bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of intraoperative breast cancer sentinel lymph node (SLN) assay to predict of ≥4 positive (+) lymph nodes (LN)
Authors: Chagpar A. B. , Blumencranz P. , Whitworth P. W. , Deck K. B. , Rosenberg A. , Simmons R. M. , Reintgen D. S. , Beitsch P. , Saha S. , Julian T. B.
Published: August 2020

530

Background: Predicting which patients will have ≥4 +LN and may need radiation therapy affects immediate breast reconstruction. We hypothesized that model s to predict the likelihood of ≥4+LN may be improved by incorporation of quantitative real time RT-PCR analysis of SLN. Methods: 728 patients were enrolled in 2 prospective studies of the GeneSearch BLN Assay (Veridex LLC) for SLN metastases. 205 (28.2%) were found to have +SLN by hematoxylin-eosin staining. Of these, 115 pts (15.8%) had tumors ≤5 cm in size with >4 total LN removed, forming the cohort of interest for this study. Quantitative cycle times (CT) for mammaglobin (MG) and CK19 were correlated with finding ≥4+LN on final pathology. Results: Median tumor size was 2.0 cm (range; 0.2–5.0 cm). Median number of SLN removed was 3 (range; 1–11). 18 patients (15.7%) had ≥4 +LN on final pathology. Median CT for MG was 29.1 (interquartile range (IQR): 24.7–39.0) in patients with <4 +LN vs. 21.4 (IQR: 18.5–26.8) in those with ≥4 +LN, p<0.001. Median CT for CK19 was 23.7 (IQR: 20.9–28.2) in patients with <4 +LN vs. 19.6 (IQR: 17.8–20.7) in those with ≥4 +LN, p<0.001. Tumor size ≥2cm, proportion of SLN+ >50%, MG CT <25.8 and CK19 <20.8 were correlated with ≥4 +LN on final pathology. On multivariate analysis, tumor size, MG CT and CK19 CT were significant (see table). A simplified CPR was created with 1 point given if tumor size was ≥2cm, 1 point if MG CT <25.8 and 2 points if CK19 CT<20.8. Of the 24 patients (20.9%) with 0 points, only 1 (4.2%) had ≥4 +LN; of the 12 patients (10.4%) with 3 points, 8 (66.7%) had ≥4 +LN on final pathology, p<0.001. Area under the receiver-operator curve was 86.2% (95% CI: 76.1%-96.2%). Conclusions: Intraoperative quantitative RT-PCR of SLN improves prediction of ≥4 +LN; further validation of this model will have clinical utility regarding the use of immediate, delayed, or delayed-immediate reconstruction approaches.

[Table: see text]

[Table: see text]
Outcome prediction by the 70-gene profile in the context of the National Comprehensive Cancer Network (NCCN) guidelines
Authors: de Snoo F. A. , Knauer M. , Bender R. A. , Stork-Sloots L. , Rutgers E. J. , Glas A. M. , Linn S. C. , Van 't Veer L. J.
Published: August 2020

535

Background: According to the NCCN consensus guidelines molecular profiling for breast cancer prognosis may be used in patients with ER-positive, Her2-negative and LN-negative disease. Current proposed NCCN clinical risk assessment suggests adjuvant treatment for the majority of these patients. The 70-gene profile (MammaPrint) is validated as an independent prognostic indicator for patients with lymph node-negative and positive disease. Prognosis prediction by MammaPrint may be more suitable to indicate who needs adjuvant chemotherapy in addition to endocrine therapy. Methods: 566 tumor samples of women with ER-positive, Her2-negative and LN- negative breast cancer from 5 previously reported studies were analyzed and classified by MammaPrint as good or poor prognosis. 10-year breast cancer-specific survival (BCSS) was analyzed according to MammaPrint and the NCCN guidelines. Results: Median follow-up was 3.5 years (range 0.1–21.1). 380 of 566 patients (67%) were classified as good and 186 (33%) as poor prognosis by MammaPrint. Using the NCCN guidelines, 7% were classified as low and 93% as high risk respectively. 349 patients (62%) received no adjuvant treatment, 17% received hormonal treatment only, 2% chemotherapy only and 20% both respectively. At 10 years, BCSS was 91% vs. 67% for the good and poor prognosis groups (HR 4.0 [95%CI 2.0–7.9], p<0.001) whith MammaPrint risk assessment. If the NCCN guidelines were used, BCSS was 86% vs. 83% for the low and high risk groups (HR 1.11 [0.3–4.6), p=0.888). In multivariate analysis, adjusted for known prognostic factors and adjuvant therapy, only MammaPrint and histological grade were independent predictors for 10-year-BCSS with HRs of 2.8 (1.3–6.1, p=0.008) and 1.9 (1.1–3.1, p=0.015), respectively. Conclusions: MammaPrint is a strong and independent prognostic indicator in ER-positive, Her2-negative, LN-negative breast cancer and is discordant in 62% of cases when compared with the NCCN guidelines. MammaPrint identifies approximately 66% of NCCN high risk patients as having a good prognosis. Integration of MammaPrint into clinical risk assessment and adjuvant treatment selection can provide a large benefit for management of patients with endocrine-responsive early breast cancer.

[Table: see text]
Use of progesterone receptor (PR) expression to predict benefit from prolonged adjuvant tamoxifen (TAM) in breast cancer: Results of a biomarker study from the TAM01 randomized Trial
Authors: Mathieu M. , De la Cruz J. , Veilllard A. S. , Koscielny S. , Bourgier C. , Rimareix F. , Spielmann M. , Delozier T. , Andre F. , Delaloge S.
Published: August 2020

536

Background: The optimal duration of endocrine therapy ranges between 5 and 7 years. Recent data suggest that a subset of patients could benefit from extended adjuvant TAM. The goal of this biomarker study was to identify potential candidates for extended TAM. Methods: After 2–3 yrs of adjuvant TAM, 3793 patients (pts) were randomized to continue TAM up to 10 yrs, or to stop treatment (Delozier, J Clin Oncol. 2000). The tumor blocks of 587/988 pts included at the Institut Gustave-Roussy, were used to construct a tissue micro-array (TMA). Immunohistochemical stainings were performed for ER, PR, bcl2, p53 (+: > 10% of stained cells), HER-2 (+: score 3+), EGFR1 (+: any positivity), PAK1, IGFR1 (+: intensity = 2 or 3). Median follow-up was 12 years. The prognostic values of biomarkers were assessed by a Cox model adjusted for clinical prognostic parameters and predictive values by interaction tests. Only statistical tests with P<0.01 were considered significant because of multi-hypothesis testing. Time-to-relapse (TTR), excluding contralateral cancer, was the main study endpoint. Results: Median age of the cohort included in the TMA was 63. Tumor characteristics : 54% node-positive, 85% ER+, 64% PR+, 7% HER-2+, 68% bcl2+, 14% p53+, 8% EGFR1+, 46% PAK1, 45% IGFR1. None of the biomarkers were prognostically significant. However, PR expression was strongly predictive for the efficacy of extended TAM on TTR (interaction test, p = 0.003). Long-term TAM was associated with a hazard ratio of 0.56, (95% CI: 0.30–1.03) and 1.94 (95%CI = 0.80–4.70) for PR+ and PR- pts respectively. A trend towards interaction between ER (p = 0.04), HER-2 (p = 0.05) and Bcl2 (p = 0.03) expression and a benefit from TAM was also observed, with a trend towards greater efficacy of prolonged TAM in ER+/HER-2-/ bcl2+ tumors. P53, EGFR1, PAK1, IGFR1 expression had no predictive value. Conclusions: PR expression, probably reflective of ER activation and functionality, strongly predicts benefit from continuation of TAM after 2–3 yrs. These data could provide a rationale for evaluating the efficacy of TAM after 5 years of anti-aromatase therapy in post-menopausal women with ER+/PR+/bcl2+/Her2-tumors.

No significant financial relationships to disclose.
Prospective randomized trial evaluating weekly paclitaxel (WP) versus docetaxel in combination with capecitabine (DC) in operable breast cancer
Authors: Buzdar A. U. , Green M. C. , Broglio K. R. , Carter C. D. , Valero V. , Ibrahim N. K. , Hunt K. K. , Hortobagyi G. N.
Published: August 2020

542

Background: Paclitaxel has scheduled-dependant efficacy, and WP is associated with better therapeutic index (J Clin Oncol. 2005;23:5983–5992). The DC combination had higher response rate, longer control of disease, and improved survival in metastatic disease (J Clin Oncol. 2002;20:2812–2823). This randomized study compared the efficacy and safety of WP to DC in patients (pts) with operable breast cancer. Methods: Pts were randomized 1:1 and stratified by the timing of therapy (preoperative vs adjuvant). The primary endpoint was disease-free survival (DFS), and the secondary endpoint in pts receiving preoperative therapy was complete pathologic response (pCR). WP arm was paclitaxel 80 mg/m2 weekly for 12 weeks, followed by 4 cycles of FEC. DC arm included docetaxel 75 mg/m2 day 1, and capecitabine 1500mg/m2 daily for 14 days of each 3 week cycle for a planned 4 cycles of DC followed by 4 cycles of FEC. The study was designed to include 930 pts to have 80% power to detect a difference in 4 year DFS from 85% on the WP arm to 92% on the DC arm, based on a two-sided test at the 0.05 significance level. Results: 601 pts were randomized, 304 on WP arm and 297 on DC arm. 37% of pts on each arm received therapy in the preoperative setting. Pts characteristics were balanced between the two arms. Median follow-up was 38 months. 4-year DFS on DC arm was 91.0% (95% confidence interval [CI], 84.8- 94.1) and the 4-year DFS on the WP arm was 89.3% (95% CI, 84.8- 94.1) (p = 0.957). A total of 107 pts have been treated with DC and 109 have been treated with WP in the preoperative setting and are evaluable for pCR. The pCR rates were 18.7% and 17.4% on each arm respectively (p = 0.81). The DC arm had higher incidence of hand foot syndrome, and myelosuppression, and WP treatment was associated with higher neurotoxicity. Interim data was presented June 2008 to the institutional data monitoring committee and the study was closed due to futility. If the trial had continued as planned, the predictive probability of concluding in favor of the DC arm for DFS and pCR were 0.005 and 0.001, respectively. Conclusions: WP and DC as utilized in this study had similar efficacy in pts with early stage breast cancer. WP was a better tolerated therapy, associated with little myelotoxicity.

[Table: see text]
ASCO-recommended prognostic factors uPA/PAI-1 in node-negative (N0) breast cancer patients (pts) compared to clinicopathological risk assessment within the NNBC 3-Europe trial
Authors: Thomssen C. , Vetter M. , Schmidt M. , Veyret C. , Meisner C. , von Minckwitz G. , Martin P. , Sweep F. C. , Paepke D. , Harbeck N.
Published: August 2020

544

Background: ASCO Tumor Marker Guidelines 2007 recommended clinical routine use of the invasion markers uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 for risk assessment in N0 breast cancer pts (Harris et al, J Clin Oncol. 2007;25:5287). Ten-year follow-up data of the confirmatory prospective clinical uPA/PAI-1 trial (CHEMO-N0) will be presented at the ASCO 2009 Meeting (Harbeck et al.). We conducted a further prospective trial (NNBC 3-Europe) addressing the direct comparison between risk-assessment by uPA/PAI-1 (UP) and clinico-pathological factors (C), and optimization of adjuvant chemotherapy for high-risk N0 pts: FEC*3-Doc*3 vs. standard FEC*6. Methods: From December 2002 to January 2009, 4,040 pts were recruited by 151 centres. For uPA and PAI-1 ELISA, tumors samples were snap frozen und processed. Risk assessment was based on grade and in G2 tumors, either by UP or by a St. Gallen adapted C algorithm. High-risk pts were randomized for adjuvant chemotherapy. All laboratories took part in central quality assurance (QA) for uPA/PAI-1 determination. Results: Risk assessment was performed for 1,590 pts based on C and for 2,445 pts based on UP. End of accrual was planned when 2,572 high risk pts were randomised for chemotherapy and thus ends Jan 31, 2009. Current status shows 1,291 high-risk pts in the FEC-Doc and 1,294 in the FEC arm. In the low-risk arm, 1,450 pts have endocrine therapy, only. By both risk stratifications, 42% of the G2 tumors were assigned as low risk, but in total, more pts were classified as low-risk by UP (39%) than by C (31%). Median uPA level were at 2.40 ng/mg protein (below cutoff), median PAI-1 at 15.9 (above cutoff). In the QA programm, mean coefficients of variations are 12% for uPA and PAI-1 determination. Conclusions: The prospective biomarker trial using uPA/PAI-1 has just ended accrual with more than 4,000 patients. Routine uPA/PAI-1 determination is reliable and feasible even in core needle specimens. Using tumor grade and uPA/PAI-1, adjuvant chemotherapy may be avoided in about 39% of N0 breast cancer pts. Cooperation: EORTC Patho-Biology Group, AGO Breast Group, GBG, Unrestricted grants by Sanofi-Aventis, Pfizer, American Diagnostica, Martin-Luther-Universitaet Halle-Wittenberg.

[Table: see text]
Modeling bone mineral density (BMD) evolution in postmenopausal patients treated by letrozole (L), tamoxifen (T), and sequences of T and L (SAKK 21/07)
Authors: Zaman K. , Thürlimann B. , Huober J. , Schönenberger A. , Pagani O. , Lüthi J. , Simcock M. , Giobbie-Hurder A. , Genton C. , Aebi S.
Published: August 2020

545

Background: Osteoporosis and fractures are long term complications of aromatase inhibitor use in the adjuvant therapy of breast cancer. Early detection of patients (pts) at risk of treatment-induced osteoporosis may allow preventive therapy and selection of the most appropriate endocrine therapy. We developed a statistical model describing the evolution of BMD in pts treated with T, L and sequences of T and L. Methods: Available dual-energy x-ray absorptiometry exams (DXA) of pts treated in trial BIG 1–98 were retrospectively collected from Swiss centers. Treatment arms: A) T for 5 years; B) L for 5 years; C) 2 years of T followed by 3 years of L; and D) 2 years of L followed by 3 years of T. Pts without DXA were used as a control for detecting selection bias. A repeated measures model using the first-order autoregressive covariance structure to allow for different times between DXA was used to model BMD (g/cm2) since trial randomisation. Prospectively defined covariates were considered as fixed effects in a multivariable model using an intention to treat analysis. Covariates at trial randomization were: age, height, weight, race, known osteoporosis, tobacco use, prior bone fracture, prior hormone replacement therapy (HRT), bisphosphonate use and previous neo-/adjuvant chemotherapy (ChT). Results: A total of 247 out of 546 pts had between 1 and 5 DXA; a total of 576 DXA were collected. Arm A contained 67 pts, B 63 pts, C 55 pts and D 62 pts. Median follow-up was 5.8 years. Factors correlated with BMD in the multivariate analysis were weight (0.003/kg, p < 0.0001), height (0.003/cm, p = 0.0083), osteoporosis (-0.130, p < 0.0001), tobacco (current / previously vs. never: -0.057, p = 0.0011 / -0.042, p = 0.0798), previous HRT (0.030, p = 0.0244), ChT (0.032, p = 0.0174), time since endocrine therapy start (-0.009/year, p = 0.0164) and treatment arm (B / C / D vs. A: -0.068, p = 0.0002 / -0.091, p < 0.0001 / -0.064, p = 0.003). Conclusions: Our statistical model describes the BMD evolution for pts treated with L and/or T. All treatment regimens affect BMD. Contrary to expectation, the switch schedule T followed by L does not seem to result in better bone protection compared to L monotherapy.

[Table: see text]
Ductal carcinoma in situ of the breast and gene expression markers for prediction of invasive recurrence
Authors: McKean H. A. , Reynolds C. , Hoskin T. L. , Suman V. J. , Grant C. S. , Erlander M. G. , Ma X. , Ingle J. , Goetz M. P.
Published: August 2020

550

Background: Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive cancers with varying propensity for recurrence. There are no validated markers that identify patients at risk for invasive recurrence following lumpectomy. HOXB13/IL17BR (H/I) is expressed in both DCIS and invasive cancer (Ma Cancer Cell. 2004) and associated with recurrence in stage I cancer. A 5-gene molecular grade index (MGI) distinguishes outcome in grade II disease (Ma Clin Cancer Res. 2008). We sought to determine whether H/I or MGI was associated with invasive recurrence in resected DCIS. Methods: We identified patients at Mayo Rochester who underwent lumpectomy ± radiation for DCIS between 1988 and 2001 and performed a nested case/control study. Cases were patients with ipsilateral invasive recurrence, matched to controls based on age, surgery date, length of follow-up, and adjuvant radiation. DCIS was macrodissected from paraffin sections and RNA extracted to obtain H/I and MGI RT-PCR profiles. The association of H/I and MGI with case-control status was assessed with conditional logistic regression; results reported are odds ratios (OR) with 95% confidence intervals (CI). The association of H/I and MGI as continuous variables with nuclear grade (low, intermediate, high) was estimated with Spearman's rank correlation. Results: 427 patients underwent lumpectomy for DCIS, and 33 were identified as possible cases. Histologic review excluded 8 (non-sufficient tissue or DCIS recurrence without invasion). 25 cases were matched to 48 controls (2 controls for 23 cases, 1 control for 2 cases). Both H/I (r = 0.43, p = 0.0001) and MGI (r = 0.41, p = 0.0004) were significantly correlated with nuclear grade. Positive H/I was associated with trend towards higher recurrence (OR 1.9; p = 0.22) that was most pronounced in cases/controls (15/28) treated with lumpectomy alone (OR 3.3; CI: 0.8–13.2, p = 0.09). Similarly, positive MGI was associated with a trend towards higher recurrence risk in patients treated with surgery alone (OR 2.0; CI: 0.6–6.4, p = 0.27). Conclusions: These data suggest that both HOXB13/IL17BR and MGI can identify a subset of patients with surgically resected DCIS who are at risk for invasive recurrence. Further studies in larger cohorts are needed to confirm these findings.

[Table: see text]
Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer
Authors: Audeh M. W. , Penson R. T. , Friedlander M. , Powell B. , Bell-McGuinn K. M. , Scott C. , Weitzel J. N. , Carmichael J. , Tutt A.
Published: August 2020

5500

Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced chemotherapy-refractory ovarian cancer. The secondary aim was to assess the safety and tolerability profile in ovarian cancer patients with BRCA1/2 deficiency. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two patient (pt) sequential cohorts received continuous oral olaparib in 28-day cycles, initially at the MTD, 400 mg bd (33 pts), and subsequently at 100 mg bd (24 pts), a previously shown clinically active and PARP inhibitory dose. Eligibility criteria included confirmed genetic BRCA1/2 mutation and recurrent, measurable, incurable disease (previous chemotherapy, median 3 lines). The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Change in CA125 was a secondary efficacy endpoint. All adverse events were reported using CTCAE v3. Results: At this interim analysis dated October 31, 2008, of 57 enrolled pts (39 BRCA1 deficient and 18 BRCA2 deficient), 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The confirmed RECIST ORR was 33% at 400 mg bd and 12.5% at 100 mg bd. Clinical benefit rate (ORR and/or confirmed >50% decline in CA125) was 57.6% at 400 mg bd and 16.7% at 100 mg bd. Toxicity was mainly mild in severity, reflecting grade 1/2 nausea (44%); fatigue (35%); and anemia (14%). Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer, with greater activity seen at the higher dose. Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers. This study provides positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers.

[Table: see text]
A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)
Authors: Ledermann J. A. , Rustin G. J. , Hackshaw A. , Kaye S. B. , Jayson G. , Gabra H. , James L. E. , Bell S. , Temple G.
Published: August 2020

5501

Background: BIBF 1120 is a new targeted therapeutic agent for maintenance therapy in OC. It is a unique triple angiokinase inhibitor, targeting 3 receptor classes involved in the formation of blood vessels (VEGFR, PDGFR, and FGFR). Methods: Continuous BIBF 1120 (250 mg, oral, twice daily) for up to 9 months (mo) was compared with placebo in a novel application of a randomized double-blind trial in pts who responded to their last (at least second line) chemotherapy. The primary endpoint, progression-free survival at 36 weeks, was confirmed by CT assessment, performed at 12-week intervals. Results: 84 pts were randomized (44 BIBF 1120; 40 placebo), mean age 60y (range 27–76). All had responded according to GCIG criteria. Treatment-free interval before prior chemotherapy was <6 mo for 41% and 6–12 mo for 59% of pts. Median treatment duration was 116 days (d), range, 2–281d (BIBF 1120) and 101 d, 2–239d (placebo). Five BIBF 1120 pts completed 9 mo of treatment vs 0 placebo pts. The 36-wk PFS rates (95% confidence interval [CI]) were 15.6% (3.8, 27.3) for BIBF 1120 and 2.9% (0.0, 8.4) for placebo. Although the trial was not powered for a direct comparison, the PFS hazard ratio was 0.68 (95% CI: 0.42, 1.09). Median time to RECIST progression (mo) was 4.8 for BIBF 1120, and 2.8 for placebo. There were no deaths during treatment. Grade 3 and 4 adverse events (AE) were seen in 54 and 7% (BIBF 1120) and 25 and 3% (placebo) of pts. Expected gastrointestinal toxicities occurred slightly more frequently in the BIBF 1120 arm (16 vs 10%, all gd 3; no gd 4 events). Elevated liver enzymes occurred in 43% (BIBF 1120) vs. 6.3% (placebo). Conclusions: Our trial suggests that maintenance BIBF 1120 could delay disease progression in OC pts who had previously responded to chemotherapy. A large phase III trial is needed to confirm the efficacy of this drug.

[Table: see text]
Prognostic impact of the time interval between primary surgery and start of first-line chemotherapy in patients with advanced ovarian cancer: Analysis of prospective randomized phase III trials
Authors: Mahner S. , Staehle A. , zu Eulenburg C. , Wegscheider K. , Reuss A. , Pujade-Lauraine E. , Harter P. , Ray-Coquard I. , Pfisterer J. , du Bois A.
Published: August 2020

5514

Background: Primary surgery followed by platinum-taxane chemotherapy is the standard therapy of advanced ovarian cancer. It is not clear, whether the time interval between surgery and start of first line chemotherapy (time to chemo - TTC) has an impact on the clinical outcome. Methods: Individual patient data meta-analysis of three prospective randomized AGO-OVAR/GINECO trials (AGO OVAR 3, 5, and 7) conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Cox proportional hazard models were applied to evaluate the prognostic impact of different variables on survival; TTC was introduced as a continuous variable. Results: A total of 3,326 patients were analyzed. Chemotherapy was started within 8 weeks after surgery. Median progression-free survival (PFS) was 17.91 months (95% CI: 17.15–18.73 months) and median overall survival (OS) 37.83 months (95% CI: 36.57–38.90 months). The median TTC was 19 days (95% CI: 18–19 days, range 1–56 days). By multivariate analysis of the total cohort, there was no significant association between TTC and PFS (p = 0.131) or OS (p = 0.372). In the subgroup of patients with no residual tumor after debulking surgery (n = 1.101), a significant and independent correlation between early start of chemotherapy and improved overall survival was observed (p = 0.022). Conclusions: Our analysis represents the largest study investigating treatment delivery and outcome in ovarian cancer. The time interval between primary surgery and start of first line chemotherapy seems to have no general impact in all patients. However, it could be demonstrated for the first time that a delayed start of chemotherapy was independently associated with decreased overall survival in patients with complete surgical debulking. As previously shown for other biological factors in ovarian cancer, the presence of residual tumor after surgery seems to prevail over the prognostic impact of therapy initiation.

No significant financial relationships to disclose.
Expression of the epidermal growth factor receptor (EGFR) pathway in cervical cancer (CC) patients (pts)
Authors: Movva S. , Arias-Pulido H. , Chavez A. , Joste N. , Lomo L. , Lee S. J. , Verschraegen C. F.
Published: August 2020

5519

Background: EGFR, a membrane tyrosine kinase receptor that regulates multiple functions such as cell growth, differentiation, gene expression and development through at least 3 pathways, is overexpressed in a wide variety of solid tumors, including CC. The downstream activation of the EGFR pathways has not been studied extensively. The aim of this study is to assess the correlation between EGFR-HER-2-HER-3-HER-4 status, downstream pathways (STAT 3, survivin, RAS) with pt characteristics, overall survival and recurrence free survival in pts diagnosed with invasive CC. Methods: Receptor expressions were assessed by immunohistochemistry on 80 pts from our clinic. Tumors were scored by percentage of cells stained multiplied by intensity for a score range of 0–300 by two pathologists. Median EGFR score was 140. Pts were categorized as low expressor (EGFR score lower than 140) or as high expressor (EGFR score greater than 140). Differences in receptor expression were compared using the Log-rank test for overall (OS) and recurrence-free survivals (RFS) and by Chi-square analyses for the clinical parameters (age, stage, histology, and grade). Results: A total of 80 pts data was analyzed. Mean age of the sample was 48 years. 23% of pts had well differentiated tumors. 80% had squamous histology. 39% had stage IIB or higher. 25% died of cancer. By Log-rank test, standard prognostic factors (age, stage, grade, and histology) showed the expected differences in survival, confirming the validity of the sample. However there were no correlations between the clinical parameters, OS, or RFS with EGFR expression. Data on HER-2–3-4, STAT3, survivin and RAS will be presented at the meeting. Conclusions: Although no correlation has been found between clinical outcome and EGFR expression, EGFR inhibitors of the extracellular domain are expected to be useful for the treatment of CC that overexpress this receptor. These results will serve as baseline data needed to test cetuximab and other EGFR inhibitors in pts with CC.

No significant financial relationships to disclose.
BRCA1 protein expression as a predictor of outcome following chemotherapy in sporadic epithelial ovarian cancer (EOC)
Authors: Carser J. E. , Quinn J. E. , Michie C. O. , McCluggage W. G. , Williams A. R. , Mullan P. B. , Gourley C. M. , Harkin D. P.
Published: August 2020

5527

Background: Reduced expression of BRCA1 is observed in a substantial proportion of sporadic EOC. First line management of EOC involves platinum and taxane based chemotherapy. In vitro studies demonstrate that reduction in BRCA1 protein expression leads to enhanced sensitivity to platinum but relative resistance to taxane chemotherapy. We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and survival in EOC patients, correlating outcome with type of chemotherapy received. Methods: 97 archival formalin-fixed, paraffin embedded tumour samples were identified from the Edinburgh Cancer Centre ovarian database. All patients received platinum based chemotherapy (platinum only n = 50, platinum/taxane n = 47). Tumour sections were stained for BRCA1 protein and scored by two independent reviewers. Tumours were graded from 0 (no BRCA1 protein) to 4 (>90% cells positive). BRCA1 protein expression was correlated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. Results: Overall, patients with no detectable BRCA1 protein had a significantly improved PFS compared to those with positive staining (17.4 months vs 12.2 months, p = 0.04). Specifically, patients receiving platinum only regimens had a significantly improved PFS if they had no detectable BRCA1 protein compared to those with positive staining (14.5 months vs 10.8 months, p = 0.035).In contrast, patients positive for BRCA1 protein (grades 1–4) had a significant increase in both OS (43.7 months vs 20.4 months, p = 0.03) and PFS (12.7 months vs 10.9 months p = 0.02) if they received platinum/taxane combination over platinum alone. Patients with no detectable BRCA1 protein (grade 0) had no significant difference in OS or PFS whether they were treated with combination or platinum only chemotherapy. Conclusions: This study provides initial evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic EOC. Specifically, patients with positive BRCA1 staining demonstrate a better clinical outcome with platinum/taxane based chemotherapy over platinum alone whereas no such difference was seen in those with no BRCA1. Further prospective clinical studies are required to validate these findings.

No significant financial relationships to disclose.
A phase II evaluation of bevacizumab in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group (GOG) Study
Authors: Aghajanian C. , Sill M. W. , Darcy K. , Greer B. , McMeekin D. S. , Rose P. G. , Rotmensch J. , Barnes M. N. , Hanjani P. , Leslie K.
Published: August 2020

5531

Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. This is the first report of the activity of bevacizumab in patients with recurrent or persistent endometrial cancer (EMC). Methods: Eligible patients had persistent or recurrent EMC after receiving 1–2 prior cytotoxic regimens, measurable disease, and GOG performance status < 2. Treatment consisted of BV 15 mg/kg IV q 3 weeks until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months, objective response rate, and toxicity by NCI CTCAE v3.0. The clinical trial was carried out in a flexible 2-stage group sequential design intended to detect either cytostatic or cytotoxic activity. Sample sizes were targeted to limit the probability of designating ineffective regimens as being active 10% with at least 90% statistical power. Clinically significant improvements were 20% increases in the proportion responding or surviving progression-free at 6 months over historical controls. Results: From March 2006 to January 2008, 56 patients were enrolled. Two were excluded due to a second primary and one due to inadequate pathology; thus, the sample included 53 patients. Median age was 62 (range 44–84) years, and prior treatment consisted of 1 or 2 regimens in 33 and 20 patients, respectively. Twenty-eight patients (52.8%) had prior radiation. Early results showed 8/53 (15.1%) response rate, with 1 complete response and 7 partial responses; and 19/53 (35.8%) of patients progression free at 6 months with 2 patients pending at the time of data analysis. Median PFS was 4.2 months. Median Overall survival (OS) was 10.5 months. The following grade 3 or 4 toxicities were observed: anemia (1 grade 3), cardiovascular (4 grade 3), constitutional (2 grade 3), hemorrhage (1 grade 3), hepatic (1 grade 3), musculoskeletal (2 grade 3), metabolic (1 grade 3, 1 grade 4), neurologic (1 grade 3), pain (4 grade 3), and vascular (1 grade 3, 1 grade 4). Conclusions: BV appears to have single agent activity in women with recurrent or persistent EMC and warrants further investigation.

No significant financial relationships to disclose.
Phase I and pharmacokinetic study of the novel VEGF-directed fusion protein, aflibercept, in combination with docetaxel in women with recurrent ovarian, fallopian tube, and primary peritoneal cancer
Authors: Coleman R. L. , Kamat A. , Iyer R. , Kundra V. , Garcia M. , Jaffe R. B. , Sood A. K.
Published: August 2020

5549

Background: VEGF blockade has proved to be a promising therapeutic strategy in solid tumors, including ovarian. Aflibercept, a novel fusion protein consisting of the extracellular domains of VEGFR1/2 binds VEGF A, B and PlGF. Aflibercept has been studied as a single agent in heavily pretreated ovarian cancer patients. We hypothesized that the combination of aflibercept and docetaxel could be safely administered to women with recurrent ovarian cancer. Correlative biomarker and imaging studies of anti-angiogenesis targeting, pharmacokinetics (PK) and preliminary efficacy were additional objectives. Methods: Eligible patients had measurable, recurrent disease with no more than 3 prior chemotherapeutic regimens. Study design was a “lead-in” phase I trial; cycle 0, administered aflibercept IV as a single agent in 1 of 3 dose levels (2, 4, or 6 mg/kg) in a 3+3 design. Aflibercept was given in subsequent cycles with docetaxel (75 mg/m2); each cycle was 21 days. Correlative studies in cycle 0 were: PK (single agent), circulating endothelial cells and precursors (CEC, CEP), and imaging FDG-PET, DCE-MRI (baseline, day 2 and day 21). Efficacy evaluation (RECIST) was conducted q2 cycles of combination therapy. Results: Nine patients were recruited, 3 at each dose level. All are evaluable. No DLTs were observed in cycles 0 and 1; The most common hematological toxicities were myelosuppression (1 Grade 4 ANC) and anemia (Grade 2). Non-hematological toxicities (Gr 3) included headache, hypertension, fatigue and ulceration. One patient each with hypertension and ulceration lead to treatment discontinuation after 4 and 13 cycles, respectively. FDG-PET defined SUVmax in target lesions within 25% of baseline in 7 patients; 2 others had >25% increase at 48 hours post treatment. CECs, CEPs, DCE-MRI and PK are being analyzed. Confirmed PR was observed in 2 (22%) with 1 additional near PR. Median number of cycles: 5 (range 3–15). All have now progressed, median time to progression: 15 weeks. Conclusions: Aflibercept can be safely administered at 6 mg/kg with docetaxel repeatedly in this population of recurrent ovarian cancer patients. Preliminary efficacy supports phase II study, which is ongoing.

No significant financial relationships to disclose.
Topotecan weekly versus routine 5-day schedule in patients with platinum-resistant ovarian cancer (TOWER): A randomized, multicenter trial of the North-Eastern German Society of Gynecological Oncology (NOGGO)
Authors: Sehouli J. , Oskay-Oezcelik G. , Stengel D. , Harter P. , Kurzeder C. , Belau A. , Belau A. , Markmann S. , Lorenz R. , Mueller L. , Lichtenegger W.
Published: August 2020

5553

Background: In women with platinum-resistant recurrent ovarian cancer, weekly administration of topotecan (Tw) may be equally effective, but better tolerated than conventional 5-day dosing (Tc). We conducted a randomized multicenter trial to validate this assumption. Methods: The trial was pre-registered at clinicaltrials.gov ( NCT00170677 ). Women with platinum-resistant ovarian and fallopian tube cancers or primary peritoneal carcinoma, and measurable or assessable disease (GCIG criteria) were randomized to receive either Tw (d1,8,15/q28d, 4 mg/m2) or Tc (d1–5/q21d, 1.25 mg/m2). The predefined stopping rule, based on the primary endpoint of best CA-125 or tumor response, was not reached (presented at ASCO 2007, Abstract 5526). This permitted the accrual of 194 patients, 154 of whom could be assessed for CA-125 or tumor response (SD + CR + PR). We also compared progression-free (PFS) and overall survival (OS), as well as toxicity between trial groups. Results: Mean age was 61.8 (SD 9.8) years, and 59 women were on third-line treatment. Patients received a total of 809 cycles of chemotherapy. Demographic baseline characteristics, tumor stages and grades, and previous lines of chemotherapy were well balanced between treatment groups. There were 35 / 75 (47%) and 45 / 79 (57%) responses in the Tw and Tc groups, respectively (risk ratio [RR] 1.22, 95% CI 0.89–1.66). Median PFS and OS did not differ markedly between both regimens (3.2 versus 4.4 months, hazard ratio [HR] 1.30, 95% CI 0.96–1.77 and 9.8 versus 10.0 months, HR 1.08, 95% CI 0.77–1.52). The risk of grade III/IV hematological toxicity was significantly lower in the Tw group (anemia: RR 0.35, p = 0.007, neutropenia: RR 0.38, p = 0.0001, thrombopenia: RR 0.23, p = 0.0004). Conclusions: Weekly administration of topotecan shows no substantial difference in endpoints of effectiveness compared to conventional dosing, but is associated with a significantly lower likelihood of severe hematological toxicity. Weekly topotecan should be considered as a possible treatment alternative in women with platinum-resistant ovarian cancer because of its favourable benefit-risk-profile.

No significant financial relationships to disclose.
Phase II study of CKD602, a camptothecin analog, in combination with carboplatin for the treatment of recurrent ovarian cancer
Authors: Choi C. , Lee Y. , Kim C. , Kang H. , Kim T. , Lee J. , Lee J. , Bae D. , Kim B.
Published: August 2020

5554

Background: Belotecan (Camtobell, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a camptothecin derivative with anti-tumor properties recently developed. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC). Methods: Belotecan 0.3 mg/m2/day (days 1–5) and carboplatin AUC 5 (day 5) were administered every 3 weeks for 6 cycles. Eligible patients had recurrent EOC, peritoneal serous cancer, or fallopian tube cancer. The primary objective was to determine response rate defined by Response Evaluation Criteria in Solid Tumors and CA-125 response; other end points included toxicities and progression free survival (PFS). Results: Until this preliminary analysis, sixteen patients had received the treatment and 13 patients were evaluable for response. Eight patients had platinum-sensitive disease (minimum treatment free interval≥6 months) and 6 had platinum-resistant disease (minimum treatment free interval <6 months). Overall response rate was 53.9%; there were 3 complete responses (23.1%), 4 partial responses (30.8%), 4 patients with stable disease (30.8%), and two patients with progressive disease (15.4%). Grade 3 and 4 hematologic toxicities included neutropenia (38%), thrombocytopenia (25%), and anemia (15%); there was one episode of febrile neutropenia. None of the patients experienced grades 3 and 4 gastrointestinal toxicities, including nausea, vomiting, and anorexia. Conclusions: The newly developed topoisomerase I inhibitor, belotecan (CKD-602), combined with carboplatin is a well-tolerated regimen with activity in recurrent EOC; further testing of this regimen is warranted.

No significant financial relationships to disclose.
Phase II study comparing volociximab (an antiangiogenic antibody) and pegylated liposomal doxorubicin (PLD) with PLD alone in recurrent ovarian or primary peritoneal cancer
Authors: Vergote I. B. , Colombo N. , Kutarska E. , Del Campo J. , Pippitt C. , Casado A. , Lengyel E. , Gilder K. , Ho S. , Schilder R. J.
Published: August 2020

5560

Background: Volociximab (V), a chimeric monoclonal antibody with direct antitumor effects, blocks α5β1 binding to fibronectin and induces apoptosis in proliferating endothelial cells. A Phase I/II study was performed to evaluate PLD with/without V in patients (pts) with recurrent ovarian or primary peritoneal cancer that relapsed after platinum/taxane-based chemotherapy (maximum 2 prior lines). Methods: A 3-arm adaptive randomization design compared efficacy and safety of PLD (40 mg/m2 q4wk) + V (15 mg/kg q2wk or qwk) vs. PLD alone. Pts were stratified by platinum sensitivity and received treatment until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Pharmacokinetic (PK) and pharmacodynamic effects were also evaluated. Results: There were 6 iterations of adaptive randomization based on accumulating PFS data. 127 pts were randomized: 66 in Group A (PLD), 34 in Group B (PLD+V [q2wk]), and 27 in Group C (PLD+V [qwk]). The incidence of AEs was balanced across treatment groups. The most common Grade 3/4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. Based on preclinical data, therapeutic levels of V were maintained during treatment, and V did not appear to alter the PK of PLD. Response rates were comparable across groups. There were no CRs; PRs were 16%, 18%, and 19%. The median PFS estimates were 193, 164, and 221 days. Conclusions: The safety profile of V+PLD appeared similar to PLD alone. Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment. Analyses correlating PFS with platinum sensitivity and α5β1 tumor expression are ongoing.

[Table: see text]
Combined weekly docetaxel (D) and gemcitabine (G) for relapsed ovarian cancer (OC) and peritoneal cancer (PC): A multi-institutional phase II study
Authors: Morris R. T. , Cohn D. E. , Fowler J. , Solomon L. A. , Vay A. , Seward S. , Heilbrun L. , Smith D. , Munkarah A. R.
Published: August 2020

5565

Background: Both D and G have demonstrated single-agent activity in OC and PC. The purpose of this study was to prospectively evaluate the efficacy and toxicity for patients (pts) with relapsed platinum-sensitive (Plat-S) and platinum-resistant (Plat-R) OC or PC treated with combination weekly D and G. Methods: Eligibility criteria included women recurrent or refractory to first line platinum based therapy, a performance status of 2 or better, and adequate renal and hepatic function. Only one prior regimen (including maintenance therapy) was allowed. D (40 mg/m2) and G (800 mg/m2) were administered on days 1 and 8 of a 21 day cycle until progression. Best response was defined by RECIST criteria. Granulocyte stimulating factor prophylaxis was not allowed. There were 2 separate 2-stage designs used, one for each stratum: Plat-R and Plat-S, separately for a total planned sample of 62 pts. The primary endpoint was overall response rate (ORR). This study was approved by each center's institutional review board. Results: Thirty pts were enrolled prior to terminating accrual due to lagging enrollment. The median age was 57.5 years (range 41–80). One pt was diagnosed with PC; the remaining 29 had OC. Twenty-seven (90%) pts were response evaluable. The ORR was 59% (90% confidence interval: 0.44 - 0.73). Six pts (22%) achieved a complete response (CR), 10 pts (37%) achieved a partial response (PR) and one pt (4%) had stable disease. Progressive disease was noted in 10 pts (37%). Plat-S pts (n = 16) had a 69% ORR (CR = 31%, PR = 38%) and Plat-R pts (n = 11) had an ORR of 45% (CR = 9%, PR = 36%). Median overall survival was 12.7 months (Plat-S = 14.2 mos. and Plat-R = 6.7 mos.). Toxicity data were evaluable for 29 (97%) pts. Twelve pts (41%) experienced grade 3 or 4 neutropenia; two of these pts also had documented infections. Three pts had grade 3 anemia and 6 (21%) had grade 3 thrombocytopenia. Dose reductions were uncommon (n = 2, 7%). Twelve pts (41%) were hospitalized at least once during treatment. Conclusions: Weekly D and G combination therapy demonstrates significant activity and moderate toxicity in both Plat-S and Plat-R disease. This non-platinum combination deserves further evaluation and may be considered in pts with Plat-S and Plat-R OC and PC.

No significant financial relationships to disclose.
A Gynecologic Oncology Group study of associations between polymorphisms in ABC transporter genes (ABCB1, ABCC2, and ABCG2) and outcome in advanced stage epithelial ovarian cancer treated with platinum and taxane chemotherapy
Authors: Darcy K. M. , Tian C. , Ambrosone C. B. , Krivak T. C. , Armstrong D. K. , Bookman M. A. , Davis W. , Zhao H. , Moysich K. , DeLoia J. A.
Published: August 2020

5567

Background: This study evaluated the relationship between known functional variants in three ATP-binding cassette (ABC) transporter genes (ABCB1 [MDR1], ABCC2 [MRP2], and ABCG2 [BCRP]) and clinical outcomes in epithelial ovarian cancer (EOC). These genes induce resistance to multiple anticancer drugs and some polymorphisms appear to affect expression, stability or activity of these transporters. Methods: Genotypes for common polymorphisms in ABCB1 (G2677T/A, A893S/T -RS2032582 and C3435T, synonymous-RS1045642), ABCC2 (G1249A, V417I-RS2273697), and ABCG2 (C421A, Q141K-RS2231138) were determined in normal blood DNA from 385 women with optimal stage III ECO who participated in a randomized phase III trial (GOG 172 or 182) and were treated with intravenous or intraperitoneal platinum+paclitaxel. Associations between polymorphisms and progression-free survival (PFS) and overall survival (OS) were examined using logrank test and adjusted Cox regression analysis. Results: The genotype distribution for the C421A polymorphism in ABCG2 was 80.7%, 18.5% and 0.8% for CC, CA and AA, respectively. Median time to disease progression or death for the CA+AA versus (vs.) CC genotype in ABCG2 was 30.3 vs. 18.1 months (p = 0.023), or 69.8 vs. 51.6 months (p = 0.172), respectively. After adjusting for clinical covariates, women with the CA+AA vs. CC genotype in ABCG2 had a significant reduction in the risk of disease progression (hazard ratio [HR] = 0.67, 95% confidence interval [CI] = 0.49–0.91, p = 0.01) but not death (HR = 0.77, 95% CI = 0.56–1.08, p = 0.125). The results were consistent across treatments. Adjusted Cox modeling demonstrated that polymorphisms in ABCB1 (G2677T/A or C3435T) and ABCC2 (G1249A) were not associated with PFS or OS. Conclusions: The ABCG2 C421A polymorphism, but not the ABCB1 G2677T/A, ABCB1 C3435T, or ABCC2 G1249A polymorphism, appears to be an independent prognostic factor for disease progression in optimal stage III EOC treated with platinum + paclitaxel therapy.

No significant financial relationships to disclose.