bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-institutional comparison of breast cancer risk stratification by 70-gene signature and 21-gene assay.
Authors: Dabbs David J. , Cox Charles E. , Shivers Steven , Bouganim Nathaniel , Asselah Jamil , Saleh Ramy , Blumencranz Lisa Eileen , Montero Alberto J. , Calhoun Benjamin C. , Treece Tina , Yoder Erin , Audeh William
Published: September 2018

522

Background: Breast cancer risk stratification with the 70-gene signature (70-GS) provides a binary low risk (LR) or high risk (HR) result; by contrast the 21-gene assay (21-GA) provides LR, intermediate (IR), and HR results. Results from these two assays were compared for 769 patients from 5 institutions. Methods: The study included patients from McGill University (n = 86), UPMC (n = 437), USF (n = 135), Morton Plant North Bay Hospital (n = 79), and Cleveland Clinic (n = 32, all 21-GA IR). Results: With the 70-GS, 487 (63%) patients had a LR and 282 (37%) patients had a HR result. Excluding 32 cases selected for 21-GA IR results (n = 737), the 21-GA gave 369 (50%), 250 (34%), and 118 (16%) patients with LR, IR, and HR scores, respectively. Using the TAILORx cutoff, there were 134 (18%), 432 (59%), and 171 (23%) patients with LR, IR, and HR scores, respectively. There were 329 (45%) and 486 (66%) patients who were not classified in the same risk category by both assays using the clinical and TAILORx cutoffs for IR, respectively. Conclusions: In a large multi-institutional study the 70-GS and 21-GA results were discordant in 45-66% of patients, and the proportion of patients with a 21-GA score in the IR range varied from 34-59%. The 70-GS provided clinically actionable results for all patients. [Table: see text]
Copy-number and targeted sequencing analyses to identify distinct prognostic groups: Implications for patient selection to targeted therapies amongst anti-endocrine therapy resistant early breast cancers.
Authors: Bayani Jane , Kornaga Elizabeth , Crozier Cheryl , Jang Gun Ho , Kalatskaya Irina , Trinh Quang M , Yao Cindy Q , Livingstone Julie , Hasenburg Annette , Kieback Dirk G , Markopoulos Christos , Dirix Luc , Boutros Paul Christopher , Spears Melanie , Stein Lincoln D. , Rea Daniel , Bartlett John
Published: September 2018

524

Background: Hormone receptor positive breast cancer is a therapeutic challenge. Despite optimal anti-endocrine therapies, most breast cancer deaths follow a diagnosis of early luminal cancer. To understand the impact of multiple aberrations in the context of current therapy, we assessed the prognostic ability of genomic signatures as a putative stratification tool to targeted therapies. Methods: This a priori study is based on molecular pathways which might predict response to targeted therapies. DNA from 420 patients from the phase III TEAM pathology cohort were used. Patients with a distant recurrence within 5 years were matched by clinical variables to those disease-free at follow up. Copy number analysis was performed using the Affymetrix Oncoscan Assay. Targeted sequencing was performed in a subset of samples for genes based on signaling cassettes mined from the ICGC. Pathways were identified as aberrant if there were copy number variations (CNVs) and/or mutations in any of the pre-determined pathway genes: 1) CCND1/CCND2/CCND3/CDK4/CDK6; 2) FGFR1/FGFR2/FGFR2/FGFR4; and 3) AKT1/AKT2/PIK3CA/PTEN. Kaplan-Meier and log-rank analyses were used for DFS between groups. Hazard ratios were calculated using the Cox proportional hazard models adjusted for age, tumour size, grade, lymph node and HER2 status. Results: 390/420 samples passed informatics QC filters. For the CCND/CDK pathway, patients with no CNV changes experienced a better DFS (HR = 1.7, 95% CI 1.3-2.3, p < 0.001). For the FGFR/FGF pathway, a similar outcome is seen among patients without CNVs (HR = 1.5, 95% CI 1.1-2.0; p = 0.005). For AKT/PIK3CA, a decrease in DFS was seen in those with aberrations (HR = 1.4, 95% CI 1.0-1.8, p = 0.03). Conclusions: We demonstrated that CNVs of genes within CDK4/CCND, PIK3CA/AKT and FGFR pathways are independently linked to high risk of relapse following endocrine treatment, with implications for identifying those patients who are at high-risk for recurrence despite optimal anti-endocrine therapy and linking molecular features driving these cancers to targeted therapies.
Overall survival results of ICON6: A trial of chemotherapy and cediranib in relapsed ovarian cancer.
Authors: Ledermann Jonathan A. , Embleton Andrew C. , Perren Timothy , Jayson Gordon C. , Rustin Gordon J. S. , Kaye Stanley B. , Hirte Hal W. , Oza Amit M. , Vaughan Michelle Margaret , Friedlander Michael , Gonzalez Martin Antonio , Clark Elizabeth , Popoola Babasola O , Farrelly Laura , Swart Ann Marie , Cook Adrian , Kaplan Richard S. , Parmar Mahesh K B ,   ICON6 Collaborators
Published: September 2018

5506

Background: ICON6 is a three-arm double-blind, placebo-controlled phase 3 trial of cediranib in platinum-sensitive relapsed ovarian cancer (NCT00532194). The primary analysis (Ledermann et al Lancet 2016) showed a significant (p < 0.0001), 2.3 month extension in progression-free survival (PFS) using cediranib with chemotherapy and as maintenance compared to chemotherapy and placebo. We present the final overall survival (OS) results. Methods: The trial was originally designed to recruit 2000 patients with OS as the primary endpoint. AstraZeneca discontinued cediranib development in Sep 2011, leading to an unplanned redesign prior to analysis. The sample size was reduced and primary outcome became PFS, comparing two arms, placebo (A) to cediranib given with chemotherapy and as maintenance (C). In arm B cediranib was given with chemotherapy followed by placebo maintenance. Analysis of PFS was performed on a sample size of 456 patients receiving a 20mg dose of cediranib. At the primary analysis, 52% patients had died; this mature OS analysis was performed after 85% patients died. Results: The OS analysis was performed at a median 25.6 months follow up; 102/118 (86%) died in A and 140/164 (85%) in C. In A the median survival was 19.9 months (95% CI: 17.4, 26.5) and in C 27.3 months (24.8, 33.0). Using the logrank test the Hazard Ratio estimate was 0.85 (0.66, 1.10) in favour of cediranib (p = 0.21). Evidence of non-proportionality of the survival curves was observed (p = 0.0029), so we measured the Restricted Mean Survival Time as an alternative to the median. Over 6 years, there was a 4.8 month (-0.1, 9.8) increase in time to death in C compared to A, from 29.4 to 34.2 months. The mean for arm B (32.0 months) was consistent with a benefit of increased use of cediranib. Conclusions: Cediranib has demonstrated a significant effect in increasing PFS. The mature survival analysis (85%) shows an improvement in median OS of 7.4 months, and an incremental benefit with increased cediranib use. The previously published significant PFS benefit coupled with the increase in OS highlights the potential value of cediranib in platinum-sensitive recurrent ovarian cancer. Further exploration of cediranib in this setting is underway. Clinical trial information: NCT00532194.
Adverse events (AEs) with maintenance olaparib tablets in patients (pts) with BRCA-mutated (BRCAm) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): Phase III SOLO2 trial.
Authors: Ledermann Jonathan A. , Lortholary Alain , Penson Richard T. , Gibbs Emma , Provencher Diane M. , Bruchim Ilan , Huzarski Tomas , Barretina-Ginesta Maria Pilar , Sabbatini Roberto , Mileshkin Linda R. , Colombo Nicoletta , Park-Simon Tjoung-Won , Matsumoto Koji , Sonke Gabe S. , Mikheeva Olga N. , Kim Jae-Weon , Girotto Gustavo Colagiovanni , Denys Hannelore , Lowe Elizabeth S. , Pujade-Lauraine Eric
Published: September 2018

5518

Background: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance therapy with the PARP inhibitor olaparib significantly improved PFS vs placebo (PBO) in BRCAm PSR SOC pts (HR 0.30, 95% CI 0.22–0.41, P<0.0001; median 19.1 vs 5.5 months) and was well tolerated (Pujade-Lauraine et al, SGO 2017). We analyzed AEs in SOLO2, the first study in PSR SOC to use the olaparib tablet formulation. Methods: Pts with BRCAm PSR SOC, who were in response to platinum chemotherapy, were treated with olaparib (300 mg bid; tablets; n=195) or PBO (n=99) until progression. AEs were graded by CTCAE v4.0. Results: The most common AEs with olaparib – nausea, fatigue/asthenia, anemia, and vomiting – were largely grade 1–2, though anemia was the most common grade ≥3 AE. AEs of fatigue/asthenia, vomiting and nausea generally improved as treatment continued, though fatigue/asthenia and anemia could last for several months (table). Most AEs were manageable by supportive treatment, dose interruptions (olaparib, 45%; PBO, 18%) and dose reductions (olaparib, 25%; PBO, 3%). Discontinuation of olaparib due to AEs was minimal (11%); anemia and neutropenia were the only AEs leading to discontinuation of olaparib in >one pt. Conclusions: Most AEs experienced by pts receiving olaparib tablets in SOLO2 were low grade and manageable. Initial nausea, vomiting and fatigue generally improved with ongoing treatment. The majority of AEs first occurred within the first three months of treatment. AEs causing treatment discontinuation were rare and mainly hematological. Clinical trial information: NCT01874353. [Table: see text]
Effect of denosumab on bone mineral density (T-score classification of −1.0 to −2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer.
Authors: Nakatsukasa Katsuhiko , Matsuda Takayuki , Taguchi Tetsuya
Published: September 2018

552

Background: Adjuvant aromatase inhibitor (AI) therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against receptor of nuclear-κB ligand, was previously proven to protect against AI-induced bone loss. In Japan, however, the efficacy of denosumab in the treatment of AI-associated bone loss has not been proven in a prospective study. Methods: This non-randomized prospective study was conducted at four institutions in Japan. we prospectively evaluated the bone mineral density (BMD) of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n=103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary endpoint was percentage change in lumbar spine BMD from baseline to month 12. The secondary endpoint was percentage change in bilateral femoral neck BMD from baseline to month 12. This is the first trial where the right and left femoral neck BMD are measured separately. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 12 months, lumber spine BMD increased by 4.7 %. The patients who were administered prior AI therapy (n=60) had a 4.8 % increase, and the patients without prior AI therapy (n=40) had a 4.6 % increase. At 12 months, the right and left femoral neck BMD increased by 2.9 % and 2.0 %, respectively. Hypocalcemia ≥ grade2, osteonecrosis of the jaw (ONJ) and non-traumatic clinical fracture were absent in this study. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000013863.
Stage I ovarian immature teratomas: Is there a role for chemotherapy?
Authors: Chan John K. , Rosenfeld Emily B , Gardner Austin Blake , Delic Lejla , Kapp Daniel Stuart
Published: September 2018

5523

Background: To determine the impact of chemotherapy on survival of patients with stage I ovarian immature teratomas. Methods: Data obtained from the National Cancer Database from 2004-2013. Kaplan-Meier methods and multivariate Cox regression models were used for statistical analyses. Results: Of 888 patients (median age 24 years), 76%, 7%, 15%, 3% were stages I, II, III, and IV, respectively. 27%, 28%, 38%, and 8% had grades 1, 2, 3 and 4. The predominant racial group was White (50%) and remainder Black (19%), Hispanic (16%), Asian (6%) and other (9%). 64% had fertility sparing surgery and 55% received chemotherapy. For all patients, 5 year survival was over 90%. Chemotherapy did not change the 5 year survival for stage I or stage II disease (p = 0.35 and p = 0.69, respectively). However, chemotherapy improved 5 year survival from 59% to 76% in stages III-IV (p < 0.01). When controlling for other factors, older age (HR 3.2, p < 0.01), stages II and III-IV (HR 6.0, p < 0.01; HR 10.6, p < 0.01) and grades 3-4 (HR 15.3, p < 0.01) had worse survival. In a subset analysis of stage I patients chemotherapy did not improve 5 year survival of those with stage I grade 1 (p = 0.75) but chemotherapy did improved the survival of those with stage I grade 2 disease from 85% to 99% (p = 0.04). Conclusions: The overall survival of patients with immature teratomas is excellent. In patients with stage I grade 2 or higher disease chemotherapy was associated with an improved overall survival.
A randomized phase II study assessing an optimized schedule of oregovomab (O) anti-CA125 vaccination with carboplatin paclitaxel (CP) relative to CP alone in front-line treatment of optimally cytoreduced stage III/IV ovarian cancer (EOC).
Authors: Ferrandina Gabriella , Braly Patricia S. , Terranova Corrado , Salutari Vanda , Ricci Caterina , Raspagliesi Francesco , Lorusso Domenica , Panici Pierluigi Benedetti , Scollo Paolo , Plotti Francesco , Brewer Molly , Method Michael W. , Holloway Robert W. , Madiyalakan Madi , Nicodemus Christopher F. , Pecorelli Sergio L. , Scambia Giovanni , Angioli Roberto
Published: September 2018

5536

Background: In a phase II study of vaccination schedule in front-line combinatorial treatment of EOC (Braly JIT 2009), simultaneous day infusion dramatically enhanced the magnitude of induced immunity relative to a one week delayed schedule & other schedules historically evaluated. The current study is exploring the clinical & biological effects of the optimized 4 vaccine schedule relative to CP alone. Methods: Stage III/IV EOC patients (pts) optimally debulked to <1cm residual disease with CA125 >2x ULN were randomized to CP+O (cycle 1,3,5, & C5 +12 weeks) vs CP and followed for clinical outcomes and immune reponse. A total of at least 80 evaluable pts were required for 80% power to detect a difference of 45% vs 15% for a primary comparative analysis of induced CA125 specific T cell immunity using an IFN-γ ELISpot. Clinical evaluations and safety were considered secondary endpoints. Results: 97 pts (47 OV+SOC & 50 SOC) were accrued at 13 centers in US & Italy. Analysis of immune markers and long term clinical outcomes is ongoing. The median duration of follow up at time of this analysis was 26 months (m). There was no difference in safety outcomes between the treatment groups. Grade 3-4 toxicity was observed in 24 (52%) CP+O vs 28 (58%) C-P pts. Toxicities were typical of standard IV C-P chemotherapy. K-M Analysis of recurrence free survival (RFS) showed median RFS not estimable for CP+O [95% CI: 21.3, NE] vs 15.4 m [10.9,19.3] for CP (p=0.0009 log rank). In the interim analysis of survival (OS), 4 deaths have been observed in CP+O vs 16 in CP (log rank p=0.0025). Cox proportional hazard analysis finds consistent results across centers, and no imbalance in identified risk factors explanatory for the emerging outcome Conclusions: This study suggests simultaneous day vaccination with O on alternate cycles of front line CP leverages CP associated temporal change in the tumor microenvironment permitting an immune treatment effect to enhance the outcomes achievable with CP alone. This observation will be further characterized in ongoing translational studies and confirmed in a future phase III study. Clinical trial information: NCT01616303.
Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.
Authors: Moore Kathleen N. , Matulonis Ursula A. , O'Malley David M. , Konner Jason A. , Martin Lainie P. , Perez Raymond P. , Bauer Todd Michael , Gilbert Lucy , Seward Shelly Marie , Oza Amit M. , Ruiz-Soto Rodrigo , Birrer Michael J.
Published: September 2018

5547

Background: The early clinical evaluation of mirvetuximab soravtansine (IMGN853), an ADC that comprises a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, has revealed encouraging signs of activity in pts with ovarian cancer. A pooled analysis of safety and efficacy was performed including individuals with platinum-resistant EOC, enrolled across three expansion cohorts of an ongoing phase I trial (NCT01609556), who met the eligibility criteria for the pivotal phase III study of IMGN853 (FORWARD I; NCT02631876). Methods: Pts were administered IMGN853 intravenously once every 3 weeks at 6 mg/kg using adjusted ideal body weight dosing. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 37 EOC pts treated as part of the three phase I expansion cohorts (pooled population; n = 113) met the FORWARD I enrollment criteria of moderate to high tumor FRα levels (≥ 50% of cells with ≥ 2+ FRα expression) and 1-3 prior lines of therapy. In this group of pts with platinum-resistant disease, confirmed objective tumor responses were observed in 17 individuals (1 complete response [CR] and 16 partial responses [PR]) for an overall response rate (ORR) of 46% (95% CI, 29.5, 63.1) and a median PFS of 6.7 months (95% CI, 4.1, 9.0). The safety profile of the pooled population was consistent with that previously reported (ASCO Annual Meeting, 2016) with the most common AEs being diarrhea, fatigue, nausea, and blurred vision; these were low grade and readily managed. Conclusions: IMGN853 continues to be characterized by favorable tolerability and encouraging activity in pts with platinum-resistant EOC. In particular, both the ORR (46%) and PFS (6.7 months) achieved in this group of pts are superior to outcomes typically seen with established single-agent chemotherapy within the setting of primary platinum resistance. Overall, these analyses provide continued, robust support for the patient eligibility strategy employed in the phase III evaluation of IMGN853. Clinical trial information: NCT01609556.
A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated platinum resistant ovarian cancer.
Authors: Becerra Carlos , Garcia Agustin A. , Hays John L. , Method Michael W. , Richey Stephen Lane , Langleben Adrian , Richards Donald A. , Cote Gregory Michael , Kossler Kimiko , Li Wei , Li Youzhi , Hitron Matthew , Li Chiang
Published: September 2018

5548

Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.
A platinum-resistant subtype of high-grade serous ovarian cancer identified by a network of somatic mutations.
Authors: Shen John P. , Bojorquez-Gomez Ana , Huang Justin , Hofree Matan , Kurnit Katie , Klepper Kristin , Beckett Alex , Kreisberg Jason F , Saenz Cheryl C. , Ideker Trey
Published: September 2018

5561

Background: High-grade serous ovarian carcinoma (HGS-OvCa) is a heterogeneous entity with a widely variable clinical course even among patients of the same stage and histological subtype. Although most patients will achieve remission with platinum-based chemotherapy, ~20% will display primary platinum resistance. Currently no biomarker exists to identify these platinum resistant patients. Methods: We have recently developed a method called Network-based Stratification (NBS), which combines genome-scale somatic mutation profiles with genetic interaction networks and performs unsupervised clustering of patients into subtypes. Results: Using NBS HGSOC patients were stratified into subtype, in both TCGA (n = 330) and the ICGC (n = 92) a high-risk (HR) subtype consisting of ~20% of the patients was identified (see table). Propagated mutation scores of the HR tumors from TCGA and ICGC cohorts we remarkably correlated (Pearson r2 = 0.94, p < 0.001), relative to the correlation between HR and standard risk subtypes within TGCA cohort (r2 = 0.18). We then identified molecularly matched cell line models for in vitro study, finding that HR cell lines (Kuramochi, Ovkate, OAW28, 59M) were significantly more resistant to cisplatin relative standard risk cell lines (COV318, TYK-NU, OVCAR4), (IC50 14.4 vs. 3.3 µM, p < 0.0001). There was no significant difference in sensitivity to paclitaxel. A genome-wide knockout screen using CRISPR-Cas9 has identified several candidate genes mediating this observed platinum resistance. Conclusions: NBS can be used to identify a molecularly distinct subtype of HGSOC characterized by poor patient survival and primary platinum resistance. [Table: see text]
Impact of genomic heterogeneity on PI3K/AKT/mTOR inhibitors (PAMi) efficacy in gynecologic cancer (GYN) patients (pts).
Authors: Rodriguez Freixinos Victor , Ruiz-Pace Fiorella , Fariñas-Madrid Lorena , Garrido Castro Ana Christina , Villacampa Guillermo , Nuciforo Paolo , Vivancos Ana , Dienstmann Rodrigo , Oaknin Ana
Published: September 2018

5569

Background: Aberrant PI3K/AKT/mTOR activation is common in GYN. Predictive biomarkers to PAMi in GYN have yet to be identified. Methods: Advanced GYN pts with available genomic data, treated with PAMi in phase I/II clinical trials were selected. Mutation (mut) allele fractions (MAFs) were corrected for tumor purity and defined as clonal (cl) (≥ 0.4) or subclonal (scl) ( < 0.4). PAMi efficacy: (i) time to progression (TTP); (ii) clinical benefit rate (CBR: complete/partial response or stable disease > 4 months [m]); and (iii) ratio TTP on PAMi/ TTP on non-standard chemotherapy pre- or post-PAMi (PAMi/nsChemo TTP). Results: From 2010 to 2016, 264 GYN pts (152 ovarian(OC); 75 endometrial(EC); 37 cervical(CC)) had genomic analysis; 50 pts (24 OC [11 PIK3CA mut, 5 KRAS mut], 15 EC [6 PIK3CA mut, 5 PTEN mut, 4 KRAS mut], and 11 CC [9 PIK3CA mut, 3 KRAS mut]) received PAMi (17 pan-PI3K/mTOR or AKT inh, 17 α-PI3K inh, 16 PAMi targeted combos). PAMi therapy was matched (MA) to PIK3CA/PTEN mut in 30 pts (60%). Median age was 57 years (30-70); median number of prior lines was 2 (1-6) and 34 pts (68%) received nsChemo. Efficacy of PAMi: (i) median TTP (3.27 m [95% CI 2.1-4.4] with trend for longer TTP in OC compared to others [3.93 vs. 2.1 m, HR 0.57; p = 0.08], without differences according to MA status [p = 0.26] or regimen [p = 0.5]); (ii) CBR (42% [95% CI 27-58%], without differences according to tumor type [p = 0.47], MA status [p = 1] or regimen [p = 0.86]); and (iii) TTP PAMi/nsChemo ≥ 1.3 (42% [95% CI 24-63%], without differences according to tumor type [p = 0.53], MA status [p = 0.23] or regimen [p = 0.41]). Partial responses were seen in 5 pts (4 PIK3CA mut on single agent PAMi; 1 KRAS mut on PI3K + MEK inh). Of 4 KRAS mut pts, none had CBR with single agent PAMi. PIK3CA mut were cl in 63% of OC, 17% of EC and 40% of CC. Clonal exon 20 PIK3CA mut were more frequent in OC (p = 0.03). We found longer TTP for cl PIK3CA events (4.0 vs. 1.5 m in scl, HR 5.1, p = 0.006) and a trend for exon 20 events (4.4 vs. 1.4 m in exon 9, HR 1.7, p = 0.25). Conclusions: Regardless of PIK3CA/PTEN mut status, PAMi confer CBR in almost 40% of GYN pts. Functionality and clonality of PIK3CA mut impact on TTP and interact with tumor type. Coexisting KRAS mut may drive resistance to single agent PAMi.
Primary operation in synchroneous metastasized invasive breast cancer patients: First oncologic outcomes of the prospective randomized phase III ABCSG 28 POSYTIVE trial.
Authors: Fitzal Florian , Balic Marija , Bjelic-Radisic Vesna , Hubalek Michael , Singer Christian F. , Steger Guenther G. , Marth Christian , Schrenk Peter , Knauer Michael , Haid Anton , Wette Viktor , Luisser Irmgard , Greil Richard , Fuegger Reinhold , Swoboda Ursula , Soelkner Lidija , Gnant Michael
Published: September 2018

557

Background: The ABCSG 28 Posytive trial compared primary surgery versus primary systemic therapy without surgery in stage IV breast cancer patients. The primary aim was to investigate whether immediate resection of the primary tumor followed by standard systemic therapy improves median survival compared with no surgical resection (NCT01015625). The trial had to be stopped early due insufficient recruitment. Methods: Untreated stage IV breast cancer patients with the primary in situ were randomly assigned to either surgery of the primary versus no surgery followed by systemic therapy between 2011 and 2015 in 15 breast health centers in Austria. Systemic therapy included endocrine therapy or chemotherapy. Patients were routinely followed every 3-6 months. Primary endpoint was median survival. Results: 90 patients (45 with surgery, 45 with primary systemic therapy without surgery) were randomized. Stratification criteria were age, endocrine responsiveness, her2 expression, planned first line therapy and bone only versus other metastases. Patients in the surgery arm had more cT3 breast cancer (22% versus 7%) and more cN2 staging (16% versus 4%) as well as more her2 positive breast cancer cases (27% versus 18%). The median follow up was 37.5 months and immunohistochemical subtype analysis showed 9% basal like, 22% her2 positive, 51% luminal A and 13% luminal B cancers. Both groups were well balanced regarding first line treatment (endocrine versus chemotherapy) however, there were more taxane treated patients in the no surgery group (24.4 versus 15.6%). The median survival in the surgery arm was 34.6 months versus 54.8 months in the no surgery arm without statistical significance (HR 0.691 CI 0.358 – 1.333; p=0.267). Time to distant progression was insignificantly longer in the no surgery arm (surgery arm 13.9 versus no surgery arm 29.0 months). Conclusions: This first analysis of the prospective randomized phase III trial POSYTIVE-ABCSG-28 demonstrated no benefit in overall survival for immediate surgery of the primary in de novo stage IV breast cancer patients. Clinical trial information: NCT01015625.
Neoadjuvant BEP regimen in the treatment of extensively advanced yolk sac tumor: A single institutional experience.
Authors: Zhang Gong-Yi , Zhang Rong , Wu Ling-Ying , Li Shu-min , Li Bin
Published: September 2018

5570

Background: Due to the highly aggressive biological behavior and early intra-abdominal spread potential of ovarian yolk sac tumor (YST), a considerable proportion of patients were inoperalbe at initial diagnosis. The aim of this study was to investigate the role of neoadjuvant chemotherapy (NACT) in this cohort of patients. Methods: Between July 1982 and December 2015, 58 patients diagnosed as YSTs were initially treated at Cancer Hospital of China Academy of Medical Science (CAMS), among which 18 were evaluated to be inoperable and received NACT. They were either too debilitated by the disease (ECOG ps≥2) to undergo a major surgery, or were with too extensively disseminated lesions to be optimally debulked. Massive ascites, pleural effusion, dyspnea, neoplastic fever, hypoproteinemia, or electrolyte disturbance were also common in these 18 patients. This cohort of patients was retrospectively reviewed. Results: One or 2 cycles of BEP regimens were prescribed to the majority of patients preoperatively. At the completion of NACT, all the 18 patients had ECOG ps≤1 . Seventeen of them (94.4%) exhibited clinical partial tumor regression and 1(5.6%) had clinical stable disease. Pathological complete tumor regression was observed in 2 (11.1%) patients, whereas the remaining 16(88.9%) had nearly complete pathological response. All these 18 patients were rendered operable at the completion of NACT, yielding a resection rate of 100%. Seventeen patients (94.4%) were cytoreduced to no macroscopic residual disease, 1 (5.6%) patient was cyto-reduced to macroscopic residual disease ≤2 cm. No major surgical complications occurred in our series. After a median follow-up of 83.5 months, 17 patients were free of recurrence. Five-year DFS and OS were both 94.4%. Fertility-sparing surgery was carried out in all the 17 patients with fertility desire, and 5 infants were delivered in 6 patients who attempted conception. Conclusions: One or 2 cycles of NACT followed by early cyto-reductive surgery offers a chance for cure in patients with extensively advanced YSTs. It allows for a more through and safe cyto-reductive surgery, improves survival outcomes, and helps pave the way for fertility-sparing surgery.
A phase I dose-escalation study of intraperitoneal (IP) cisplatin, IV/IP paclitaxel, IV bevacizumab, and oral olaparib for newly diagnosed adenxal carcinoma.
Authors: Konner Jason A. , Boucicaut Nicole N , O'Cearbhaill Roisin Eilish , Zamarin Dmitriy , Makker Vicky , Sabbatini Paul , Tew William P. , Cadoo Karen Anne , Grisham Rachel N. , Aghajanian Carol
Published: September 2018

5572

Background: IP cisplatin (Cis) plus IV/IP paclitaxel (Tax) is a standard therapy for optimally debulked adnexal cancer. We previously demonstrated the feasibility of combining bevacizumab (Bev) with this IV/IP regimen. In this study IP Cis, IV/IP Tax, and IV Bev are combined with olaparib (Ola) as front-line therapy. Methods: Patients with newly diagnosed adnexal (ovarian, fallopian tube, or primary peritoneal) carcinoma, acceptable organ function, and KPS ≥ 70% are eligible. Patients receive 6 cycles of chemotherapy plus Bev: Tax 135 mg/m2 IV over 3 hours on Day 1, Bev 15 mg/kg IV on Day 1 (starting cycle 2), Cis 75 mg/m2 IP on Day 2, Tax 60 mg/m2 IP on Day 8. Bev is continued every 3 weeks for 21 treatments after chemotherapy is complete. In addition, Ola is given at escalating doses (50/100/200mg tabs BID) on Days 2-8 during cycles 1-6, and then 300mg BID Daily during cycles 7-22. The primary objective is to evaluate the MTD and safety/tolerability of Ola when combined with IP Cis, IV Bev and IV/IP Tax using a 3+3 dose escalation scheme. Results: Seventeen women have been treated [median age 57 (47-73)]: 8 in cohort 1 (50mg), 3 in cohort 2 (100mg) and 6 in cohort 3 (200mg). Thirteen (76%) completed all 6 cycles of IV/IP cis/tax; 2 (12%) experienced IP port malfunction (both were removed and replaced); 2 (12%) switched from IP Cis to IV carboplatin due to nephrotoxicity (via ATN and/or OCT-2 inhibition). Grade 3/4 toxicities have included: neutropenia (50%), hyperglycemia (12.5%), leukopenia (12.5%), anemia (18.8%), fatigue (12.5%), and lymphopenia (31.3%). There were 2 occurrences of related grade 3 small bowel obstructions (12.5%), during cycles 2 and 7, respectively. There were no perforations or fistulae. Maintenance therapy with Bev + Ola was generally well tolerated. Conclusions: The addition of Ola to this IV/IP regimen appears to be feasible. Ola may increase the risk of creatinine elevation and myelotoxicity. The MTD of intermittent dosing of Ola tabs concurrent with chemotherapy appears to be 200mg BID, while maintenance bev + full-dose ola at 300mg BID continuous appears feasible following IV/IP. Updated results will be presented. Clinical trial information: NCT02121990.
Circulating tumor DNA analysis using targeted sequencing of 508 clinically actionable genes in patients with high grade serous ovarian cancer.
Authors: Färkkilä Anniina , Salminen Liina , Huhtinen Kaisa , Hietanen Sakari , Grenman Seija Elisa , Lehtonen Rainer , Hynninen Johanna , Carpen Olli , Hautaniemi Sampsa
Published: September 2018

5582

Background: The prediction of tumor chemoresponse and treatment toxicity is crucial for optimal patient care in high grade serous ovarian cancer (HGSC). We employed a targeted sequencing panel of 508 clinically annotated cancer genes to screen for actionable genetic variants in tumor tissue and ctDNA of patients with advanced HGSC. Methods: Tumor tissue, and serial plasma samples at diagnosis and during primary therapy were obtained from five patients with FIGO Stage IIIc HGSC. All patients were surgically debulked and received standard carboplatin and paclitaxel chemotherapy. DNA isolated from tumor tissue and plasma was analyzed for genetic alterations by targeted deep-sequencing of 508 previously annotated cancer genes. Somatic variants were systematically reported for alterations related to drug sensitivity and treatment toxicity, and analyzed with respect to clinical parameters and primary therapy outcomes. Results: In tumor tissues, and the corresponding pre-treatment ctDNA, oncogenic mutations were detected at a median of 13.0 and 1.6 allelic frequencies, respectively. The mutation frequency was higher, and also more unique mutations were detected in ctDNA of patients presenting with high tumor spread. Interestingly, a de-novo ctDNA MAPK1 mutation was detected in a sample taken during chemotherapy with partial response, while, no new mutations emerged in a patient with complete response. Analysis of the pretreatment plasma ctDNA revealed profiles of low and high drug sensitivities consistent with the clinical course of the patients. In two patients, increased risk profiles for treatment toxicities were identified via e.g. GSTP1. Consistently, these two patients were forced to discontinue standard therapy. Conclusions: Panel-based targeted sequencing of ctDNA identified potentially actionable mutations, and reflected tumor heterogeneity of HGSC. Further, the ctDNA gene panel annotations showed concordance with the chemoresponse- and treatment toxicity profiles, suggesting that ctDNA gene panel maybe a feasible approach to individualize treatment of HGSC patients.
Utility of multi-gene panel testing with next generation sequencing in women with endometrial cancer.
Authors: Chern Jing-Yi , Madden Nigel , Lee Jessica , Gerber Deanna , Cantor Anna , Asgari Shabnam , Martineau Jessica , Pothuri Bhavana
Published: September 2018

5588

Background: Lynch syndrome (LS) accounts for 2-6% of all endometrial cancers (EC), and women with a germline mutation in the mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, and PMS2) have an average lifetime risk of EC of 40%. As with breast and ovarian cancer syndromes, there are likely other genes implicated in the development of EC outside of the MMR genes. Multi-gene panel testing (MGPT) with next generation sequencing (NGS) allows for simultaneous analysis of numerous genes.We sought to evaluate the characteristics and incidence of gene mutations in women with newly diagnosed EC. Methods: We conducted a review of EC patients diagnosed from 6/2013 to 12/2016 who had MGPT at our institution. Demographics, family history, genetic testing results, and tumor characteristics were collected and analyzed using χ2 tests. Results: Of the 129 patients who had MGPT, 13 (10%) had a mutation and only 5 (38%) were in patients < 50 years old. The median age of EC diagnosis is 55 (31-100) years and median BMI = 27.5 (21-59). Majority were stage 1, 76 (59%) and grade 1, 50 (39%). Patients with additional primary cancers, breast or colon were not more likely to have a mutation. However, patients with a family history of gynecologic cancer were more likely to have a mutation identified, 10 (77%) mutation vs no mutation 34 (29%), p = 0.003. Among all patients tested, 8 (6%) had a mutation in LS genes, and 6 (5%) had mutations in other genes ( BRCA1, BRCA2, RAD51C, MUTYH, CHEK2); 1 (0.8%) had both MSH2 and CHEK2 mutation. Three patients had prior testing for breast cancer; 2 were found to have a BRCA1/ 2 mutation and the other was on Tamoxifen and BRCA negative. IHC was performed on 7 of 13 patients, and 5 (71%) had a loss of MMR protein expression. Variants of uncertain significance were noted in 35/129 (27%) of patients tested. Conclusions: Majority of EC patients with a mutation detected with NGS were > age 50. We identified additional new mutations in non-LS genes including, CHEK2, RAD51C, and MUYTH with MGPT. These accounted for 29% of the mutations and would have not been not detected using classic LS gene testing. These genes are implicated in breast, ovary or colon cancer. MGPT testing is feasible and useful in identifying additional actionable gene mutations.
High-intermediate risk endometrial cancer: Can gene expression predict recurrence?
Authors: Tawfik Cindy , Kim Beomjy , Londono Angelina , Katre Ashwini A. , Della Manna Deborah L , Huh Warner King , Yang Eddy Shih-Hsin , Bevis Kerri S. , Straughn John Michael , Leath Charles A. , Arend Rebecca Christian
Published: September 2018

5591

Background: Studies have shown that adjuvant therapy increases progression free survival, but does not affect overall survival in patients with high-intermediate risk (H-IR) endometrial cancer (EMCA). Our objective was to develop a gene expression signature that may help identify H-IR EMCA patients with the highest risk of recurrence to help guide treatment strategies. Methods: Data was collected on all patients that met H-IR EMCA criteria diagnosed between 2000-2010 at UAB (n = 292). Of the patients that did not receive adjuvant treatment, 13 patients that recurred were matched to 13 patients that did not recur and original tumor was compared. Of those that recurred, 5 patients had original and recurrent tumor available for analysis. Gene expression data was collected using the Nanostring nCounter PanCancer Pathway 770 gene panel. Data was analyzed using nSolver Advanced Analysis Software. A fold change (FC) of ≥ ± 2 (p < 0.05) was used to identify genes with a significant expression difference. Results: Comparing the 13 patients that recurred to the 13 that did not, there were 5 genes with FC ≥ +2: BAIAP3, PLCB1, IL1R1, NOS3 and RAD50. There were 29 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -10) were: BMP7, FGF18, WNT7A. Genes in the Cell Cycle (CC) pathway were significantly different in the patients that recurred (p = 0.02). There were 61 genes with FC ≥ +2 when comparing the original tumor to recurrent tumor; the top 3 genes with increased expression (FC ≥ 10) were: FGF18, CCND1, HIST1H3H (p < 0.05). There were 50 genes with FC ≥ -2; the top 3 genes with decreased expression (FC ≥ -1000) were: HOXA11, LEFTY2 and SFRP4. Wnt, Hedgehog, Chromatin Modification, DNA repair, TGF-β, MAPK, and CC pathways were significantly different in the recurrent samples compared to the original tumor (p < 0.05). Conclusions: Our data suggests that gene expression panels could better identify patients that warrant adjuvant treatment. The CC pathway, which is significantly different in the original tumor from those that recurred and those that did not, was further altered in the recurrent tumor samples. Additional studies are on-going to validate these findings and to further investigate DNA mutation differences in larger cohort of patients.
Assessment of a custom designed next generation DNA sequencing gene panel to profile endometrial cancers.
Authors: Miller Eirwen M , Patterson Nicole E , Karabakhtsian Rouzan G , Bejerano-Sagie Michal , Ravi Nivi , Maslov Alexander , Quispe-Tintaya Wilber , Wang Tao , Lin Juan , Smith Harriet Olivia , Kuo Dennis Yi-Shin , Goldberg Gary L. , Montagna Cristina
Published: September 2018

5593

Background: Using whole genome sequencing (WGS), the Cancer Genome Atlas (TCGA) identified four genomic subtypes of endometrial cancer (EC) with survival differences. Limited clinical data is available in the TCGA dataset restricting correlation of WGS with clinical endpoints. We sought to determine if high depth target sequencing allows for genomic classification of EC and prediction of the tumor biology when clinical variables are known. Methods: Using a custom designed sequencing panel targeting the coding regions of 156 EC genes we analyzed 47 EC samples and matching normal controls. Variants were annotated for pathogenicity. Charts were reviewed for clinicopathologic data. Routine statistical analyses were applied. Results: Endometrioid (EEC) tumors had a significantly higher frequency of total and pathogenic SNVs than serous (USC). Pathogenic PTEN and PIK3CA SNVs were more common in EEC while pathogenic TP53 SNVs were more frequent in USC. The presence of pathogenic TP53 SNVs was significantly associated with disease recurrence/progression. A pathogenic SNV at PTEN locus chr10:89692904 was associated with grade 1 EEC. Six hypermutated specimens were identified with 99-272 SNVs (mean 185.8 v 8.7 in non-hypermutated samples). All 6 were grade 3 EEC, of which 4 patients are alive without clinical evidence of disease (mean follow up 35 months). NTRK3, LRP1B, SLIT2, APC, RAD50, PIK3R1, and JAK2 SNVs were more common in grade 3 EEC than the other histologies. Conclusions: Pathogenic variants in EC associated with PTEN, PIK3CA, and TP53 and the number of somatic variants, as identified by a targeted sequencing, can predict histologic features and clinical behavior. Targeted sequencing panels may be a useful tool to predict the clinical phenotype and guide individualized therapeutic intervention. [Table: see text]
Prognostic importance of p16 status for women with vulvar squamous cell carcinoma (SCC) treated with radiotherapy.
Authors: Lee Larissa Janeen , Howitt Brooke E. , Oliva Esther , Zhang Hongkai , Catalano Paul J. , Crum Christopher , Bu Paula , Cimbak Nicole , Demaria Rebecca , Murphy Rita , Horowitz Neil S. , Matulonis Ursula A. , Russo Andrea Lyn
Published: September 2018

5599

Background: To evaluate the association between p16 status and in-field recurrence (IFR), progression-free (PFS) and overall (OS) survival in patients with vulvar SCC treated with radiation (RT) with or without surgical resection. Methods: In a multi-institutional retrospective cohort study, we identified 105 women with vulvar SCC who received RT between 1985-2011. Immunostaining for p16 was performed on archival tumor tissue using the Leica Bond III staining platform. Histopathology and p16 stains were reviewed by pathologists with expertise in gynecologic cancer; the intensity and extent of p16 staining in tumor cells were classified as negative (focal, weak, patchy) or positive (moderate or strong diffuse linear positive). Actuarial estimates of PFS, OS and IFR were calculated using the Kaplan-Meier method and compared by the logrank test. Multivariable analysis (MVA) was performed using the Cox proportional hazards model. Results: Patients with p16-positive disease were significantly younger at diagnosis (median 67 vs. 77 years) and were more likely to be current smokers (51% vs. 0%) and to have received concurrent chemotherapy (68% vs. 47%, all p<0.05). FIGO stage distribution, RT intent and median RT doses were similar by p16 status. With a median follow-up of 61 months, 5-year PFS and OS rates were 35% and 40%, respectively. Women with p16-positive tumors had significantly better 5-year PFS and OS rates than those with p16-negative tumors (61% and 23%, p<0.01 and 64% and 29%, p=0.01, respectively). The 5-year IFR rate was also lower for those with p16-positive disease (17% vs. 65%, p<0.01). On univariate analysis, use of concurrent chemotherapy was not associated with PFS (p=0.5), OS (p=0.3) or IFR (p=0.8). On MVA adjusted for age and stage, p16 positivity was significantly associated with better PFS (HR 0.57, 95% CI 0.33-0.97) and lower IFR (HR 0.24, 95% CI 0.09-0.6). Conclusions: In a multi-institutional setting, women with p16-positive vulvar SCC treated with RT had a lower IFR rate and longer survival than those with p16-negative disease. The magnitude of prognostic importance of p16 status is similar to that seen in oropharyngeal, anal and cervical cancers treated with RT.
Impact in delay of start of chemotherapy and surgery on pCR and survival in breast cancer: A pooled analysis of individual patient data from six prospectively randomized neoadjuvant trials.
Authors: Loibl Sibylle , Werutsky Gustavo , Nekljudova Valentina , Seiler Sabine , Blohmer Jens Uwe , Denkert Carsten , Hanusch Claus , Huober Jens Bodo , Jackisch Christian , Kummel Sherko , Schneeweiss Andreas , Untch Michael , Rhiem Kerstin , Fasching Peter A. , Von Minckwitz Gunter , Furlanetto Jenny
Published: September 2018

571

Background: Time interval from diagnostic biopsy to neoadjuvant chemotherapy (NACT) start (TBC) and from last chemotherapy application to surgery (TCS) are influenced by many factors. It is unclear whether a delay of systemic therapy or surgery impacts patients (pts) outcome. Methods: 9127 pts with early BC from 6 German neoadjuvant trials receiving an anthracycline-taxane based NACT were included. pCR (ypT0/is ypN0), disease free survival (DFS) and overall survival (OS) were compared according to TBC and TCS length (cut-off of ≤4 vs >4weeks (w)), overall and in subgroups (BC subtypes [luminal, HER2+, triple-negative breast cancer (TNBC)] and pCR [yes vs no] for survival endpoints) adjusted by study. Results: Data on TBC were available for 8072 pts, on TCS for 6420, on follow-up (FU) for 7889. Median age was 49 yrs, 25.6% had cT3-4, 48.6% N+, 44.1% G3, 46.0% luminal, 26.4% TNBC, 27.6% HER2+ tumors. Median (m) FU-time was 65 months [0-201]. mTBC was 23 days [0-228] (67.5% ≤4w vs 32.5% >4w), mTCS was 28d [0-204] (53.7% ≤4w vs 46.3% >4w), with inter-study variability for mTBC ranging from 14 to 32d and for mTCS ranging from 24 to 29d from the oldest to the most recently conducted study. TBC did not influence the pCR rate, neither in all patients nor in subgroups. At multivariable logistic regression analysis TBC length did not independently predict pCR. TBC did not influence DFS or OS, neither in all patients nor in subgroups. TCS<4w was associated with a trend towards a better DFS in all patients (HR=1.11 95%CI (0.99-1.24), p=0.08) and in pts not achieving pCR (HR=1.12, 95%CI (0.99-1.26), p=0.08). No difference was observed within BC subtypes. OS was not impacted by TCS length. At multivariable Cox regression analysis TBC or TCS≤4 vs >4w did not independently influence DFS or OS. Conclusions: A delay in starting NACT does not impact the pCR rate, DFS or OS and results are independent of the subgroup. However, early surgery after NACT in pts without pCR seems to influence outcome. Our analysis is explorative, but indicates for the first time, that time interval of starting NACT and undergoing surgery might be uncritical. Further research is ongoing.