bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose escalation by high-dose 3D-conformal radiotherapy (HD-3D-CRT) or low-dose 3D-conformal radiotherapy plus HDR brachytherapy (LD-3D-CRT+HDR-B) for intermediate- or high-risk prostate cancer: Early results of a prospective comparative trial
Authors: Guix B. , Bartrina J. , Tello J. , Quinzanos L. , Lacorte T.
Published: August 2020

5118

Background: To report early and late toxicity and preliminary biochemical outcome in 445 patients with intermediate- or high-risk clinically localized prostate cancer treated with either HD-3D-CRT or with LD-3D-CRT+HDR-B. Methods: Between December 1999 and October 2005, 445 patients (pts) with PSA'10, Gleason score'6 and/or T2b-T3 N0 M0 prostate cancer entered the study. Pts were assigned to one of the two treatment groups: 76 Gy HD-3D-CRT to the prostate in 38 fractions (group 1; 223 patients) or 46 Gy LD-3D-CRT+ 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2, 222 patients). Both groups were well balanced taking into account patient's as well as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. Results: All pts completed treatment. None pts included in the group 1 or 2 experienced grade 3 rectal toxicity. 28 pts of group 1 (12.5%) and 6 pts of group 2 (2.7%) developed grade 2 rectal toxicity (rectal bleeding or urgency). 15 pts in group 1 (6.7%) and 3 pts in group 2 (1.3%) developed grade 1 rectal bleeding (less than 2 times/week). In group 1 and 2, 81.8%and 95,9% of pts were free from rectal reactions respectively (p < 0.005). 19 pts in each group developed acute Grade 2 urinary symptoms (mainly dysuria), and none experienced urinary retention. No pts (0%) developed Grade 3 or 4 rectal or urinary complications. With a mean follow-up of 55 months, the 5-year actuarial PSA relapse-free survival rates for intermediate- and high-risk group 1 pts were 92 and 91 % respectively and 97 and 96 % for group 2 pts (p < 0.06). Conclusions: High-dose 3D-EBRT +HDR brachytherapy is a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute and late rectal and urinary complications were significantly reduced with the combined treatment, compared with what was observed with high-dose conventional, 3D-CRT. Short-term PSA control rates tends to be better with in the HDR-boosted patients as spected by higher effective-dose.

No significant financial relationships to disclose.
Five-year relapse-free survival and predictors of relapse following preoperative docetaxel and mitoxantrone for high-risk localized prostate cancer
Authors: Rademacher B. L. , Garzotto M. , Higano C. S. , O'Brien C. A. , Janeba N. , Fazli L. , Lange P. H. , Lieberman S. , Beer T. M.
Published: August 2020

5121

Background: Efforts to incorporate systemic therapy with activity against castration-resistant prostate cancer into the early management of high-risk disease are motivated by persistent risk of relapse when neoadjuvant androgen suppression therapy (AST) is combined with surgery. As docetaxel and mitoxantrone exert anti-tumor effects through distinct cellular mechanisms, this combination has the potential for synergistic activity against prostate cancer. Here we report the 5-year outcomes of patients treated with a novel regimen that combines these agents without AST prior to prostatectomy. We also examined pathologic, biomarker and clinical predictors of early relapse. Methods: 57 high-risk prostate cancer patients were enrolled in a phase I/II study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 delivered weekly for 3 of every 4 weeks per cycle for 4 cycles over 16 weeks followed by radical prostatectomy. A tissue micro-array constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum PSA > 0.4 ng/mL. Results: 54 of 57 pts received all 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months (range 7 to 86 months), 27 of 57 (47.4%) patients recurred. The Kaplan-Meier progression-free survival at 2 years was 65.5% (95% CI 53.0% to 78.0%) and 49.8% at 5 years (95% CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions: Preoperative combination chemotherapy with docetaxel and mitoxantrone is safe. Approximately half of the high risk pts remain relapse free at 5 years and clinical and molecular predictors of early relapse in this population have been identified.

[Table: see text]
Weekly paclitaxel (P) with concurrent external beam radiation (EBRT) and androgen deprivation therapy (ADT) in high-risk prostate cancer (PC) patients with or without prior prostatectomy (RP)
Authors: Wu Y. , Kwok Y. , Mirmiran A. , Goloubeva O. , Mannuel H. , Dawson N. , Amin P. , Hussain A.
Published: August 2020

5122

Background: EBRT with ADT (4 mos to 2–3 yrs) is standard treatment for high risk PC. In this trial, we evaluated weekly P given concurrently with EBRT and ADT in high risk PC. Methods: For pts undergoing RP, high risk was defined as: pT3 and/or pN+, M0, and/or rising PSA (> 0.5) post RP. For pts not undergoing RP (i.e. locally advanced PC [LAPC]) high risk included: cT2b-4N0, N+, M0; bGS 8–10; bGS ≥ 7 + PSA ≥ 10 but ≤ 150; and/or PSA ≥ 20 but ≤ 150. Treatment included ADT (4 or 24 mos, preplanned based on clinical presentation), P (40, 50, or 60 mg/m2/wk) x 7 with EBRT, and whole pelvis EBRT 45 Gy with 19.8 Gy boost (total 64.8 Gy) to prostate bed in RP pts and 25.2 Gy boost (total 70.2 Gy) to prostate in LAPC pts. Results: Between October 1999 and December 2006, 59 pts (29 W, 28 AA) were enrolled (n = 29 LAPC, n = 30 RP); median age 67 yrs, median PSA at trial entry 5.9 (27.5 LAPC, 1.6 RP), median GS 8. Pts were enrolled at different weekly doses of P: 40 mg/m2 n = 10 pts; 50 mg/m2 n = 31 pts; 60 mg/m2 n = 18 pts. ADT for 4 mos was given in 29 pts and for 24 mos in 30 pts. At 40 mg/m2 67/70 (96%), 50 mg/m2 202/217 (93%), and 60 mg/m2 98/126 (78%) planned doses of P were given. There were no acute grade 4 toxicities. Most common grade 3 toxicities were diarrhea 15%, urinary urgency or incontinence 10%, tenesmus 5%, and leukopenia 3%. Median duration of f/u was 75.3 mos, OS 78%, biochemical progression 24/59 (41%) pts, clinical progression 11/59 (19%) pts. Time to biochemical progression was similar between RP vs. LAPC (p = 0.17), between ADT 4 mos vs. 24 mos (p = 0.61), and between AA vs. W (p = 0.54). Conclusions: This trial establishes the feasibility of tri-modality therapy with ADT, EBRT and weekly paclitaxel in high risk PC, both in RP pts and in LAPC pts with intact prostate glands. The maximum tolerated dose of paclitaxel is 50 mg/m2 /wk when given weekly with concurrent radiation to the pelvis and hormone ablation.

No significant financial relationships to disclose.
PITX2 methylation and biochemical recurrence in postradical prostatectomy prostate cancer patients
Authors: Heiden E. , Weiss G. , Banez L. , Freedland S. , Sun L. , Hartmann A. , van Leenders G. , Bangma C. , Ittmann M. , Wheeler T.
Published: August 2020

5124

Background: PITX2 is a bicoid-related transcription factor induced by the Wnt pathway and required for effective cell-type-specific proliferation during development. We previously reported prognostic potential of PITX2 gene promoter methylation for outcome prediction in breast and prostate cancer (PC) patients. Radical prostatectomy (RP) is potentially curative in patients with clinically localized PC. However, biochemical recurrence (BCR) affects 15–30% of patients undergoing RP. In the current study, we validate PITX2 methylation status as a predictor of BCR following RP. Methods: PITX2 methylation status was assessed in formalin-fixed paraffin-embedded RP tumor tissue samples from 476 patients from four different institutions in USA and Europe using customized microarrays. Associations between PITX2 methylation and BCR were assessed using log-rank test and Cox regression controlling for PC features. Results: In multivariate analysis, patients with a high methylation status were at significantly higher risk for BCR compared to patients with low methylation status (HR = 3.0; 95%CI = 2.0–4.5; p < 10-5). BCR-free survival at five years after surgery was 85% and 61% for patients in the low and high methylation group, respectively. In patients with pathological Gleason 7 tumors, the relative risk of suffering BCR was twice as high for a patient with high PITX2 methylation relative to patients with low PITX2 methylation (HR = 2.0; 95%CI = 1.2–3.3; p = 0.005). Moreover, PITX2 methylation status was significant in the group of patients with tumor involvement of the surgical margins in the prostatectomy specimen. (HR = 3.36, 95% CI: 2.24–5.06, p = 0.001). Conclusions: PITX2 methylation status identifies PC patients most likely to experience BCR. This test independently adds to prognostic information provided by standard clinico-pathological analyses improving stratification of RP patients into high- or low-risk for BCR. This new clinical tool would be of particular benefit in assessment of intermediate-risk patients (Gleason 7) or patients with positive surgical margins wherein risk stratification remains a challenge.

[Table: see text]
Gene-based prediction of PSA recurrence for clinically localized prostate cancer patients
Authors: Talantov D. , Jatkoe T. , Bohm M. , Zhang Y. , Stricker P. , Kattan M. W. , Sutherland R. L. , Kench J. G. , Wang Y. , Henshall S.
Published: August 2020

5132

Background: Accurate estimates of the risk of recurrence are needed for the optimal management of patients with clinically localized prostate cancer. We combined an established nomogram and novel molecular predictors into a new prognostic model of prostate specific antigen (PSA) recurrence. Methods: Gene expression profiles from formalin-fixed, paraffin-embedded (FFPE) localized prostate cancer tissues were analysed to identify genes associated with PSA recurrence. The profiles of the identified markers were reproduced by reverse-transcriptase-polymerase-chain-reaction (RTPCR). The RTPCR profiles from 3 of these genes, along with the output from the Kattan post-operative nomogram, were used to produce a predictive model of PSA recurrence. Results: After variable selection, a model of PSA recurrence was built that combined expression values of 3 genes and the postoperative nomogram. The 3-gene plus nomogram model predicted 5-year PSA recurrence with a concordance index (c-index) of 0.77 in a validation set compared to a c-index of 0.67 for the nomogram. This model identified a subgroup of patients that were at high risk for recurrence which were not identified by the nomogram. Conclusions: This new gene-based classifier has superior predictive power when compared against the 5-year nomogram to assess risk of PSA recurrence in patients with organ-confined prostate cancer. Our classifier should provide a more accurate stratification of patients into high and low risk groups for treatment decisions and adjuvant clinical trials.

[Table: see text]
A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CRPC) (CA180085)
Authors: Yu E. , Massard C. , Gross M. , Wilding G. , Posadas E. , Culine S. , Carducci M. A. , Trudel G. , Paliwal P. , Sternberg C.
Published: August 2020

5147

Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory function of dasatinib in pre-clinical models supports its potential as a targeted therapy for prostate cancer. Previously we presented results on BID dosing of dasatinib in the treatment of CRPC (ASCO. 2008 Abstract 5156). A second group of patients (pts) was enrolled to investigate the activity, safety and bone effects of 100 mg once daily dosing. Methods: Male pts with progressive metastatic CRPC, rising PSA, castrate levels of testosterone (< 50 ng/dL) and no prior chemotherapy were enrolled. Dasatinib dose was 100 mg QD. Continuation of bisphosphonates was permitted. Primary endpoint was a composite of: PSA responses, bone scans and disease control by RECIST. Urinary N-telopeptide (uNTX) and bone alkaline phosphatase (BAP) were determined Q 4-weeks as indicators of bone metabolism. Results: 47 pts were treated (median treatment duration was 2.3 months). 11 patients were evaluable by RECIST; of these 64% achieved SD. The composite response rate was (8/47) 17%. Of 22 pts with bone scans, 50% were stable at 12 weeks and 3/9 (33%) were stable at 24 weeks. A prolonged PSA doubling time was observed in 32 of 39 pts (82%), including one pt with a PSA response. Of the pts with evaluable bone markers, including those who continued on bisphosphonate therapy, 20/41 (49%) had a ≥ 35% decrease in uNTX and 21/42 (50%) had a decrease from baseline in BAP. Grade 3/4 adverse events (AEs) were experienced by 13% of pts (diarrhea, asthenia, and pleural effusion [n=1]). Grade 1/2 AEs (≥ 15% of pts) were diarrhea, nausea, headache, fatigue, asthenia, anorexia and dyspnea. Conclusions: Fewer and less severe AEs were observed in all categories for the QD dosing group compared to the previously reported BID dosing cohort. In addition, preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing. These data support the relevance of further studies of dasatinib in metastatic CRPC.

[Table: see text]
A phase I study of sorafenib in association with docetaxel-prednisone in chemonaive metastatic castration-resistant prostate cancer
Authors: Mardjuadi F. , Medioni J. , Kerger J. , Canon J. L. , Duck L. , Oudard S. , Clausse M. , D'Hondt L. , Moxhon A. , Machiels J. P.
Published: August 2020

5153

Background: Docetaxel (D)-prednisone (P) is the standard regimen for metastatic castrate-resistant prostate cancer (mCRPC). Sorafenib (S) is a dual-action kinase inhibitor that blocks cell proliferation and angiogenesis with antitumor activity in CRPC. The objectives were dose limiting toxicities (DLTs)/recommended dose (RD) of S in combination with D-P, pharmacokinetics (PK), and safety at the RD in an expanded cohort. Methods: 6 pts were enrolled per dose level (DL). All pts received D 75 mg/m2/3 wks in 6 chemotherapy cycles and P 10 mg/d. S dose escalation included 4 DL. DL 1: S 200 mg bid from day 3 to 19 of each chemotherapy cycle. DL 2: S 200 mg bid started at day 3 of the 1st cycle and continued without interruption through the cycles. DL 3: S 400 mg bid from day 3 to 19 of each cycle. DL 4: S 400 mg bid started at day 3 of the 1st cycle without interruption through the cycles. DLTs were determined during the first cycle. Results: 24 chemo-naive mCRPC pts (median age 68) were included in the dose-escalation study. PK analysis showed that mean Cmax and AUC of D were increased at cycle 2 in cohort 2, 3, and 4 indicating a PK interaction dependent on the exposure to S. For the 24 pts, the main Gr 3–4 toxicities (N pts) were febrile neutropenia (8), uncomplicated neutropenia (5), and hand-foot syndrome (4). No DLT was found. PSA response (> 50% in PSA decrease) was recorded in 15 out of 20 pts. Conclusions: The RD of S in combination with D is 400 mg bid continuously. PK analysis revealed an interaction between D and S that may explain the high rate of febrile neutropenia and Gr4 neutropenia. 14 pts were included in an expanded cohort to further explore the safety of this regimen. Updated data will be presented.

[Table: see text]

No significant financial relationships to disclose.
A phase I open-label study using lenalidomide and docetaxel in castration- resistant prostate cancer
Authors: Petrylak D. P. , Resto-Garces K. , Tibyan M. , Mohile S. G.
Published: August 2020

5156

Background: Based on efficacy of docetaxel (D) and possible synergism with antiangiogenic agents in AIPC demonstrated by results from a NCI trial of D ± thalidomide, a phase I trial evaluating escalating doses of D and lenalidomide (Ln), a derivative of thalidomide with immunomodulatory and antiangiogenic properties, was designed. Methods: Eligibility requirements include progressive measurable disease or rising PSA levels after antiandrogen withdrawal and < 2 prior chemotherapy regimens. All patients were required to have a castratete testosterone <50 ng/dl and to continue medical castration. Dose of D was 60 mg/m2 on Day 1 of 21-day cycle for dose level (L)1 and 75 mg/m2 for L 2–6. Ln dose levels were: 10 mg (L1–2), 15 mg (L3), 20 mg (L4), 25 mg (L5) and 30 mg (L6) for days #1–14. Pts were given prednisone 5 mg po |[BI]D continuously and 8 mg of decadron 12, 8 and 1 hour prior to D without prophylactic anticoagulation. 6 patients (pts) were entered at each level, escalation to the next level occurred if no more that 1 dose limiting toxicity|[(D]LT) was observed during cycle 1. Results: Thirty four pts were enrolled in L1–6; all pts are evaluable for toxicity. Pt characteristics include median age of 70 yrs (range 47–85), median baseline PSA of 101.9 ng/ml (range 5.9–7480), 14 pts (41%) had received prior chemotherapy (7 with 2 prior regimens). All had overt metastatic disease to viscera or bone; 21 pts had measurable disease. Median number of cycles for L1-L5 was 8 (range 2–19). DLT's observed: L2: Grade 4 Neutropenia (1 pt); L3–5 None. Of the 3 patients treated at L6, 2 developed DLTs (febrile neutropeina, grade 4 neutropenia) precluding further dose escalation. Other Grade 3/4 toxicities observed after cycle 1 included deep venous thrombosis (2 pts), grade 3 neutropenia (2 pts), grade 3 facial edema (1 pt) Of 31 pts evaluable for post treatment PSA declines; 8/17 (47%) untreated pts 7/14 (50%) previoustly treated pts had a >50% decline in PSA. Five pateints achieved a partial response in measurable disease, one had a near complete resolution of a biopsy proven metastatic pulmonary nodule. Conclusions: The recommended dose for is 75 mg/m2 D Q 3 weeks day 1 and Ln 25 mg PO D1–14. An expanded cohort of 10 patients will be treated at this level to further define toxicities.

No significant financial relationships to disclose.
The prognostic significance of bone metastases and skeletal-related events (SREs) in prostate cancer survival: A population-based historical cohort study in Denmark (1999–2007)
Authors: Fryzek J. P. , Cetin K. , Nørgaard M. , Jensen A. Ø. , Jacobsen J. , Sørensen H. T.
Published: August 2020

5160

Background: Common among advanced prostate cancer patients, bone metastases indicate cancer progression and poor prognosis but few studies have quantified their influence on patient survival, particularly in the presence of subsequent skeletal-related complications. We therefore sought to examine this in a large population-based cohort of prostate cancer patients. Methods: Using data from the Danish National Patient Registry (covering all Danish hospitals), we studied 23,087 patients diagnosed with prostate cancer between 1999 and 2007, with follow-up through April 2008 (median follow-up: 2.2 years). We estimated the incidence of bone metastases following cancer diagnosis and the subsequent occurrence of SREs (radiation and surgery to the bone, fracture, spinal cord compression). We then computed and compared survival for three prostate cancer subgroups - no bone metastases, bone metastases, and bone metastases with SREs - using Kaplan-Meier and multivariate Cox proportional hazards models. Results: Across the study period, 14% (n = 3,261) of the prostate cancer patients developed bone metastases: 6.8% (n = 1,570) had bone metastases and no SRE and 7.3% (n = 1,691) had both bone metastases and at least one SRE (radiation to the bone was most frequent). One-year survival was lowest for prostate cancer patients with bone metastases and SREs (40%) compared to the groups with no bone metastases (87%) and with bone metastases but no SREs (47%). Similarly, after adjusting for age and the presence of comorbidities, short-term prognosis was poorest in patients with both bone metastases and SREs: compared to prostate cancer patients with no bone metastases, the 1-year mortality rate was 6.7 times greater for those with bone metastases and SREs (95% confidence interval (CI): 6.0–7.6) versus just 4.7 times higher in those with only bone metastases (95% CI: 4.3–5.2). Less than 1% of prostate cancer patients who developed bone metastases and suffered any SRE survived beyond five years. Conclusions: Although the presence of bone metastases confers a short-term prognosis in prostate cancer patients, survival is even poorer for patients who also experience skeletal-related complications.

[Table: see text]
Impact of Asian American race on prostate cancer outcomes
Authors: Brassell S. A. , Raymundo E. , Chen Y. , Zhao J.
Published: August 2020

5165

Background: The global increased incidence of prostate cancer (CaP) is of growing concern, notably in Asia where a 118% rise has been documented. Recent publications report that Asian Americans are more likely to have advanced clinical stage, higher tumor grades, and worse survival rates compared to other racial groups. It remains unclear if these adverse outcomes are attributable to intrinsic biologic differences of CaP in Asians or socioeconomic and cultural differences. Methods: Men registered into the Center for Prostate Disease Research multi-center military national database from 1989–2007 with biopsy-proven CaP and categorized as Asian American, Caucasian, or African American descent were included. Demographic and clinical characteristics were examined. Frequencies were reported for categorical features. Measures of central tendency and dispersion were reported for continuous features. Chi-square, ANOVA and Kruskal-Wallis test were used to examine association between race and clinico-pathologic features. Differences of PSA recurrence and overall survival rates were analyzed by Kaplan-Meier. The multi-variate Cox proportional hazard model was used to examine predictive value of clinico-pathologic features. Results: Included patients were 10,964: 583 (5.3%) Asian Americans, 2,046 (18.7%) African Americans, and 8,335 (76.0%) Caucasians. At diagnosis, Asian Americans had lower clinical stage (p<0.0001) but worse biopsy grade (p = 0.0006) than other groups. They had a higher percentage of organ confined disease (p < 0.0001) and were more likely to choose radical prostatectomy (RP) (p < 0.0001). Asian Americans had improved biochemical recurrence free (p<0.01) and overall survival (p < 0.001) compared to African Americans or Caucasians treated with RP or external beam radiation. Conclusions: Asian Americans with CaP treated in an equal access military health care system have improved pathologic outcomes and survival characteristics compared with other races. Asian ethnicity's negative impact on survival noted by others appears to be from factors other than the tumor's intrinsic behavior such as language barriers, socioeconomic status, and cultural norms.

No significant financial relationships to disclose.
Results of a multicenter pilot study of weekly nab-paclitaxel, carboplatin with bevacizumab, and trastuzumab as neoadjuvant therapy in HER2+ locally advanced breast cancer with SPARC correlatives
Authors: Yardley D. A. , Raefsky E. , Castillo R. , Lahiry A. , LoCicero R. , Thompson D. , Shastry M. , Trieu V. , Knauer D. , Desai N.
Published: August 2020

527

Background: The addition of targeted therapies to standard chemotherapy has resulted in improved outcomes in metastatic, neoadjuvant and early stage breast cancer. A phase III study in MBC demonstrated improved efficacy with nab paclitaxel (nab-P) compared with standard solvent-based paclitaxel. The secreted protein acidic rich in cysteine (SPARC) is a poor prognostic factor for survival and may mediate enhanced intratumoral accumulation of nab-P via an interaction with albumin. This multicenter phase II pilot study was designed to evaluate the feasibility, safety, and preliminary efficacy of dual VEGF and HER-2 monoclonal antibodies of bevacizumab (B) and trastuzumab (T) administered in with neoadjuvant nab-P and carboplatin (C) with SPARC tumor correlatives. Methods: Eligibility: clinical T1c-T4d and/or N0–3, M0 (T1N0M0 excluded) chemo naive, ECOG PS 0–2, normal LVEF, adequate organ function. Treatment: nab-P 125 mg/m2 D1, 8, 15 with C AUC 6 D1 q28 days plus T 4 mg/kg load followed by 2 mg/kg/wk and B 5 mg/kg/wk x 6 cycles followed by surgery. Post surgery T and B continued for 52 wks. SPARC tumor expression was measured by immunohistochemistry. Results: 29 pts are enrolled and evaluable for safety. Median age: 52 years (29–76), ECOG PS 0–93%, median tumor size 3.2 cm, 54% ER-/PR-, 72% node positive. G3/4 neutropenia was 38% with no febrile neutropenia. Nonheme toxicity: G3/4 hyperglycemia 10%, proteinuria and hypertension, each in 7%. 8 pts were hospitalized (infection-4, ↓LVEF-1, wound dehiscence-1 pt, other-2). 5 pts did not complete neoadjuvant therapy (↓LVEF-1, noncompliance-1, pt request-3) and 10 pts did not complete post op therapy ((pt request-2, toxicity-3, wound-2, unk-3). Pathologic responses are available for 20 pts. pCR was noted in 13/20 pts (65%) and PR was noted in 7/20 pts (35%). 77% of the pCR pts (10/13) and 86% of the PR pts (6/7) were positive for SPARC. Conclusions: Neoadjuvant B, T with nab-P and C is feasible and highly active with a remarkable pCR of 65%. SPARC tumor correlations with pathologic response data reveal a concordance between the high response rate and high incidence of SPARC positivity.

[Table: see text]
DNA repair gene expression profile and risk of locoregional relapse in locally advanced breast cancer patients
Authors: Le Scodan R. , Cizeron-Clairac G. , Fourme E. , Meseure D. , Vacher S. , Spyratos F. , Cvitkovic F. , de la Lande B. , Lidereau R. , Bieche I.
Published: August 2020

528

Background: The cytotoxicity of radiation therapy appears mainly mediated through the induction of DNA-double strand breaks. We explore whether DNA repair gene expression could be associated with the risk of locoregional recurrence (LRR) in locally advanced breast cancer patients. Methods: mRNA levels of 21 selected DNA repair genes were measured in tumors samples of 97 locally advanced breast cancer patients included in a phase III trial (CRH cohort), using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with LRR-free survival (LRR-FS) and overall survival (OS). Results were validated in an independant cohort (Netherlands Cancer Institute: NKI cohort). Multivariate analysis, including known prognostic factors, was done to assess the association between gene expression profile of DNA repair genes and outcomes. Results: Overexpression of RAD51, PRKDC, and XRCC6 were associated with a higher risk of LRR in the CRH cohort. RAD51 was the only gene associated with LRR in the NKI cohort. With a median follow-up of 126 months (CRH cohort), the 5-year LRR-FS rates were 100% in patients (n = 61) with low RAD51, compared with 70% in patients (n = 36) with high RAD51 (p < 0.0001). The 5-year OS rates were 95% in patients with low RAD51, compared with 69% in patients with high RAD51 (p = 0.00026). RAD51 overexpression was associated with a higher risk of LRR (multiadjusted hazards ratio [HR], 12.83, 95% CI: 3.6 - 45.6) and a higher risk of death (multiadjusted hazards ratio [HR], 4.10, 95% CI: 1.7 - 9.7). RAD51 was also significantly associated with shorter LRR-FS and OS in the NKI cohort. Conclusions: Our results suggest that overexpression of RAD51, a key component of the homologous recombination and the DNA DSBs repair, is associated with a higher risk of LRR and death, and may be a prognostic marker of LRR in locally advanced breast cancer patients.

No significant financial relationships to disclose.
The influence of margin width and volume of disease near margin on benefit of radiation therapy after breast-conserving surgery for DCIS: Results of long-term follow-up
Authors: Rudloff U. , Brogi E. , McCormick B. , Brockway J. P. , Goldberg J. I. , Wynveen C. A. , Reiner A. S. , Patil S. , Van Zee K. J.
Published: August 2020

531

Background: There remains variation in the use of radiation (RT) in women with DCIS, despite prospective randomized trials documenting its benefit in reducing the risk of ipsilateral breast tumor recurrence (IBTR). Methods: Patients with DCIS treated with excision alone or excision plus radiation at our institution from 1991–1995 were identified. A dedicated breast pathologist assessed margin width, number of involved ducts at closest margin, nuclear grade, and presence of necrosis and lobular neoplasia. Pathological variables, age, and presence of palpable mass were tested in uni- and multivariate analysis for association with risk of IBTR and added value of RT. Results: 294 patients with a median follow-up of 11 years had actuarial 10- and 15-year overall IBTR rates of 22 and 29%. For lesions excised with margins of <1mm, 1–9mm, and ≥10mm, the actuarial 10-year IBTR rates were 28, 21, and 19%, respectively. RT reduced adjusted IBTR rates by 62% (12 vs. 28%; p=0.002) for all patients; 83% for lesions with <1mm margins (p=0.002), 70% for 1–9mm (p=0.05), and 27% (p=0.55) for ≥10mm. Following adjustment for other variables, higher volume of disease near the margin was associated with risk of IBTR in the no RT group (HR=3.37, p=0.002) and greater benefit of RT (HR 0.14; p=0.004). Conclusions: Effect of RT on local recurrence risk is influenced by both margin width and number of involved ducts at nearest margin. Patients with higher volume of disease near the margin derive a greater benefit from the addition of RT. Despite margins of ≥10mm, the risk of local recurrence remains substantial in patients with DCIS.

[Table: see text]

No significant financial relationships to disclose.
Serum 1-OH vitamin D (D) and prognosis of postmenopausal breast cancer (BC) patients: NCIC-CTG MA14 trial
Authors: Piura E. , Chapman J. W. , Lipton A. , Zhu L. , Leitzel K. , Wilson C. F. , Pritchard K. I. , Shepherd L. , Pollak M. N.
Published: August 2020

534

Background: In vitro, D has demonstrated regulatory functions in breast cancer cells and the bone microenvironment. Higher serum D levels were associated in some prior studies with favorable BC prognosis. We previously found that the baseline serum bone resorption marker, beta C-terminal telopeptides of type I collagen (B-CTx), was associated with bone-only first relapse, and that higher levels of insulin secretion as estimated by c-peptide level was associated with reduced event-free survival (EFS). We hypothesized that baseline serum D might be associated with relapse of breast cancer in bone and/or other metastatic sites. Methods: Baseline D was determined for the phase III MA.14 trial of adjuvant tamoxifen (20 mg/day oral for 5 years) ± octreotide (90 mg/month depot injection for 2 years). Stratification was by adjuvant chemotherapy, axillary lymph node status, and hormone receptor status. EFS, time from randomization to recurrence, second malignancy, or death due to any cause, was the primary endpoint. Recurrence-free survival (RFS), time from randomization to recurrence of the primary disease alone, was a secondary endpoint. For both endpoints, step-wise forward multivariate Cox regression adjusted for stratification factors was used to examine the association of D and outcome; a factor was added if p < 0.05. Results: Baseline D levels were available for 607 (91%) patients. As expected, D levels for a population far from the equator varied with month of blood draw (p = 0.007), which gives confidence in assay performance. Continuous D was not associated with RFS of any relapse (p = 0.57), bone only relapse (p = 0.19), bone + other site of relapse (p = 0.73), or all bone relapse types (p = 0.66). D was not associated with EFS (0.43), even when adjusted by season (p = 0.64), level deficiency/insufficiency vs sufficiency/toxicity (p = 0.69), age (p = 0.54), and BMI (p = 0.32). As well, interactions between D and season, age, and BMI were non-significant (respectively, p = 0.90, 0.84, 0.23). Conclusions: D was not associated with EFS or RFS in postmenopausal breast cancer patients in this well controlled hormonal therapy study, a result consistent with some, but not all, studies of this issue.

No significant financial relationships to disclose.
Correlation of levels of Akt phosphorylation at Ser473 with benefit from paclitaxel chemotherapy in NSABP B-28 patients with node-positive breast cancer
Authors: Yang S. X. , Costantino J. P. , Nguyen D. , Jeong J. , Mamounas E. P. , Wolmark N. , Kim C. , Kidwell K. , Paik S. , Swain S. M.
Published: August 2020

537

Background: We investigated the levels of tumor phospho-Akt(Ser473) (pAkt) and treatment outcome of patients with node-positive breast cancer after adjuvant treatment with doxorubicin/cyclophosphamide (AC) followed by four cycles of paclitaxel (PTX) (AC→PTX) compared with AC chemotherapy alone in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Methods: The primary tumors on B-28 tissue microarray were available from 1581 of 3060 patients enrolled. pAkt status was examined by immunohistochemistry with the antibody to pAkt(Ser473) (Cell Signaling Technology) at the National Cancer Institute. Levels of pAkt were quantitatively scored with the assistance of an Automated Digital Imaging System blinded to clinical outcome, and categorized by the staining index (intensity X % of staining /100) of > 2 (high) and ≤ 2 (low). The association between tumor pAkt level and clinical outcome at 10 years was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor and HER2 status. Results: Among patients with low tumor pAkt levels (n = 975), there was no DFS difference between those treated with or without PTX (adjusted HR = 1.02, p = 0.81). However, among patients with high tumor pAkt levels (n = 606), those treated with AC→PTX had a 26% reduction in DFS event rate compared to those treated with AC only (adjusted HR = 0.74, p = 0.02). There was no OS difference between treatment groups for those with low pAkt cancer (HR = 0.97, p = 0.80). In patients with high pAkt cancer, those treated with AC→PTX had a 20% reduction in death rate compared to those treated with AC only but this difference did not reach statistical significance (adjusted HR = 0.80, p = 0.17). Conclusions: High levels of Akt phosphorylation at Ser473 independently predict a DFS benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide in node-positive breast cancer. Patients with low levels of pAkt breast cancer may not benefit from the sequential addition of PTX to doxorubicin plus cyclophosphamide.

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In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer
Authors: Huh W. K. , Straughn J. M. , Cohn D. E.
Published: August 2020

5503

Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer.

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Influence of residual disease and extreme drug resistance assays on outcome in patients with epithelial ovarian cancer
Authors: Karam A. , Wang Chiang J. , Fung E. , Nossov V. , Karlan B. Y.
Published: August 2020

5504

Background: Extreme drug resistance (EDR) assays have been used as tools in identifying those agents that are least likely to be of clinical benefit in the treatment of epithelial ovarian cancer (EOC). We sought to examine the effect of obtaining EDR assays on the outcome of patients with EOC in the primary and recurrent setting. Methods: We conducted a retrospective review of demographic, pathologic, EDR assay and outcome data from 377 patients with EOC who had an assay sent at the time of their diagnosis or at recurrence. Univariate followed by multivariate analyses using Cox proportional hazards method were performed to identify and estimate the impact of independent prognostic factors on time to progression (TTP), overall survival (OS) and survival after recurrence (RS). Results: Increasing age was associated with a worse OS and RS (HR = 1.34; 95% CI, 1.14–1.58 and HR = 1.14; 95% CI, 1.00–1.31, for each decade increase in age respectively). Compared with patients with microscopic residual disease, patients who were left with 0.1 to 1.0 cm and >1.0 cm residual disease had an increased risk of recurrence (HR=1.94; 95% CI, 1.33 to 2.84 and HR=3.61; 95% CI; 2.07 to 6.39, respectively) and death (HR = 1.59; 95% CI, 1.03 to 2.45; and HR = 2.14; 95% CI, 1.09 to 4.20, respectively). For patients who recurred, those who did not undergo secondary cytoreductive surgery and patients who were left with >1.0 cm residual had an increased risk of death compared to patients with microscopic residual (HR = 2.13; 95% CI, 1.28 to 3.54; and HR = 2.84; 95% CI, 1.71 to 4.71, respectively). EDR assay results for single agents or combinations did not independently predict patient outcomes. Conclusions: The amount of residual disease continues to be an important prognostic factor, especially when all macroscopic disease is removed both in the primary and recurrent setting. Increasing age is also an independent predictor of OS and RS. EDR assay results do not independently predict or alter the outcomes of patients with EOC who are treated with the current standard of care including optimal cytoreductive surgery followed by platinum and taxane combination chemotherapy in either the primary or recurrent setting.

No significant financial relationships to disclose.
Sentinel node (SN) biopsy in patients with vulvar cancer: A Gynecologic Oncology Group (GOG) study
Authors: Levenback C. F. , Tian C. , Coleman R. L. , Gold M. A. , Fowler J. M. , Judson P. L.
Published: August 2020

5505

Background: Vulvar cancer is a good target for SN strategy because lymphatic drainage is predictable and the morbidity of regional lymphadenectomy is significant. GOG 173 is a validation study of SN biopsy in a multi-institutional setting. Methods: Eligible patients have squamous carcinoma, nonsuspicious lymph nodes and tumor diameter between 2 cm and 6 cm. No surgeon skill verification was required. Use of radiocolloid for SN identification was an optional adjunct to blue dye until 2001 when it became mandatory. All patients underwent completion inguinal femoral lymphadenectomy. The study goal is to enroll 120 patients with nodal metastases to validate the sensitivity of SN > 88% (which would lead to a false negative predictive rate of <5% assuming the node metastases rate is ≤30%). Results: The study was opened in 12/1999 with 510 patients enrolled from 47 institutions (median = 5; range: 1–78 and 25th-75th percent: 3–14) as of 12/2008. 445 patients have data review completed. Of 403 evaluable patients, the median age was 66.9 years and 92.8% were white. 109 patients (27.1%) had lateralized lesions and unilateral groin dissections and 294 (72.9%) had midline involvement and bilateral dissections, resulting in 697 groins evaluated. SN was successfully identified in 78.8% (67/85) of patients using blue dye only and in 96.2% (306/318) using combination of radiolocalization and blue dye. For 294 patients with midline lesion treated by bilateral dissection, 159 (54.1%) had SN identified on both sides,114 (38.8%) on one side, and 21 (7.1%) not identified on either side. SN identification was successful in 373 (92.6%) patients. Nodal metastases were identified in 117 patients (31.4%). Conclusions: The combination of blue dye and radiocolloid appear superior to blue dye alone. Confirmed results for the entire cohort will be reported.

No significant financial relationships to disclose.
Effect of six courses of neoadjuvant chemotherapy on pathological complete remission in advanced ovarian cancer
Authors: Zamagni C. , De Iaco P. , Rosati M. , Cacciari N. , Rosati F. , Rubino D. , Martoni A. A.
Published: August 2020

5513

Background: The role and the duration of NACT in ovarian cancer are debated. A randomized trial comparing upfront surgery versus 3 courses of NACT (Vergote 2008) demonstrated similar survival, but less morbidity in favor of NACT. However, pathological complete remissions (pCR) were rare and 68% of pts still had lesions greater than 2 cm after 3 courses of NACT. The rate of pCR correlates with a better survival in other tumors, such as breast cancer, and its rate is higher after 6–8 courses of NACT. We conducted this study to verify the incidence of optimal pathological remission after 6 courses of NACT. Methods: Eligible pts had stage IIIC-IV EOC unsuitable for optimal upfront surgery and were treated with 6 cycles of carboplatin AUC 5 and paclitaxel 175 mg/sm, every 3 weeks before surgery. We considered as optimal pathological responders: 1) the pts with absence of cancer cells in surgical specimens, and 2) the pts with no macroscopic residual after surgery and with only small clusters or individual cancer cells in surgical specimens. All the other cases were considered as pathological nonresponders, even if a relevant shrinkage of tumor burden and an optimal surgical debulking were obtained. Results: 35 stage IIIC/IV pts were enrolled; 33 (94%) completed 6 courses of NACT. We observed 18 (51%) pathological responders, and 17 pathological nonresponders (as defined above). Overall, in 20 (57%) pts the goal of no residual tumor after surgery was achieved. After a median follow-up of 21 mo.s, 21 pts progressed (median PFS 15 mo.s) and 10 pts died. As expected, pts with tumor residual after surgery less than 1 cm survived significantly longer than patients with a greater residual (p .0005). The median overall survival was longer in pathological responders (median not reached) vs nonresponders (19.8 mo.s) (p.03). Conclusions: In our study an optimal pathological response occurred in 51% of cases after 6 cycles of carboplatin-paclitaxel, doubling the results described in the literature with 3 courses of NACT. Given that an optimal pathological response correlates with a longer survival compared to a sub-optimal one, a randomized study of 6 vs 3 courses of NACT in order to verify if the increase in pathological response rate will translate into a survival benefit is warranted.

No significant financial relationships to disclose.
Paclitaxel (T), ifosfamide (I), and carboplatin (Cb) (TICb) combination chemotherapy in advanced uterine and adnexal malignant mixed mullerian tumors (MMMTs)
Authors: Kosmas C. , Mylonakis N. , Tsakonas G. , Vorgias G. , Pantelis N. , Politis P. , Kalinoglou N. , Tsavaris N. , Akrivos T. , Karabelis A.
Published: August 2020

5517

Background: Malignant mixed mullerian tumors (MMMTs) of the uterus and adnexa represent aggressive gynecologic malignancies with a high rate of locoregional and distant failure. For that reason we evaluated the TICb combination in patients with advanced MMMTs. Methods: Patients with advanced MMMTs [stages III-IV and relapses after surgery (Sx)±RT], WHO-PS 0–2, no prior chemotherapy, unimpaired hematopoietic/organ function were eligible. Chemotherapy was administered as follows; T: 175 mg/m2 d1, I: 2.0 g/m2/d-d1+2, and Cb at a target AUC = 5 (according to creatinine clearance based on Calvert's formula) on d2 after I. G-CSF was administered from day 3–7. Results: Thirty-two patients with MMMTs of the uterus (n = 28), tubes (n = 2), or ovary (n = 2) have entered so far and all are evaluable for response and toxicity: median age = 61 (45–72), PS = 1 (0–1), stages; III = 18 (56%), IV = 14 (44%), histologies were; with homologous sarcoma component: 21, with heterologous component: 11. Prior treatment for locoregional disease included Sx: 23, Sx+RT: 9. Disease sites at diagnosis included: pelvic disease 12; pelvic/paraortic lymph nodes 14; peritoneal implants 16; liver 4; lung nodules 9; bone metastases 1; malignant pleural effusion 4. Responses were as follows: 21/32 (66%) evaluable patients responded, with 9 complete responses (CR) and 12 partial responses (PR), while 8 had stable disease (SD), and 3 developed progressive disease (PD). The median response duration was 8 mo (4–28), median time-to-progression (TTP) 12.5mo (4–26), while median overall survival (OS) has not been reached yet since most patients receive second-line therapy. Grade (Gr) 3/4 toxicities included: neutropenia 18/32 (56%)-with 11 developing Gr4 (≤7 days) and 19% of patients at least one episode of febrile neutropenia managed successfully by broad spectrum antibiotics, thrombocytopenia Gr3: 5/32 (16%) and Gr4 3/32 (9%), no Gr3 neuropathy, Gr1 CNS toxicity in 1, no renal toxicity, 15 Gr2 myalgias, and 4 Gr3 vomiting. Conclusions: In the present study, it appears that the TICb combination, yielded important activity with acceptable toxicity in females with advanced MMMTs.

No significant financial relationships to disclose.