with Doc might be associated with an adequately high and durable PSA response to merit further study. Methods: Pts are required to have progressive metastatic AIPC and no prior chemotherapy for AIPC. Treatment consists of Doc 75 mg/m2 plus Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus T 200 mg qhs and prednisone 10 mg qd. Enoxaparin is used for thrombosis prevention and pegfilgrastim initiated after detection of grade ≥3 neutropenia. PSA is assayed q C and staging studies are done at C 0, C 2, & then q 3 Cs. Results: 39 pts were enrolled, median age 66 [54–79], Gleason score 8 [74% Gs 10∼8, 26% Gs 7∼6], on-study PSA 92 ng/ml [5.9–4399] and pre-study PSA doubling time 1.6 months [0.3–18.2, 87 % <3 months]. Median treatment Cs is 14 [1- 28]. 34 pts (87%) had PSA declines of ≥50%, with median ≥50% PSA-duration 12 Cs [0∼28]. 3 pts have PSA declines around 40% and 2 stable. 26 pts (67%) had >80% PSA declines. 17 pts with measurable disease were evaluable: 1 CR, 9 PR, & 7 SD, with 59% ORR. Significant toxicities: febrile neutropenia (5/39), syncope (4/39), colon perforation or fistula (2/39), grade 3 bleeding (2/39), thrombosis (2/39). Conclusions: This trial is the first study to combine antiangiogenic agents of different mechanisms with Doc in metastatic AIPC. Most of the accrued patients have unfavorable characteristics as evidenced by a high Gleason score and a short PSA doubling time. However, the combination of T and Bv with Doc appears to result in both a high durable PSA decline rate (87%) and a high response in measurable disease (59%) with acceptable toxicities.

No significant financial relationships to disclose.
Pharmacogenetics of organic anion transporting peptides (OATP): An association of a SLCO1B3 polymorphism with the overall survival in white Caucasian patients with androgen independent prostate cancer
Authors: Hamada A. , Price D. K. , Sissung T. , Venzon D. , Duhut W. L. , Figg W. D.
Published: March 2020

5118

Background: Steroid hormone have been implicated in playing a fundamental role in pathogenesis of prostate cancer and several studies have reported an association between clinical outcome and polymorphism of genes involved in steroid metabolism. Recently we observed that polymorphic enzyme CYP17 which influences the rate-limiting steps in androgen biosynthesis was associated with overall survival. However, the effect of genetic variation on the transport of steroid hormones remains unknown. The purpose of this study was to evaluate the association between clinical outcomes in patients with androgen independent prostate cancer, and polymorphism in the SLCO1B3 gene that are potentially important in the differential uptake of steroid hormones. Methods: One hundred seventy nine white Caucasian patients with androgen independent prostate cancer were enrolled in this study. The duration of survival was computed from the date of prostate cancer diagnosis until the date of death or last follow-up. The SLCO1B3 polymorphism (-334 T>G) was analyzed using an automated sequencer. Results: The T allele (TT or TG) and G allele (GG) frequency of SLCO1B3 among all patients was 0.16 and 0.84, respectively. The frequency of the SLCO1B3 genotype was similar in patients and healthy volunteer. No significant differences were observed in the frequencies of the SLCO1B3 genotype in relation to categorized Gleason scores and age at diagnosis. Interestingly, the median survival was significantly longer in 134 patients with the SLCO1B3 G allele (8.4 years) genotype than 45 patients carrying at least one T allele (6.4 years) genotype (hazard ratio=1.58, 95%CI: 1.13 - 2.26, p=0.0105 by Logrank test). Similarly, the survival probability at ten years (22.9% in T allele vs 41.1% in G allele) is observed. Conclusions: Our results indicate that the SLCO1B3 polymorphism is associated with overall survival in white Caucasian patients with androgen independent prostate cancer. Large population-based studies are needed to confirm these results.

No significant financial relationships to disclose.
Phase II trial of oral capecitabine (C) and weekly docetaxel (D) in patients with metastatic androgen independent prostate cancer (AIPC)
Authors: Marur S. , Eliason J. , Heilbrun L. , Smith D. , Dickow B. , Santucci R. , Cher M. , Forman J. , Vaishampayan U.
Published: March 2020

5121

Background: Due to demonstrated synergistic anti-tumor effect of D and C related to docetaxel-mediated up-regulation of thymidine phosphorylase (TP), a phase II trial with weekly D and C in metastatic AIPC was performed. Endpoints of response and survival were correlated with biomarker levels of TP, dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) in tumor tissue and DPD in serum Methods: Patients with metastatic AIPC, with no prior chemotherapy for metastatic disease were eligible to receive D 36 mg/m2/week IV on days 1,8, and 15 and C 1,250 mg/m2 /day in two divided doses on days 5–18. Cycles were repeated every 28 days and response was assessed every 2 cycles. Biomarker correlative study for Serum DPD and TP/DPD ratio and TS/DPD ratio on tissue were performed using mouse anti-TP, rat anti-DPD and mouse anti-TS monoclonal antibodies Results: 30 patients enrolled with median age of 69 years, median pretherapy PSA of 110 ng/ml (range 1.2 to 3716.9). 21(70%) had bone pain, Gleason score ≥ 8 in 18 (61%) patients; measurable disease progression in 9, bone scan progression in 18 patients and PSA only progression noted in 22 patients. 144 cycles have been administered (range 0–10 cycles). Grade 3 or 4 neutropenia seen in 3 patients and Grade 3 hand-foot syndrome in 2 patients. No treatment related deaths seen. PSA response (≥50% decline) noted in 22 (73.3%) with ≥90% PSA decline in 9 (30%) pts. Measurable disease PR noted in 5 of 9 patients (56 %). Median follow-up is 11 months (range 2.1 to 30.4). Median time to progression is 9.1 months (90% CI 6.2–15.1 months), and the median overall survival (OS) is 18.9 months (90% CI 14.9–26.4 months). 1 year PFS and OS is 44% and 84% respectively. Samples for DPD were available for 25 patients and pre-therapy tumor tissue for 23 patients. Quantitative fluorescence IHC has been performed on available samples, the final analysis is ongoing. Conclusions: The combination is well tolerated and demonstrates favorable and durable remission and survival outcomes. Correlation with biomarker analysis will be reported. This may help in selecting patients more likely to derive benefit from combination of D and C. Supported in part by Aventis Inc.

No significant financial relationships to disclose.
RHAMM (CD168) is overexpressed on the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease
Authors: Ringhoffer M. , Hofer M. , Perner S. , Varambally S. , Chinnayian A. M. , Rubin M. A. , Greiner J. , Schmitt M. , Kuefer R.
Published: March 2020

5129

Introduction: Treatment options for early stage prostate cancer are well defined, and localized prostate cancer can be cured by several strategies. However therapeutic outcome in advanced tumor stages is still disappointing. One approach is to deliver targeted therapy based on identified human tumor antigens, specifically expressed in neoplastic tissue and recognised by CD4/CD8 T-cells or antibodies. Materials and Methods: We employed serological identification of antigens by recombinant expression cloning (SEREX) and data mining in SEREX related databases to identify potential immunological target structures. Consequently, candidate antigens were screened by DNA microarrays consisting of approximately 20K genes, designed to profile benign and malignant prostate tissues. Genes overexpressed on the cDNA level were evaluated on the protein level by tissue microarrays representing various disease stages including about 900 tissue cores. Protein expression was measured by the Chromavision system. Results: Ten of the targets identified by SEREX and data mining showed a significant overexpression on the 20k cDNA array in localized prostate cancer compared to benign prostatic hyperplasia and in metastases compared to localized prostate cancer. One gene which has been identified earlier as an immunogenic antigen in leukemia by our group, CD168, showed a highly significant overexpression in prostate cancer metastases compared to localized disease (p=0.007). On the protein level CD168 was highest in metastatic tissue samples and significantly higher in neoplastic localized disease compared to benign tissue (p=0.03). High CD168 expression had an association to clinical parameters known to be associated with better clinical outcome. Patients with high CD168 expression in the primaries had a significantly lower risk for biochemical failure (log rank p=0.023; RR:0.621). In cell culture experiments, the number of viable cells was reduced in blocking experiments using hormone sensitive (LNCaP) and hormone insensitive metastatic (PC3 and DU 145) prostate cancer cell lines. Conclusion: Acknowledging the proven immunogenic effects of CD168 in leukemia, this antigen is an intriguing therapeutic target in advanced prostate cancer disease.

No significant financial relationships to disclose.
The relationship between biochemical failure and TP53 genetic polymorphism in patients with prostate cancer
Authors: Silva E. , Calais da Silva F. M. , Sousa A. , Coelho A. , Medeiros R.
Published: March 2020

5133

Background: TP53 is a tumour suppressor gene, located at chromosome 17p13, referred as altered in 50–55% of cancer cases. The p53 protein, encoded by the TP53 gene, is known as the cellular gatekeeper for growth and division, as it plays an essential role in safeguarding the integrity of the genome. This protein is involved in processes as cell cycle arrest, gene transcription, DNA repair and apoptosis and may influence cancer progression. Few studies have been published regarding TP53 codon 72 genetic polymorphism and prostate cancer behaviour. Methods: We analysed the frequency of TP53 codon 72 genetic polymorphism in DNA isolated from blood samples of 265 individuals with prostate cancer using the Real-time PCR methodology. Biochemical failure was defined as two successive post- treatment rises in serum PSA, greater than 50 %. Results: From the 265 prostate cancer cases, we observed that 54.7% were found to be homozygous for the Arg allele (AA), 38.1% were heterozygous (AP) and 7.2% homozygous for the Pro allele (PP). We find that individuals carriers of PP genotype have three fold increased risk of biochemical relapse (OR=3.43, 95% CI 1.31–9.01; p= 0.008). Furthermore, we observed that this genotype was not associated to the gleason score (OR=1.66, 95%CI 0.53–5.13; p=0.372) or the presence of advanced disease (OR=1.69, 95%CI 0.62–4.6; p=0.296). Conclusions: We demonstrate that TP53 codon 72 genetic polymorphism may influence the clinical progression of patients with prostate cancer. Furthermore, our results are consistent with literature regarding other neoplasia suggesting that the Pro allele was associated to a poorer prognosis and survival.

No significant financial relationships to disclose.
Subclinical hemostatic activation and surgical volume predict peri-operative bleeding with radical prostatectomy
Authors: Tagawa S. T. , Dorff T. B. , Rochanda L. , Ye W. , Hannoun D. , Eiseler N. , Lieskovsky G. , Skinner D. G. , Liebman H. A. , Quinn D. I.
Published: March 2020

5136

Background: Subclinical activation of hemostasis and fibrinolysis is common in cancer and has been linked with outcome. We have previously presented (2007 Prostate Cancer Symposium) preliminary data on the relationship of laboratory markers to age and prognostic variables. We now expand our report on peri-operative (op) complication implications in early prostate cancer. Methods: With IRB approval and informed consent, blood was collected prior to open radical retropubic prostatectomy with lymph node dissection. Pre-op therapy, thrombosis, and anticoagulation were exclusion criteria. Plasma was assayed in duplicate for D-dimer, thrombin-antithrombin complex (TAT), IL-6, and IL-8. Relationships to peri-op bleeding/thrombotic events (pre-op to POD#2 hemoglobin (Hgb) drop, estimated blood loss (EBL), transfusion, post-op thrombosis) were analyzed in univariate then multivariable linear regression. Results: 153 subjects have been analyzed. Median age was 63.1 (range 35–81), pre-op PSA was 5.92 ng/mL (0.23–26.2), and 118 (77%) were clinical stage T1c. 117 (76.5%) had disease confined to the prostate; 36 had pT3 and/or lymph node involvement. Pathologic Gleason scores were 6 or less in 68 (44.4%), 7 in 71 (46.4%), and 8 or higher in 14 (9%). Median EBL was 400 mL (range 50-3000), median Hgb drop was 3.5 g/dL (-0.1–6.6), and 8 (5.2 %) required RBC transfusion. One subject experienced a DVT. On univariate analysis, pre-op TAT (p<0.001) and D-Dimer (p=0.023) levels correlated with hemoglobin drop. Platelet count, INR, and aPTT did not predict EBL nor Hgb drop. The 8 who required transfusions had lower pre-op platelet counts than those not requiring transfusion (p=0.004). Higher surgeon volume correlated with lower EBL (p<0.001) and Hgb drop (p=0.002). Multivariable linear regression showed that TAT remained significantly associated with Hgb drop (p=0.008) and surgeon volume with EBL (p<0.001) and Hgb drop (p=0.002). Conclusions: Pre-op activation of the hemostatic system is associated with less surgically related bleeding when assessed by objective measures, predicting drop in Hgb better than PT, aPTT, or platelet counts. Surgeon volume may also predict bleeding by subjective and objective measures.

No significant financial relationships to disclose.
Using patient-reported outcomes for technology assessment (TA) and quality improvement (QI) in prostate cancer brachytherapy
Authors: Chen R. C. , Zietman A. L. , D’Amico A. V. , Kaplan I. , Clark J. A. , Manola J. , Talcott J. A.
Published: March 2020

5139

Background: Despite their sensitivity, validity and increasing prominence in clinical reports, patient-reported outcomes have played little role in TA and QI. We used our validated disease-specific instrument to compare outcomes after alternative brachytherapy techniques for early prostate cancer, both experimental vs. standard technique and between implementations of the standard technique. Methods: One radiation oncologist performed experimental MRI-guided brachytherapy (MRB) on protocol and 2 performed standard ultrasound-guided brachytherapy (USB1 and USB2). We prospectively measured urinary and bowel function of 237 men before brachytherapy and at 1, 3 and 12 months after treatment. Each symptom index is scored from 0 (no dysfunction) to 100 (maximum dysfunction). We report outcomes both as mean change in scale score from baseline and as the distribution of functional categories, grouped by pretreatment functional level: normal, intermediate, and poor (severe dysfunction). Results: Among all patients, MRB caused less urinary obstruction/irritation at 3 months after treatment than ultrasound-guided brachytherapy (mean score change 9.2 vs. 23.6, p<.001). Significant differences in outcome also existed between USB1 and USB2 (19.5 vs. 29.0, p=.01). When baseline function was normal, 15% of MRB patients reported severe 3-month dysfunction, compared to 50% of USB1 and 71% of USB2 patients ( Table ). Outcomes of patients with pretreatment urinary dysfunction differed less. Preliminary results documenting inferior outcomes prompted modification of the USB2 brachytherapy technique, producing a trend toward improved outcomes in small patient numbers (mean score change: 30.4 vs. 22.8, p=.25). Bowel symptom outcomes varied less. Conclusions: Patient-reported outcomes can provide sensitive and valid indicators of TA and QI that may contribute to optimal patient-centered care.

[Table: see text]

No significant financial relationships to disclose.
Correlation of prostate-specific antigen (PSA) levels and survival in men with bone metastatic hormone-refractory prostate cancer (HRPC) and normal alkaline phosphatase (ALK)
Authors: Xie W. , Regan M. M. , Nakabayashi M. , Oh W. K.
Published: March 2020

5140

Background: PSA and ALK are recognized factors for predicting survival in men with metastatic HRPC. However, few studies have evaluated the combined effects of PSA and ALK on survival of patients with metastatic HRPC. Methods: 224 patients treated with chemotherapy for bone metastatic HRPC between 1999 and 2006 were identified from an institutional database. 143 patients had ALK as well as PSA values at start of chemotherapy. There were no statistically significant differences in baseline characteristics (including age, Gleason score, PSA, clinical stage at diagnosis or at the initiation of chemotherapy) between groups with and without available ALK (p>0.05). The primary endpoint was overall survival (OS) after chemotherapy. ALK was dichotomized to normal and abnormal groups based on institutional normal range (38–126 U/L). The effect of PSA was evaluated both as categorical (low, median and high group using the 33%, 66% cut-off values) and continuous values with log transformation in Cox regression. Results: Of 143 eligible patients, median ALK was 159 U/L (range: 52–2,020 U/L); 89 (62%) had elevated ALK. Median PSA at start of chemotherapy was 147 ng/mL; 93 ng/mL in patients with normal ALK and 171 ng/mL in those with elevated ALK. With median follow-up of 30 months after chemotherapy, 93 patients have died. Median OS after chemotherapy was 15.8 (range 0–57) months and was significantly longer if ALK was in the normal range (21.3 vs. 14 months, p=0.005). For the group with normal ALK, median OS was 12.5, 24.5 and 36.9 months for patients with low, median and high PSA, respectively; while there was no effect of PSA on survival if ALK was beyond the normal range (16.5 vs. 11.9 vs. 12.1 months) (p=0.21 for the interaction). In multivariable analysis after adjusting for age, the interaction effect of PSA and ALK on OS was statistically significant (p=0.02). The relative risk due to one unit increase in the value of Ln(PSA) was 0.68 (95% CI: 0.51–0.92) if ALK in the normal range, compared to 1.07 (95% CI: 0.85–1.35) in the group with elevated ALK. Conclusions: ALK was a significant factor in predicting OS for men with bone metastatic HRPC. In patients with normal ALK, a higher PSA was associated with improved survival.

No significant financial relationships to disclose.
Randomized trial of toremifene to reduce high grade prostatic intraepithelial neoplasia (HGPIN) prior to radical prostatectomy (RP)
Authors: Day R. , Mohanty S. , Bisceglia M. , Acquafondata M. , Dhir R. , Becich M. , Trump D. , Nelson J.
Published: March 2020

5150

Background HGPIN may be a precursor lesion for prostate cancer (PCA). The selective estrogen-receptor modulator toremifene (TOR) has shown chemopreventive activity in preclinical models of PCA. The effect of TOR on HGPIN was studied in men with PCA prior to RP. Methods Men with biopsy-proven PCA, scheduled for RP were randomized (2:1) either to TOR 40 mg po qd for 3 to 6 weeks prior to RP or to no therapy. The primary endpoint was the proportion of HGPIN in the RP specimen. Planned sample sizes were 35 and 17 per arm respectively, providing 93% power if treatment increased the proportion of patients with no RP HGPIN from 15% to 35% and decreased the mean log nonzero HGPIN values from 1 to ¼ standard deviation. Expression of bcl2, ki67, and CD31 were determined on biopsy (BX), and RP tissues, separately for normal adjacent to tumor (NAT), HGPIN, and PCA tissues. Serum hormone levels and toxicity were also assessed. Results The treatment arm accrued 31 patients, the control arm 13 patients. RP HGPIN ranged from 0.5% to 12%. There was no difference in HGPIN means between treatment (3.8%) and control (3.3%) (P=0.77 one-sided Wilcoxon) HGPIN at baseline predicted HGPIN at RP (Spearman correlation=0.64, P=0.0005) but 66% of patients had no detected HGPIN at baseline. Bcl2, ki67, and CD31 were mutually positively correlated in all 3 tissues, in both BX and RP specimens. In both BX and RP specimens, bcl2 was highest by far in HGPIN, and lowest in PCA. Ki67 was lowest in NAT, elevated in HGPIN and highest in PCA. CD31 showed no differences. In treated patients but not in controls, dihydrotestosterone, testosterone, androstenedion, and estradiol increased significantly between baseline, day 14 and final. TOR was well tolerated. Conclusions These data do not support an effect of TOR on HGPIN over 3 to 6 weeks at 40 mg po qd.

No significant financial relationships to disclose.
Efficacy of CAB therapy in stage C prostate cancer: Exploratory analyses based on results of a double-blind, randomized, placebo-controlled phase III study of bicalutamide
Authors: Akaza H. , Arai Y. , Kanetake H. , Naito S. , Usami M.
Published: March 2020

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Background: Although the efficacy of CAB in advanced prostate cancer (PC) has been demonstrated by the PCTCG and others, more evidence is required in locally advanced (Stage C) PC. The results of a Japanese P III study of bicalutamide in Stage C/D PC suggested the efficacy of CAB was better than monotherapy. When time to progression (TTP) was evaluated in Stage C and D separately, CAB had significant benefits in both stages and results in stage D were consistent with PCTCG data. Thus, this exploratory analysis was conducted to evaluate more thoroughly the efficacy of CAB in Stage C. Methods: 205 untreated PC patients with Stage C/D were randomized to CAB (goserelin 3.6 mg/4 weeks or leuprorelin 3.75 mg/4 weeks + bicalutamide 80 mg/day) or LHRHa monotherapy (same LHRHa + placebo). Among these patients, 99 had Stage C (52/47 on CAB/monotherapy). The median of the following parameters were calculated, and log-rank tests performed: TTP in all Stage C patients; TTP in Stage C patients by age, PSA value at diagnosis, and histopathological class; time to PSA normalization when normal level was defined as =4, =1 and =0.2 ng/mL. Results: The median observation period in Stage C patients was 144 weeks. The median TTPs by each parameter in Stage C are shown below. The median times to PSA normalization on CAB and monotherapy were 7 and 16 weeks (p<0.01), 8 and 93 weeks (p<0.01) and 20 weeks and NR (p<0.01) with normal values defined as =4, =1 and =0.2 ng/mL, respectively. Conclusions: These results suggest that CAB with bicalutamide possesses superior efficacy to LHRHa monotherapy in Stage C regardless of age, PSA value at diagnosis, or degree of tumor differentiation. It is suggested that CAB in Stage C could decrease PSA to lower levels in a shorter period than with LHRHa monotherapy. The study is ongoing to assess long term survival outcome.

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No significant financial relationships to disclose.
Response to docetaxel (D)/carboplatin (C)-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Nakabayashi M. , Sartor O. , Jacobus S. , Regan M. M. , McKearn D. K. , Ross R. W. , Kantoff P. W. , Taplin M. , Oh W. K.
Published: March 2020

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Background: Effective treatment options for HRPC patients are limited. We evaluated efficacy of D/C-based chemotherapy as first- and second-line chemotherapy. Methods: We retrospectively identified all patients with HRPC treated with D/C-based chemotherapy at DFCI. Regimens either included estramustine (EDC) or not (DC). Patients treated with EDC received D 20–70 mg/m2 q1–4 weeks, E 140mg TID and C AUC 4–6 q 3–4 weeks. Patients treated with DC received D 50–70 mg/m2 and C AUC 4–5 q 3–4 weeks. PSA declines and measurable response were assessed per PSA Working Group and RECIST criteria, respectively. Time to event from chemotherapy initiation based on Kaplan-Meier method. Results: 58 patients were included: 27 patients received EDC, 35 received DC, and 4 received both regimens. Median age and PSA at initiation of chemotherapy was 58 years (range: 42–78) and 132.6 ng/ml (range: 0.3–5352.5), respectively. Table shows median duration of PSA response and TTP, by regimen. Most patients received EDC as first-line chemotherapy (89%). PSA declines ≥ 50% were observed in 24 patients (88.9%, 95% C.I. 71–98) and PSA declined in all 27 patients by a median of 81.3 % (range 33–100). Of 8 patients with measurable disease (MD), 2 had confirmed PR and 4 had SD. Median survival was 17.5 months (95% C.I. 12.0–24.5). 34 out of 35 patients received DC as ≥ 2nd line chemotherapy. PSA declines ≥ 50% were seen in 7 DC patients (20%, 95%C.I. 8–37) and PSA declined in 24 patients with a median of 37.7 % (range 2.0–100). Of 15 patients with MD at baseline, one had confirmed CR, one had PR, and 6 patients had SD. Median survival was 14.8 months (95% C.I. 9–19). The most common reversible grade 4 toxicity with either regimen was neutropenia (6.9%). Conclusions: D/C-based chemotherapy is well tolerated and active in HRPC. As first line chemotherapy, EDC demonstrated PSA declines ≥50% in 88.9% of patients. DC was active as ≥ 2nd-line chemotherapy with PSA declines ≥50% seen in 20%.

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No significant financial relationships to disclose.
Molecular signatures characterize early stage breast cancer arising in young women and have prognostic and therapeutic implications independent of ER status
Authors: Anders C. K. , Hsu S. D. , Acharya C. R. , Zhang Y. , Wang Y. , Foekens J. A. , Marcom P. K. , Marks J. R. , Nevins J. , Potti A. , Blackwell K. L.
Published: March 2020

522

Background: Breast cancer in young women [YW] has a poorer prognosis, is less likely hormone sensitive, and has yet to be defined as a unique biologic phenotype. The identification of molecular pathways unique to YW should enable refinement of treatment strategies. Methods: To optimize characterization of breast cancer arising in YW vs. older women [OW], we prospectively defined 2 age groups constituting pre- and post-menopausal women [YW = 45 yrs (median 40 yrs); OW = 65 yrs (median 71 yrs)]. Age groups were applied to 784 clinically-annotated microarray (Affymetrix) data. 411 patients (n = 200 = 45yrs; n = 211 = 65 yrs) were eligible. In addition to clinical parameters and differential gene expression analysis, genomic signatures of oncogenic pathway deregulation (Ras, E2F, β-catenin, PI3K, Myc, Src) and chemotherapeutic sensitivity were evaluated. Results: In the 2 age-defined tumor sets, there was no difference between ER or PR status by IHC (p = ns). Consistent with previous data sets, YW demonstrated higher IHC expression of ErbB2 (p = 0.037), higher grade tumors (p < 0.0001), larger tumor size (p = 0.0002) and greater lymph node positivity (p = 0.045). Quantitative ER expression (mRNA) was lower (p < 0.0001) among YW. In comparing deregulation of oncogenic pathways between age groups, a statistically higher probability of PI3K (p = 0.005) and Myc (p = 0.02) pathway deregulation was observed among YW. Importantly, hierarchical clustering revealed unique patterns of pathway deregulation. In YW, PI3K and β-catenin deregulation conferred a worse prognosis compared to those with Myc and Src deregulation (HR = 4.15; p = 0.008). In contrast, among OW, E2F deregulation with concurrent low probability of PI3K and Myc deregulation was associated with a poorer outcome (HR = 2.7; p = 0.006). Conclusion: Results of this large study demonstrate that breast cancer arising in YW represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinical variables such as ER. Further data, including unique patterns of chemotherapeutic sensitivity as they relate to clinical parameters and oncogenic pathway status, will also be presented.

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Cyclin D1 expression in breast cancer patients and tamoxifen therapy
Authors: Filipits M. , Rudas M. , Lehnert M. , Kubista E. , Dietze O. , Greil R. , Lax S. , Samonigg H. , Jakesz R. , Gnant M.
Published: March 2020

523

Background: Adjuvant tamoxifen therapy improves survival of hormone receptor-positive breast cancer patients, but there is a subset of patients who fails to respond or develops resistance to tamoxifen. Cyclin D1 plays a central role in cell cycle regulation, directly affects the estrogen receptor and may predict outcome of tamoxifen therapy. Methods: We determined expression of cyclin D1 in formalin-fixed, paraffin-embedded surgical breast cancer specimens by means of immunohistochemistry. The patients had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 (test set) or ABCSG Trial 6 (validation set). Comparison of cyclin D1 expression with clinical parameters and survival of the patients was performed with cyclin D1 as a continuous variable and as a dichotomized variable. The median value of the percentage of cyclin D1-positive tumor cells was a priori chosen as cut-off point to classify cyclin D1- positive and cyclin D1-negative tumors. The cutpoint was established in the test set and validated in the validation set. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathological factors. Results: Cyclin D1 was positive (>10% cyclin D1-positive tumor cells) in 140 of 253 (55%) tumors of the test set and in 569 of 948 (60%) tumors of the validation set. A benefit from adjuvant endocrine therapy was associated with absence of cyclin D1 in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors as compared to patients with cyclin D1-negative tumors (adjusted hazard ratio for death [test set], 2.47, 95% confidence interval [1.08–5.63] P=0.03; adjusted hazard ratio for death [validation set], 1.91, [1.45–2.51] P<0.001). Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors (adjusted hazard ratio for recurrence or death [test set], 2.73, [1.50–4.96] P=0.001; adjusted hazard ratio for recurrence or death [validation set], 1.60, [1.19–2.16] P=0.002). Conclusions: Women with early-stage, hormone receptor-positive breast cancer and cyclin D1-negative tumors benefit more from adjuvant tamoxifen therapy than women with cyclin D1-positive tumors.

No significant financial relationships to disclose.
BCIRG 001 molecular analysis: Identification of prognostic factors in patients (pts) receiving adjuvant therapy for node- positive (N+) breast cancer (BC)
Authors: Dumontet C. M. , Reed J. C. , Krajewska M. , Treilleux I. , Mackey J. R. , Martin M. , Vogel C. , Rupin M. , Brunel E. , Hugh J.
Published: March 2020

525

Background: BCIRG 001 (1,491 pts) demonstrated significant superiority of docetaxel/doxorubicin/cyclophosphamide (TAC) over fluorouracil/doxorubicin/cyclophosphamide (FAC) given as adjuvant therapy for N+ operable BC in terms of disease-free survival (DFS) and overall survival (OS) (Martin et al, N Eng J Med, 2005). This ancillary study was aimed to identify tumor-associated factors related to DFS and OS. Methods: Formalin-fixed primary tumors from pts in BCIRG 001 were analysed by immunohistochemistry. Protocol- specified assessment of histological grade (GR), tumor size (TS), estrogen (ER) and progesterone receptors (PR), lymph node status (LN), HER2, MUC1, Mib, p53, Bcl-2, Bax, Bcl-X, Bag-1, tubulin β isotypes II, III and IV, tau protein and detyrosinated a tubulin was performed. Parameters were scored as the percentage of positive cells and analysed as lower or greater than median values. The samples were randomly split into training (2/3) and validation (1/3) sets. Associations between selected parameters and DFS or OS were tested through univariate analyses using the Kaplan Meier method (log-rank test) on the training set. A backward stepwise Cox regression analysis was performed to identify the final model of prognostic factors on the training set. Multivariate analyses were applied to the validation set. Results: 1,350 samples were split into a training (n=906) and a validation (n=444) set. In univariate GR, TS, LN, ER and PR, Mib, tau protein and HER2 were correlated with DFS in both sets. In multivariate ER, PR, TS, LN, Mib (all p<0.01) and tau (p=0.043) were significantly associated with DFS in the training set. In univariate GR, TS, LN, ER and PR, Mib, MUC1, Bcl-2, tubulin III and IV and tau were correlated with OS in both sets, with a trend for p53. In multivariate ER, TS, LN, Mib, p53 (all p<0.01) and PR (p=0.028) were independently correlated with OS in the training set. Conclusions: These data suggest that tau and p53 are independent markers of DFS and OS, respectively, while Mib is correlated with both DFS and OS in pts receiving these forms of adjuvant chemotherapy for N+ BC. Complementary analyses will be presented.

No significant financial relationships to disclose.