bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).
Authors: Oliveira Mafalda , Navarro Alejandro , De Mattos-Arruda Leticia , Sánchez-Ollé Gessamí , Bellet Meritxell , Balmaña Judith , Gómez-Pardo Patricia , Perez-Garcia Jose Manuel , Muñoz-Couselo Eva , Vidal Maria , Ortega Vanessa , Dienstmann Rodrigo , Aura Claudia , Prudkin Ludmilla , Vivancos Ana , Rodon Ahnert Jordi , Baselga José , Tabernero Josep , Cortes Javier , Saura Cristina 
Published: March 2020

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]
Prognostic factors and treatment-related outcomes in patients with uterine serous cancer (USC).
Authors: deLeon Maria , Lu Lingeng , Hui Pei , Santin Alessandro , Rutherford Thomas J. , Arin-Silasi Dan , Azodi Masoud , Ratner Elena , Schwartz Peter E. 
Published: March 2020

5099 Background: USC an uncommon (10%) but aggressive form of uterine cancer, causes 50% of uterine cancer deaths. The purpose of this study is to report a large single-institution experience with USC investigating the effects of clinicopathological parameters and treatment on overall (OS) and disease-free survival (DFS). Methods: Records from our institution were reviewed from 1987-2009. All 334 USC patients (pts) identified were surgically staged. Postoperative treatments used were: (1) observation (OBS, n=33); (2) platinum-based chemotherapy (PCH, n=78); (3) whole pelvis radiation therapy (WPRT, n=16); (4) PCH and vaginal apex brachytherapy (PCHR, n=165); (5) vaginal apex brachytherapy (VAB, n=35). The cancer stages were 121 pts IA (36.2%), 36 IB (10.8%), 27 II (8.1%), 39 IIIA (11.7%), 2 IIIB (0.6%), 32 IIIC1 (9.6%), 9 IIIC2 (2.7%), 28 IVA (8.4%) and 40 IVB (12%). Results: The 5-year OS for stage IA/IB, II, IIIA/IIIB, IIIC1/IIIC2, IVA/IVB were 82%, 70%, 64%, 36%, and 9%, respectively. The 5-year DFS for stage IA/IB, II, IIIA/IIIB, IIIC1/IIIC2, IVA/IVB were 82%, 68%, 56%, 24%, 6%, respectively. Advanced stage was associated with significantly shorter OS and DFS (p <0.01). The 5-year OS for stage IA/IB disease was 94% for pts who received PCHR, 90% for OBS, 75% for PCH, 65% for VAB and 0% for WPRT. The 5-year DFS for PCHR, OBS, PCH, VAB and WPRT for Stage IA/IB were 89%, 82%, 86%, 72% and 0% respectively. For stage II-IVB pts, the 5-year OS was 51% for PCHR, 0% for OBS, 23% for PCH and 20% for WPRT. The 5-year DFS for stage II-IVB with PCHR, OBS, PCH and WPRT were 42%, 0%, 17% and 13% respectively. Older age pts had worse survival, (p<0.01). Race and BMI did not impact survival. Incomplete surgical debulking (p<0.01), depth of myometrial invasion >50% (p<0.01) and lymph node metastasis (p<0.01) were all associated with worse prognosis. Conclusions: PCHR overall exhibited better OS and DFS regardless of disease stage. Age, incomplete surgical debulking, depth of myometrial invasion and lymph node involvement were independent prognostic factors in USC patients in this study.
SU2C phase Ib study of pan-PI3K inhibitor BKM120 with letrozole in ER+/HER2- metastatic breast cancer (MBC).
Authors: Mayer Ingrid A. , Abramson Vandana Gupta , Balko Justin M. , Isakoff Steven J. , Kuba Maria Gabriela , Sanders Melinda , Forero-Torres Andres , Yap Jeffrey T. , Van Den Abbeele Annick D. , Li Yisheng , Arteaga Carlos L. , Winer Eric P. ,   Stand Up to Cancer - PI3K in Women's Cancers
Published: March 2020

510 Background: Mutations in PIK3CA, the gene encoding the p110a subunit of PI3K, have been associated with antiestrogen resistance in ER+ BC. In general, antiestrogen-resistant cancers retain ER and responsiveness to estradiol. This suggests that treatment of ER+/PI3K mutant BC should include PI3K inhibitors plus antiestrogens. Methods: We conducted a phase Ib trial of letrozole (2.5 mg/d) with the pan-PI3K inhibitor BKM120 in post-menopausal patients (pts) with ER+/HER2 MBC. BKM120 (100 mg/d) was given continuously (Arm A) or intermittently (5 on/2 off days; Arm B). Upon toxicity, BKM120 was reduced to 80 and 60 mg/d. Treatment continued until unacceptable toxicity or disease progression. Disease was assessed every 2 months. FDG-PET was done at baseline and at 2 weeks in all pts in Arm A. Results: Fifty-one pts were accrued; 49 had progressed on an AI previously. Median age was 56 years (range 34-77); 95% had bone and 70% visceral metastases. Toxicities and outcomes are summarized in the table. The only DLT* in Arm A and B were transaminitis and depression, respectively; both at 100 mg. Over 50% of Arm A pts had >25% reduction in their peak SUV at the 2-week FDG-PET. Pts who did not exhibit a metabolic response by FDG-PET progressed rapidly on therapy. Three pts in Arm A had a PI3K mutation; one of them has had stable disease on treatment for >12 months. Conclusions: The combination of letrozole/ BKM120 is safe in pts with AI-refractory ER+/HER2 MBC. Arm B is ongoing and will be updated at the meeting. All tumor biopsies will be analyzed for PI3K pathway alterations. FDG-PET at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition in most patients. Its value in predicting treatment response remains to be determined. [Table: see text] [Table: see text]
Phase II trial of topotecan, cisplatin, and bevacizumab for recurrent or persistent cervical cancer.
Authors: Zighelboim Israel , Wright Jason D. , Gao Feng , Case Ashley Stephens , Massad L. Stewart , Mutch David Gardner , Powell Matthew A. , Thaker Premal H. , Eisenhauer Eric Lawernce , Cohn David E. , Valea Fidel A. , Secord Angeles Alvarez , Lippmann Lynne T. , Rader Janet Sue 
Published: March 2020

5101 Background: The prognosis associated with recurrent or persistent cervical cancer is exceedingly poor. GOG-179 demonstrated a survival benefit with the combination of cisplatin and topotecan compared to single-agent cisplatin, with the former showing median PFS of 4.6 months, median OS of 9.4 months, and a 27% objective response rate. The role of angiogenesis in cervical carcinogenesis and progression has been well documented. We evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with incurable carcinoma of the cervix. Methods: Patients with histologically proven measurable recurrent or persistent cervical carcinoma not amenable to curative intent treatment were eligible. No prior chemotherapy for recurrence was allowed. Cisplatin 50 mg/m2 day 1, topotecan 0.75 mg/m2 days 1, 2 and 3 and bevacizumab 15 mg/kg day 1 were prescribed in a 21-day cycle. Cytokine support was allowed at physician discretion. The primary endpoint was 6-month PFS. Additionally, objective clinical response and toxicity were evaluated. Accrual goal (N=27) was based on a 50% improvement goal in 6-month PFS in relation to GOG-179 (40% to 60%), with a one-sided 0.10 significance and 80% power. Results: 27 eligible patients received a median of 3 treatment cycles (range, 1-19). All patients received radiotherapy as part of their first line treatment. Median follow-up was 8.5 months (1.2-32.9). The 6-month PFS was 59% (95%CI: 38.0-74.7). Among 26 RECIST-evaluable patients, objective response rates were (%; 95%CI): 1 CR (4%; 1-19.6), 7 PR (27%; 11.6-47.8), 11 SD (42%; 23.4-63.1) and 7 PD (27%; 11.6-47.8). Median OS was 9.8 months (95%CI: 7.7-20.6) and median PFS was 7.1 months (95%CI: 2.0-12.1). Grade 3-4 hematologic toxicity occurred in 96% of patients (thrombocytopenia 93% leukopenia 70%, anemia 70%, neutropenia 59%). Other grade 3-4 toxicities were also common (metabolic 48%, pain 37%, genitourinary 30%, constitutional 22% and gastrointestinal 19%). Conclusions: The addition of bevacizumab totopotecan and cisplatin results in a highly active but toxic regimen. Future efforts should focus on identification of predictive biomarkers and treatment modifications to minimize toxicity.
ADXS11-001 immunotherapy targeting HPV-E7: Preliminary survival data from a phase II study in Indian women with recurrent/refractory cervical cancer.
Authors: Basu Partha , Petit Robert G. ,   Gynecologic Oncology Group
Published: March 2020

5106 Background: ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lm vector serves as its own adjuvant and infects APC where it naturally cross presents, stimulating both MHC class 1 and 2 pathways resulting in specific T-cell immunity to tumors. Here we describe the preliminary survival data associated with ADXS11-001 administration in Lm-LLO-E7-015, a randomized phase II study being conducted in India in 110 patients with recurrent/refractory cervical cancer who have been treated previously with chemotherapy, radiotherapy or both. Methods: Patients are randomized to either 3 doses of ADXS11-001 at 1 x 109 CFU or 4 doses of ADXS11-001 at 1 x 109 CFU with cisplatin chemotherapy. Naprosyn and oral promethazine are given as premedications and a course of ampicillin is given 72h after infusion thereby clearing any residual vector. Patients receive CT scans at baseline and Days 84, 184, 273, 365 and 545. The primary endpoint is 12 month survival. Results: As of January 26, 2012, 88 patients have received 200 doses of ADXS11-001; with the percentage of patients alive at 6 months at 62% (34/55); at 9 months at 41% (15/37) and at 12 months at 40% (6/15). Tumor responses have been observed in both treatment arms with 3 complete responses (elimination of tumor burden) and 4 partial responses (≥30% reduction in tumor burden) by RECIST. One serious (Gr3) adverse event and 77 mild-moderate (Gr 1-2) adverse events possibly related to study treatment have been reported in 35% (31/88) of patients. The non-serious adverse events consisted predominately of transient, non-cumulative flu-like symptoms associated with infusion that responded to symptomatic treatment, or resolved on their own within hours of treatment. Conclusions: This immunotherapy can be safely administered to patients with advanced cancer alone and in combination with chemotherapy. ADXS11-001 is well tolerated and presents a predictable and manageable safety profile. Early signs of clinical benefit merit further investigation. Updated findings will be presented at the meeting.
Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.
Authors: Modi Shanu , Elias Anthony D. , LoRusso Patricia , Samant Meghna , Guardino Ellie , Althaus Betsy , Krop Ian E. 
Published: March 2020

528 Background: The antibody–drug conjugate T-DM1 has shown single-agent activity in phase II studies in patients (pts) with HER2–positive MBC. Preclinical data suggest synergy for T-DM1 combined with taxanes and with P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study evaluating the safety and tolerability of T-DM1 (qw and q3w) + T (qw) ± P (q3w) in pts with HER2-positive MBC previously treated with trastuzumab. A 3+3 dose-escalation scheme is used for T-DM1 + T to determine the maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive dose-limiting toxicity (DLT) criteria were modified to establish a more clinically relevant MTD. Results: We report interim results with T-DM1 (qw and q3w) + T (+ P) using modified DLT criteria. 24 pts have been enrolled in these cohorts; median age was 53 yrs (range, 23–69)*; median number of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. Conclusions: Data support combining T-DM1 + T ± P at the MTD for future clinical trials. The MTD for weekly T-DM1 + T is 2.4 mg/kg + 80 mg/m2 qw; MTD for weekly T-DM1 + T + P is 2.4 mg/kg + 80 mg/m2 qw + 840 mg LD, 420 mg q3w. Updated results will be presented, including the MTD for T-DM1 q3w + T qw ± P q3w, outcomes from pts with prolonged follow-up, and duration of response from an extension trial. [Table: see text]
A phase I trial of the IGF-1R antibody IMC-A12 in combination with temsirolimus in patients with metastatic breast cancer.
Authors: Fleming Gini F. , Suman VeraJean , Goetz Matthew P. , Haluska Paul , Moynihan Timothy Jerome , Nanda Rita , Olopade Olufunmilayo I. , Pluard Timothy J. , Erlichman Charles , Chen Helen X. , Guo Zhanfang , Ellis Matthew James , Ma Cynthia X. 
Published: March 2020

534 Background: mTOR plays a critical role in promoting tumor cell growth. In preclinical studies, the anti-tumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated by IGF-1R. We designed a phase I trial to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacodynamic effects of the IGF-1R antibody IMC-A12 in combination with temsirolimus (tem) in patients (pts) with metastatic breast cancer (MBC) where mTOR is frequently activated. Methods: A 3+3 phase I design was chosen. Tem and IMC-A12 were administered IV days (d) 1, 8, 15, and 22 of a 4-week cycle in pts with MBC refractory to standard therapies. Tumor response was evaluated by RECIST. Adverse events (AE) were reported using CTC v3.0. Serum IGF 1 and C-peptide levels on d2 (24h post infusion) and d8 prior to drug infusion were compared to baseline (BL) using paired t-test. Results: Of 26 pts enrolled, 4 did not complete cycle 1 due to progression (3) or co-morbid condition (1). MTD was determined from remaining 22 pts aged 34-72 (median 48) years with ECOG PS 0 (55%) or 1 (45%). 86% had ER+ cancer. Median number of regimens for MBC was 4. Two DLTs at the starting DL (DL 1) necessitated dose de-escalation of tem to 20mg (DL-1), then to 15 mg (DL-2) which was tolerable (Table). Subsequent dose escalation of IMC-A12 led to DLTs in 0 of 6 in DL-2A and 2 of 3 pts in DL-2B. The MTD was defined as DL-2A. Other AEs included gr 1/2 fatigue, neutropenia, anemia, and hyperglycemia. No CR or PR, but 4 SD lasting ≥ 4 months were observed. At DL-2, -2A and -2B, serum IGF 1 levels were significantly elevated on d2 (p <0.002) and d8 compared to BL (p <0.001), but C-peptide levels were not found to differ from BL. Conclusions: The MTD for the combination of IMC-A12 and tem in pts with MBC is lower than that observed for single agents alone. A phase II study is ongoing in MBC. The study is supported in part by ASCO CDA, Komen Craft to CXM, N01-CM62205 and N01-CM-2011-00071. [Table: see text]
A meta-analysis of receptor status discordance between primary breast cancer and metastases.
Authors: Aurilio Gaetano , Disalvatore Davide , Bagnardi Vincenzo , Munzone Elisabetta , Adamoli Laura , Curigliano Giuseppe , Pruneri Giancarlo , Sciandivasci Angela , De Vita Fernando , Goldhirsch Aron , Nole Franco 
Published: March 2020

546 Background: There is an increasing awareness that biology of breast cancer may evolve over time. The discordance in estrogen (ER), progesterone (PgR) and HER2 receptor status between primary breast cancer and metastases is being intensively investigated and a large amount of data has been produced. However, results from different studies seem to be conflicting and heterogeneous. To highlight this issue, a meta-analysis of published data was performed. Methods: A literature search was performed with Medline. All studies published from 1983 to 2011 comparing changes inER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumors were included. We used random-effects models to estimate pooled discordance proportions. Results: We selected 42 articles, mostly reporting retrospective studies. Twenty-eight, 20 and 27 articles were focused on ER, PgR and HER2 changes, respectively. A total of 2806 tumors were evaluated for ER discordance, 1809 for PgR discordance and 2801 for HER2 discordance. The heterogeneity between study-specific discordance proportions was high (I2 >75%, p<0.0001) for ER, PgR and HER2. Pooled discordance proportions were 20% (95% CI: 16-25%) for ER, 33% (95% CI: 28-38%) for PgR and 9% (95% CI: 6-12%) for HER2. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 24% and 12% for ER (p=0.0115), respectively. The same figures were 44% and 15% for PgR (p<0.0001), and 14% and 6% for HER2 (p=0.04). Conclusions: To our knowledge, this is the first meta-analysis addressing this topic. The findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer and therefore clinical implications with possible impact on treatment choice cannot be excluded. However, the high heterogeneity observed in our analysis may explain the disagreement among oncologists on performing a reassessment of the biological features. In our opinion, only high-powered prospective and randomized trials could clarify the controversies in this field.
CYP2D6 genotype and adverse effects as indicators of plasma endoxifen in breast cancer patients taking tamoxifen.
Authors: Balakrishnar Bavanthi , Menzies Alexander M. , Ali Sayed Sahanawaz , Yeap Shang Heng , Gao Bo , Liddle Chris , Coulter Sally , Provan Pamela , Gebski Val , Hui Rina , Kefford Richard , Wilcken Nicholas , Balleine Rosemary L , Gurney Howard 
Published: March 2020

550 Background: Tamoxifen is a prodrug. Its principal active metabolite endoxifen is a product of cytochrome P450 2D6 (CYP2D6) metabolism. The CYP2D6 gene is highly polymorphic with a number of relatively common reduced function alleles. The aim of this study was to determine whether plasma endoxifen levels were reflected by CYP2D6 genotype or adverse effects in individuals taking tamoxifen. Methods: Plasma endoxifen was measured by High Performance Liquid Chromatography / Mass Spectroscopy in 90 breast cancer patients taking 20mg tamoxifen per day. Ten CYP2D6 single nucleotide polymorphisms were assessed to designate four putative CYP2D6 functional categories: ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. CYP2D6 inhibitor use and adverse effects were documented. The study was part of an ongoing Australian trial of tamoxifen dose escalation. Results: There was marked variation in plasma endoxifen levels across the cohort (mean 27.6 nM, SD 14.3). Endoxifen levels were significantly associated with metabolizer categories (p<0.001, r= -0.44), but were not distinctive between categories. For example, in the EM category (n=46) endoxifen levels ranged from 3.8-72.2 nM (mean 32.6 nM) with levels in the lowest quartile (3.8-19.7 nM) substantially overlapping the PM category (n=11); 6.1-24.7 nM. Consistent with an impact of non-CYP2D6 genotype related factors on endoxifen levels, endoxifen was significantly lower in 18 patients taking CYP2D6 inhibitor medications (p=0.005). There was no association between endoxifen levels and vasomotor symptoms or other adverse effects of tamoxifen. Conclusions: Endoxifen levels were highly variable in patients taking standard dose tamoxifen, and not predicted by CYP2D6 genotype or adverse effects. Therapeutic monitoring of endoxifen levels may be a useful approach to assess tamoxifen activity.
A molecular diagnostic panel for thyroid cancer disease management.
Authors: Cheng Shih-Min , Qu Kevin , Abdool Adam , Sferruzza Anthony , Waldman Frederic , Reitz Richard E 
Published: March 2020

5510 Background: In 2009, the American Thyroid Association revised its guidelines for patients with thyroid nodules and differentiated thyroid cancers, recommending BRAF, RAS, RET/PTC, and PAX8-PPARγ molecular testing in patients with indeterminate fine-needle aspirate (FNA) cytology. Alterations in any of these markers in thyroid nodules are strongly associated with malignancy. We studied the prevalence of these alterations in thyroid FNA specimens in order to establish a strategy to improve disease management. Methods: DNA and RNA were extracted from thyroid FNA specimens (N=149) and tested for BRAF mutations using allele-specific PCR (V600E and K601E); for RAS (H-, K-, N-) mutations using pyrosequencing (codons 12, 13, and 61); and for RET/PTC1 and RET/PTC3 rearrangements and PAX8-PPARγ translocations using RT-PCR. Results: Overall, 90 (60.4%) of the specimens had alterations in ≥1 of the 4 molecular markers (Table). BRAF V600E mutations (54.4%) were the most prevalent mutations in papillary thyroid cancer (PTC); no K601E mutations were found. RAS mutations were found in PTC, follicular adenoma (FA), and follicular thyroid cancer (FTC) specimens; half of these mutations involved N-RAS Q61. RET/PTC rearrangements were detected in 3.5% of PTC specimens and were evenly distributed between the 2 major subtypes, RET/PTC1 and RET/PTC3. PAX8/PPARγ translocations were detected in 18.8% of FTC but not in FA, probably due to small sample size. Out of 7 indeterminate thyroid nodules, 2 had BRAF mutations and 2 had RAS mutations. The presence of the 4 markers was generally mutually exclusive; only 1 PTC specimen had concurrent RAS and RET/PTC1 alterations. Conclusions: The prevalence of BRAF, RAS, RET/PTC, and PAX8/PPARγ alterations in thyroid cancer specimens highlights the potential for targeted therapeutic strategies. The mutually exclusive pattern of alterations also suggests a hierarchical screening strategy for samples with limited availability. [Table: see text]