bluuebunny/crossref_metadata_2025 huggingface dataset:
An elevated body mass (BMI) index predicts for better clinical outcomes in men with metastatic hormone refractory prostate cancer (HRPC)
Authors: Halabi S. , Ou S. , Vogelzang N. J. , Small E. J.
Published: March 2020

4556

Background: Previous articles have reported that an elevated BMI was associated with an increased risk of biochemical failure in hormone sensitive patients. We asked the question as to whether an elevated BMI predicts for worst clinical outcomes, namely overall survival (OS) and prostate-cancer survival (PCS), among 1,216 men with HRPC. Methods: Patients were enrolled on eight clinical trials conducted by the Cancer and Leukemia Group B (CALGB). Eligible patients had progressive prostate cancer during androgen deprivation therapy (with documented castrate levels of testosterone), an ECOG performance status of 0–2, adequate hematologic, renal and hepatic function. We used the NIH definition to classify patients as: normal (<25 kg/m2), overweight (25–29 kg/m2 ), mildly obese (30–34 kg/m2), and moderately to severely obese (≥35 kg/m2). PCS was defined as the time from study entry to the time of death due to prostate cancer. The proportional hazards model was used to explore the prognostic significance of BMI in predicting OS and PCS. Results: The median BMI was 27.7 kg/m2 (inter-quartile range = 25.2–31.0 kg/m2 ). Twenty three percent (285/1216) of the patients had normal BMI, 46% (555/1216) were overweight, 23% (280/1216) were mildly obese, and 8% (96/1216) were moderately to severely obese. In multivariate analysis, adjusting for age, race, performance status, hemoglobin, PSA, LDH, alkaline phosphatase, testosterone, years since diagnosis, presence of visceral disease and Gleason scores, BMI was a statistically significant predictor of OS and PCS. Compared to normal men, the hazard ratios (HR) of overweight patients was 0.80 (95% CI = 0.69–0.93, p-value = 0.003), for mildly obese patients was 0.86 (95% CI = 0.72–1.02, p-value = 0.087) and for moderately to severely obese men it was 0.60 (95% CI = 0.47–0.78, p-value < 0.001). In addition, the HRs for PCS for overweight patients was 0.83 (95% CI = 0.70–0.97, p-value = 0.023), was 0.88 (95% CI = 0.72–1.06, p-value = 0.179) for mildly obese and for moderately to severely obese was 0.62 (95% CI = 0.47–0.81, p-value = 0.001) compared to men with normal BMI. Conclusions: Contrary to what was reported, these findings demonstrate an inverse relationship between BMI and clinical outcomes in men with HRPC.

[Table: see text]
Clinical outcome of taxane-resistant (TR) hormone refractory prostate cancer (HRPC) patients (pts) treated with subsequent chemotherapy (ixabepilone (Ix) or mitoxantrone/prednisone (MP)
Authors: Lin A. M. , Rosenberg J. E. , Weinberg V. K. , Kelly W. K. , Michaelson M. D. , Hussain M. , Wilding G. , Gross M. E. , Small E. J.
Published: March 2020

4558

Background: The clinical course of TR HRPC pts has not previously been evaluated in a large, prospective study. No standard treatment exists for this pt population, although MP is frequently used. Ix is an epothilone B analogue with activity against TR cell lines. Methods: Metastatic HRPC pts with disease progression during or within 60 days of stopping T chemotherapy were eligible. In a 2-arm, non-comparative randomized phase II study, pts were assigned to receive either: 1) M 14 mg/m2 IV q3wks and P 5 mg PO BID or 2) I × 35 mg/m2 IV q3wks. Crossover was allowed for progression or toxicity. The study’s primary endpoint was to detect a ≥ 50% PSA decline by Consensus Criteria in at least 25% of 2nd-line pts (H0 = 10%, α = 0.04, β = 0.18 for each arm). Pts were followed for survival. Results: Forty-one evaluable pts each were accrued to Ix and to MP. The median follow-up is 5.0 months (range: 0.3–19.5). The median number of cycles administered to each 2nd-line arm is 3 (range: Ix: 1–8, MP: 1–12). Median survival from protocol entry is 13.0 months with Ix and 12.5 months with MP. Confirmed 2nd-line post-therapy (rx) ≥50% PSA declines were observed in 17% of Ix pts (95% CI = 7–32) and 20% of MP pts (95% CI = 9–35). Of pts with measurable disease, partial responses were observed in 1/18 pts on 2nd-line Ix (6%; 95% CI = 0.1–27.3) and in 1/15 pts on 2nd-line MP (7%; 95% CI = 0.2–31.9). Median duration on 2nd-line Ix and MP was 2.2 months and 2.3 months, respectively. Crossover to 3rd-line rx occurred in 39% of Ix pts and 68% of MP pts. Confirmed 3rd-line post-rx ≥50% PSA declines were observed in 3/24 Ix pts and in 4/13 MP pts. The most common grade 3/4 toxicity associated with 2nd-line rx was neutropenia as previously reported (41% of Ix pts, 54% of MP pts). Conclusions: This prospective trial has characterized TR HRPC pts as having an observed median survival of approximately 1 year. This may be a useful reference for the screening of effective agents in the 2nd-line setting for TR HRPC. Both Ix and MP appear to have only modest activity as 2nd- and 3rd-line rx in this highly selected TR HRPC population. This study was supported by Bristol-Myers Squibb and the Prostate Cancer Foundation.

No significant financial relationships to disclose.
Neoadjuvant GM-CSF and thalidomide in men with high-risk prostate carcinoma undergoing radical prostatectomy
Authors: Garcia J. A. , Magi-Galluzzi C. , Rothaermel J. , Elson P. , Zhou M. , Klein E. , Dreicer R.
Published: March 2020

4564

Background: Granulocyte macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DC’s) and promotes uptake of tumor antigens by DC’s leading to T cell cross-priming. Thalidomide is an anti-inflammatory agent with immunomodulatory and antiangiogenic activity. Administration of GM-CSF and Thalidomide can induce PSA responses in 20–25% of patients (pts) with Hormone-Refractory Prostate Cancer (HRPC). In an effort to further evaluate this novel combination we conducted a phase II trial in pts with locally advanced PCA. Methods: High-risk PCA pts undergoing radical prostatectomy (RP) were eligible. ECOG 0–1, adequate organ function, and no prior hormonal therapy were required. All pts received GM-CSF at 250 μg administered SC three times weekly. Thalidomide was escalated to reach the study dose of 200 mg/day. Patients were assessed every 4 weeks with therapy continuing to a maximum of 8 weeks. The primary endpoints were pathologic response, rate of PSA decline and toxicity. High-throughput tissue microarrays (TMAs) were also used to assess exploratory tissue endpoints including tumor expression of PTEN, CD3, Ki-67, and CD68 by immunohistochemistry. Results: To date 22 of a total planned of 29 pts are enrolled. Median age is 59 (43–72), median PSA of 10.4 (3.6–64.8). Baseline Gleason Scores (9 pts-GS7, 10 pts-GS8, and 3 pts GS9). 19/22 pts received all 8 weeks of therapy. Three pts discontinued therapy early due to toxicity or drug intolerance. A maximum PSA decline of 15–55% was observed in 86% of pts. Grade (G) 1–2 toxicities included dizziness/paresthesias (68%), constipation (64%), injection site reactions (64%) and fatigue (50%). Only one pt developed G3 toxicity (DVT). Tumor tissue expression of PTEN, Ki-67, CD3 and CD68 was significantly higher in treated pts when compared with matched controls (PTEN p = 0.03, Ki-67 p = 0.004, CD3 p < 0.001, and CD68 p < 0.001). Conclusions: Neoadjuvant therapy with GM-CSF and Thalidomide is well tolerated, and does not appear to impact on the perioperative morbidity of RP. This combination therapy appears to induce overexpression of PTEN, Ki-67, CD3 and CD68 in PCA tissue. Ongoing tissue and serum immune studies are underway to better define the significance of these tissue findings.

[Table: see text]
Public health impact of PSA doubling time after radical prostatectomy on prostate cancer specific and overall survival
Authors: Freedland S. J. , Humphreys E. B. , Mangold L. A. , Eisenberger M. , George D. J. , Partin A. W.
Published: March 2020

4568

Background: Among patients treated with radical prostatectomy (RP) with a PSA recurrence, we previously found men with a PSA doubling time (PSADT) <3 months were at increased risk of prostate cancer death, though these men constituted a small subset of patients. We sought to determine the actual and predicted number of prostate cancer deaths stratified by PSADT. Methods: We retrospectively studied 379 men treated with RP between 1982 and 2000 with a PSA recurrence. We calculated the actual and 15-year actuarial number of prostate cancer deaths in each of the following PSADT categories: <3, 3.0–8.9, 9.0–14.9, and ≥15.0 months. Results: Median follow-up after PSA recurrence was 7 years. During this time, there were 76 prostate cancer deaths; the majority (51%) were among men with a PSADT of 3.0–8.9 months. Though men with a PSADT <3 months were at the greatest risk of death, this group accounted for only 20% (n=15) of all prostate cancer deaths. Using actuarial 15-year estimates of prostate cancer specific survival, 50% of all prostate cancer deaths were among men with a PSADT of 3.0–8.9 months while men with a PSADT <3 months accounted for only 13% of prostate cancer deaths. Using actuarial 15-year estimates of all-cause and prostate cancer specific mortality, among men with a PSADT <15 months, prostate cancer was estimated to be the cause of death in 94% (145/155). Only among men with a PSADT >15 months was the risk of competing causes of mortality high enough such that the majority of deaths were not attributed to prostate cancer. Conclusions: Among a select cohort of men treated with RP who experienced a PSA recurrence, prostate cancer was estimated to account for 75% of all deaths. Though men with a PSADT <3 months were at the greatest risk, the majority of deaths occurred among men with a PSADT of 3.0–8.9 months. Efforts to reduce prostate cancer mortality should focus on men with intermediate PSADT times (3.0–15.0 months) as they represent the greatest public health concern among men with PSA recurrence following RP.

[Table: see text]

No significant financial relationships to disclose.
Erythropoietin receptor expression in bladder cancer
Authors: Belda Iniesta C. , De Castro Carpeño J. , Casado Saenz E. , Feliu Batlle J. , Bernabeu F. , Alves J. , Cejas P. , Sereno M. , Perona R. , Gonzalez Baron M.
Published: March 2020

4584

Background: Several groups have implicated erythropoietin receptor (EPOR) expression in cancer progression, angiogenesis and cell survival. No clinical data about its implication in bladder cancer has been reported. So, our main objective was to determine the expression of EPOR in bladder cancer specimens after radical cystectomy and its potential relation with disease free survival (DFS) and overall survival (OS). Methods: Patients diagnosed with invasive grade 3 bladder cancer were included after radical cystectomy. None of them had node involvement after pathological examination. Data about pathological stage (pT), DFS and OS were recorded. EPOR expression was analyzed by immunohistochemistry in paraffin embedded samples. An expert uro-pathologist ensured enough tumoral proportion in every sample. EPOR antibody was targeted against the extracellular domain of this receptor (Santa Cruz, CA). Positive immunostaining was defined when more than 80% tumoral cells showed a cytoplasmatic staining pattern. Results: Of the 75 consecutive patients included (pT1 = 11; pT2 = 21; pT3 = 21; pT4 = 22), 40 (53.3%; 95% CI 42.61- 64.23) had EPOR expression. No correlation was observed between EPOR expression and pathological stage. Median DFS was 10 months for patients with EPOR expression and was not reached for individuals without receptor expression after 22 months of follow-up (logrank test p < 0.0001). Furthermore, univariate analysis showed that pathological stage had no statistical influence. Finally, multivariate analysis showed only EPOR expression as predictor for DFS and OS (p = 0.0009). Conclusions: EPOR expression is a strong prognostic factor after radical cystectomy in grade 3 bladder cancer patients without node involvement.

No significant financial relationships to disclose.
Nuclear magnetic resonance spectroscopy of expressed prostatic secretions: Metabolite citrate and derivatives are potential markers of prostate cancer
Authors: Crawford D. , Serkova N. , Gamito E. , Jones R. , O’Donnell C. , Hedlund T.
Published: March 2020

4623

Background: Nuclear magnetic resonance spectroscopy (NMRS) along with a novel method for determining absolute concentrations of metabolites were utilized to analyze expressed prostatic secretions (EPS) from men with prostate cancer (PCa) and from healthy controls. Methods: Flash frozen EPS samples from 66 men (40 with PCa and 26 controls) were analyzed by high-resolution 1H-NMR spectroscopy using a Bruker 500 MHz DRX NMR spectrometer with a 1-mm microprobe. The total number of scans per fully relaxed 1H-NMR spectrum was n = 40 with water suppression. Absolute concentrations of endogenous metabolites (citrate, spermine, myo-inositol, lactate, alanine, phosphocholine, glutamate, acetate, hydroxybutyrate) were quantified using trimethylsilyl-propionic acid as an external standard reference. Stepwise multivariable logistic regression (LR) was used to model the risk of PCa based upon the levels of the measured metabolites. Results: The average age of the EPS donors was 54.7 ± 9.8 years. The median Gleason score for the men with PCa was 6 (range 5–9). The Wilcoxon rank sum test indicated that citrate, spermine, inositol, citrate/spermine, and citrate/lactate were all significant predictors of PCa (p < .001). The LR models indicated that the absolute concentration of citrate was highly predictive of PCa with lower concentrations resulting in a higher risk of cancer. The area under the receiver operating characteristic curve (AUROC) for citrate alone was 0.79 (95% CI 0.75–0.83). Using relative concentrations (metabolite ratios) in a two-variable LR model, citrate/spermine and citrate/lactate were also predictive of PCa with an AUROC of 0.76 (95% CI 0.71–0.81). Conclusions: The results suggest that absolute concentration of citrate and its derivatives in EPS as measured by NMRS have promising potential as accurate markers of prostate cancer.

No significant financial relationships to disclose.
Effect of bicalutamide 150 mg on PSA progression in M0 prostate cancer: Results from the Early Prostate Cancer program
Authors: See W. A. , McLeod D. G. , Iversen P. , Wirth M. P. , Armstrong J. , Navani S.
Published: March 2020

4624

Background: Prostate-specific antigen (PSA) progression is the first sign of prostate cancer recurrence after primary therapy. In the Early Prostate Cancer (EPC) program, men with locally advanced disease who received bicalutamide 150 mg (CASODEX) in addition to standard care (radiotherapy [RT], radical prostatectomy [RP], or watchful waiting [WW]) had significantly improved objective progression-free survival (PFS) vs standard care alone. In the RT setting, this translated into improved overall survival (OS). Here, we compare PSA-PFS in the 3rd analysis of the EPC program with the results for objective PFS. Methods: The EPC program consists of 3 trials in which patients (all M0) with either localized (T1–2, N0/Nx) or locally advanced (T3–4, any N; or any T, N+) prostate cancer were randomized to receive standard care plus either bicalutamide 150 mg (n = 4052) or placebo (n = 4061). The primary end points were OS and objective PFS. PSA-PFS was a secondary end point. A PSA progression event was defined as PSA rising to ≥2× baseline or ≥0.4 ng/mL in men with non-quantifiable baseline PSA, death, or objective progression. PSA-PFS and objective PFS were analyzed for stage/therapy subgroups using a Cox proportional hazards model. Results: At 7.4 years’ median follow-up, bicalutamide plus standard care was associated with significantly improved PSA-PFS vs placebo (p < 0.001), irrespective of primary therapy or disease stage. However, PSA-PFS benefit only translated into a significant objective PFS benefit in locally advanced disease ( table ). Conclusion: Adding bicalutamide 150 mg to standard care significantly improves PSA-PFS for men with early, non-metastatic prostate cancer. The significant improvement in PSA-PFS was only accompanied by a significant improvement in objective PFS in locally advanced disease. Consequently, a significant PSA-PFS benefit cannot always be assumed to translate into a significant objective PFS benefit.

[Table: see text]

[Table: see text]
Diethylstilbestrol and docetaxel: A phase II study in patients with metastatic, androgen independent prostate cancer
Authors: Montgomery B. , Lin D. , Ryan C. , Garzotto M. , Beer T. M.
Published: March 2020

4627

Background: The combination of diethylstilbestrol (DES) and docetaxel has additive to synergistic activity against prostate cancer in preclinical models and DES inhibits expression of taxane resistant tubulin isoforms. The objective of this study is to determine the effects of the combination of DES and docetaxel on PSA, overall response, and toxicity. Methods: Twenty nine patients with metastatic androgen independent prostate cancer progressing by rising PSA or scan were treated with DES 5 mg daily the day prior to docetaxel and 1 mg daily continuously in combination with Docetaxel 36mg/m2 IV weekly for 3 weeks of a 4 week cycle. Prophylactic anticoagulation was used in all patients. All patients were assessed by PSA monthly and CT or bone scans every 3 cycles. Dose modifications for hematologic, hepatic and renal toxicity were made. The RECIST criteria and PSA decline by >50% which was maintained for 4 weeks were used. Results: The median age is 69 years (56–84), SWOG PS 0 (0–1), alkaline phosphatase 120 U/L (45–523), Hgb 12.6 g/dL (9.2–16.3), PSA 67 ng/dL (6–1962). The median number of cycles is 5. The median follow up after completion of therapy is 6 mos (1–18). Soft tissue metastases were present in 46% of patients and bone metastases in 96%. Twenty four patients are evaluable for response and toxicity. Of these, 18 patients (75%) had PSA responses and the PSA declined by >90% in 9 patients (38%). The overall response for was 75%. 11 patients suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid induced ulcer. The median number of cycles for responding patients is 9. Two patients developed thrombosis and were positive for Factor V mutations. Conclusions: The combination of DES and docetaxel is well tolerated and toxicity is indistinguishable from docetaxel alone. The overall response rate was 75%, with approximately half of responding patients achieving a PSA < 4.0, suggesting that DES improves the therapeutic index of docetaxel substantially and is an effective regimen using easily administered drugs. (Supported by Sanofi Aventis).

[Table: see text]
Serum c-erbB-2 ectodomain (ECD) correlates with immunohistochemical c-erbB-2 expression and predicts an aggressive clinical outcome in hormone-independent prostate cancer (HIPC) patients (pts) treated with docetaxel (D)
Authors: Domingo-Domenech J. , Gallardo E. , Filella X. , Fernandez E. , Fernandez P. , Gascon P. , Mellado B.
Published: March 2020

4632

Background: The overexpression of c-erbB-2 has been described as a common event associated to the hormone-independent progression in prostate cancer. The clinical implications of c-erbB-2 expression in HIPC pts are not fully established. In this study we investigated the clinical significance of c-erbB-2 serum levels in HIPC pts treated with D and the correlation between serum c-erbB-2 ECD and c-erbB-2 tissue expression. Methods: Pts with HIPC treated with D were tested for serum c-erbB-2 ECD levels by immunoassay before chemotherapy. In pts with available biopsy specimens of hormone-independent tumor, c-erbB-2expression was determined by immunohistochemistry in paraffin-embedded tissue sections. PSA response to D, time to PSA progression and survival were analyzed. Results: Forty-one pts were included in the study. Median follow-up time was 23.3 (3.7–43.1) months. Median time to D progression was 4.1 (0,4–15.1) months and median survival was 11.3 (1,6–43.1). Serum c-erbB-2 correlated with PSA (r=0.351, p=0.025), inversely with time to PSA progression (r = −0.338, p = 0.033) and inversely with survival (r = −0.305, p = 0.05). Median time to PSA progression in pts with high serum c-erbB-2 (≥15 ng/ml) was 1.5 months compared to 4.6 months in pts with low levels (p = 0.0003). Survival in pts with high c-erbB-2 was 11 months and in pts with low c-erbB-2 was 15 months (p = 0.053). HIPC tissue samples from 10 pts were assessed for c-erbB-2 expression. Immunohistochemical c-erbB-2 positive staining (score +2 and +3) was detected in 4 (40%). C-erbB-2 staining showed correlation with serum c-erbB2 levels. Pts with positive staining had 19.1 ± 1.78 ng/ml and negative pts 8.8 ± 2.6 ng/ml (p = 0.001).The 4 pts with tissue c-erbB-2 overexpression had serum c-erbB-2 levels >15 ng/ml, while pts with no c-erbB-2 overexpression in tissue had also low c-erbB-2 levels in serum. Conclusions: High c-erbB-2 ECD in serum is associated with a worse clinical outcome of HIPC. Our data suggest that the determination of c-erbB-2 ECD in serum translates the c-erbB-2 status in the hormone-independent tumor and may be useful to select pts for c-erbB-2-targeted therapy.

No significant financial relationships to disclose.
Meta-analysis of neo-adjuvant androgen deprivation therapy (AD) in localised prostate cancer
Authors: Kumar S. , Harrison C. , Shelley M. , Mason M.
Published: March 2020

4643

Background: AD before primary therapy, either prostatectomy (P) or radiotherapy (RT) is increasingly used in routine practice. Clinical trials of surgical series have shown an improvement in pathological variables but with limited survival data. A few RT studies have shown a clinical benefit. We performed a systematic review and meta-analysis to assess the true impact of NA treatment. Methods: Data from published clinical trials of patients with non-metastatic PC were extracted for quality, and included design, participants and comparisons and meta-analysis was performed for comparable data. The primary endpoint was overall survival (OS) and secondary endpoints included disease-specific, disease-free survival (DFS) and disease recurrence rates. Analysis was performed using Revman 4.2.8. For dichotomous data the odds ratio was calculated with 95% confidence interval (CI) and the results were tested for homogeneity at a significance level of p < 0.1. A fixed effects model was used if there was no evidence of heterogeneity between studies. Results: AD before P led to a significant reduction in disease recurrence (number (n) of patients 973 in 3 trials-overall odds ratio OR 0.74; 95% CI 0.55–1.0; p = 0.05). In addition there was a significant reduction of positive surgical margins (n 1802 in 8 trials-OR 0.34; 95% CI 0.27–0.42; p < 0.00001).There were no comparable data for pooled analysis of DFS or OS. The use of AD before RT resulted in a significant improvement in disease-specific survival (n 1082 in 3 trials-OR 1.37; 95% CI 1.06–1.77; p =0.02) and DFS (n 991 in 2 trials-OR 1.86; 95% CI 1.93–2.40; p < 0.00001). The data for biochemical DFS was heterogenous due to differences in definition of PSA recurrence but the overall effect was highly significant in favour of AD (n 1097 in 3 trials-OR 1.93; 95% CI 1.45–2.56 p < 0.00001). There was a trend to improvement of OS at 1, 2 and 5 years, not statistically significant. Conclusions: Despite a significant improvement in pathological variables with AD before surgery, available evidence is limited regarding a survival benefit which requires prolonged follow-up of patients. In selected patients undergoing RT, the addition of AD results in improved disease specific survival and DFS, likely improvement of biochemical DFS and trend to improvement in OS.

No significant financial relationships to disclose.
The role of surgical staging in grade 1 endometrioid corpus cancer
Authors: Chan J. K. , Guo H. , Cheung M. K. , Osann K. , Husain A. , Teng N. N. , Berek J. S. , Kapp D. S.
Published: March 2020

5009

Background: To evaluate the role of surgical staging of patients with grade 1 endometrioid uterine cancer. Methods: Data including stage, histology, grade, lymph nodes involvement and disease-specific survival were extracted from Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival. Results: 12,712 women were diagnosed with endometrioid carcinoma which included 3,867 (30.4%) with grade 1, 5,285 (41.6%) with grade 2, and 3,560 (28%) with grade 3 disease. The 5-year disease specific survival of patients with grade 1, 2, and 3 disease was 97.78% ± 0.29, 92.14% ± 0.45, and 78.04% ± 0.82, respectively. Of all the patients with nodal involvement, 10% had grade 1, 39% had grade 2 and 51% had grade 3 disease (p < 0.001). Positive nodes were found in 3% of grade 1, 9% of grade 2 and 18% in grade 3 tumors (p < 0.001). Of the 3,867 patients with grade 1 disease, 3,281 (84.9%) had stage I, 317 (8.2%) had stage II, 166 (4.3%) had stage III, and 103 (2.7%) had stage IV disease. Fifteen percent of the patients with grade 1 disease had extra-uterine spread, including 8% to the cervix, 4% to the pelvis and 3% to the upper abdomen or distant metastases. Conclusions: Grade 1 uterine cancers have a risk of extra-uterine spread. Given that the information obtained from a thorough staging procedure clearly influences adjuvant treatment decisions, complete surgical staging is recommended.

No significant financial relationships to disclose.
Screen-and-treat colposcopy as public health strategy for cervical cancer early detection in high-risk population: The experience of the Centro de Estudios y Prevencion del Cancer (CEPREC) in indigenous population of Southern Mexico
Authors: Marcial-Toledo S. , Cortes-Guzman J. , Chavez L. , Guzman-Patraca C. , Terrazas-Espitia S. , Sanchez-Ruiz J. , Perez-Romero J. , Torres R. , Ramirez M. , Gutierrez-Delgado F.
Published: March 2020

5012

Background: The incidence of cervical cancer in Mexico remains high, due to ineffective Papanicolau smear screening, social, educational, cultural and financial issues. Southern Mexico is a region with a high incidence of cervical cancer. CEPREC has designed educational, preventive and early cancer detection programs in that population (Onkologie 27:211). We propose screen-and-treat colposcopy for cervical cancer prevention as public health strategy in selected high-risk population. This study evaluates the feasibility and acceptability of this approach through an educational program. Methods: From 12/2002 to 12/2005, women living in Southern Mexico were educated about cervical cancer and its prevention and were offered colposcopy either in CEPREC facilities or in ambulatory clinics. Colposcopy diagnosis and cervical cytology were established according to the 1990 IFCPC criteria and the 2001 Bethesda System, respectively. A cone biopsy was indicated in patients diagnosed as having human papilloma virus (HPV), cervical intraepithelial neoplasia (CIN 1, CIN 2, CIN 3), or carcinoma. Patients diagnosed as having HPV, CIN 2 and CIN 3 were treated by large loop excision of the transformation zone under local anesthesia. Results: 8281 women (median age 39 years, range: 14–87) were evaluated. 5645 (68%) of them underwent colposcopy in ambulatory clinics. 1171 (14%) women were illiterates and the highest education level was 9 years in 4881 (59%). Median age at first intercourse and first Papanicolau smear were 19 and 29 years, respectively. 4251 (51%) women had vaginal symptoms before colposcopy. Abnormal colposcopy (HPV, CIN 1, CIN 2 or CIN 3), was diagnosed in 1073 (13%) patients and 9 (<1%) had carcinoma. 238 (22%) of them were treated on site. Low-Grade (n = 190) (80%), and high-grade squamous intraepithelial lesions (n = 48) (20%), were diagnosed in those patients. Conclusions: Screen-and-treat colposcopy is a feasible public health strategy with high acceptability in selected high-risk population and could be an alternative to cytology-based screening programs.

No significant financial relationships to disclose.
The number of lymph nodes with metastatic disease portends for a poorer prognosis in women with stage IIIC-IV endometrioid uterine cancer
Authors: Chan J. K. , Cheung M. K. , Osann K. , Husain A. , Teng N. N. , Berek J. S. , Kapp D. S.
Published: March 2020

5039

Background: To determine the prognosis of women with IIIC-IV endometrioid uterine cancer based on the number lymph nodes with metastatic disease Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results Program from 1988–2001 and analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of the 1,222 women diagnosed with stage IIIC-IV endometrioid uterine cancer with nodal disease, the median age was 64 (range: 28–93). All patients underwent surgical staging including a lymph node assessment and were found to have nodal metastases. 639 (52.3%) had stage IIIC, 24 (2.0%) IVA, and 559 (45.7%) IVB disease. The study cohort was divided in three subgroups based on the number of positive nodal metastases: 1, 2–5, and >5. The 5-year overall disease-specific survivals of women with 1, 2–5, and >5 positive nodes were 68.1%, 55.1% and 46.4%, respectively (p < 0.0001). The increasing number of positive nodes was associated with a worsening survival in stage IIIC (77.1%, 60.9%, 69.1%; p = 0.003) and stage IV (50.9%, 49.8%, 38.9%; p = 0.09) diseases. It appears that the extent of benign nodal resection attenuates the increase in the mortality associated with a higher number of positive nodes (see table ). Women with higher number of positive nodes received significantly less adjuvant radiotherapy at 76.8%, 59.5%, and 56.7% respectively. On multivariate analysis, age, stage, grade, number of positive lymph nodes and extent of lymph node resection were significant independent prognostic factors for survival. However, adjuvant radiation was not an important independent prognostic factor in multivariate analysis. Conclusion: Women with node positive endometrioid uterine cancers have a decreased survival associated with increasing number of positive nodes. Our data suggests that the extent of lymph node resection improves the survival of patients with node-positive uterine cancer.

[Table: see text]

No significant financial relationships to disclose.
Development of invasive disease in 433 women treated for vulvar, vaginal or perianal intraepithelial neoplasia
Authors: Fehr M. K. , Dedes K. J. , Heinzl S. , Mueller M. D. , Baumann M. , Fink D.
Published: March 2020

5043

Background: The incidence of intraepithelial neoplasia (IN) of the lower anogenital tract is increasing. Due to small case-series, the malignant potential of treated high-grade IN is not well defined and risk factors for progression are not established. Methods: Patients with IN of the vulva (VIN), vagina (VAIN) and perianal skin (PAIN) were identified in the electronic databases of three university colposcopy clinics. Inclusion criteria were biopsy proven IN grade 2–3 (high-grade) and no history of vaginal, vulvar or anorectal cancer. Excluded were patients with the diagnosis of invasive disease within one year from initial diagnosis of IN. Results: 442 patients were identified from 1977 to 2005 with a mean follow up of 69.9 ± 56.1 months. Initial diagnosis was VIN III in 75.3%, VIN II in 17.2%, VAIN II in 4.3%, VAIN III in 2%, and PAIN II/III in 1.1% of patients. Mean age at initial diagnosis was 47.1 ± 14.1 (range, 18–102). Initial treatment was biopsy and laser evaporation in 61.5%, surgical excision in 32.8%, and other locally destructive methods in 3.1% of patients. 9 patients refused any treatment (2.0%). In the 433 treated patients, recurrent disease (e.g. diagnosed >1 year after initial diagnosis) occurred in 32.2%. In patients with a follow up longer than 5 years, 14.4 % were still experiencing recurrences. In multivariate analysis, immunosuppression (OR: 2.33, 95% CI 1.06–5.06, p = 0.035) was associated with recurrence but not smoking, age or histological grade. Progression to invasive disease occurred in 3.8% of treated patients within a mean time of 7.9 ± 6.8 years (range, 1.3–24.5). In multivariate analysis, immunosuppression (OR:3.31, 95% CI 1.01–10.93, p = 0.049) and smoking (OR:3.12, 95% CI 1.07–9.08, p = 0.037) were independent risk factors for progression. Conclusions: Anogenital IN is a chronic disease in a substantial proportion of patients. The malignant potential is remarkably high despite repeated treatments. Therefore, long lasting surveillance is mandatory, especially in immunosuppressed or smoking patients.

No significant financial relationships to disclose.
Short-term survival of ovarian cancer patients waiting more than six weeks after surgery before chemotherapy is given
Authors: Paulsen T. , Kærn J. , Kjærheim K. , Haldorsen T. , Tropé C.
Published: March 2020

5070

Background: To investigate the impact on short-term survival of time between surgery and start of first chemotherapy cycle in patients with advanced ovarian cancer. Methods: This prospective, population-based study comprised 371 patients with epithelial ovarian, tubal or peritoneal cancer diagnosed in 2002–2003. All patients underwent primary surgery, followed at different intervals by chemotherapy. The data were derived from notifications to the Norwegian Cancer Registry and included medical, surgical and histopathological records. Kaplan-Meier plots were used to show differences in survival, and Cox regression analysis was used to show the effect of prognostic factors on survival, expressed as hazard ratios (HRs). Results: No difference in survival between patient groups was seen when time between surgery and start of chemotherapy was divided into quartiles. The group of patients with interval between surgery and chemotherapy less than six weeks had inferior survival if they had residual disease after surgery. Adjusted HR = 2.36 (95% CI, 1.22–4.57). However, in the patient groups with interval more than six weeks, there was no significant difference in survival between patients without and with residual disease. Adjusted HR = 1.35 (0.51–3.56) versus HR = 1.64 (0.76–3.57). Conclusions: The interval between surgery and start of chemotherapy had no major impact on short-term survival after ovarian cancer. Patients might be included in chemotherapy trials when interval between surgery and start of chemotherapy is more than six weeks.

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No significant financial relationships to disclose.
Phase I trial of liposomal doxorubicin and ZD 1839 in patients with refractory gynecological malignancies or metastatic breast cancer
Authors: Campos S. M. , Parker L. , Chen W. , Bunnell C. A. , Atkinson T. , Lee J. , Matulonis U. A. , Harris L. N. , Krasner C. N.
Published: March 2020

5085

Background: Liposomal Doxorubicin has activity in both breast and ovarian cancer. Preclinical data reported by several investigators have suggested that ZD1839 acts synergistically with chemotherapy in ovarian cancer cells expressing high levels of EGFR. Given the lack of cross resistance and the different targets for these agents a Phase I trial was initiated examining the safety and the efficacy of the combination of Liposomal Doxorubicin and ZD1839. Methods: Dose limiting toxicity was defined within the first two cycles of treatment. The dose escalation schema was described as such: Results: As of January 2006, 23 patients have been enrolled in this study (GYN = 6; Breast 17). Six patients were enrolled in dose level 1 and no DLTs were observed. Dose level 2 enrolled six patients. One DLT was observed (febrile neutropenia). As defined by protocol an additional 6 patients were accrued to dose level 2. Accrual to dose level 3 began on 11/2005. One patient has completed 2 cycles and no additional DLTs have been noted. MTD has not yet been reached. SAEs have included mental status changes, and two CNS bleeds (believed most likely to be unrelated to study drug combination). Toxicities noted in cycle 3 and above have been mild with the exception of 2 grade 3 and 2 grade 4 toxicities related to skin and GI toxicity. No cardiac toxicity was observed. Doxil dose modifications (cycle 3 +) occurred in 7 patients. Best response to therapy has included 2 PRs and 10 patients with SD. Eleven patients to date have had progressive disease. The trial continues to accrue. Correlative studies including EGFR expression and CECs and PKs (at MTD) are planned. Conclusion: Liposomal Doxorubicin in conjunction with ZD1839 is tolerable regimen in patients with advanced breast and ovarian cancer. To date MTD has not been reached.

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A phase I study of a hypomethylating agent azacitidine in combination with carboplatin in patients with platinum resistant epithelial ovarian cancer
Authors: Fu S.
Published: March 2020

5087

Background: Hypermethylation is a common event associated with inactivation of a variety of genes and pathways involved in tumorigenesis and progression as well as drug resistance. Previous evidence displayed that hypomethylating agents could resensitize epithelial ovarian cancer cells to platinum treatment through reexpression of platinum sensitivity-related genes. Therefore, it is of great interest to use a hypomethylating agent to resensitize platinum resistant epithelial ovarian cancer cells to platinum treatment. Methods: This proof-of-concept study used a modified dose-escalation schema (3+3 design). All patients, who have progressed within the 6 months after a platinum-based regimen, are eligible if they have a pathologically confirmed epithelial ovarian cancer. All patients receive subcutaneous injection of azacitidine 75 mg/m2/day for 5 days on days 1–5 and intravenous infusion of carboplatin once on day 2 of each treatment cycle (28 days). Azacitidine is maintained at the same dosage during dose-escalation of carboplatin from AUC4 to AUC5. Results: Six patients have received a total of 16 cycles of treatment. There was no grade 2 or higher toxicity observed. Three patients were evaluable for response: 1 patient, who received 6 cycles of treatment, achieved complete response by CA125 criteria and stable disease by imaging criteria; 1 patient, who received 5 cycles of treatment, displayed stable disease; and the 3rd patient, who received 2 cycles of treatment, showed mixed response by imaging criteria. Conclusions: Preliminary data showed that a regimen of azacitidine 75 mg/m2/day for 5 days plus carboplatin AUC 5 on day 2 was well tolerated in patients with extensive prior treatment.

No significant financial relationships to disclose.
Study participants’ perceptions of the process and impact of receiving results of N9831
Authors: Partridge A. H. , Wolff A. C. , Marcom P. K. , Kaufman P. A. , Moore C. , Lake D. , Fleming G. , Rugo H. S. , Collyar D. , Winer E. P.
Published: March 2020

518

Background: There has been growing interest in providing clinical trial participants with study results. We sought to evaluate the process of sharing results from a large cooperative group trial in an effort to guide clinicians and clinical investigators. Methods: We mailed surveys to a subset of women who participated in NCCTG 9831, Phase III Trial of Adjuvant Chemotherapy with or without Trastuzumab for Women with HER2+ Breast Cancer, after the preliminary study results were mailed to participants. Surveys were sent to all trial participants enrolled through 9 CALGB/ECOG institutions. Results: Of 228 surveys sent, 160 (70%) have been returned. Average age of respondents was 51 years (range 26–76); 84% were white; 61% were college graduates; 4% reported recurrent disease. Women reported receiving results by mail (84%), from a health care provider in person or by phone (43%), and/or from the media (47%); 2% reported that they were not informed of the results. 29% heard the results first from the media; 27% first heard by mail. 35% of women might have preferred to be offered results, with the option of not receiving them, but only 4% of women indicated that they would have declined results had they been offered first. 89% of women found the results information easy to understand; 69% correctly interpreted the results of the study; 31% either had an incorrect interpretation or were unsure of the findings. 81% of women were satisfied with how results were shared; 63% of women felt that learning results had an impact on their lives, 24% were more anxious after learning the results; 36% were less anxious. Multivariable analyses evaluating factors associated with greater satisfaction and increased anxiety will be presented. Conclusions: Sharing results is met with overwhelmingly favorable responses from patients, although a substantial proportion of patients may not initially understand the findings. Some patients desire to be offered results first, but few would decline them. The potential for increased anxiety should be considered, and psychosocial support may be required by some. A plan to share results should be routinely and prospectively included in the design of clinical trials. (Supported in part by an ASCO Career Development Award (AHP)

No significant financial relationships to disclose.
Congestive heart failure (CHF) in older women treated with anthracycline (A) chemotherapy (C)
Authors: Giordano S. H. , Pinder M. , Duan Z. , Hortobagyi G. , Goodwin J.
Published: March 2020

521

Background: There are little available data on the long-term cardiac safety of anthracycline chemotherapy in women over age 65, so we evaluated rates and predictors of CHF in this population of older women. Methods: We used data from the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database and included women aged 66–90 years who were diagnosed with breast cancer from 1992–1999, had no other cancers, and no history of CHF. Multivariable Cox regression analysis was used to estimate the 5- and 10-year cumulative rates of CHF and to determine the factors independently associated with the development of CHF. Results: A total of 34,621 women were included in this observational study: 28,640 who received no C, 3253 who received non-A C, and 2728 who received A C. Women who received A tended to be younger, have lower comorbidity scores, and have more advanced disease than women treated with non-A chemo or women who did not receive chemotherapy (p<0.001 for each). By multivariable Cox regression analysis, the 5- and 10-year rates of CHF in women aged 66–70 years were 19% and 47% for the A C cohort, 14% and 33% for the non-A C cohort, and 12% and 28% for the no C cohort. The adjusted hazard ratio was 1.45 (95% CI 1.19–1.76) for A C versus other C and was 0.97 (95% CI 0.82–1.14) for no C versus other C. The rates of CHF were not statistically different among women in the older age cohorts, although selection biases were likely stronger. Other significant predictors of CHF included black race (HR 1.28, 1.17–1.40), increasing comorbidity, and preceding diagnosis of hypertension (HR 1.40, 1.34–1.47), diabetes (HR 1.23, 1.16–1.30), and peripheral vascular disease (HR 1.26, 1.19–1.34). Conclusions: Although women ages 66–70 treated with A tended to be healthier than women treated with other types of chemotherapy, the rates of CHF among women treated with A were significantly higher. The difference in rates of CHF continued to increase through 10 years of follow-up.

No significant financial relationships to disclose.
Proteomic profiling of breast cancer serum via two-dimensional liquid-chromatography—tandem mass spectrometry
Authors: Ru Q. C. , Zhu L. A. , Silberman J. , Mural R. , Shriver C. D.
Published: March 2020

542

Background: Discovering biomarkers for early cancer detection is a major goal of translational research. We have applied modern proteomic technology, two-dimensional liquid-chromatography-tandem mass spectrometry (2-D LC-MS/MS), to large-scale breast cancer serum profiling. Methods: 189 human sera from breast disease or cancer patients (14 atypical hyperplasia, 63 benign, 29 DCIS, and 83 invasive CA) were analyzed via 2-D LC-MS/MS method. Patient ages ranged from 19 to 97 years, with a mean of 55. Ethnicities included African American, Asian, Hispanic, Native American, and Caucasian. This methodology utilizes only 10 μL of human serum per specimen. Every sample was run three times to ensure reproducibility and to maximize identification. The protein identification was conducted using the Bioworks Browser 3.1 and the IPI_human protein database (version 6.23.04) and filtered via HUPO criteria to ensure confidence. Results: 230 high-confidence proteins were identified from analyses of 189 sera. 26 common serum proteins were detected in all samples and 17 were found in two- or three- diagnostic stages. 83 proteins such as insulin receptor substrate 4, serine/threonine-protein kinase WNK4, DNA mismatch repair protein MSH6, and signal recognition particle 72 kDa protein were detected only in invasive sera. 30 proteins including breast carcinoma amplified sequence 3, uncharacterized bone marrow protein BM032, fibroblast growth factor receptor 2, and tumor necrosis factor receptor superfamily member 4 were detected only in DCIS sera. The 15 proteins detected only in atypical hyperplasia sera included cholecystokinin type A receptor and cell division cycle 2-related protein kinase 7. 59 proteins including serine/threonine protein phosphatase 6, probable transcription factor CST, insulin-like growth factor IA, and connective tissue growth factor were found in benign samples. Conclusions: Identification of signaling pathway/transcriptions proteins and cell cycle related proteins in breast cancer sera, and identification of breast cancer amplified sequence 3 proteins in the DCIS sera, suggest that high-throughput proteomic technologies like 2-D LC - MS/MS may facilitate the discovery of diagnostically useful breast cancer biomarkers.

No significant financial relationships to disclose.
High level analysis of genomic data reveals complex predictors of response to trastuzumab (T) and chemotherapy for early stage breast cancer
Authors: Harris L. N. , Carter S. , You F. , Eklund A. , Hilsenbeck S. , Szallasi Z. , Chang J.
Published: March 2020

544

Background: Trastuzumab (T) with chemotherapy has been shown to improve survival in breast cancer patients but de novo resistance is common. Identifying predictors of response to T in primary cancers may lead to an understanding of mechanisms of resistance. We investigated whether combined microarray datasets from patients with early breast cancer treated with preoperative T and chemotherapy could predict for response to therapy. Methods: Two cohorts of patients with HER2 3+/FISH+, stage II-III breast cancer were included in this analysis: trial 1- T and docetaxel (n=38), trial 2 -T and vinorelbine (n=48), both for 12 weeks. Frozen tissue core biopsies were available and successfully amplified in 41 patients (trial 1: 20, trial 2: 21 patients), with standard sample processing, RNA extraction, amplification and hybridization to Affymetrix U133 chips. Differential expression of genes and chromosomal regions, (defined as >10 genes in a given chromosomal cytoband), between patients with pathologic complete response (pCR) vs. those with residual invasive disease were examined. A measure of total functional aneuploidy (tFA) was calculated by summing net deviation in expression of all chromosomal regions and a gene expression signature of genomic instability (CIN) was derived by the identification of genes showing a high level of correlation with tFA . Results: By unsupervised hierarchical analysis, both datasets interdigitated suggesting no inherent bias. Gene expression patterns of individual genes showed weak associations with pCR. However, distinct statistically significant chromosomal regions, Chr2p23 Chr6q24 Chr7q33 Chr2p2 Chr12q21.31 Chr14q32.2 Chr1p34.2 Chr8q21.3, were associated with pCR to T therapy (p<0.005), and were confirmed in more than 50% samples by SNP analysis. In addition, resistant tumors showed higher levels of the CIN signature (p<0.005). Conclusions: We have shown that gene expression data can be merged and used for discovery predictive chromosomal regions associated T response. In addition, chromosomal instability was associated with T resistance. If validated, these distinct dysregulated chromosomal regions may serve as predictive markers of response to trastuzumab therapy.

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