bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemotherapy and radiation therapy in UPSC
Authors: Viswanathan A. , Horick N. , Tanaka C. , Campos S. , Matulonis U. , Berkowitz R.
Published: March 2020

5535

Purpose: To analyze the impact of chemotherapy (Ch) and radiation therapy (RT) on relapse rates in patients with uterine papillary serous carcinoma (UPSC). Materials and Methods: The outcomes of 160 women with UPSC seen between 1980–2005 at the BW/DFCC were analyzed. Exclusion criteria included stage IVB disease, no hysterectomy, unknown stage, or unknown type of RT. Results: The median age was 67 years (range 31–90). FIGO Stage was IA (21), IB (28), IC (13), IIA (7), IIB (10), IIIA (42), IIIB (2), IIIC (21), and IVA (16). Treatment included none (40), Ch alone (20), Ch and whole abdominal radiation (WA) (11), Ch and pelvic radiation (P) (30), Ch and vaginal brachytherapy (VB) (2), WA alone (24), P alone (19), and VB alone (14). The median dose of RT was WA 30 Gy and P 45 Gy. Ch was given to 63 patients; the median number of cycles of Carboplatin, Adriamycin and Paclitaxel was 3. Overall survival (OS) and disease-free survival (DFS) for the entire group were 67% and 57% at 2 years, 62% and 51% at 3 years and 51% and 38% at 5 years. A total of 58 patients relapsed. Among those who received no RT or Ch, 48% (19/40) relapsed; among those treated with Ch only, 50% (10/20) relapsed; in the group treated with RT only, 26% (15/57) relapsed; and, in those treated with Ch and RT, 33% (14/43) relapsed. A significant difference in recurrence rate was seen in patients treated with RT compared to those who received no treatment (OR 0.40, p=0.03). This difference persisted after controlling for Stage, which did significantly affect the relationship between RT treatment and recurrence. Local recurrence (in an RT field) was a component of failure for 14% (14/100) treated with RT, versus 42% (25/59) that received no RT (OR 0.22, p=0.0001). Distant metastases were a component of first failure in 15% (9/61) that received Ch versus 11% (11/97) that did not; there was no significant difference in distant recurrence rate for patients treated with Ch (OR 1.35, p=0.53). Conclusion: This single-institution study represents the largest series of UPSC to date. The use of RT significantly decreases the overall recurrence rate of UPSC in this series and should be considered in patients with stages I-IVA UPSC. Future studies looking at the optimal type, dose and duration of chemotherapy, as well as the use of novel agents, are needed to improve outcomes in this population.

No significant financial relationships to disclose.
Markers of angiogenesis in cervical cancer: A Gynecologic Oncology Group study
Authors: Randall-Whitis L. , Monk B. J. , Han E. S. , Darcy K. , Burger R. A. , Liao S. , Peters W. A. , Stock R. J. , Fruehauf J. P.
Published: March 2020

5536

Background: Extensive tumor angiogenesis has correlated with poorer progression-free and overall survival in cervical cancer; however, specific markers of angiogenesis have not been studied prospectively. Methods: Cervical cancer patients with high-risk features on radical hysterectomy were eligible for randomization to adjuvant pelvic irradiation ± radiosensitizing platinum. Following central pathology review, formalin-fixed, paraffin-embedded tumors were sectioned into 4-micron specimens. Semi-quantitative immunohistochemisty (IHC) was performed using previously validated antibodies against mutant p53 (mp53), vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), and endothelial markers CD 31 and CD 105. Tumoral histoscores (HS) were calculated for mp53 and VEGF using the formula: [% cells positive × (intensity +1)], with a 5% threshold for positivity and intensity ranging 1–4+ (3+ = intensity of positive control). Intensity scores (0–4+) were assigned to TSP-1 specimens referencing the positive control (3+). MVD “hotspots” were counted in a 20X high-power field. HS and MVD counts were considered as continuous variables and TSP-1 intensity as an ordinal variable. Associations between markers were determined by Pearson’s and Spearman’s correlation tests, between markers and clinico-pathologic variables by Wilcoxon rank test, and between markers and survival by Cox regression modeling. Results: One hundred seventy-six specimens were analyzed. Acquisition of mp53 and increased VEGF expression were associated with increased MVD assessed by both CD31 (p=0.08 and p=0.002, respectively) and CD105 (p=0.02 and p=0.012, respectively). Statistically significant associations between markers and high-risk pathologic factors included: low-level TSP-1 and high CD-105 counts with lymph node metastases; high VEGF scores with advanced stage, non-squamous histologic subtype, and depth of tumor invasion; and high CD 31 counts with parametrial metastases. Survival analysis is currently being performed. Conclusions: Angiogenesis occurs early in cervical carcinogenesis, and may be a rational target for biologic therapy in cervical cancer.

No significant financial relationships to disclose.
The prognostic factors responsible for survival of women with neuroendocrine small-cell cervical carcinoma—A study of 188 women
Authors: Kapp D. S. , Cohen J. , Shin J. Y. , Husain A. , Teng N. N. , Berek J. S. , Osann K. , Chan J. K.
Published: March 2020

5539

Background: To determine the clinical and pathological factors associated with survival in women with neuroendocrine small-cell cervical carcinoma. Methods: A review of the literature identified 136 patients with neuroendocrine small-cell carcinoma and an additional 52 patients identified from tumor registry databases at four hospitals. Survival analyses and predictors of outcome were analyzed using Kaplan-Meier method and Cox regression analysis. Results: Of 188 patients, the median age was 41.5 years (range: 20–87 years); 135 had stages I-IIA, 45 IIB-IVA, and 8 had stage IVB disease. Of all patients, 55.3% underwent primary surgery, 16.0% had chemoradiation therapy, 12.8% primary radiation therapy, 3.2% chemotherapy alone, and 12.8% had unknown or no primary treatment. Of the women who had initial surgery, 46.8% patients underwent a radical hysterectomy, and 6.4% had a simple hysterectomy. 49.5% of patients with nodal information had lymph node metastases. After initial surgery, 15.4% of all patients had adjuvant radiation therapy, 13.8% chemoradiation, 6.9% chemotherapy, and 2.1% had neoadjuvant chemoradiation. Of the 81 patients who received chemotherapy, 51.9% had etoposide and cisplatin combinations, 25.9% other cisplatin combinations, and 7.4% had cisplatin alone. The 5-year disease-specific survivals for those stage I-IIA, IIB-IVA, and IVB were 36.8%, 9.8%, and 0.0%, respectively (p<0.001). Those with tumors <2 cm showed a trend toward better survival (67.4% vs. 34.4%) compared to those with larger tumors (p=0.057). Women with stage I-IIA disease who underwent a radical hysterectomy had a survival of 42.5% vs. 38.4% without radical surgery. Chemotherapy (adjuvant or radiation sensitizer) was associated with improved survival in patients with stages IIB-IVA disease compared to those who did not receive chemotherapy (17.8% vs. 6.0%; p=0.043). On multivariable analysis, early stage of disease and chemotherapy were independent prognostic factors for improved survival. Conclusions: Advanced stage of disease is a poor prognostic factor for survival in neuroendocrine small-cell cancer of the cervix. Chemotherapy appears to offer a survival advantage, particularly in patients with stage IIB-IVA disease.

No significant financial relationships to disclose.
Cardiotoxicity after doxorubicin and AZD2171, an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, in patients (pts) with breast cancer
Authors: Denduluri N. , Berman A. W. , Vatas U. , Chow C. K. , Rosing D. R. , Swain S. M.
Published: March 2020

554

Background: AZD2171 selectively inhibits VEGFR 1,2,3. This trial examined the safety and efficacy of AZD2171 with anthracycline-containing therapy. Methods: Pts with previously untreated Stage IIB and III breast cancer received neoadjuvant AZD2171 (30mg) alone for one cycle (1 week) followed by daily AZD2171 and TAC chemotherapy with docetaxel (T), doxorubicin 50 mg/m2 (A) cyclophosphamide (C) for 6 cycles (Cy) every 3 weeks. Pts underwent breast surgery after completing neoadjuvant therapy. Eligible pts had left ventricular ejection fraction (EF) = 50%, and no uncontrolled HTN or cardiac history. Pts underwent electrocardiogram (EKG), and troponin first day (D) of every Cy and 24 hours after TAC as well as serial echocardiograms (echo). Cardiac stress MRI with dipyridamole was performed when pts had decreases in EF by echo. Results: Two pts received 2 Cy of AZD2171 alone, 9 Cy with TAC and AZD2171, and 1 Cy with TAC alone. Pt 1 and Pt 2 developed hypertension requiring medical therapy Cy4, D1 (148/97 mm Hg) and Cy2, D2 (169/93 mm Hg) respectively. Pt 1 had asymptomatic decrease in EF from 65% to 40% (grade 2) with global hypokinesis pre-Cy5 by echo. Troponin and EKG were negative for acute ischemia. Cardiac stress MRI was normal and EF returned to 60% within 48 hours. The pt continued therapy and pre-Cy7 EF was 51% by echo. Cumulative A dose received was 250mg/m2 pre-Cy7. AZD2171 was held while Cy7 TAC was continued. EF was 57% by echo 1 month after Cy7 TAC. Pt 2 had asymptomatic decrease in EF from 65% to 50% pre-Cy4 by echo with mild global hypokinesis. Troponin and EKG were negative for acute ischemia. Cardiac stress MRI showed EF of 56% with no ischemia. She continued AZD2171 and TAC. Pre-Cy5 EF was 35–40% (grade 3) with global hypokinesis. Troponin and EKG were negative. Cumulative dose of A received was 150mg/m2. AZD2171 and A were stopped; T and C were continued. EF normalized to 55% by cardiac stress MRI and echo within 21 days. Conclusion: Due to the systolic dysfunction that occurred with concurrent AZD2171 and doxorubicin administration, the study is closed. Future trials should administer AZD2171 and anthracyclines sequentially with stringent monitoring of blood pressure and ejection fraction.

No significant financial relationships to disclose.
Impact of physical activity on insulin levels in breast cancer survivors
Authors: Ligibel J. A. , Campbell N. , Chen H. , Salinardi T. , Chen W. , Partridge A. , Mantzoros C. , Winer E.
Published: March 2020

555

Background: Accumulating data suggest that body weight and physical activity may affect breast cancer risk and outcomes. Biological mechanisms underlying these relationships are not clear. Studies have demonstrated that high levels of insulin, often seen in obese and sedentary individuals, are also associated with an increased risk of breast cancer recurrence and breast cancer-related death. We sought to analyze whether exercise lowers insulin levels in a population of breast cancer survivors. Methods: Inactive women with early stage breast cancer who had completed adjuvant treatment were randomized to a 16 week, mixed cardiovascular and strength training exercise intervention, or to a normal care control group. Target exercise goals included 2 supervised strength training sessions and 90 minutes of unsupervised cardiovascular exercise each week. Fasting insulin and glucose levels, as well as measurement of weight, body composition, and circumference at the waist and hip, were collected at baseline and after 16 weeks in both groups, and changes in these measures were assessed. Results: One hundred and one women were randomized. Comparison of changes in anthropometric measures are presented in Table 1 . Baseline insulin levels were similar in the 2 groups. After the 16-week exercise or control period, insulin levels decreased by 2.86 μIU/ml in the exercise group (p=0.03), and by 0.27 μIU/ml in the control group (p=0.65). A comparison of the change in insulin levels across time in the 2 groups approached statistical significance (p=0.07). There was also a trend toward improvements in insulin sensitivity in the exercise group (p=0.09), with no change seen in fasting glucose levels. Conclusions: Physical activity was associated with a decrease in insulin levels and in hip circumference in breast cancer survivors. The relationship between physical activity and breast cancer prognosis may be mediated, at least partially, through changes in insulin levels and/or changes in fat mass or deposition.

[Table: see text]

No significant financial relationships to disclose.
Molecular correlates (EGFR status) and plasma VEGF levels associated with a phase II study of bevacizumab plus erlotinib (BE) for patients with recurrent ovarian cancer (OC) and fallopian tube (FT) cancer
Authors: Nimeiri H. S. , Faoro L. , Oza A. M. , Morgan R. J. , Gandara D. , Janamanchi V. , Salgia R. , Stadler W. M. , Vokes E. E. , Fleming G. F.
Published: March 2020

5554

Background: The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are commonly over- expressed in OC and may correlate with poor prognosis. EGFR mutations, although rare, have recently been reported in ovarian cancer. We examined these factors for prognostic value in the setting of treatment with BE. Results of a phase II trial of BE in recurrent OC pts have previously been reported; there were 1 CR and 1 PR among 13 patients. The trial was closed to accrual due to 2 bowel perforations. Methods: Pretreatment plasma VEGF, urine VEGF, and serum VEGFR2 levels are available on 9, 8, and 8 pts to date. VEGF levels were determined using an ELISA (R& D Systems, Minneapolis, MN). Tumor from 8 pts: 1(CR), 1 (PR), 5 (SD), 1 (PD) was available for immunohistochemical analysis for EGFR. Genomic DNA was successfully isolated from 6 paraffin embedded tumor specimens. EGFR exons 18 to 21 were amplified by PCR using primary and secondary PCR primer pairs. PCR products were purified and submitted for DNA sequencing against forward and reverse primers (analyzed with Sequencher). Results: Mean baseline plasma VEGF level was 107.6 pg/ml (range, 52–198 pg/ml). For analysis, we combined CR+PR+SD versus PD. Wilcoxon rank-sum test was used to compare baseline plasma VEGF levels, urine VEGF and serum VEGFR2 between the two response groups. There were no significant differences between response and baseline VEGF levels (p=0.39), urine VEGF (p=0.56), and VEGFR2 (p=0.56) respectively. The pt with prolonged CR (18 mos) had the highest baseline VEGF level. Cox proportional hazards regression models was used to look at the association between overall survival (OS) and VEGF levels. There was no significant relationship between (OS) and baseline plasma VEGF (p= 0.38), urine VEGF (p=0.33) or serum VEGFR2 (p=0.63) respectively. No EGFR mutations were found in exon 19 (n=4) or exon 21 (n=6). EGFR expression is being evaluated. Conclusions: Our results indicate that there were no significant relationship between response or OS and baseline VEGF or VEGFR2 levels in our treated pts. The study was supported by NCI Grant N01-CM-17102.

[Table: see text]
Maintenance erlotinib (E) following first-line treatment with docetaxel, carboplatin and erlotinib in patients with ovarian carcinoma
Authors: Vasey P. A. , Paul J. , Rustin G. , Wilson R. , Guastalla J. , Pujade-Lauraine E. , Gore M. , Gabra H. , Carty K. , Kaye S. ,   The Scottish Gyn Cancer Trials Group
Published: March 2020

5560

Background: We previously reported on the feasibility of a combination of erlotinib (E; a HER1/EGFR tyrosine-kinase inhibitor) with platinum and taxane chemotherapy (Agarwal et al, Ann Oncol 2004) and reported that almost 1/3rd patients (pts) stopped E during treatment due to toxicities which included intolerable rash, diarrhea and neutropenic sepsis. This update reports on those pts who then received E at 150mg daily as maintenance treatment. Methods: 48 pts initially received docetaxel (75 mg/m2) and carboplatin (AUC 5) following surgery q21d for 6 cycles in combination with daily oral E (50–100 mg) in dose-escalating cohorts. After 6 cycles, pts could continue with E alone (150mg/d) until progression. Results: 27 pts (56%) continued E beyond chemotherapy for a median of 8.6 months (mo) (range 2.3–32.5 mos), and 23/27 were escalated as planned to daily. Subsequently, 12/27 (44%) pts had their dose either reduced or interrupted for toxicity, which was cutaneous in 10/12 (83%) pts. However, the incidence of = grade 2 toxicity was low apart from alopecia (24%), rash (18%) and fatigue (15%). During follow-up (36 mo) 22/27 (81%) pts stopped E due to progressive disease and 3/27 (11%) stopped E due to cutaneous toxicity. Only 2/27 (7%) pts continue to receive E without evidence of progression, both at doses less than 150mg, again due to cutaneous toxicity. Pts receiving maintenance E had a median progression-free survival of 14.8 mo (95% CI 12.6–17.1 mo) and median overall survival 37.0 mo (95% ci 31.6–42.4 mo); for all pts these figures were 12.5 mo (95% CI 9.1–15.9 mo) respectively, and 37.0 mo (95% ci 27.3–46.7 mo). Conclusions: Maintenance E at 150mg daily following initial treatment with E plus docetaxel-carboplatin for ovarian carcinoma is associated with cutaneous toxicity which limits the dose and duration of treatment in a proportion of pts. The potential benefit of this approach can only be addressed in a randomized trial, and this is now underway under the auspices of the EORTC. A parallel translational study will examine the possibility that patients most likely to benefit can be predicted by molecular tumor analysis.

[Table: see text]
Phase I trial of PTK787/ZK222584 (PTK/ZK) in combination with carboplatin (C) and paclitaxel (T) in platinum-sensitive recurrent epithelial ovarian (EOC), fallopian tube (FT), or primary peritoneal (PPC) cancers
Authors: Juretzka M. M. , Aghajanian C. , Hensley M. L. , Tew W. P. , Spriggs D. , Konner J. , Chiang A. C. , Pezzulli S. , Kim M. , Sabbatini P.
Published: March 2020

5564

Background: Targeting vascular endothelial growth factor (VEGF) in patients (pts) with ovarian cancer achieves objective responses. PTK/ZK is an orally active angiogenesis inhibitor which blocks all known VEGF receptor and platelet-derived growth factor receptor tyrosine kinases. A previous study administered PTK/ZK only on days 3–21 of C and T cycle based on pre-clinical data suggesting PTK/ZK increases T levels (PROC ASCO # 5042, 2005), and recent data supports bid dosing (JCO 18:1–10, 2005). Methods: In this open label, single institution phase I study, pts with platinum sensitive recurrent EOC, FT, or PPC were treated with C and T every 21 days with increasing continuous daily doses of PTK/ZK (250 mg to 1,250mg with bid dosing). Primary endpoints were safety and maximum tolerated dose (MTD). Pharmacokinetic (PK) analysis is planned to describe C and T pharmacokinetics when combined with PTK/ZK. Results: To date, 14 pts with median age 61 (range 45–73) have been enrolled on the first 3 dose levels, including 13 EOC and 1 PPC. All patients were evaluable for toxicity and 8 were evaluable for investigator assessed response. MTD has not been reached. Febrile neutropenia was dose limiting toxicity requiring expansion at levels II and III. PK analysis is ongoing. To date, best responses are: 4 (PR), 3 (SD) and 1 (POD). Other G III toxicity included: C hypersensitivity reaction (1, gr 3), hyperglycemia (4, gr 3), hypertension (1, gr 3), diarrhea (1, gr 3), and elevated liver function tests (1, gr 3). Conclusion: PTK/ZK can be administered continuously in combination with standard doses of C and T using bid dosing. MTD is not yet reached and accrual is ongoing. PK data and MTD will be presented. Supported by Novartis and Bayer Schering Pharma.

[Table: see text]

No significant financial relationships to disclose.
Microtubule-regulatory phosphoproteins and NER system are involved in platinum and paclitaxel-based chemotherapy resistance in ovarian cancer
Authors: Nadal R. , Romero M. L. , Ojeda B. , Gallardo A. , Rodríguez M. , Boguñà I. , Gich I. , Prat J. , Barnadas A.
Published: March 2020

5567

Background: The treatment of ovarian cancer is hindered by intrinsic resistance to platinum and paclitaxel-based chemotherapy (CT). Nucleotide excision repair system plays a central role in DNA repair and is related with resistance to platinum compounds. Excision repair cross-complementation 1 (ERCC1) and 3 (ERCC3) genes confer a differential sensitivity to CT. OP18/stathmin and mDIA are involved in regulation of microtubules dynamics and may represent a mechanism of resistance to paclitaxel. Both mechanisms have been recently investigated in ovarian cancer (OC). Methods: Formalin and paraffin-embedded tissues obtained from 33 patients with advanced OC were retrospectively collected to investigate ERCC1, ERCC3, OP18, and mDIA mRNA levels by quantitative RT- PCR. All patients received a median of 6 cycles platinum based CT in combination with taxanes. Median age was 62 years. Tumors were classified: 52% serous, 9% endometrioid, 27% clear cell, and 12% poorly differentiated carcinomas. FIGO stage: 4 (12%) stage II, 19 (58%) stage III, and 10 (30%) stage IV. 12 chemoresistant tumors (time to recurrence (TTR) < 6 months) and 21 chemosensitive tumors (TTR = 6 months) were analyzed. Median follow-up was 31 months. Results: An increase in mRNA levels was consistently observed in the chemoresistent group: 1.9-fold increased in ERCC1 and 1.6-fold increased in ERCC3. Both genes exhibited comparable expression levels. Statistically significant differences on ERCC1 and ERCC3 mRNA levels were encountered when chemoresistant and chemosensitive tumors were compared (p=0.01 and p= 0.03, respectively). Statistically differences on OP18 mRNA levels were found when chemoresistant and chemosensitive tumors were compared (p=0.05). No differences in mDIA mRNA levels were encountered. Conclusions: Our results suggest that determination of ERCC1-ERCC3 before chemotherapy is potentially useful to predict the effectiveness of platinum-based therapy. Microtubule drug resistance in OC may be associated with altered OP18/stathmin expression. Novel treatment approaches based on molecular markers could be useful predictors of response and could identify targets for therapeutic strategies. Further studies are required.

No significant financial relationships to disclose.
Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer
Authors: Steffensen K. D. , Waldstrøm M. , Jeppesen U. , Brandslund I. , Jakobsen A. , University of Southern Denmark G.
Published: March 2020

5568

Background: The response of tumor cells to platinum-based drugs involves DNA repair mechanisms. Platinum-DNA adducts are repaired by nucleotide excision repair (NER) enzymes that recognize the DNA damage and excise the platinum-DNA adducts from the injured DNA strand. Excision repair cross-complementation group 1 (ERCC1) is one of the genes that encode the proteins of the NER complex and several studies have linked ERCC1 to platinum resistance in cell lines and in human cancers. Cells with a high repair capacity, e.g. high level of ERCC1 expression may therefore be resistant to platinum-based chemotherapy, and conversely, polymorphisms within encoding DNA repair enzymes or low repair capacity may confer sensitivity. A common single nucleotide polymorphism (SNP) of ERCC1 at codon 118 have been proposed to impair ERCC1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum based chemotherapy. The aim of this study was to evaluate ERCC1 expression and ERCC1 118 polymorphism in epithelial ovarian cancer and the potential association with response to platinum-based chemotherapy. Methods: Formalin-fixed, paraffin-embedded tissue sections from 159 patients with epithelial ovarian cancer, FIGO stage IIb-IV, were used for immunohistochemistry (monoclonal mouse antibody, clone 8F1, Neomarkers). ERCC1 codon 118 SNP genotyping was performed by real time PCR, Taqman SNP genotyping assay. Results: ERCC1 protein overexpression was found in 37.7 % of the tumors. The response rate (normalization of CA125 during platinum-based chemotherapy) was 63.6 % (35/55) in patients with ERCC1-negative tumors compared to only 35.6 % (16/45) in patients with ERCC1-positive tumors. (p = 0.0052, χ2). Furthermore increasing immunohistochemical score (H-score) was associated with poorer response to chemotherapy. (p = 0.0006, Spearman`s). The T/T genotype (44 %) showed better response to chemotherapy than C/C + C/T (15 % + 41 %) variants (p=0.042). Conclusions: Patients with ERCC1-negative tumors appear to have significantly better response to platinumbased chemotherapy compared to patients with ERCC1-positive tumors. In addition the TT genotype seems to be favorable towards better response to platinum-based chemotherapy.

No significant financial relationships to disclose.
Comparison of the cost per distant disease-free year gained for upfront letrozole or anastrozole, or switched exemestane compared to tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: The UK perspective
Authors: Karnon J. , di Trapani F. , Kaura S.
Published: March 2020

557

Background: Due to subsequent poor prognosis, prevention of distant recurrence (DR) is a primary aim of adjuvant hormonal therapy for early breast cancer. Compared to 5 years TAM in hormone receptor positive (HR+) postmenopausal women, DR relative risks are 0.73 (95% CI 0.6 - 0.88) for 5 years letrozole (LET), 0.84 (95% CI 0.7 - 1.0) for 5 years anastrozole (ANA), 0.73 (95% CI 0.59 - 0.9) for 2–3yrs exemestane after 2–3 years (EXE/TAM). This analysis evaluates the incremental cost per distant disease free year gained from a UK NHS perspective of LET, ANA, EXE/TAM versus 5 years TAM using the same health economic model. Methods: A Markov model described pathways through relevant health states over the remaining lifetime of a cohort of HR+ women aged 61 yrs. Probabilities of breast cancer events (contralateral; locoregional; soft tissue, bone, and visceral metastases) adverse events (endometrial cancer, hip and other fractures, cardiovascular disease, thromboembolic events, and arthralgia) were based on the latest early breast cancer overview, published results of the BIG 1–98, ATAC, and IES trials, and UK population-based studies as appropriate. Conservatively, no carry-over effect was assumed for the AIs after therapy discontinuation. Costs (2005 UK£) of breast-cancer care were obtained from a primary costing study in Scotland, and treatment costs for AEs were obtained from published studies. Costs and DR-free years were discounted at 3.5% annually. Results: The mean durations of DDFS were estimated to be 12.81, 12.66, 12.57, and 12.35 years for LET, ANA, TAM/EXE, and TAM, respectively. The incremental cost per distant disease free year gained of LET vs TAM is £10,379 (95% CI £5,286-£17,818), of ANA vs TAM is £11,428 (95% CI £5,071- £48,856), and of TAM/EXE vs TAM alone is £11,020 (95% CI £4,820-£36,947). Conclusion: Compared to 5 years TAM, adjuvant treatment of postmenopausal HR+ women with an AI is a cost-effective use of UK NHS resources. Based on the mean results, LET appears to be the most cost-effective of the three AIs, despite its higher acquisition cost compared to ANA in the UK, though the confidence intervals are wide.

[Table: see text]
Trabectedin (T) in relapsed advanced ovarian cancer (ROC): A pooled analysis of three phase II studies
Authors: McMeekin S. , del Campo J. M. , Colombo N. , Krasner C. , Roszak A. , Braly P. , Ciuleanu T. E. , Lebedinsky C. , Izquierdo M. A. , Sessa C.
Published: March 2020

5579

Introduction: Trabectedin is a DNA minor groove binding drug with a distinct MoA under development in sarcoma, prostate, breast and ROC. We have performed a pooled analysis of efficacy and tolerability of all phase II trials with T as 2nd - 3rd line in ROC. Methods: Three Trabectedin schedules were investigated: two every 3weeks (q3w; A: 1.3 mg/m2 3-h or B: 1.5 mg/m2 24-h) and one weekly (C: 0.58 mg/m2 3-h ×3 q4w). Endpoints were response rate (RR), time to progression (TTP), response duration (RD) and safety. 294 patients from 3 phase II (one randomized A vs B) trials were included: 108 were resistant (R) and 186 sensitive (S) to last platinum, based on progression-free interval <6 months or longer.Results: Overall RR and median TTP were 8% and 2.1mo in R and 34% and 5.8 mo in S patients. Median RD was 5.8 m. Schedules A & B q3w showed significant better RR (33% vs 16%, p=<0.0001) and median TTP (5.8 vs 2.8 m, p=0.0001) than the weekly schedule C. No efficacy difference was seen between 3-h and 24-h q3wk. In patients with = 2 prior platinum-based regimens, RR (R:7% and S:37%) and median TTP (R: 2.5 m and S:6.3 m) were similar than patients with only 1 prior platinum [RR (R:9%; S:33%) and TTP (R: 2 m; S: 5.5 m)]. 1,404 cycles were delivered [median A: 5(1–23), B: 5(1–19), C: 3(1–22)], with similar dose intensity (mg/m2/wk) across regimens (0.38, 0.42, 0.39). Most common drug-related AEs of any grade by cycle were (A, B, C) fatigue: 38, 35, 63% and vomiting: 16, 27, 21%. Grade 3/4 lab abnormalities were non-cumulative neutropenia: 21, 28, 1% and ALT increase: 32, 26, 3%. Low incidence of febrile neutropenia, neurotoxicity, stomatitis and alopecia was seen regardless of schedule. Conclusions: Trabectedin as single agent has shown clinical activity in both R and, particularly in S ROC. Activity was fully retained in patients with =2 prior platinum lines. Trabectedin q3w schedules (with no difference between 3 and 24-h) showed higher efficacy than T weekly. Toxicities were manageable and non-cumulative. Trabectedin is a promising new drug for the treatment of ROC and is under evaluation in a phase III trial.

No significant financial relationships to disclose.
Integrated FDG-PET/CT for initial staging of breast cancer
Authors: Khan Q. J. , O’Dea A. P. , Dusing R. , Sharma P. , Roling S. M. , Fabian C. J. , Kimler B. F.
Published: March 2020

558

Background:
Integrated FDG-PET/CT improves the diagnostic accuracy of staging of some cancers. The value of FDG-PET/CT in initial staging of breast cancer for detection of distant metastases has not been defined.
Methods:
Retrospective analysis of 83 consecutive women at the University of Kansas Medical Center who had a FDG-PET/CT from Jan 2005 to July 2006, at the time of initial diagnosis of invasive breast cancer. Women with symptoms suspicious for metastatic disease were excluded. Radiographic reports and patient charts were reviewed. All suspicious CT scans were re-read by a single radiologist who was blinded to the PET results. All suspicious scans were confirmed either by a biopsy or follow-up scans according to the discretion of the treating physician.
Results:
Median age was 52. 23 (28%) cancers were stage I, 44 (53%) stage II and 16 (19%) were stage III. 15/83 (18%) women had a suspicious FDG-PET/CT. Only 2 of these 15 women were confirmed to have metastatic disease, while 13 (16 %) had a false positive (FP) scan. In 5 women where both CT and PET were suspicious, 2 were true positives (TP) whereas 3 were FP. All 3 women who had suspicious PET but a non-suspicious CT were FP. All 7 women who had a non-suspicious PET and a suspicious CT were FP. PET influenced the CT classification by the radiologist in 5 (6%) women. 71/83 (86%) women had a negative or a non-suspicious CT. 3 women had lesions classified as non-suspicious with the help of a negative PET, two had lesions classified as suspicious with the help of a positive PET and seven had suspicious lesions on CT regardless of the PET. FDG-PET/CT resulted in unnecessary follow-up scans in eleven women, and unnecessary biopsies in two. One TP had metastatic bone disease. The other TP had a solitary liver metastasis detected by FDG-PET/CT which was resected and she has no evidence of disease after two years of follow-up.
Conclusions:
Given the high false positive rate and overall low incidence of metastases, routine use of FDG- PET/CT in asymptomatic women diagnosed with invasive breast cancer cannot be recommended.

No significant financial relationships to disclose.
Adjuvant (adj) bevacizumab (B) plus dose-dense (dd) doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin- bound paclitaxel (nab-p) in early stage breast cancer (BC) patients (pts): Cardiac safety
Authors: Dickler M. N. , Traina T. , Panageas K. , Steingart R. , Dang C. , Fornier M. , Sugarman S. , Norton L. , Hudis C. , Rugo H.
Published: March 2020

567

Background: Dose dense, q2 wk AC-paclitaxel (T) is superior to q3 wk therapy (Rx) (Citron, JCO 2003). The risk of congestive heart failure (CHF) with ddAC-T is not increased at <1%. In MBC, B improves PFS when added to T (Miller, SABCS 2005). It is unclear if doxorubicin plus B increases risk of CHF. Hence, we are testing the cardiac safety of ddAC-nab-p with concurrent B as adj therapy. Based upon the accepted cardiac event (CE) rate of ≤4% in trials with adj trastuzumab (an agent with known cardiac toxicity), we designed this study with similar monitoring & tolerability thresholds. The primary endpoint is cardiac safety, defined as discontinuation of B due to cardiac death from LV dysfunction or symptomatic CHF (dyspnea and LVEF<50%). Secondary endpoints: toxicity, disease-free & overall survival. Methods: Eligible pts have resected HER2(-) BC and normal LVEF. Rx consists of q2wk AC (60/600 mg/m2) ×4 then nab-p (260 mg/m2) x4 with pegfilgrastim on Day 2 plus B for one year (10mg/kg IV q2wk ×8 with chemoRx then B 15mg/kg q3wk); radiation & endocrine Rx per standard of care. MUGA obtained at baseline & mos. 2, 6, 9, 18. Pts with significant asymptomatic ↓LVEF during Rx may have B held per protocol. These pts are not counted as CEs but will have long-term cardiac monitoring. Accrual goal is 75 pts. If ≥3 CE (∼4.7%) or >1 cardiac death from LV dysfunction, B + ddAC-nab-p will not be considered safe. Results: 44 pts have enrolled, median (med) age 46.5 yrs (33–67). 28 pts have baseline & month 2 LVEF data: med baseline LVEF 68% (61–82), med LVEF at mo. 2 after ddAC+B 68% (53–75); 1 pt had an 18 point asymptomatic drop to 53% - B held but reinitiated in 4 wks with repeat LVEF 63%. 12 pts completed nab-p+B but none have reached the 6 mo. MUGA. Rx-related Gr 3/4 toxicity: neutropenia gr4 (6.8%), diarrhea gr3 (2.3%), hypertension gr3 (2.3%), neuropathy gr 3 (2.3%), fatigue gr 3 (2.3%), mucositis gr 3 (2.3%). 4 pts have withdrawn from study Rx, but only 1 due to toxicity including gr3 fatigue, mucositis & neuropathy. Conclusions: No LV dysfunction has been observed with B + ddAC-nab-p; this trial is on-going. Long-term follow-up and analysis of troponin, renin and circulating endothelial & tumor cells are planned.

No significant financial relationships to disclose.
How well do standard prognostic criteria predict oncotype DX (ODX) scores?
Authors: Kamal A. H. , Loprinzi C. L. , Reynolds C. , Dueck A. C. , Geiger X. J. , Ingle J. N. , Carlson R. W. , Hobday T. J. , Winer E. P. , Perez E. A. , Goetz M. P.
Published: March 2020

576

Background: In node-negative, ER + breast cancer, gene expression profiling can identify level of risk and, in the case of ODX, may also identify pts with a higher chance of benefiting from adjuvant chemotherapy. Because the gene profile in ODX includes an assessment of ER, HER2, and proliferation, we hypothesized that clinicians using standardized criteria could discriminate risk (high versus low/intermediate) as specified by ODX. Methods: We identified Mayo Clinic patients with node-negative, ER + breast cancer, for whom ODX scores were available. Tumor slides were reviewed by an expert breast pathologist to confirm tumor size, histology, and tumor grade. Both ER and PR were quantitated; HER-2 was determined by IHC (FISH, if 2+). These clinical cases were presented to six academic oncologists, blinded to the ODX score, to predict ODX risk (low, intermediate, or high) and give their recommendation for chemotherapy (CTX) (yes/no). Afterwards, they were presented with the same cases with the actual ODX score, to give recommendations regarding CTX. Results: ODX scores in tumors from 31 patients were low in 18 pts, intermediate in 10 pts, and high in 3 pts. Concordance between predicted and actual ODX scores being low/intermediate vs high exceeded 87% for each oncologist. The most frequent discrepancies were actual low scores predicted as intermediate (31/80 discordant) and actual intermediate scores predicted as low (29/80 discordant). Overall agreement of predicted scores (high vs low/intermediate) among the oncologists was substantial (kappa=0.75, p<0.0001). CTX recommendations following provision of the ODX scores changed on average 18.2% (range 12.9%-25.8%) of the time, with slightly fewer changing for, versus against, a CTX recommendation. Conclusions: Our findings suggest that the proper evaluation and interpretation of traditional prognostic criteria will identify most node negative, ER + patients at high risk of recurrence (as predicted by ODX) but poorly discriminate low versus intermediate risk. The provision of ODX data changed the recommendation for CTX in approximately 20% of cases.

No significant financial relationships to disclose.
Adjuvant therapy for early stage breast cancer (EBC): Distant disease-free survival (DDFS) as a predictor of overall survival (OS)
Authors: Melisko M. , Lin A. , Rugo H.
Published: March 2020

583

Background: OS advantages are often difficult to demonstrate in trials evaluating treatment for EBC, as this requires long follow-up (FU) and large trials. Results are also confounded by factors such as further treatment. DFS, the primary endpoint in many adjuvant trials, is not a consistent predictor of OS and lack of standard definitions renders its interpretation difficult. A better, quicker endpoint is needed as a surrogate for OS. Distant metastases (DM), the most common type of recurrence, are responsible for the initial peak of relapse seen at 2 years post surgery and are associated with the highest risk of death compared to locoregional and contralateral events. DDFS may be a better short-term OS predictor. Methods: The impact of common adjuvant therapies (chemotherapy [CT], tamoxifen [TAM], and aromatase inhibitors [AIs]) on DM risk and OS was examined. Results: CT trials show that improvements in DDFS often precede subsequent improvements in OS. In NSABP B14, TAM significantly improved DDFS at 4 years and OS at 10 years. In ATAC and BIG 1–98, over half of EBC recurrences are DM, but OS differences are limited by short FU. BIG 1–98 showed a significant reduction in DM risk with letrozole versus TAM, but ATAC showed no significant reduction in DM risk with anastrozole in hormone receptor-positive patients. The reason for this difference is unclear. IES initially showed a significant reduction in DM risk, which was later followed by a borderline significant OS benefit in estrogen receptor-positive/unknown patients, favoring exemestane. Conclusion: Data from several adjuvant trials show that improvements in DDFS often precede significant improvements in OS. AIs show superiority over TAM in reducing DM risk (IES, BIG 1–98). DDFS may be a better, more achievable endpoint than OS for women with EBC and could quicken the development of future adjuvant breast cancer therapies.

[Table: see text]

No significant financial relationships to disclose.
Adjuvant LH-RH agonists for premenopausal early breast cancer: A meta-analysis of randomized clinical trials (RCTs) exploring the magnitude of the disease-free and overall survival (DFS/OS) benefit
Authors: Carlini P. , Bria E. , Cuppone F. , Papaldo P. , Nisticò C. , Fabi A. , Ruggeri E. M. , Terzoli E. , Cognetti F. , Giannarelli D.
Published: March 2020

592

Background: LH-RH agonists are considered as a milestone for adjuvant treatment for premenopausal early breast cancer patients (pts). All RCTs in which ovarian ablation (OA) with/without tamoxifen (TAM) and/or chemotherapy (CT) was compared with tamoxifen (TAM) and/or chemotherapy (CT) were pooled to estimate the magnitude of the benefit in both DFS and OS. Methods: A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model according to the inverse variance and heterogeneity (Het) test were applied as well. Absolute benefits (AB) and the number of pts needed to treat (NNT) were calculated. A sensitivity analysis to test for effect robustness in 4 sub-populations (OA/OS vs CT; OA/OS + CT vs CT; OA + TAM vs CT; OA + TAM vs observation) was accomplished. Results: Fifteen RCTs were gathered (12,545 pts); one RCT did not report the OS result. Results are depicted in the table . Conclusions: Although differences across RCTs exist in median follow-up time (as demonstrated by heterogeneity), OA seems to significantly improve DFS when combined with CT over CT alone, when combined with TAM versus CT alone and when combined with TAM versus observation. Actually, these DFS benefits do not translate into an OS benefit, with the exception of the last subgroup.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of axitinib (AG-013736 [AG]) in patients (pts) with advanced thyroid cancers
Authors: Cohen E. E. , Vokes E. E. , Rosen L. S. , Kies M. S. , Forastiere A. A. , Worden F. P. , Kane M. A. , Liau K. F. , Shalinsky D. R. , Cohen R. B.
Published: March 2020

6008

Background: Elevated VEGF-A and VEGF-C have been reported in thyroid tumor tissue compared with normal thyroid. AG is a potent, small molecule inhibitor of VEGF receptors 1, 2 and 3. The efficacy and safety of AG therapy in pts with advanced thyroid cancers was examined in this single-arm, multi-center study. Methods: 60 pts with metastatic or unresectable locally-advanced thyroid cancer refractory to, or not suitable candidates for, 131iodine (131I) treatment, with measurable disease received AG at a starting dose of 5 mg orally BID. The primary endpoint was response rate (RR) by RECIST criteria. A Simon 2-stage minimax design was used (a=0.1; β=0.1; null RR=5%; alternative RR=20%). Samples were collected pretreatment and q8wks to explore relationships between clinical response and plasma soluble proteins. Results: Median age was 59 yrs (26–84), 35 (58%) were male. Histological subtypes included papillary: 29 pts (48%); follicular: 15 pts (25%)-11 (18%) with Hurthle cell variant; medullary: 12 pts (20%); anaplastic: 2 pts (3%), and other/unknown: 2 pts (3%). 53 pts (88%) had prior surgery, 42 (70%) had prior 131I treatment, 27 (45%) had prior external beam radiation, and 9 (15%) had prior chemotherapy. Partial response (PR) by investigator report was achieved in 13 pts (22% CI: 12.1, 34.2), with 31- 68% maximum tumor regression and duration of response (DOR) of 1–16 months. 30 pts (50%) have stable disease with a duration range of 4–13 months and 13–67% maximum tumor regression in 28 pts. Response assessments are ongoing. The treatment duration range is 6–670 days with 38 pts currently on study. Median PFS has not been reached with a median follow up of 273 days. The most common treatment-related adverse events were fatigue (37%), proteinuria (27%), stomatitis/mucositis (25%), diarrhea (22%), hypertension (20%) and nausea (18%). AG therapy consistently decreased soluble VEGFR2 and VEGFR3, and increased VEGF in the blood, demonstrating pharmacodynamic activity against targeted VEGF receptors. Conclusions: AG has substantial anti-tumor activity in advanced thyroid cancer with demonstrated pharmacodynamic activity. A global pivotal trial testing AG in doxorubicin refractory thyroid cancer is ongoing.

[Table: see text]
Intratumoral epidermal growth factor receptor (EGFR) antisense (AS) DNA in recurrent squamous cell carcinoma of the head and neck (SCCHN): A phase I trial
Authors: Lai S. Y. , Lui V. W. , Koppikar P. J. , Thomas S. M. , Gooding W. E. , Seethala R. R. , Branstetter B. F. , Argiris A. , Grandis J. R.
Published: March 2020

6009

Background: SCCHN is characterized by upregulation of the EGFR where EGFR expression levels in the tumor correlate with decreased survival. We developed a novel anti-EGFR therapy with a therapeutic gene consisting of an EGFR AS sequence under the control of the U6 promoter in a pNGVL backbone. We conducted a phase I clinical trial to evaluate the safety and biological effects of EGFR AS in patients with advanced SCCHN. Methods: Patients (pts) with recurrent SCCHN refractory to standard therapies with at least one evaluable and accessible lesion were enrolled in a phase I trial. EGFR AS dose was escalated in successive cohorts of pts (classic “3+3” design) in 6 dose levels: 60 μg, 120 μg, 240 μg, 480 μg, 960 μg and 1920 μg at a concentration of 1 μg/μL. Pts received weekly intratumoral injections of EGFR AS × 4 weeks. Tumors were biopsied before and after the completion of therapy. In addition to treatment response as assessed by tumor volume measurements (PET/CT), levels of target proteins and phosphoproteins were assessed in the tumors. Results: 17 pts were enrolled (median age: 57 years; 15 M / 2 F). No grade 3/4 or dose-limiting toxicities were noted. 4 grade 1 toxicities were reported: injection site pain/swelling (2), localized edema (1) and lethargy (1). EGFR AS was present in the tumor after injection as demonstrated by PCR. 5 pts (29%; 95% CI 10–56%) achieved an objective response (RECIST), including 2 CRs (pCRs confirmed by biopsy) and 3 PRs; 2 pts had stable disease as best response. Median duration of response was 4.5 months (3.0–23.1). Median survival for the entire cohort was 5.4 months with a median survival in responders of 7.9 months. 1 pt who achieved CR is alive without progression at 23.1+ months. Immunohistochemical studies demonstrated decreased EGFR in 2 pts with CR. Assessment of downstream signaling molecules is in progress. Conclusions: Intratumoral EGFR AS was safe and resulted in impressive antitumor activity in pts with recurrent, incurable SCCHN. We plan to study further the use of EGFR AS as an integral component in the curative therapy of SCCHN.

No significant financial relationships to disclose.