bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of prognostic factors for patients with advanced pancreatic cancer by proteomics
Authors: Matsubara J. , Ono M. , Ueno H. , Okusaka T. , Furuse J. , Furuta K. , Sawada J. , Saijo N. , Hirohashi S. , Yamada T.
Published: August 2020

4615

Background: Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer (PC). Its efficacy, however, varies significantly depending on individuals. This study was aimed at discovering a new diagnostic biomarker that can estimate the outcome of patients after receiving the therapy. Methods: All patients included in this study (304 patients) had metastatic PC and received at least two cycles of gemcitabine monotherapy. We compared the baseline plasma proteome between representative 29 short-term survivors (survived for less than 100 days) and 31 long-term survivors (survived for more than 400 days) using quantitative mass spectrometry (MS). Results: Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities were significantly different (p<0.001, Welch's t-test). The 2 MS peaks with the highest statistical significance (p=2.57×10-4 and 5.03×10-4) were revealed to be derived from α1-antitrypsin (AT) and α1-antichymotrypsin (ACT), respectively, by tandem MS. The levels of AT and ACT, WBC count, platelet count, alkaline phosphatase, and ECOG performance status were selected using a forward stepwise procedure by Akaike's information criterion, and a scoring system (nomogram) was constructed to estimate the prognosis of individual patients. Among the selected parameters the AT level was found to be the second most significant contributor to the nomogram (p=0.0003; Table ). This survival prediction model was internally validated using a bootstrap approach with 200 resamples. Conclusions: Our survival prediction model including values of AT and ACT seems to have high practical utility and may lead to tailoring the treatment of patients with advanced PC. Modification of therapeutics may need to be taken into consideration for patients with increased AT and ACT.

[Table: see text]

[Table: see text]
A randomized phase II study of FOLFOX or FOLFIRI.3 as second-line therapy in patients with advanced pancreatic cancer previously treated with gemcitabine-based chemotherapy
Authors: Hwang J. Y. , Yoo C. , Kim T. , Lee J. , Park D. , Seo D. , Lee S. , Kim M. , Han D. , Kim S. , Lee J.
Published: August 2020

4618

Background: Only few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. We conducted a randomized phase II trial of modified FOLFOX vs. modified FOLFIRI.3 as second-line regimen for the patients with gemcitabine refractory pancreatic cancer ( NCT00786006 ). Methods: Patients with advanced pancreatic adenocarcinoma previously treated with gemcitabine were randomly assigned to FOLFOX or FOLFIRI.3 stratifying by age (≤ 65 vs. >65), performance status (0–1 vs. 2) and prior response to gemcitabine (PR/SD vs. PD). FOlFIRI.3 regimen consisted of Irinotecan 70 mg/m2 (over 60 min) D1, leucovorin 400 mg/m2 (over 2h) D1, 5-FU 2000 mg/m2 (over 46 hours) from D1, then irinotecan 70 mg/m2 (over 60 min) at the end of the 5-FU infusion every two week. FOLFOX regimen is composed of oxaliplatin 85 mg/m2 (over 120 min) D1, LV 400 mg/m2 D1, 5-FU 2,000 mg/m2 (over 46 hours) every two week. The primary end-point was 6-month overall survival (P0=20%) and Simon-Wittes-Ellenberg design was used to calculate the sample size (29 evaluable patients for each treatment arm). Results: From January 2007 to December 2008, sixty patients were enrolled and randomized to FOLFOX (N=30) or FOLFIRI.3 (N=30). Baseline characteristics were well balanced between each arm; median age 56 (35–60) vs. 56 yo (37–73); ECOG PS 0/1/2, 5/24/1 vs. 5/25/0; prior response to gemcitabine-based chemotherapy PR/SD/PD 10/13/7 vs. 10/11/9. With a median follow-up period of 6.0 months (95% CI, 4.7–7.3) the median overall survival was 4.0 months in both group (HR=0.95, 95% CI 0.52–1.75) with 6-month survival rates of 25% and 20%, respectively. The median PFS was 1.4 months for FOLFOX and 1.9 months for FOLFIRI.3 (HR=1.11, 95% CI, 0.64–1.92). Disease control (PR+SD) was achieved in 20% (5/25 in FOLFOX) and 28% (7/25 in FOLFIRI.3) of patients with measurable disease. The incidences of grade 3/4 toxicities were similar in both groups. Conclusions: Both FOLFOX and FOLFIRI.3 were tolerated with manageable toxicity, offering modest activity as second-line treatment of patients with advanced or metastatic pancreatic cancer, previously treated with gemcitabine.

No significant financial relationships to disclose.
Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma
Authors: Oettle H. , Hilbig A. , Seufferlein T. , Schmid R. M. , Luger T. , von Wichert G. , Schmaus S. , Heinrichs H. , Schlingensiepen K.
Published: August 2020

4619

Background: TGF-beta 2 is one of the most potent immunosuppressors and mediates escape from immunosurveillance. It also plays a crucial role in tumor progression by regulating metastasis, angiogenesis, and proliferation. Trabedersen, a TGF-beta 2-specific inhibitor has already shown a clear survival benefit in a randomized active-controlled phase II study in high-grade glioma patients, compared to standard chemotherapy. Methods: 33 patients with advanced pancreatic carcinoma (stage IVA/IVB) (N=23), malignant melanoma (stage III/IV) (N=5) or colorectal carcinoma (stage III/IV) (N=5) were treated with trabedersen as 2nd-4th-line treatment. Two treatment schedules (1st schedule:7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles) were evaluated in a cohort dose-escalation design. Primary study objective: maximum tolerated dose (MTD); secondary objectives: safety and tolerability, pharmacokinetics and antitumor activity. Results: Patient recruitment for both schedules is completed. Very good safety and tolerability of trabedersen was observed, with moderate thrombocytopenia as main adverse event. Max. grade 3 dose-limiting toxicities (2 thrombocytopenias, 1 exanthema) occurring with 240 mg/m2/d in the 1st schedule established the MTD at 160 mg/m2/d. MTD has not been reached in the 2nd schedule. Of the 5 melanoma patients one from the 1st schedule showed stable disease and lived for 13.8 months; 3 patients from the 2nd schedule are still alive. Median overall survival (mOS) for pancreatic carcinoma patients in the 1st schedule was 6.8 months. One pancreatic carcinoma patient showed a complete response and is alive 38 months after trabedersen therapy. Current mOS for pancreatic carcinoma patients in cohort 1 (N=5) of the 2nd schedule is 13.2 months; 2 of these patients are alive, one with stable disease 14.8 months after begin of trabedersen treatment. Conclusions: Trabedersen has a very good safety and tolerability profile. The survival data are very encouraging. The study will continue with one dose in at least 12 patients. A randomized, active-controlled phase II study compared to standard therapy in patients with pancreatic carcinoma is in preparation; another one in malignant melanoma is being planned.

[Table: see text]
Inhibition of mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: The results of two prospective phase II studies
Authors: Javle M. M. , Xiong H. , Reddy S. , Bhosale P. , Davis D. , Varadhachary G. , Fogelman D. , Kaseb A. , Wolff R. A. , Abbruzzese J. L.
Published: August 2020

4621

Background: PI3-kinase/ Akt pathway is constitutively activated in pancreatic cancer and is mediated by mTOR kinase. Our in vitro studies suggest that prolonged exposure to mTOR inhibitors can promote insulin receptor substrate-PI3-kinase interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin down-regulates rapamycin-stimulated Akt in preclinical models. Methods: Study A: CCI-779 (Temsirolimus), Study B: RAD001 (Everolimus) + Erlotinib. Inclusions: Adult patients with gemcitabine-refractory pancreatic cancer, ECOG PS 0–1, adequate laboratories and measurable disease. Dose and schedule: CCI-779 25 mg IV weekly; RAD001 30 mg weekly + erlotinib 150 mg daily. Primary endpoint: overall survival at 6 months. Secondary endpoints: time-to-progression, response and toxicity. Tumor biopsies analyzed by immunofluorescence and laser scanning cytometry analysis for expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1, PTEN and for k-ras mutations. Results: Study A: 5 patients enrolled, 4 patients received 2–4 doses. 2 patients died within a month; one from rapid progression other from hemorrhagic stroke. 2 developed SAEs: dehydration and asthenia. Study B: 16 patients enrolled; 12 males, all ECOG PS=1. Median cycles=1 (range 1–2). Grade 4 toxicity: hyponatremia (n=1), Grade 3: diarrhea (n=1), cholangitis (n=3), hyperglycemia (n=1), fatigue (n=1). Grade 2: pneumonia (n=2), dehydration (n=2), neutropenia (n=1), mucositis (n=2) & rash (n=2); hospitalizations=4. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed increased pAkt/ Akt ratio in tumor specimens as compared with non malignant pancreatic tissue. No such trends occurred for pErk/Erk or pmTOR/ mTOR. K-ras mutations occurred in 2/7 patient samples. Conclusions: Neither study with mTOR inhibitors demonstrated objective responses or disease stability. Negative feedback loop seen preclinically may account for the rapid progression noted with mTOR inhibitors in pancreatic cancer. The addition of erlotinib may not counter this effect in the clinical setting.

[Table: see text]
Effects of adjuvant intra-operative radiation therapy after curative resection in pancreatic cancer patients : Results of a randomized study by 11 institutions in Japan
Authors: Kinoshita T. , Uesaka K. , Shimizu Y. , Sakamoto H. , Kimura W. , Sunada S. , Sunada S. , Imaizumi T. , Ozawa I. , Okamoto A. , Oda T.
Published: August 2020

4622

Background: To evaluate the benefits of adjuvant intra-operative radiation therapy after curative resection in advanced pancreatic cancer (APC) patients, a multi-center phase III trial was conducted by 11 participating institutions in Japan. Methods: Eligibility included pts with potentially resectable APC (duct cell origin) by image diagnosis. Patients were randomized in a 1:1 ratio to adjuvant IORT or surgery alone less than a week before surgery. Stratification factors were tumor size (TS1/TS2,3,4), location (head/body and tail), and institution. Patients who were assigned to adjuvant IORT arm received IORT after curative resection before reconstruction. IORT consisted of 25Gy with electron beam energies of more than 6MeV and was delivered by the round shaped acrylic cylinder of 6–8cm diameter. The radiation field included the tumor bed and in most cases included the celiac axis, superior mesenteric artery, and the portal vein. The primary endpoint was overall survival. The secondary endpoint was local control rate at 2 years after surgery. Assuming 65 eligible pts in each arm, the study had 0,8 power to detect 20% difference in 2-year survival rate. Results: Between 05/2002 to 12/2006 198 pts were randomized and 153 pts underwent curative resection with assigned treatment. Among the 153 pts with curative resection, seven pts revealed ineligible by the histological examination. Finally full analysis sets were 144 pts. Seventy three pts were in the IORT arm and 71 pts in the surgery alone arm. There was only one hospital death in the IORT arm. Cause of the death was intraabdominal arterial bleeding due to pancreatic fistula. Conclusions: We now are collecting the final follow up data. The final analyses will be presented at the meeting.

No significant financial relationships to disclose.
Phase II trial of GTX chemotherapy in metastatic pancreatic cancer
Authors: Fine R. , Moorer G. , Sherman W. , Chu K. , Maurer M. , Chabot J. , Postolov I. , Prowda J. , Schreibman S. , Levitz J.
Published: August 2020

4623

Background: Preclinical studies suggest synergy between gemcitabine (G), docetaxel (T) and capecitabine (X). This GTX regimen was designed to inhibit MEK-ERK phosphorylation and increase BAX and BAK and also decrease BCL-2 in pancreatic cancer cell lines. Based on these findings, we pursued a prospective clinical trial evaluating the activity of GTX in previously untreated patients with metastatic pancreatic cancer. Methods: Patients with histologically confirmed metastatic adenocarcinoma of the pancreas, median age 60, 63% male, ECOG PS 0–2, received capecitabine 1500mg/m2/day total orally in divided doses, days 1 thru 14, gemcitabine 750mg/m2 IV over 75 minutes followed by docetaxel 30mg/m2 IV on days 4 and 11 on a 21 day cycle. Scans were completed every 9 to 10 weeks to assess for tumor response by RECIST criteria. Treatment was continued until evidence of disease progression, intolerable toxicity, surgery or a delay in treatment greater than 6 weeks. The primary endpoint was response rate. Secondary endpoints were overall survival (OS) measured as time from start of GTX to death, time to treatment failure (TTF) measured as time from start of GTX to disease progression or other reason for a halt in therapy. Results: Forty-three patients were enrolled at two centers between May 2004 and January 2007. Forty-one patients were eligible for assessment by intent to treat analysis. 35 patients (85%) had liver metastases. 9 patients (21.9%) had partial responses and 17 patients (41.5%) had stable disease. The one year survival rate was 56%. Two year survival rate was 14.6%. The median OS was 14.5 months. The median TTF was 6.9 months. Grade 3 and 4 toxicities included leukopenia (31.6%), neutropenia (29.2%), thrombocytopenia (12.2%), infection (12.5%), and mucositis (7.5%). Conclusions: The combination of gemcitabine, docetaxel, and capecitabine has activity in metastatic pancreatic cancer with a median survival over 1 year. A randomized phase III trial is in planning.

[Table: see text]
Salivary biomarkers for pancreatic cancer detection
Authors: Wong D. T. , Zhang L. , Farrell J. , Zhou H. , Elashoff D. , Gao K. , Paster B.
Published: August 2020

4630

Pancreatic cancer is the 4th leading cause of cancer death. Lack of early detection technology for pancreatic cancer invariably leads to a typical clinical presentation of incurable disease at initial diagnosis. We evaluated the performance and translational utilities of the salivary transcriptomic and microbial biomarkers for pancreatic cancer detection. Biomarker discovery strategies were used to profile transcriptome in saliva supernatant and microflora in saliva pellet. The Affymetrix Human Genome U133+2.0 array was used to discover altered gene expression in saliva supernatant. The Human Oral Microbe Identification Microarray (HOMIM) was used to investigate microflora shift in saliva pellet. Biomarkers selected from both studies were subjected to an independent clinical validation using a cohort of 30 pancreatic cancer, 30 chronic pancreatitis and 30 healthy matched-control saliva samples. Two panels of salivary biomarkers, including eleven mRNA biomarkers and two microbial biomarkers were discovered and validated for pancreatic cancer detection. The logistic regression model with the combination of three mRNA biomarkers (ACRV1, DMXL2 and DPM1) yielded a ROC-plot AUC value of 0.974 (95% CI, 0.896 to 0.997; P < 0.0001) with 93.3% sensitivity and 90% specificity in distinguishing pancreatic cancer patients from healthy subjects. The logistic regression model with the combination of two bacterial biomarkers (Neisseria elongata and Streptococcus mitis) yielded a ROC-plot AUC value of 0.895 (95% CI, 0.784 to 0.961; P < 0.0001) with 96.4% sensitivity and 82.1% specificity in distinguishing pancreatic cancer patients from healthy subjects. More importantly, the logistic regression model with the combination of four biomarkers (mRNA biomarkers, ACRV1, DMXL2 and DPM1; bacterial biomarker, S. mitis) could differentiate pancreatic cancer patients from all non-cancer subjects (chronic pancreatitis and healthy control), yielding a ROC-plot AUC value of 0.949 (95% CI, 0.877 to 0.985; P < 0.0001) with 92.9% sensitivity and 85.5% specificity. This is the first report demonstrating the value of multiplex salivary biomarkers for the non-invasive detection of a high impact systemic cancer.

No significant financial relationships to disclose.
Met160Val TMPRSS2 gene polymorphism and early onset prostate cancer in high-risk men
Authors: Giri V. N. , Hughes L. , Ruth K.
Published: August 2020

5000

Background: The TMPRSS2-ERG gene fusion has been found in over 50% of prostate tumors and its role is being characterized in various clinical settings. The T-allele of the Met160Val single nucleotide polymorphism (SNP) has been found to be associated with translocation and multiple copies of the TMPRSS2-ERG fusion. This SNP needs clinical characterization in men at high risk for prostate cancer (PCA) (men with a family history [FH] of PCA and African American [AA] men) to determine the role in personalizing PCA early detection. The Prostate Cancer Risk Assessment Program (PRAP) is a prospective screening program for high risk men. PRAP has > 700 participants, and 60% are AA. Here we evaluated the Met160Val SNP (rs12329760) in the TMPRSS2 gene with respect to race, FH of PCA, and time to PCA diagnosis. Methods: Eligibility for PRAP includes men ages 35–69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Criteria for biopsy and biopsy approach have been reported previously. Genotyping of the Met160Val SNP was performed using the Taqman SNP Genotyping Assay (Applied Biosystems). Standard statistical methods were used to determine risk-genotype distributions. Cox models were used for time to PCA diagnosis by risk genotype. Results: Out of 700 men in PRAP, 631 were able to be genotyped for the Met160Val SNP. There was no difference in distribution of genotypes (CT/TT vs. CC) among 231 White men with familial PCA and 400 AA men in PRAP. Among 183 White men with familial PCA with > one follow-up visit, those with the CT/TT genotypes were found to have a significantly earlier time to PCA diagnosis vs. the CC genotype (p = 0.0058). In addition, the hazard ratio for PCA among high-risk White men of the CT/TT genotypes vs CC genotype was 2.55 (p = 0.022) after controlling for age and PSA. No trends were seen among AA men for time to PCA diagnosis for any of the Met160Val SNP genotypes. Conclusions: The T-allele of the Met160Val variant in the TMPRSS2 gene may be informative of time to PCA diagnosis among White men who have a FH of PCA. This genetic variant warrants further study in high-risk men with familial PCA for its role in personalizing PCA early detection.

No significant financial relationships to disclose.
Use of CA9 gene single nucleotide polymorphisms to predict prognosis and treatment response of metastatic renal cell carcinoma
Authors: de Martino M. , Klatte T. , Seligson D. B. , LaRochelle J. , Shuch B. , Caliliw R. R. , Li Z. , Kabbinavar F. F. , Pantuck A. J. , Belldegrun A. S.
Published: August 2020

5003

Background: Carbonic anhydrase 9 gene (CA9) is located in a prognostically relevant chromosomal area on chromosome 9p and is encoding for one of the most significant protein markers in metastatic renal cell carcinoma (MRCC), CAIX. In contrast to CAIX protein, however, no efforts have been made to date to study CA9 gene in metastatic RCC. Here, we test the hypotheses that single nucleotide polymorphisms (SNPs) and mutations of the CA9 gene are associated with CAIX expression, response to immunotherapy and survival. Methods: Genomic DNA was extracted from frozen tumor samples of 54 patients with clear cell MRCC. All exons of the CA9 gene were PCR-amplified and sequenced. The antibody M75 was used to evaluate CAIX protein expression immunohistochemically. Statistical associations of CA9 gene status and CAIX protein expression with response to IL-2 based immunotherapy and overall survival were assessed with chi-square tests, t-tests, Kaplan-Meier survival estimates and Cox proportional hazards regression models. Results: CA9 reference SNP (rs) 2071676 was found in 59%, rs12553173 in 15%, rs3829078 in 11% and rs1048638 in 33% of the patients. The deletion c.376del393 was observed in two patients. CAIX expression was high (>85%) in 65% of the patients. None of the SNPs was significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs. 13.6 months, p = 0.0431) and a greater likelihood of response to IL-2 (57% vs. 22%, p = 0.081) Likewise, high CAIX expression was associated with longer median survival (25.5 vs. 8.5 months, p < 0.0001) and a greater IL-2 response rate (37% vs. 8%, p = 0.070). In a multivariate Cox model, both C allele variant of CA9 SNP rs12553173 and CAIX expression were retained as independent prognostic factors. Conclusions: CA9 SNPs are frequently found in patients with MRCC. The C allele variant of rs12553173 is associated with improved overall survival and a greater likelihood of response to IL-2. CA9 rs12553173 and CAIX are both independent prognostic factors of overall survival and complementary in predicting prognosis of MRCC.

No significant financial relationships to disclose.
Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity
Authors: van Erp N. , Mathijssen R. H. , van der Veldt A. A. , Haanen J. B. , Reyners A. K. , Eechoute K. , Boven E. , Wessels J. A. , Guchelaar H. , Gelderblom H.
Published: August 2020

5006

Background: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities; thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome and ‘any toxicity according to Common Terminology Criteria > grade 2.’ Methods: A multicenter pharmacogenetic association study was performed in 219 patients treated with single agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several non-genetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results: The risk for leukopenia was increased when the G-allele in CYP1A1 2455A/G (OR = 6.24; p = 0.029) or the T-allele in FLT3 738T/C (OR = 2.8; p = 0.008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR = 1.74; p = 0.041) was absent. ‘Any toxicity > grade 2’ prevalence was increased when the T-allele of VEGFR-2 1191C/T (OR = 2.39; p = 0.046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR = 2.63; p = 0.016) were present. The risk for mucosal inflammation was increased in the presence of the G-allele in CYP1A1 2455A/G (OR = 4.03; p = 0.021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR = 2.56; p = 0.035) was present. Conclusions: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters and drug targets are associated with sunitinib related toxicities. A better understanding of genetic and non-genetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.

[Table: see text]
The natural history of metastatic progression in men with PSA-recurrent prostate cancer after radical prostatectomy: 25-year follow-up
Authors: Antonarakis E. S. , Trock B. J. , Feng Z. , Humphreys E. B. , Carducci M. A. , Partin A. W. , Walsh P. C. , Eisenberger M. A.
Published: August 2020

5008

Background: In men with prostate specific antigen (PSA) recurrence following radical prostatectomy (RP) and no other therapy, the natural history of metastatic progression was previously described in 1999. We now report data reflecting up to 25 years of follow-up. Methods: We performed a retrospective analysis of 774 men treated with RP between 4/1982 and 7/2008 who developed PSA recurrence (>0.2 ng/ml) and never received adjuvant or salvage therapy. We investigated factors influencing the development of metastases. Results: Mean follow-up after RP was 8.5 y (median 8 y). Of 774 men with PSA recurrence, 295 (38%) developed metastases, and 433 had data on PSA doubling time (PSADT), forming our cohort. The mean time from RP to PSA recurrence in the entire cohort was 4.2 y (median 3 y). In those who developed metastases, the mean time from PSA recurrence to metastasis was 3.1 y (median 2 y). The mean PSA at the time of metastasis was 90.3 ng/ml (median 31.4 ng/ml). In Cox regression analysis: PSADT, Gleason score, and time to PSA progression were predictive of the development of metastases ( Table ). In Kaplan-Meier survival analysis, the median actuarial time from PSA recurrence to metastasis was 10 y (95% CI 9 - 15 y). Median actuarial metastasis-free survival from PSA recurrence for men with PSADT <3 mo, 3 - 8.9 mo, 9 - 14.9 mo, and >15 mo was 1 y (95% CI 0 - 1 y), 4 y (95% CI 2 - 6 y), 9 y (95% CI 7 - 13 y), and 15 y (95% CI 12 - 20 y), respectively. Conclusions: PSADT, Gleason score, and time to PSA progression are strong independent predictors of metastasis-free survival in men with PSA-recurrent prostate cancer. These data facilitate patient counseling and logical risk-based treatment planning. They also provide the background for appropriate selection of patients, treatments, and endpoints for clinical trials.

[Table: see text]

No significant financial relationships to disclose.
Antitumor activity of MDV3100 in a phase I/II study of castration-resistant prostate cancer (CRPC)
Authors: Scher H. I. , Beer T. M. , Higano C. S. , Taplin M. , Efstathiou E. , Anand A. , Hung D. , Hirmand M. , Fleisher M. ,   The Prostate Cancer Clinical Trials Consortium
Published: August 2020

5011

Background: MDV3100 is a novel AR antagonist selected for activity in prostate cancer model systems with overexpressed AR. In contrast to bicalutamide, MDV3100 blocks nuclear translocation of AR and DNA binding, and has no known agonist activity when AR is overexpressed. Antitumor activity of MDV3100 in a Phase I/II trial was assessed by prostate-specific antigen (PSA), soft tissue and osseous disease, circulating tumor cells (CTC), and time on treatment. Methods: Patients (pts) with progressive CRPC were enrolled in sequential cohorts of 3–6 pts at 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses >60 mg/day to include 12 chemotherapy-naïve (naïve) and 12 post-chemotherapy pts per cohort. Results: 140 pts were enrolled. 114 pts at 30–360 mg/day have been followed for >12 weeks. PSA declines (>50% from baseline) were observed at week 12 in 57% (37/65) of naïve and 45% (22/49) of post-chemo pts. Data suggest a dose-response trend particularly in post-chemo pts where PSA responses were 32% at 60 and 150 mg/day and 58% at 240 and 360 mg/day. At 12 weeks, radiographic control (no progression) was observed in 35/47 pts (74%) with evaluable soft tissue lesions per PCWG2 guidelines and 50/81 pts (62%) with bone lesions. CTC counts on 101 of 114 pts showed 92% (56/61) with favorable (<5) counts pretreatment maintained favorable posttreatment counts, while 53% (21/40) converted from unfavorable to favorable posttreatment. For post-chemo pts, favorable retention was 100% (17/17) and unfavorable to favorable conversion at 240 and 360 mg/day was 60% (6/10). 87 pts at 30–240 mg/day have been followed for >24 weeks; 35 (40%) received treatment >24 weeks. At 600 mg/day, 2 of 3 pts had dose limiting toxicity (rash; seizure). Dose reductions due to fatigue were noted at 480 and 360 mg/day. Conclusions: MDV3100 is a promising candidate for the treatment of prostate cancer assessed by PSA, imaging, CTC, and time on treatment. The data suggest a dose-response trend and consistency across endpoints. Pt follow-up is continuing. The efficacy comparable to that at higher doses and the better adverse event profile, led to the selection of 240 mg/day as the recommended dose for a phase III trial in CRPC.

[Table: see text]
Mature results of a randomized phase II study of OGX-011 in combination with docetaxel/prednisone versus docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer
Authors: Chi K. N. , Hotte S. J. , Yu E. , Tu D. , Eigl B. , Tannock I. , Saad F. , North S. , Powers J. , Eisenhauer E. ,   National Cancer Institute of Canada Clinical Trials Group
Published: August 2020

5012

Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of <640 mg. Methods: Pts with CRPC and chemo-naive received docetaxel (DOC) 75mg/m2 q3w + OGX 640mg IV weekly + prednisone (Arm A) or DOC + prednisone (Arm B) in a single stage randomized phase II design. Primary endpoint was PSA response rate (RR). Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Planned sample size was 40/arm: Arm A the hypotheses (PSA RR<40% vs. >60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI<13% if PSA RR=40%. Results: 82 pts (41 Arm A, 41 Arm B) were randomized from 09/05–12/06. At this analysis time, all pts are off therapy and 49 have died. One pt was ineligible but included in ITT survival analysis. Baseline characteristics were similar: median age 69 (49–87), PSA >100 μg/L in 51%, Hgb ≥100 g/L in 98%, alk phos >ULN in 44%, LDH >ULN in 36%, ECOG performance status (PS) 0:1 in 51%:49%, bone/lymph node/visceral metastases in 69%/50%/28%. Median cycles for Arm A and B was 9 and 7. Adverse events associated with OGX included fatigue, fever, rigors, diarrhea and rash. Mean serum clusterin change on day 1 cycle 2 was -18% in Arm A and +8% in Arm B (p = 0.0005). PSA RR was 58% (Arm A) and 54% (Arm B). PSA declines at 12 weeks of any/>30%/>50% was observed in 87%/65%/45% (Arm A) and 68%/58%/34% (Arm B). PSA/objective disease progression as best response occurred in 0%/4% (Arm A), and 3%/17% (Arm B). PFS for Arms A and B was 7.3 (5.3–8.8) and 6.1 months (3.7–8.6). Median OS for Arms A and B was 27.5 (19.2-∞) and 16.9 months (12.7–26.0) (unadjusted HR = 0.60 [0.34–1.06], p = 0.07). Variables predictive of OS on multivariate analysis: PS 0 vs 1 (p = 0.0002), presence of visceral metastasis (p = 0.006) and treatment assignment (HR = 0.54 [0.29–0.97], p = 0.04). Conclusions: The PSA RR in both arms met criterion for further study. OGX reduced serum clusterin and OS appears superior with DOC/OGX. This combination warrants further evaluation. Supported by a grant from the NCI-Canada/Canadian Cancer Society.

[Table: see text]
Excision repair cross-complementing 1 (ERCC1) and survival in advanced bladder cancer: Confirmatory results using immunohistochemistry
Authors: Guix M. , Lema L. , Lloreta J. , Rojo F. , Suárez C. , Carles J. , de la Cruz J. , Sánchez-Carbayo M. , Albanell J. , Bellmunt J.
Published: August 2020

5025

Background: DNA damaging agents are the backbone of combination chemotherapy regimens for the treatment of advanced bladder cancer. We hypothesized that levels of DNA repair genes such as ERCC1 could predict survival in patients receiving platinum based therapy. Our previous work (Bellmunt J et al, Ann Oncol. 2007) showed that survival was significantly higher in advanced bladder cancer patients with low gene expression levels of ERCC1 measured by RT-qPCR (25.4 versus 15.4 months; p = 0.03). We aimed to confirm these findings using immunohistochemistry (IHC) in an independent cohort of advanced bladder cancer patients treated with cisplatin-based chemotherapy at our institution. Methods: Formalin-fixed paraffin-embedded tumor tissue was available from 51 patients. IHC stains for ERCC1 protein levels were scored as percentage and intensity of positive cells. ERCC1 staining was considered positive if detected in ≥1% tumor cells. The Kaplan-Meier method was used to calculate survival and the Cox proportional hazards model was used to examine the prognostic value of protein expression levels. Results: ERCC1 staining was negative in 60% of patients, weakly positive (1–10% positive cells) in 21% and strongly positive (>10% positive cells) in 19%. Median overall survival for all patients was 14.4m (95% CI 6.7–16.1m). Median disease-specific survival was significantly higher in patients negative for ERCC1 by IHC (12.6m versus 8.6m; p = 0.032). Conclusions: Our results using the more simple IHC technique confirm the prognostic value of ERCC1 expression in advanced bladder cancer. Patients with high expression of ERCC1 by IHC have a worse disease-specific survival than patients with no expression. A correlative study of IHC and RT-qPCR in both sets of samples is ongoing.

No significant financial relationships to disclose.
Long-term follow-up of chemotherapy-induced remissions in patients with disseminated nonseminomatous germ cell tumors
Authors: Ehrlich Y. , Brames M. J. , Beck S. D. , Foster R. S. , Einhorn L. H.
Published: August 2020

5029

Background: There is controversy concerning management of patients (pts) with nonseminomatous germ cell tumor (NSGCT) who obtain a chemotherapy-induced complete radiographic (<1cm node diameter) and serologic remission (CR). It has been our policy not to recommend retroperitoneal lymph nodes dissection (RPLND). Proponents of mandatory RPLND cite a 20% to 30% rate of residual microscopic tumor, mostly teratoma, despite achieving CR. Methods: Retrospective analysis of 141 patients with metastatic NSGCT who obtained CR to cisplatin-based first-line chemotherapy. All were observed without RPLND. Included were 78 consecutive pts treated between Jan 1987 and Sept 1994. Additionally included were 63 pts recruited in 4 prospective trials between Oct 1984 and Apr 2005. Seven pts were lost to follow-up (FU) after <2 year. Results: At a median a FU of 15 years (range 3 months to 23.8 years), 12 pts recurred and 4 are dead of disease (DOD). The estimated 15 year recurrence free and disease specific survival was 90% and 97% respectively. The estimated 15 years recurrence free survival for 109 pts with good risk and 32 pts with intermediate or poor risk was 95% and 73% respectively (p = 0.001). Five pts recurred >2 years (range 3–13 years). All 5 are currently disease free. Six pts recurred in the RP and 2 are DOD. Six pts recurred outside the RP. Two of these 6 are DOD. Conclusions: Pts obtaining CR after primary chemotherapy can be safely observed without RPLND. Relapses are rare and potentially curable with further treatment.

No significant financial relationships to disclose.
Prognostic factors in relapsed or refractory male germ cell tumors: Results from an international study of 1,593 patients
Authors: Lorch A. , Beyer J. , Mollevi C. , Guerra M. , Kramar A. ,   for the International Group on Prognostic Factors in Relapsed or Refractory Germ-Cell Tumors
Published: August 2020

5030

Background: The results of salvage treatment in male patients (pts) with relapsed or refractory germ-cell tumors (rr-GCT) depend considerably on prognostic factors. However, individual factors are not broadly accepted. Methods: Between 09/2007 and 12/2008 data on 1984 pts with rr-GCT were collected from 38 centers/groups worldwide. Inclusion criteria were (1) First line treatment for metastatic GCT after January 1, 1990; (2) Cisplatin and etoposide as part of first-line regimens; (3) No first-line high-dose chemotherapy (HDCT); (4) Relapse or progression after first-line treatment; (5) Cisplatin- based conventional-dose regimens or HDCT as salvage treatment. Data were centrally reviewed and checked for consistency. The primary endpoint was progression-free survival (PFS). Prognostic factors were identified using Cox multivariate regression analysis. Results: Overall 1593 (80%) pts fulfilled the strict inclusion criteria. Salvage treatment given as consolidation of first-line treatment in patients without progression was the most frequent cause of exclusion. Median follow-up was 58 months (range 1 to 206 months). Three-year PFS for the entire group was 38% (95% CI: 35%-40%), the overall survival was 51% (95% CI: 48%-54%). Multivariate analysis on a randomly selected 2/3 training dataset identified the following variables as the most significant ones for PFS: see Table . Cisplatin-refractory or absolute refractory disease was a confounding factor for response to first-line treatment. Conclusions: This preliminary analysis of a large dataset allowed the identification of important prognostic factors in rr- GCT. A prognostic score for first-salvage treatment based on the results of a final analysis will be presented.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of BAY 73–4506, a multikinase inhibitor, in previously untreated patients with metastatic or unresectable renal cell cancer
Authors: Eisen T. , Joensuu H. , Nathan P. , Harper P. , Wojtukiewicz M. , Nicholson S. , Bahl A. , Tomczak P. , Wagner A. , Quinn D.
Published: August 2020

5033

Background: BAY 73–4506 is an orally active, potent multikinase inhibitor targeting both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (RAF and p38MAPK). In tumor xenograft models, BAY 73–4506 demonstrated a broad spectrum of antitumor activity. The results of a phase I study (3 weeks on/1 week off schedule) indicated good tolerability and antitumor activity, including objective responses. Methods: Previously untreated patients with predominantly clear cell renal cell carcinoma (RCC) and measurable disease according to RECIST were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, low or intermediate risk as per Motzer score, and adequate bone marrow and organ function. Treatment consisted of BAY 73–4506 160 mg once daily on a 3 weeks on/1 week off schedule. The primary end point was overall response rate. Results: 49 patients started treatment (accrual completed October 2008): 27 male, 22 female, median age 62 years (range 40–76). All patients were evaluable for safety, 33 patients are currently available for efficacy evaluation. The most common drug-related adverse events (all grades) reported in >20% of patients were hand-foot skin reaction (HFSR) (48%), fatigue (48%), hypertension (43%), mucositis (35%), dysphonia (33%), rash (30%), diarrhea (25%), and anorexia (23%). Grade 3–4 drug related toxicities (in >5% of patients) included HFSR (13%), rash (8%), fatigue (8%), and renal failure (8%). Renal failure occurred only in patients who continued taking study medication despite having inadequate fluid intake and/or diarrhea. Preliminary efficacy data of the 33 patients evaluable for response show a 27% partial response (PR) and a 42% stable disease (SD) rate. Further tumor assessments are scheduled for the patients (n = 35) remaining on study. Conclusions: Preliminary data show promising antitumor activity and good tolerability of BAY 73–4506 in patients with RCC. The observed toxicities were typical of the drug class and were manageable. Updated results will be presented at the meeting.

[Table: see text]
Activity of a multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen in metastatic renal cell carcinoma (mRCC): A phase II study of sorafenib, gemcitabine (Gem), and metronomic capecitabine (Cap) in patients with advanced mRCC (SOGUG-02–06)
Authors: Bellmunt J. , Trigo J. , Calvo E. , Carles J. , Perez-Gracia J. , Rubió J. , Virizuela J. , López R. , Lázaro M. , Albanell J.
Published: August 2020

5040

Background: Maximal tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses administered on a frequent schedule) acts on tumor vascular endothelial cells and enhances the antitumor effect of anti-angiogenic agents (Pietras et al. J Clin Oncol. 2007). This study investigated treatment of mRCC with Gem at MTD combined with metronomic Cap and the multikinase inhibitor sorafenib. Methods: Eligible patients had cytologically or histologically confirmed mRCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and no previous targeted therapy or chemotherapy, and were unsuitable for or intolerant to immunotherapy. Treatment consisted of six 3-week cycles of Gem 1000 mg/m2 i.v. (days 1 and 8), oral Cap 500 mg/m2 b.i.d. (days 1 to 14) and oral sorafenib 400 mg b.i.d. (every day), followed by sorafenib monotherapy (at the discretion of the investigator). Study endpoints included median progression-free survival (PFS, primary endpoint), disease control rate according to Response Evaluation Criteria in Solid Tumors, and safety. Results: Forty patients were enrolled and received at least one dose of treatment (median age 63 yrs, male n = 24, ECOG 0/1 n = 18/22, 1–2/>2 metastatic sites n = 31/9). Median duration of treatment was 6 months. Among 36 evaluable patients, 17 (47%) had a partial response and 17 (47%) achieved stable disease. Median PFS was 10.2 months (95% CI 7.6, 20.5). The most common adverse events (AEs) were fatigue/asthenia (78%) hand-foot syndrome (75%) and mucositis (69%). Most AEs were grade1/2, no grade 4 toxicities occurred. One patient had grade 5 dyspnea; 6 patients discontinued treatment for AEs. Conclusions: PFS and objective responses in this study were greater than those observed in previous studies with Gem and Cap or sorafenib monotherapy in patients with mRCC, while AEs remained moderate in the majority of patients. These findings confirm the synergistic activity of the “chemo-switch” concept seen in preclinical models. The combination of sorafenib with MTD Gem and metronomic Cap warrants further investigation in mRCC.

[Table: see text]
Prognostic factors for overall survival with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC)
Authors: Patil S. , Figlin R. A. , Hutson T. E. , Michaelson M. D. , Négrier S. , Kim S. T. , Huang X. , Motzer R. J.
Published: August 2020

5042

Background: Sunitinib demonstrated superior progression-free survival (PFS; the primary endpoint) over interferon-alfa (IFN-α) as first-line mRCC therapy (NEJM 2007;356:115). Median overall survival (OS) with sunitinib compared to IFN-α was: 26.4 vs. 21.8 months (HR=0.821; P=0.051 by unstratified log-rank test; Proc ASCO 2008;26, May 20 suppl; abstr 5024). An analysis of prognostic factors for OS was performed on data from this trial. Methods: 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib or IFN-α. By Cox proportional hazards model, selected pretreatment variables were evaluated univariately and in a multivariate model for each treatment arm. Multivariate models for each treatment arm were based on a stepwise algorithm with a type I error of 0.25 for entry and 0.15 for elimination. Further elimination was applied to identify variables significant at P<0.05. Results: In multivariate analysis of sunitinib patients, factors associated with longer OS include: interval from diagnosis to treatment ≥1 yr, ECOG PS of 0, lower corrected calcium, absence of bone metastases, lower lactic dehydrogenase (LDH), and higher hemoglobin (Hgb) ( table ). For the IFN-α treatment arm, male gender, absence of bone or lymph node metastases, lower LDH, higher Hgb, lower corrected calcium, higher neutrophil count, and interval from diagnosis to treatment ≥1 yr were associated with longer OS. Conclusions: For patients in the sunitinib treatment arm, prognostic factors identified were similar to the factors previously identified in the MSKCC risk groups (J Clin Oncol 2002;20:289). Additional prognostic factors were identified for the IFN-α arm. Further studies are warranted to independently validate these findings as well as to identify tumor-specific prognostic factors.

[Table: see text]

[Table: see text]
A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)
Authors: Reid A. H. , Attard G. , Danila D. , Ryan C. J. , Thompson E. , Kheoh T. , Molina A. , Small E. , Scher H. , De-Bono J. S.
Published: August 2020

5047

Background: Despite castration, androgens remain critical to prostate cancer. Abiraterone acetate (AA) specifically and irreversibly inhibits CYP17, a key enzyme in androgen biosynthesis. Methods: 47 CRPC pts who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally (1000mg QD) in 28 day cycles. Low dose glucocorticoids were allowed. Results: Patient demographics in table . Total maximal PSA declines with AA at any point on study of ≥30%, ≥50%, and ≥ 90% were observed in 32 (69%), 24 (51%) and 7 (15%) pts respectively. A similar trend in PSA response was seen at wk 12. 35 pts were evaluable by RECIST; 6 (17%) pts had a partial response and 23 (66%) pts had stable disease. 23% of pts showed ECOG improvement (PS 1 to 0 in 10 pts, PS 2 to 1 in 1 pt); 53% of pts maintained PS. Median duration on treatment was 167 days (95% CI 130–201). 17 pts received >6 cycles of AA; 8 pts received ≥ 12 cycles. Toxicities related to mineralocorticoid excess were mainly grade 1–2 (hypokalemia 51%; HTN 17%; edema 13%) and were treated with eplerenone or corticosteroids. Conclusions: AA has anti-tumor activity in these heavily pretreated pts, as evidenced by sustained PSA declines, improvement in PS and RECIST responses. A phase III trial assessing the efficacy and safety of AA and prednisone in CRPC pts who have failed docetaxel chemotherapy is underway.

[Table: see text]

[Table: see text]
Disseminated tumor cells in primary breast cancer: Evaluation of the percentage of breast cancer stem cells in bone marrow aspirates of patients receiving neoadjuvant chemotherapy
Authors: Reuben J. M. , Lee B. , Lucci A. , Gao H. , Cohen E. N. , Li C. , Krishnamurthy S. , Hortobagyi G. N. , Woodward W. A. , Cristofanilli M.
Published: August 2020

505

Background: Disseminated tumor cells (DTC) in the bone marrow (BM) are related to poor prognosis of primary breast cancer (PBC). Cancer-initiating stem cells (CSC) have been detected in BM of PBC patients. Downregulation of the Notch pathway leads to murine mammary stem cell expansion and its expression is an early event in breast cancer. We enumerated CSC in BM mononuclear cells (BMC) and assessed the expression of Notch-1, ER, and HER-2 to study the differences between untreated patients and those treated with neoadjuvant chemotherapy. Methods: BM was collected from 90 PBC patients at time of surgery to assess DTC (CD326+CD45-) and CSC (CD326+CD45-CD44+CD24-) by FACS analysis. BM samples were also interrogated for the presence of CSC with ALDH activity using the Aldefluor® detection kit. RNA extracted from 61 BMC was analyzed for Notch-1, ER, and HER-2 transcripts by RT-PCR; the level of each transcript was normalized to that of the housekeeping gene, GAPDH. Results: The median age of patients is 51 years old (range, 27–77 years). A total of 29 patients (32%) received neoadjuvant chemotherapy, including 8 patients with anti-HER-2 targeted therapy. BMC of neoadjuvant-treated patients had a significantly higher median percentage of CSC in BMC (P= 0.046) and a significantly higher proportion of CSC cells within the Aldefluor+ population (P= 0.013) than those of untreated patients. Median level of Notch-1 transcripts in BMC was lower in neoadjuvant-treated patients compared with that of untreated patients (P= 0.07). There was an inverse correlation between the level of Notch-1 transcripts and the percentage of CSC in BMC of untreated (Spearman's rho= -0.519, P < 0.001), but not in neoadjuvant treated (Spearman's rho= -0.483, P= 0.058) patients. Conclusions: Neoadjuvant chemotherapy is associated with expansion of CSC in the BMC of patients with PBC. Untreated patients with higher level of Notch-1 transcripts in the BMC tend to have lower percentages of CSC and suggest that Notch signaling may be crucial for differentiation of CSC. The prognostic value of this finding is under investigation and gene expression profile of CSC may provide indications for novel neoadjuvant therapies.

No significant financial relationships to disclose.