bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma (mRCC) with severe renal impairment or on haemodialysis
Authors: Josephs D. H. , Hutson T. E. , Pickering L. M. , Larkin J. M. , Choueiri T. K. , Patel T. V. , Mcdermott D. F. , Powles T. , Harper P. G. , Chowdhury S.
Published: August 2020

5109

Background: Sunitinib is currently a standard of care for the treatment of mRCC. Due to the inclusion criteria of clinical trials, no studies of sunitinib have enrolled patients with severe renal impairment or those undergoing haemodialysis, and thus further investigation of the effect of sunitinib in this population is required. Methods: Clinical databases were used to identify all patients with mRCC treated with sunitinib in five institutions internationally. Medical records were searched to identify only those patients with a creatinine clearance (CLcr) of <30ml/min or who had end stage renal disease (ESRD) requiring haemodialysis. Baseline characteristics, toxicity data and progression free survival (PFS) were collected. Results: 21 patients met inclusion criteria with 9 (43%) undergoing haemodialysis. Baseline characteristics include a median age of 62 years (range 44–80); 90% of patients had ECOG PS of 0 or 1; 38% of patients had > 2 metastatic sites and 86% had prior nephrectomy. The estimated median PFS of this cohort was 38 weeks (range 2–120) although progression has not yet been reached in 8 (38%) patients. PR or SD was observed as best response in 17 (81%) patients. The most common treatment-related adverse events (AEs) included fatigue, diarrhoea, hand foot skin reaction (HFSR), nausea and vomiting and rash. Grade 3 treatment related AEs including fatigue, HFSR, diarrhoea and rash occurred in a total of 7 (33%) of patients. Only one patient experienced grade IV toxicity (HFSR). Conclusions: These data suggest that patients treated with sunitinib who have severe renal impairment, or ESRD on haemodialysis, have a PFS that is comparable to patients with normal renal function. In addition sunitinib appears to be reasonably well tolerated in this group of patients. These preliminary results warrant confirmation in a larger cohort of patients.

[Table: see text]
Cost implications of intravenous bevacizumab treatment in patients with renal cell carcinoma (RCC): A retrospective claims database analysis
Authors: Dial E. , Duh M. , Fournier A. , Antras L. , Rodermund D. , Neary M. P. , Oh W. K.
Published: August 2020

5112

Background: Angiogenesis inhibitor (AI) therapies are promising novel treatments for patients with RCC. However, IV therapy may impose transportation burdens for patients, infection risk from IV catheters and increased costs. The incremental costs associated with IV vs. oral administration of selected AI therapies (oral sunitinib or sorafenib, or IV bevacizumab off-label) for the treatment of RCC were evaluated. Methods: Patients with ≥ 2 RCC claims (ICD-9 189.0, 198.0) were identified from a large US commercial health insurance claims database from 1/02 to 12/07. Patients receiving bevacizumab (N=109) were matched 1:1 to patients receiving sorafenib or sunitinib, and observed from their first AI therapy claim until the last treatment date. Inpatient, outpatient and pharmacy costs were calculated on a per- patient per-month (PPPM) basis over the treatment period. Cost comparisons between the IV AI group and each separate oral AI group were performed using multivariate Tobit regressions for each category separately, adjusting for age, gender, region, health plan, time from first RCC claim and first metastasis claim to treatment initiation. Results: Mean total medical cost was $13,351, $6,998, and $8,213 PPPM for bevacizumab, sorafenib, and sunitinib, respectively (p<0.05 for equality). Adjusted incremental total medical cost for the bevacizumab group was $5,045 PPPM higher than for sorafenib (p<0.05), and $4,902 PPPM higher than for sunitinib (p<0.05). Bevacizumab patients incurred higher incremental PPPM outpatient services cost by $7,687 and $7,995 compared to sorafenib and sunitinib, respectively (both p<0.05) largely driven by the cost of bevacizumab itself. Conclusions: Patients with RCC treated with bevacizumab incur an incremental $58,826 to $60,546 total medical cost per patient per year compared to those treated with sunitinib or sorafenib. Oral AI therapies may result in cost savings to patients and healthcare payers over IV therapies.

[Table: see text]

[Table: see text]
Radical prostatectomy in clinically localized prostate cancer—The risk of extraprostatic spread by NCCN risk group and its implications for adjuvant therapy: An analysis of 23,988 patients
Authors: Schreiber D. , Rineer J. , Olsheski M. , Vongtama D. , Wortham A. , Sura S. , Nwokedi E. , Han P. , Choi K. , Rotman M.
Published: August 2020

5125

Background: Swanson et al recently reported an update of SWOG 8794 (ASTRO 2008, oral presentation) revealing a 10% absolute overall survival benefit at 15 years with adjuvant radiation therapy for patients with extraprostatic extension (EPE) or positive margins after radical prostatectomy (RP). In this population based analysis, we analyze and report on the pathologic rates of EPE or positive margins in clinically localized prostate cancer as well as how often these patients have received adjuvant radiation therapy. Methods: The Surveillance, Epidemiology and End Results (SEER) registry was used to identify patients between 2004–2005 with clinically staged T1-T2c prostate cancer who underwent RP. Patients were stratified using NCCN risk groups into low (T1c- T2a, PSA less than 10ng/ml, Gleason 2–6), intermediate (T2b, PSA 10–20ng/ml, Gleason 7), and high (T2c, PSA greater than 20ng/ml, Gleason 8–10). Results: 23,988 patients were identified: 6,314 in the NCCN low risk group (LR), 12,052 in the NCCN intermediate risk group (IR), and 5,622 in the NCCN high risk group (HR). Overall, 68.2% of patients had organ-confined disease with negative margins. However, the risk of EPE or positive margins increased with the NCCN risk group, PSA value, and Gleason score (see table ). Of those who met criteria for adjuvant radiation, 11.9% received the treatment: 4.7% of the LR group, 9.2% of the IR group and 18.9% of the HR group. Conclusions: This is, to our knowledge, the largest reported multi-institutional surgical series of clinically localized prostate cancer. Patients can use this data to be counseled on their risk of requiring adjuvant radiation based on their pre-treatment parameters. This data also reveals that nearly one third of all patients met the indications for adjuvant radiation, but only a small percentage of them received this treatment.

[Table: see text]

No significant financial relationships to disclose.
Initial phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Slovin S. F. , Beer T. M. , Higano C. S. , Tejwani S. , Hamid O. , Picus J. , Harzstark A. , Scher H. I. , Lan Z. , Lowy I. ,   Prostate Cancer Clinical Trials Consortium
Published: August 2020

5138

Background: IPI is a fully human, monoclonal anti-CTLA-4 antibody capable of enhancing anti-tumor immunity. In preclinical models, XRT releases tumor antigens and enhances anti-tumor activity of CTLA-4 blockade. In the dose escalation part of this Phase I/II trial 10 mg/kg dosing of IPI with or without prior priming by single fraction XRT was feasible. We now report initial phase II results. Methods: 45 patients (pts) with mCRPC and ECOG PS of 0–1 received 10 mg/kg q3 weeks (wks) X 4 of IPI in 3 groups: (1) IPI alone n=16, (2) IPI + XRT n=15 chemotherapy naïve (NoCHEMO), and (3) IPI + XRT n=14 chemotherapy experienced (CHEMO) pts. XRT (800 cGy) was given to up to 3 involved bony sites (GI tract sparing) just prior to starting IPI. PSA was monitored monthly, with scans q 3 months. Endpoints were to confirm safety and an initial assessment of activity. Results: 17 pts (38%) experienced 26 immune-related adverse events (irAEs) including diarrhea/colitis (12), rash/pruritus (6), hepatitis (4), endocrinopathy (4). 11 pts (24%) experienced 13 ≥ Grade 3 irAEs: GI (9; 20%) and hepatitis (4; 9%); all resolved with immunosuppression. 10 of 45 pts (22%; 95% CI 10–34%) had confirmed PSA declines ≥ 50% as follows in the table below. Median time to PSA decline was 5.7 wks (r 3 to 21 wks); median duration 23 wks (r 3 to 84+ wks). In one pt dosed with IPI alone, PSA ≤ 0.05 ng/ml, as well as a CR of bone, nodal and prostate lesions continue for 54+ and 84+ wks, respectively. Conclusions: irAEs in the 10 mg/kg cohorts are similar in type and rate to IPI in melanoma. irAEs and PSA declines occurred in chemotherapy naïve and post chemotherapy patients, and with or without XRT. Addition of XRT to 10 mg/kg is well tolerated. Time to response can be delayed, with a durable median response of 23 wks. Further study of IPI in mCRPC is warranted, with or without XRT as a potential immunosupportive maneuver to augment clinical responses to IPI.

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[Table: see text]
A phase II study of patupilone in patients (pts) with metastatic castration- resistant prostate cancer (CRPC) who have progressed after docetaxel
Authors: Beardsley E. K. , Saad F. , Eigl B. , Venner P. , Hotte S. , Winquist E. , Ko Y. J. , Sridhar S. S. , Chi K. N.
Published: August 2020

5139

Background: Chemotherapy for pts with CRPC who have progressed after docetaxel remains to be defined. Patupilone is an epothilone with broad spectrum pre-clinical activity including in taxane resistant models. Methods: Multicenter, 2-stage design. Pts with metastatic CRPC with progressive disease during or within 6 months of receiving docetaxel were eligible. Patupilone was initially given 10mg/m 2 IV every 3 weeks. PSA response rate (≥50% decline) was the primary endpoint (H0 = 15%, H1 = 25%, α = 0.1, β = 0.2). Secondary endpoints were measurable disease response, serial pain and analgesics scores, progression free survival (PFS) and overall survival (OS). Results: 83 pts were enrolled from March 2007-June 2008. 401 cycles administered (median 5, range 1–15). Baseline characteristics (range): median age 67 (47–85), PSA 212 (2.6–11520), hemoglobin 118 (89–160), median time to progression after docetaxel 1.0 months (0.0–6.0), number of prior chemotherapy regimens 1:2:3+ in 45:28:10 pts, ECOG PS 0–1:2 in 73:10 pts, disease in bone/lymph nodes/viscera in 76/47/14 pts respectively. In the first 6 pts, gastrointestinal serious adverse events (AE) occurred in 4 pts (diarrhea and vomiting) which lead to a dose reduction of patupilone to 8 mg/m2 for subsequent patients. Grade 3/4 related adverse events at this dose included fatigue (16%), diarrhea (13%) and anorexia (5%). There were no grade 3/4 hematologic AEs. In 78 pts evaluable for PSA response, PSA declines of ≥30% and ≥50% have occurred in 44/78 (56%) and 35/78 (45%) with a confirmed PSA response in 25 pts (32%). Partial response occurred in 5% and stable disease in 64% of 44 evaluable pts. Pain response (2 point decline on 6 point scale) occurred in 36 (51%) of 71 pts eligible for analysis. Median PFS for PSA and non-PSA outcomes (measurable disease/symptomatic progression or death) was 7.6 months (3.7–11.5) and 5.6 months (3.9–7.3) respectively. Follow up for OS is continuing. Conclusions: Patupilone 8 mg/m2 every 3 weeks was well tolerated and associated with encouraging PFS, PSA and pain responses in pts with docetaxel resistant/refractory disease. Further investigation of patupilone in this population is warranted.

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Results of a phase II study of picoplatin with docetaxel and prednisone in first-line treatment of castration-resistant prostate cancer (CRPC)
Authors: De Jager R. L. , Roman L. , Lopatkin N. , Karlov P. , Breitz H. , Earhart R.
Published: August 2020

5140

Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. Previously, a PSA response rate of 25% was observed when Pico monotherapy was infused at 120 mg/m2 Q3W (N = 20). Recently, a 34-patient Phase I study was performed to investigate the safety and efficacy of Pico in combination with docetaxel (D) + prednisone (pred) as first-line therapy for metastatic CRPC. Picoplatin therapy was well-tolerated at a dose of 120 mg/m2 and 19 of 32 evaluable pts (59%) achieved a confirmed PSA response. Methods: 32 patients with chemotherapy-naïve CRPC and disease progression received Pico (120 mg/m2) and D (75 mg/m2) Q3W with pred 5 mg po bid for up to 10 cycles. PSA responses were defined as a reduction from baseline of at least 50% maintained for at least 4 weeks. CT and bone scans were also evaluated. Tumor response was measured using RECIST. Results: Patients received a median of 10 cycles (range = 1–10). Median baseline PSA was 340.8 ng/mL (range 5.6–3019). One pt had no baseline PSA data. Of the 24 patients with evaluable post-treatment PSA, 83% (95% CI 64–93%) had PSA decreases <50% of baseline, and in 8 of these (33% of the evaluable population), PSA reached normal levels (< 4 ng/mL). In the intent-to-treat population, the PSA response rate was 63% (95% CI 45–77%). 13 patients evaluated by CT scan had measurable disease; 6 pts had SD by RECIST, 4 had PD, and 3 were not evaluable. The most common adverse events were alopecia (36%), asthenia (32%), neutropenia (29%), increased creatinine (23%), and thrombocytopenia (19%). No neurotoxicity ≥ grade 2 was observed. Conclusions: Picoplatin was safely administered to patients with CRPC as 1st-line therapy at 120 mg/m2 Q3W with full doses of docetaxel and prednisone, resulting in a PSA response rate of 83% of evaluable patients. These results support further development of picoplatin as a novel combination with docetaxel for the treatment of CRPC.

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Cediranib (AZD2171) in docetaxel-resistant, castration-resistant prostate cancer (CRPC)
Authors: Karakunnel J. J. , Gulley J. L. , Arlen P. , Mulquin M. , Wright J. , Turkbey I. B. , Choyke P. , Figg W. D. , Dahut W.
Published: August 2020

5141

Background: There is no standard therapy for prostate cancer patients who have progressed following docetaxel therapy. VEGF is implicated in tumor blood vessel formation and in disease progression in several solid tumors. Cediranib is an oral, small molecule inhibitor of receptor tyrosine kinases which influence VEGF. Methods: Patients must have clinical and/or radiographic evidence of progression on docetaxel with no limit on the number of prior chemotherapy regimens or radioisotopes. The starting dose is 20 mg daily, imaging is every 2 months. The primary objective is a 30% 6 month probability of progression free survival as determined by clinical (not by PSA rise alone) and radiographic criteria Simon two stage optimal design is being utilized with twelve patients enrolled in the first cohort. If 2 or more patients are progression-free at 6 months, the cohort will be expanded to 35 evaluable patients. Patients receiving cediranib were scanned by DCE-MRI pre- and post-treatment. A two compartment model was used to analyze the volume transfer. Results: Thirty-four of a planned 35 patients have been enrolled and 4 remain on active treatment (2–7 months). There have been 13 of 23 evaluable patients with tumor shrinkage and 4 have met the criteria for partial response. Decreases in lymph node metastases as well as in lung, liver and bone lesions have occurred. PSA levels have not corresponded well with imaging responses. Adverse events have been similar to other drugs in this class including hypertension, dysphonia and fatigue. Grade 3 toxicities included vomiting (2), prolonged QTc interval (1) and muscle weakness (3), weight loss (3), dehydration (4), fatigue (6), hypoxia (1), renal failure (1), transaminitis (3), and anorexia (1). There have been 30 patients who were evaluated by DCE-MRI. Targeted lesions included bone (17) and soft tissue (15). Conclusions: The safety profile and early activity makes cediranib a promising drug in CRPC post docetaxel. Preliminary data suggests that cediranib does have direct effect on the microcirculation and vasculature. Additional accrual is required to better characterize the response rate, the discrepancy between PSA and standard imaging changes and establish evidence of clinical correlation for DCE-MRI.

No significant financial relationships to disclose.
Intragenic expression profile in tissue and plasma for the detection of TMPRSS2 rearrangements associated with prostate cancer
Authors: Sanders H. R. , Li H. , Qu K. Z. , Zhang Z. J. , Sferruzza A. D. , Albitar M.
Published: August 2020

5162

Background: TMPRSS2 gene rearrangements have been reported in 40%-85% of prostate cancer (PCa) patients and have not been found in normal individuals or those with benign prostate hyperplasia (BPH). However, multiple partner genes, including ETS transcription genes, and breakpoints have been reported. We developed an assay based on TMPRSS2 5′ and 3′ intragenic differential expression (IDE) to potentially serve as a diagnostic or prognostic marker for PCa. Methods: We analyzed TMPRSS2 in FFPE tissue from 20 patients (9 PCa and 11 BPH) and plasma from 42 patients (32 PCa and 10 BPH). IDE was expressed as a ratio of 3′:5′ transcript levels which were determined by real-time RT-PCR using distinct primer/probe sets. A normal 3′:5′ ratio (≥30) was established by comparing nonmalignant cells to tumor cells from FFPE tissue. This cutoff was subsequently used to identify abnormal ratios in plasma specimens. Results: In FFPE tissue, 100% of PCa samples had a 3′:5′ratio <30 and 91% of BPH samples were ≥30 ( Table ). RNA in 48% of plasma samples passed our QC criteria for acceptability. The 3′:5′ ratios were <30 in 47% and ≥30 in 6.7% PCa plasma. Conclusions: By measuring IDE, we are not limited to screening for known TMPRSS2/ETS gene translocations. In tissue, this approach enabled us to identify patients with PCa vs. BPH with high specificity. Although work is needed to improve plasma RNA quality, IDE of plasma TMPRSS2 may be a useful non-invasive diagnostic or prognostic tool.

[Table: see text]

No significant financial relationships to disclose.
Anthracyclines in basal breast cancer: The NCIC-CTG trial MA5 comparing adjuvant CMF to CEF
Authors: Cheang M. , Chia S. K. , Tu D. , Jiang S. , Shepherd L. E. , Pritchard K. I. , Nielsen T. O.
Published: August 2020

519

Background: MA5 randomized premenopausal women with node-positive early breast cancers to cyclophosphamide- methotrexate-fluorouracil (CMF) or cyclophosphamide-epirubicin-fluorouracil (CEF) adjuvant chemotherapy. This and other trials have shown that adjuvant regimens containing anthracyclines confer significant survival benefit to breast cancer patients. Meta-analyses have revealed most benefit in women with HER2(+) or TOPO2 (+) tumors. Population-based data suggest that patients with a core basal phenotype (negative for hormone receptors and HER2, positive for CK5/6 or EGFR) conversely have worse survival on anthracycline containing vs. CMF regimens. Here we test the hypothesis specified a priori that for basal breast cancers anthracyclines may be inferior, using data from MA5. Methods: From 710 patients in MA5, blocks suitable for tissue microarray construction were recovered for 549. Immunohistochemistry for ER, PR, HER2, Ki67, CK5/6 and EGFR was obtained, allowing stratification of 511 cases into intrinsic biological subtypes by published methods (Cheang MC et al. Clin Cancer Res 2008;14:1368–76). Prespecified analyses were conducted independently by the NCIC- CTG statistical centre. Results: In the CEF arm, patients with core basal tumors had a hazard ratio of 1.8 (log rank p=0.02) for overall survival (OS) relative to the other biological subtypes. In the CMF arm, there was no significant difference (HR 0.9, p = 0.7). The interaction between core basal status and treatment was borderline significant (p=0.06). Relapse free survival differences did not reach significance. Conclusions: Data from this randomized trial supports the hypothesis that anthracycline containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer.

[Table: see text]

No significant financial relationships to disclose.
Neo-tAnGo: A neoadjuvant randomized phase III trial of epirubicin/cyclophosphamide and paclitaxel ± gemcitabine in the treatment of women with high-risk early breast cancer (EBC): First report of the primary endpoint, pathological complete response (pCR)
Authors: Earl H. M. , Vallier A. , Hiller L. , Fenwick N. , Iddawela M. , Hughes-Davies L. , Provenzano E. , McAdam K. , Hickish T. , Caldas C.
Published: August 2020

522

Background: Neo-tAnGo used a 2-by-2 factorial design, addressing: (i) gemcitabine (G) in a sequential neoadjuvant chemotherapy (CT) regimen of epirubicin/cyclophosphamide (EC) and paclitaxel (T); and (ii) the sequencing of these treatment components (EC then T ± G versus T ± G then EC). Methods: Patients (Pts) with early breast cancer (T2 tumours or above) were randomised to EC then T, T then EC, EC then TG or TG then EC. All components were given x 4 cycles. (E= 90 mg/m2 day (d)1 every (q) 21d; C = 600 mg/m2 d1 q21d; T = 175 mg/m2 d1 q14d; G = 2,000 mg/m2 d1 q14d.) The primary endpoint was pCR, defined as absence of invasive disease in the breast and axillary lymph nodes. 800 pts were required to detect 10% differences in the primary endpoint pCR rates, at the 5% (2-sided) significance level with 85% power. Stratification was by age, inflammatory/locally advanced disease, tumour size, clinical involvement of axillary nodes and oestrogen receptor (ER) status. Results: Between January 2005 and September 2007, 831 pts were randomised by 88 consultants from 57 UK centres. Characteristics were balanced across groups: 63% <50 years old, 25% had inflammatory and/or locally advanced disease, 79% of tumours <50 mm, 50% node positive and 34% ER negative. Two-reader review of 813 (98%) eligible pts'. pathology reports, blinded to treatment arm, were carried out. pCR rates were 17% (95% CI 14–21) for EC&T pts and 17% (95% CI 14–21) for EC&TG pts (p = 0.98). However the sequence T±G then EC, showed pCR of 20% (95% CI 16–24) compared with 15% (95% CI 11–18) for EC then T±G pts (p = 0.03). Adjustment by stratification did not alter results. Conclusions: The Neo-tAnGo results confirm those of the adjuvant tAnGo trial in terms of gemcitabine effect (ASCO 2008). The sequence of T±G-first has demonstrated a significant advantage in pCR compared with the more conventional anthracycline-first sequencing.

[Table: see text]
Neoadjuvant chemotherapy in operable breast cancer with docetaxel, doxorubicin, and cyclophosphamide (TAC) or TAC followed by vinorelbine and capecitabine (NX): Final results and analysis of markers predicting response to treatment
Authors: Huober J. , von Minckwitz G. , Denkert C. , Kleine-Tebbe A. , Weiss E. , Zahm D. , Köhler G. , Mehta K. , Loib S.
Published: August 2020

524

Background: The aim of this analysis was to determine the pathological complete remission rate (pCR) for the entire Gepartrio study population and to identify markers predicting response to NACT. Methods: The design of the Gepartrio study was described elsewhere (von Minckwitz et al.). Age at diagnosis, tumor size, lymph node status, estrogen (ER), progesterone (PgR), HER-2 status, histological type, and grade were assessed in uni- and multivariate analysis. Clinical response after 2 cycles TAC and pCR at surgery were used as efficacy endpoints. Results: 2072 pts were randomized depending on response after 2 cycles TAC. 1122 pts (54.2%) had a clinical response after 2 cycles and 385 (18.6 %) pCR. The highest pCR rate (60%) was observed in pts with triple neg tumors and < 40 years. In the HR pos/HER-2 pos pts the pCR rates were 17.6% vs. 9% for HR pos/HER-2 neg pts (p<0.001). In the HR neg subset absence of HER-2 overexpression (“triple neg tumors”) resulted in significantly improved pCR rates compared to the HR neg HER-2 pos subset (40.7% versus 31.6%, p=0.041). In univariate analysis predictors for both an early response and a pCR at surgery were age < 40 years, non T4 tumor, grade 3, neg hormone receptors (HR) and a triple neg status. Non lobular histology was only predictive for a pCR in univariate analysis. In multivariate analysis independent factors for early response were non T4 tu, tumors ≥ 40 mm, poor grading and neg HRs. Independent predictors for a pCR remained age < 40 years, poor grading, a non lobular subtype and triple neg tumors. Conclusions: The pCR rate for the whole study population of the Gepartrio trial was comparable to other neoadjuvant regimens. Markers identified as independent predictors may help in decision making for pts being considered for neoadjuvant chemotherapy.

[Table: see text]
Molecular characterization of male breast cancer by standardized quantitative RT-PCR analysis: First large genomic study of 347 male breast cancers compared to 82,434 female breast cancers
Authors: Shak S. , Palmer G. , Baehner F. L. , Millward C. , Watson D. , Sledge G. W.
Published: August 2020

549

Background: Because male breast cancer (BC) is rare, there is little known about the disease and treatment is extrapolated from female BC. Newer molecular technologies have not been used to profile male BC. We report here a study of quantitative gene expression by gender status in tumor specimens submitted for Recurrence Score testing. Methods: All estrogen receptor positive tumor specimens successfully examined in the Genomic Health laboratory from June 2004 through December 2008 were included. Quantitative expression for each gene was measured by the 21 gene oncotype DX assay on a scale from 0 to 15 (relative to reference genes), where a one unit increment is associated with a 2-fold change in expression. Results: There were 347 male and 82,434 female BCs. The males were older (mean age 63.8 vs 57.4 yrs). Standard histopathology was similar, although slightly more male BCs were ductal (83% vs 78%). Like female BC, there was a wide variation in gene expression in male BC. The distribution of RS in males and females was similar - RS mean (±SD) 18.1 (±11.2) in males and 19.1 (±10.2) in females (p = NS). The proportion of tumors with RS <18, 18 - 30, and ≥ 31 was 53.6%, 35.2%, and 11.2% in males and 53.4%, 36.3%, and 10.3% in females. Although the patterns of expression of the Oncotype DX genes were more similar than different in males and females some differences were notable. Mean expression of ER, PR, and SCUBE2 were 0.5 units higher in males. Mean expression of the proliferation genes, Ki-67, MYBL2, Survivin, Cyclin B1, and STK15, were 0.5 units higher in males. Mean expression of STMY3 was 0.9 units higher in males. Of note, whereas the level of quantitative ER significantly increased with increasing patient age in females (0.4 units per decade), little increase was observed in males (<0.1 units per decade). Conclusions: This large genomic study of male BC reveals a heterogeneous biology as measured by the standardized quantitative oncotype DX breast cancer assay, similar to that observed in female BC. Some differences, which may reflect the differences in hormone biology between males and females, were noted and deserve further study.

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Systematic review of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for ovarian peritoneal carcinomatosis: A more efficacious way of delivering intraperitoneal chemotherapy
Authors: Chua T. C. , Robertson G. , Farrell R. , Liauw W. , Yan T. D. , Morris D. L.
Published: August 2020

5524

Background: Advanced and recurrent ovarian cancer results in extensive dissemination of tumor within the peritoneal cavity. The current evidence suggests that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) may be a feasible option with potential benefits compared to the current standard of care in the treatment of peritoneal carcinomatosis from ovarian cancer. Methods: A systematic review of relevant studies before August 2008 was undertaken to document and report its efficacy. Each study was appraised using a predetermined protocol. The quality of studies was assessed. The patient characteristics, protocol of treatment, perioperative morbidity and mortality, and treatment outcomes were synthesized through a narrative review with full tabulation of results of all included studies. Results: In total, 15 non-randomized, observational studies were reviewed, comprising of 512 patients. All patients received HIPEC as part of the combined treatment with cytoreductive surgery. Cisplatin was the most common chemoperfusate. The mortality associated with the treatment ranged from 0 to 10%. The rates of severe morbidity ranged from 0 to 40%. The median time of follow up ranged from 14 to 64 months, the median disease-free survival ranged from 10 to 57 months and the overall median survival ranged from 22 to 64 months. In patients who had an optimal cytoreduction, the median survival ranged from 29 to 66 months, with a 3- and 5-year survival rate that ranged from 35 to 63% and 12 to 66%, respectively. Conclusions: The future for cytoreductive surgery and HIPEC in ovarian cancer is promising. More studies are called for to validate the efficacy of this treatment. For it to become generally accepted, the oncology community must commit to a randomized trial. Before this, the current treatment of cytoreductive surgery combined with adjuvant intraperitoneal and intravenous chemotherapy should remain the mainstay of treatment.

No significant financial relationships to disclose.
Comprehensive CYP2D6 genotyping in a multiracial U.S. breast cancer population
Authors: Irvin W. J. , Carey L. A. , Olajide O. , Dees E. C. , Peppercorn J. , Chiu W. K. , Walko C. M. , McLeod H. L. , Evans J. P. , Weck K. E.
Published: August 2020

553

Background: CYP2D6 genotyping has been suggested to avoid suboptimal responses to tamoxifen (T). Most studies to date are in white patients (pts) and focus on a limited number of genetic variants. In this clinical trial, we comprehensively examined CYP2D6 allele frequencies in women of heterogenous ethnicity taking tamoxifen (T). Methods: In LCCC 0801, pts on T ≥ 4 months and not on potent CYP2D6 inhibiting medications were genotyped using the CYP450 AmpliChip for 2D6 alleles: *1-*11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41XN. T dose was increased in pts with any intermediate or poor metabolizing (IM or PM) alleles [but not in pts homozygous for extensive metabolizing (EM) alleles]. Serial T metabolite levels are being assessed. Here we report the allele frequency data from this study compared to previously published cohorts. Results: 108 pts participated in the study: 24 (22%) African-Americans (AA), 76 (70%) non-Hispanic whites, 4 Asians, 3 Hispanics and 1 Spanish European. Genotyping revealed 28 (26%) EM/EM, 1 EM/UM (ultra-rapid), 29 (27%) EM/IM, 22 (20%) EM/PM, 8 (7%) IM/IM, 10 (9%) IM/PM, 9 (8%) PM/PM and 1 unknown. Conclusions: Pts in this trial had a similar frequency of PM alleles to previous reports, however a high proportion of pts have IM alleles. In particular, the majority (79%) of AA pts possess at least one variant allele. Since PM and IM genotypes have been associated with reduced T metabolism, this may have implications for T efficacy and emphasizes the importance of trials examining CYP2D6 genotyping as a determinant of T use. (Supported by Laboratory Corporation of America, Roche Diagnostics, NC UCRF, NCI SPORE.)

[Table: see text]

[Table: see text]
Association of ERCC1 protein expression to platinum resistance in epithelial ovarian cancer
Authors: Steffensen K. D. , Waldstrøm M. , Jakobsen A.
Published: August 2020

5530

Background: Although platinum-based chemotherapy remains the cornerstone for treatment of ovarian cancer, some patients are resistant to the treatment and will therefore not benefit from the standard platinum-based chemotherapy. Preclinical and clinical data have suggested a potential use of ERCC1 (excision repair cross-complementation group 1 enzyme) as a molecular predictor of clinical resistance to platinum-based chemotherapy. ERCC1 is a key enzyme in the nucleotide excision repair pathway which is involved in the DNA repair mechanisms in tumor cells. The primary aim of the present study was to investigate if immunohistochemical expression of ERCC1 protein was associated with resistance to standard combination carboplatin and paclitaxel chemotherapy in newly diagnosed ovarian cancer patients. Methods: Formalin-fixed, paraffin-embedded tissue sections from 101 patients with newly diagnosed ovarian cancer were used for immunohistochemical staining for the ERCC1 protein. The percentage of positive tumor cells in each slide were scored as 0 if 0 % of the tumor cells were positive, 0.1 if 1 %-9 %; 0.5 if 10 %-49 %; and 1.0 if 50 % or more were positive. A semi quantitative H-score was calculated by multiplying the staining intensity (0–3) with the percentage score. The tumor was considered positive when the H-score was > 1.0. All patients received carboplatin-paclitaxel combination chemotherapy. Results: ERCC1 protein overexpression was found in 13.9 % of the tumors. Platinum resistance were found in 75 % of the tumors with positive ERCC1 protein expression compared to 27 % among the patients with negative tumor staining for ERCC1 (p = 0.0013). These findings translated into a significant difference in progression free survival in both univariate (p = 0.0012) and in multivariate analysis (p = 0.006). Conclusions: The data presented suggests a positive association between positive ERCC1 protein expression and clinical resistance to platinum-based chemotherapy.

No significant financial relationships to disclose.
Randomized phase III study of canfosfamide (C, TLK286) plus pegylated liposomal doxorubicin (PLD) versus PLD as second-line therapy in platinum (P) refractory or resistant ovarian cancer (OC)
Authors: Vergote I. , Finkler N. J. , Hall J. B. , Melnyk O. , Edwards R. P. , Jones M. , Meng L. , Brown G. L. , Rankin E. M. , Burke J. J. , Rose P. G.
Published: August 2020

5552

Background: Canfosfamide (C) is a glutathione analog prodrug activated by glutathione S-transferase P1–1. C is synergistic with PLD and PLD increases the expression of GST P1–1 and sensitivity to C in OC cells. Methods: 244 pts were planned with P refractory or resistant (progression within 6 mos. after P) OC following ≤ 2 P regimens, and measurable disease (RECIST). Pts received C at 1,000 mg/m2 and PLD at 50 mg/m2 IV or PLD at 50mg/m2 q4wks until tumor progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: This multinational study randomized 125 pts until June 4, 2007 when the study was temporarily placed on clinical hold to review another C trial. The 65/60 pts were well-balanced for disease characteristics and received a median 3/3.5 cycles per patient (range 1–11/0–17) of C + PLD/PLD, 35 pts (21/14) discontinued study treatment(s) due to the hold, respectively. Most common adverse events (AEs) for C + PLD were hematologic at 66% vs. 44% for PLD and were manageable with dose reductions. Non-hematologic AEs were similar for both arms, except the incidence of Grade 2–3 Palmar-Plantar Erythrodysesthesia (PPE) (9% vs. 21%) and stomatitis (17% vs. 23%) was lower and less severe with C+PLD vs. PLD. Grade 4 PPE (2%) was only observed on the PLD arm. Overall median PFS, the primary endpoint, was 5.6 mos. for C + PLD and 3.7 mos. for PLD (p = 0.7243, HR = 0.92). Objective response rate (ORR) by RECIST was 12.3% for C + PLD vs. 8.3% for PLD. In a planned analysis, 75 pts (40 /35) who were P refractory or primary P resistant observed a median PFS of 5.6 mos. for C + PLD vs. 2.9 mos. for PLD (p = 0.0425, HR = 0.55). ORR for C + PLD was 15.0% (with 1 CR) vs. 5.7% for PLD. Stable disease was observed 42.5% on C + PLD and 37.1% on PLD; median duration of SD was 7.4 mos. and 4.1 mos., respectively (p = 0.0439, HR = 0.49). The median time to response was 2.8 mos. on C + PLD vs. 4.8 mos. on PLD. Conclusions: The overall PFS showed a positive but not statistically significant trend for C +PLD vs. PLD. In the P refractory or primary P resistant population, the median PFS was significantly longer for C+PLD than PLD alone. C may ameliorate the AEs of stomatitis and PPE known to be associated with PLD.

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Combined topotecan and lapatinib in patients with early recurrent ovarian or peritoneal cancer after first line of platinum-based chemotherapy: A French FEDEGYN-FNCLCC phase II trial
Authors: Joly F. , Weber B. , Pautier P. , Fabbro M. , Selle F. , Krieger S. , Leconte A. , Bourgeois H. , Henry-Amar M.
Published: August 2020

5555

Background: High HER1 expression is associated with poor prognosis. Preliminary data have shown links between HER1 expression and topotecan efficacy. The objective of the trial was to evaluate the efficacy of the association of topotecan and lapatinib in non-HER screened patients who failed first line platinum-based chemotherapy within 12 months. Methods: Chemotherapy consisted of 4-week course of topotecan (d1, d8, d15, 3.2 mg/m2 IV) and lapatinib (1250 mg/d PO). Response was assessed using RECIST or RUSTIN criteria. The primary objective was global response (GR, i.e. CR, PR, and SD). Biomarker profiles were evaluated according treatment response. A two-step phase II trial was designed to include 54 patients assuming a GR rate of 75% for the combination compared to 55% for topotecan alone. Results: From March to September 2008, 39 patients (37 ovarian and 2 peritoneal carcinomas), median age 60 (18 to 80), were included in 16 institutions. Patients presented with FIGO stage I (n = 1), II (n = 2), III (n = 29), and IV (n = 7) disease. Twenty and 19 patients had disease relapse occurring < 6 and 6–12 months after initial chemotherapy respectively. 2 patients were non evaluable. After 1 to 8 cycles (median 2) of topotecan-lapatinib there were 0/2 PR, 7/9 SD, 12/7 progressions in patients who failed <6 or 6–12 months respectively. The GR rate was 46% (35 and 58%; 95% confidence limits, 30–63%) and the trial was prematurely stopped. Three patients developed toxicity leading to treatment discontinuation after 3 cycles. Biological data will be presented at meeting. Conclusions: Combined topotecan and lapatinib is associated with modest GR rate. Biological profiles of responders are pending.

No significant financial relationships to disclose.
A phase II trial of combination irinotecan and oral etoposide chemotherapy in recurrent ovarian cancer: A Tohoku Gynecologic Cancer Unit (TGCU) study
Authors: Kumagai S. , Shoji T. , Yokoyama Y. , Takano T. , Mizunuma H. , Yaegashi N. , Sugiyama T.
Published: August 2020

5558

Background: Various problems still exist in the management of recurrent ovarian cancer and there are limited treatment options especially for the platinum resistant patients (pts). We conducted a phase II study to evaluate the efficacy and safety of the combination irinotecan/oral etoposide chemotherapy. Methods: Eligibility criteria included recurrent ovarian cancer with measurable disease or positive CA125, preserved organ function, and aged 20–75. Treatment was conducted with irinotecan (60 mg/m2 iv, day 1, 15) and oral etoposide (50 mg/body day 1–21), q 28 days until disease progression or unacceptable toxicity. Primary endpoint was response rate (RR) and secondary endpoints included toxicity, progression-free survival (PFS), and overall survival (OS). Results: 38pts were enrolled on this study from May 2003 to April 2007, and all pts were eligible. Median age was 57 yrs (range 37–74). PS 0 in 24 pts, 1 in 10 pts, and 2 in 4 pts. Median number of previous regimen was 2 (range 1–4). Median treatment cycles were 6 (range 2–27). RR (CR+PR) was 18/38 (47.4%), and CR+PR+SD rate was 31/38 (81.6%). Grade 3/4 adverse effect included leukopenia (50.0%), neutropenia (52.6%), anemia (18.4%) and thrombocytopenia (2.6%), nausea/vomiting (7.9%) and diarrhea (2.6%). Treatment-related death was not observed. Median PFS was 7 months (range 1–33) and OS was 19 months (range 4–60). Among 20 pts with platinum resistant cases, RR was 6/20 (30.0%), CR+PR+SD rate was 14/20 (70.0%), median PFS was 6 months (range 1–33), and OS was 24 months (range 5–60). Conclusions: Combination irinotecan/oral etoposide chemotherapy can achieve a superior management for the recurrent ovarian cancer without declining QOL, and also has the possibility to be one of the most effective regimens as second-line chemotherapy.

No significant financial relationships to disclose.
Randomized phase II study of decitabine in combination with carboplatin compared with carboplatin alone in patients with recurrent advanced ovarian cancer
Authors: Glasspool R. M. , Gore M. , Rustin G. , McNeish I. , Wilson R. , Pledge S. , Paul J. , Mackean M. , Halford S. , Kaye S. ,   on behalf of the Scottish Gynaecological Cancer Trials Group
Published: August 2020

5562

Background: Experimental and clinical data (Gifford et al, Clin Cancer Res. 2004) indicate the potential importance of methylation in mediating resistance to carboplatin in ovarian cancer. A previous phase I trial (Appleton et al, J Clin Oncol. 2007) established the feasibility of combining carboplatin with the demethylating agent decitabine on a day 1 + 8 q4 weekly (w) schedule and PD data provided evidence of target cell demethylation. Methods: Patients (pt) with ovarian cancer relapsing 6–12 months following first line treatment were randomised to receive either 6 cycles of carboplatin AUC 6 q4 w (Arm A), or 90 mg/m2 decitabine as a 6 hour infusion on day 1 and carboplatin AUC 6 on day 8 q4 w (Arm B). The primary endpoint was response rate. An interim analysis was planned after 11 patients were enrolled into Arm B. Results: 29 pt were enrolled. After the first 4 pt had been treated (at 90 mg/m2 decitabine) the frequency of dose delays due to neutropenia was considered unacceptable, and therefore the starting dose of decitabine was reduced to 45 mg/m2 for the subsequent 11 pt. 7 out of 14 pt in Arm A completed 6 cycles compared with 0 of 11 in Arm B (at 45 mg/m2 decitabine). Grade 2/3 hypersensitivity reactions were more common in Arm B than Arm A (64% vs. 21%), as were prolonged treatment delays due to neutropenia (36% vs. 10%). At the interim analysis, in the 11 pt treated with 45mg/m2 (Arm B), there were no RECIST responses, while 2 pt had short-lived CA125 responses (59 and 63 days). In contrast 6 of 14 patients in Arm A had RECIST responses consistent with the expected efficacy of carboplatin in this population. Conclusions: The lack of efficacy, as well as the difficulties in treatment delivery in Arm B, led the project team to conclude that the study should be closed. With this dose and schedule, decitabine is ineffective in reversing carboplatin resistance. Further investigations are ongoing to understand (a) the apparent increased incidence of hypersensitivity and (b) the trend towards reduced efficacy in Arm B.

[Table: see text]
Clinical presentation and sensitivity to platinum-based chemotherapy (CT) of mucinous advanced epithelial ovarian carcinoma (M-AEOC): The GINECO-Group experience
Authors: Alexandre J. , Ray-Coquard I. , Selle F. , Floquet A. , Cottu P. , Weber B. , Falandry C. , Lebrun D. , Pujade-Lauraine E.
Published: August 2020

5572

Background: M-AEOC have been consistently associated with worse prognosis than the most common serous (S) histologic subtype; however it is unclear if this observation is related to more aggressive clinical presentation and/or chemoresistance behaviour. Methods: Data from four randomized phase III and one phase II AEOC first-line clinical trials were collected and retrospectively analyzed. Study selection criteria included: completed study, platinum-based chemotherapy and stage IIB to IV AEOC patients (pts). Results: Data on 1118 pts with advanced AEOC were analysed, of whom 94% were treated with paclitaxel-carboplatin-based CT. 786 pts had S-AEOC and 54 pts M-AEOC (5%). Peritoneal metastasis (mets) appeared more limited in M- than in S-AEOC pts since stages IIB-IIIB were more frequent (31% versus 19%, p = 0.001) and complete resection more frequently obtained (45% of stage II-III pts versus 29%, p = 0.06) in M-AEOC. Extra-peritoneal mets (stage IV) were more frequent in M- than in S-AEOC pts (30% versus 15%, p = 0.004), specially liver mets (44% of stage IV pts versus 23%, p = 0.06). Progressive disease during CT was observed in 40% of pts with stage IV M-AEOC. Progression free survival (PFS) was worse in M- than in S-AEOC pts both in stage IV (1y PFS: 15% versus 51%, p = 0.02) and in stage III with optimal resection (2y PFS: 42% versus 66%, p = 0.05). Conclusions: Compared to S-AEOC, M-AEOC is characterized by more limited peritoneal carcinomatosis but more frequent liver mets. M-AEOC appears to be a highly chemoresistant disease and complete resection of peritoneal mets is unable to reverse its adverse prognosis. New therapeutics options are needed.

No significant financial relationships to disclose.
Prognostic value of gene expression of p63 by microarray analysis in estrogen receptor positive and negative breast cancer
Authors: Hanker L. C. , Karn T. , Rody A. , Ruckhäberle E. , Solbach C. , Kaufmann M.
Published: August 2020

566

Background: The protein 63 (p63) represents a member of the p53 family (p53/p63/p73) located on chromosome 3q27. This gene family seems to play an important role in carcinogenesis and its members may act as oncogenes or tumor suppressor genes. P63 is overexpressed in many different tumors like head and neck cancer, lung cancers, uterine tumors and breast cancer, and has been associated with poor prognosis in some studies. P63 was found to be overexpressed in a subset of highly aggressive breast cancers that represent a basal and myoepithelial phenotype and have a poor clinical outcome. This protein seems to be a specific myoepithelial cell marker in normal breast tissue and might represent a prognostic factor in breast cancer. Methods: Large scale analysis was performed using Affymetrix microarray data from n=1581 breast cancer patients to evaluate p63 expression. Results: P63 expression showed a strong correlation with patient's age (χ2-test, p < 0.001), tumor size (p < 0.003), proliferation rate (p < 0.001), Topo2α expression (p = 0.001) and estrogen receptor expression (p = 0.017). Survival analysis of all patients with available follow up data (n = 1263) showed a significant difference due to high and low p63 expression (log rank p < 0.001). Patients with a low p63 expression had the worst prognosis. In univariate Cox regression analysis p63 showed a hazard ratio (HR) of 1.61 (95% CI 1.31–2.00, p < 0.001) for disease free survival. This prognostic impact remained significant when samples were stratified by estrogen receptor status. High expression of p63 was significantly associated with longer OS in both ER negative (n = 334, log rank p = 0.022) and ER positive (n = 929, log rank p < 0,001) breast cancer. The prognostic impact of p63 expression was independent of Ki67 expression (p = 0.011 and p = 0.001 for high and low Ki67, respectively). Moreover a worse prognosis of low p63 expressing tumors was found in both subgroups of ErbB2 positive tumors (p < 0.001) and ErbB2 negative tumors (p < 0.001). Conclusions: P63 expression is a prognostic factor in both ER positive and negative breast cancer and could be helpful for risk assessment in breast cancer patients.

No significant financial relationships to disclose.