bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of metformin on sex hormones in non-diabetic breast cancer patients in CCTG MA.32: A Phase III randomized adjuvant trial of metformin versus placebo in addition to standard therapy.
Authors: Pimentel Isabel , Chen Bingshu E. , Lohmann Ana Elisa , Ennis Marguerite , Ligibel Jennifer A. , Shepherd Lois E. , Hershman Dawn L. , Stambolic Vuk , Mayer Ingrid A. , Hobday Timothy J. , Lemieux Julie , Thompson Alastair Mark , Rastogi Priya , Gelmon Karen A. , Whelan Timothy Joseph , Rabaglio-Poretti Manuela , Dowling Ryan JO , Parulekar Wendy R. , Goodwin Pamela Jean 
Published: May 2019

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or > 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = < 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = < 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.
Influence of competing risks on estimates of recurrence risk and breast cancer-specific mortality in analyses of the Early Breast Cancer Trialists Collaborative Group.
Authors: Saleh Ramy , Nadler Michelle , Desnoyers Alexandra , Rodin Danielle Lee , Abdel-Qadir Husam , Amir Eitan 
Published: May 2019

533 Background: Early stage breast cancer is a curable disease with the majority of patients dying of causes other than breast cancer. The influence of these competing risks of death on the interpretation of Kaplan-Meier(KM)-based analyses such as those performed by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) are unknown. Methods: We searched the Clinical Trial Service Unit and Epidemiological Studies Unit website at Oxford University to identify all meta-analyses published by the EBCTCG between 2005 and 2018. Studies were included if they contained KM curves with risk estimates for either breast cancer mortality and/or breast cancer recurrence. The potential influence of competing risks was estimated using a validated multivariate linear model that predicts the amount that the KM risk estimates are biased relative to outcome risk measured with the cumulative incidence function (CIF). Results: The initial search identified 14 analyses published by the EBCTCG with 10 of the 14 studies (71%) susceptible to competing risk bias cited both the number of events of interest and competing events. Eight of the ten studies (80%) had a relative difference between the KM estimate and the competing risk adjusted estimate of more than 10% while 2 of 10 (20%) had a difference of less than 10%. The relative difference between the KM and adjusted estimates was 28.4% for local recurrence, 16.8% for distant recurrence, and 6.7% for breast cancer-specific mortality. There was 2.2% difference between KM and adjusted analyses between 0-4 years and 18.9% beyond 10 years of follow up. Use of KM and CIF-based analysis did not influence treatment effect in the majority of included studies. Conclusions: This study provides estimates for the overestimation of risk in Kaplan-Meier analyses resulting from failure to address competing risk bias. CIFs are more appropriate to measure outcome risk over time and should be used especially for long-term follow-up studies and for analysis of rare events.
Adjuvant enzalutamide for the treatment of early-stage androgen receptor-positive (AR+) TNBC.
Authors: Traina Tiffany A. , Boyle Leigh Ann , Arumov Artavazd , Patil Sujata , Edelweiss Marcia , DeFusco Patricia Anne , Gorsky Mila , Lamparella Nicholas E. , Modi Shanu , Sanford Rachel Ann , Gucalp Ayca 
Published: May 2019

546 Background: A subset of TNBC is dependent on AR signaling. Enzalutamide (ENZA), an AR-antagonist, has activity in patients (pts) with metastatic AR+ TNBC, with a clinical benefit rate of 33%. This study tests the feasibility of adjuvant ENZA for the treatment (tx) of early stage, AR+ TNBC. We now report the primary endpoint (endpt) and safety. Methods: Eligible pts have centrally confirmed, Stage I-III, ER/PR < 1%, HER2(-), AR ≥1% BC and completed all planned surgery, chemotx and radiation (RT) < 6 months of tx start. AR testing by IHC per MSK methods. Tx consists of ENZA 160mg daily for 1 year (y) with the option to extend tx to 2y. Toxicity per NCI CTCAEv4 every (q) 4 weeks (wk) for 12 wk, then q3 months. Primary endpt: feasibility of 1y ENZA defined as the discontinuation rate due to toxicity, consent withdrawal or tolerability. 50 pts are enrolled to have 46 evaluable pts required to discriminate between feasibility of 50% and 70%, with type I error 5% and 88% power. Pts who have disease progression (PD) or die during 1st y of ENZA and do not have tx discontinuation due to the above will not be included in the primary analysis. If 29 pts complete 1y, adjuvant ENZA will be deemed feasible. Secondary endpts: safety and 3y DFS and OS. Exploratory endpts: PROs and biomarker development. Results: Between 5/2016-6/2018, 50 pts were enrolled. Pt and tumor characteristics (N = 50): Median age 55y (33-81); Stage: I 20 (40%), II 23 (46%), III 7 (14%); Grade (gr): 2 = 26%, 3 = 74%. AR > 10% = 35 (70%), AR ≤10% = 15 (30%). Chemotx 47/50 (94%): Neoadjuvant (neo) 40%, Adjuvant (adj) 60%; Anthracycline/Taxane-based 38/47 (81%), Platinum 1/47 (2%), Docetaxel/Cyclophosphamide 3/47 (6%), other 5/47 (11%). 13/19 who received neo tx failed pCR; 9/13 (69.2%) received adj capecitabine. RT: 38/50 (76%). 27 pts completed 1y of tx. 7 pts will be evaluable by 6/1/19. 1 pt to complete 1y 6/21/19. 15 pts are off tx: PD (3), toxicity (5), noncompliance (4), withdrawal of consent (3). Tx-related AEs, any gr, > 10% (N = 50): fatigue (48%), hot flashes (22%), headache (18%), hyperglycemia (18%), nausea (18%), WBC decreased (16%), dizziness (14%), arthralgia (12%), dyspnea (12%). Tx-related, gr 3 AEs: fatigue (6%), hyperglycemia (2%), hypertension (2%). No gr 4/5 AEs or seizures. 11 pts had dose reduction. Conclusions: Feasibility of adjuvant ENZA will be fully evaluable in 4/2019 and is anticipated to meet the prespecified statistical expectations for primary endpt. ENZA is well tolerated following locoregional tx and standard of care systemic tx. Secondary analyses and correlatives are ongoing to define the role of AR in TNBC. Clinical trial information: NCT02750358.
Phase 2, two-group, two-stage study of avelumab in patients (pts) with microsatellite stable (MSS), microsatellite instable (MSI), and polymerase epsilon (POLE) mutated recurrent/persistent endometrial cancer (EC).
Authors: Konstantinopoulos Panagiotis A. , Liu Joyce F. , Luo Weixiu , Krasner Carolyn N. , Ishizuka Jeffrey Joseph , Gockley Allison Ann , Buss Mary K. , Campos Susana M. , Stover Elizabeth , Wright Alexi A. , Growdon Whitfield Board , Curtis Jennifer , Peralta Ariana , Basada Patrice , Quinn Roxanne , Gray Kathryn P. , Penson Richard T. , Cannistra Stephen A. , Fleming Gini F. , Matulonis Ursula A. 
Published: May 2019

5502 Background: This non-randomized phase 2 study evaluated the PD-L1 inhibitor avelumab in two cohorts of EC: i) MSI/ POLE cohort including ECs with immunohistochemical (IHC) loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) MSS cohort including ECs with normal IHC expression of all MMR proteins. Methods: Eligibility criteria included measurable disease, unlimited prior therapies, and any EC histology. Co-primary endpoints were confirmed objective response (OR) and progression-free survival rate at 6 months (PFS6). Avelumab 10 mg/kg IV was given every 2 weeks until progression or unacceptable toxicity. In the 1st stage, 16 pts were enrolled in each cohort; if there were ≥2 ORs or ≥2 PFS6 responses, accrual would continue to the 2nd stage with enrollment of 19 additional pts. Overall, if there are ≥4 ORs or ≥8 PFS6 responses, avelumab would be considered worthy of further study in each cohort. Results: As of 12/2018, 33 pts were enrolled. The MSS cohort was closed at the 1st stage due to futility; of 16 pts in the MSS cohort, only 1 pt exhibited an OR and PFS6 response [ORR and PFS6 rate 6.25% (95% CI 0.16%-30.2%)]. Conversely, the MSI/POLE cohort reached the primary endpoint of 4 ORs after accrual of only 17 pts. Two pts in the MSI/POLE cohort did not initiate protocol therapy and were excluded from all analyses. Of 15 pts in the MSI/POLE cohort, 4 pts exhibited OR [1CR+3PRs, OR rate (ORR) 26.7% (95% CI 7.8%-55.1%)] and 6 pts (including the 4 pts with OR) exhibited PFS6 responses [PFS6 rate 40.0% (95% CI 16.3%-66.7%)], 4 ongoing and 3 approaching 2 yrs. Twenty-two pts (71%) reported treatment related toxicities, 6 patients (19%) G3 toxicities; there were no treatment-related G4 and G5 toxicities. In the MSI/POLE cohort, 5 of 6 PFS6 responses were observed in pts with ≥3 lines of prior therapy (p = 0.011) and in tumors who were PD-L1 negative by IHC. Further correlative work will be reported at the meeting. Conclusions: In EC pts stratified by MSI/POLE status, MSI vs MSS status appears to be correlated with avelumab response even in PD-L1 negative tumors. Responses in the MSI/POLE cohort were more frequent in more heavily pretreated patients, a finding that warrants further investigation. Clinical trial information: NCT02912572.
Prediction of neoadjuvant chemotherapeutic efficacy by CTC and cfDNA in patients with locally advanced breast cancer.
Authors: Ma Ge , Wang Jingyi , Liu Xiaoan , Xia Tiansong , Wang Shui 
Published: May 2019

551 Background: Neoadjuvant chemotherapy (NCT) is the standard treatment for patients with locally advanced breast cancer (LABC). Liquid biopsy, including circulating tumor cells (CTCs) and cell free DNA (cfDNA) represent an important paradigm shift in precision medicine. The aim of this study was to estimate the value of CTCs and cfDNA in efficacy prediction of the response to NCT in patients with LABC. Methods: Patients with LABC received EC4-T4 regimen NCT. CTCs and cfDNA obtained at time of biopsy, after first course of NCT and after the last course of NCT. All patients were divided into two groups according to pathological reactivity. A novel SE-iFISH strategy, improved for detection of CTCs, was applied. CTCs(CD45-/CD31-) with different cytogenetic abnormality of aneuploid chromosome 8 and small cell size CTCs (≤5 mm of WBCs) were analyzed separately in LABC patients subjected to NCT for the first time. Plasma DNA biomarkers ALU 111 and ALU 260 elements were evaluated using qRT-PCR. DNA integrity was calculated relative to the breast cancer cell line MCF-7. Clinical significance of diverse subtypes of CTCs and cfDNA was systematically investigated. Results: A total of 45 patients was enrolled in this study. According to the therapy response, 6/45 patients had high response (High-R) and 39/45 patients had low response (Low-R). There were no significant differences in CTC number and small cell size CTC number between High-R and Low-R groups in all three detections. However, the CTC number kept stable in the High-R group, but increased continually during NCT in Low-R group. In 45 patients, the percentage of CTCs with trisomy 8, which were related to cancer metastasis, incresed in the Low-R group at the third dectection. The concentration of cfDNA in all three detections did not indicate outcome of NCT. However, concentration of ALU 111 increased in Low-R patients during NCT. In High-R patients, no significant increase was observed. A CTC and cfDNA panel were constructed to discriminate High-R patients from Low-R patients. The areas under the receiver-operating characteristic (ROC) curves of the pannel for the three times were 0.803, 0.859 and 0.667, respectively. DNA integrity index(CFDI) was significantly higher in High-R group than Low-R after first course of NCT. The areas under the ROC curves of the CFDI for the three times were 0.675, 0.863 and 0.697, respectively. Conclusions: The trend of cfDNA concentration changed resembled to the number of CTCs, small cell size CTCs and triploid CTCs during NCT, and could predict tumor response to ongoing treatment.
Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results.
Authors: Liao John B. , Gwin William Rayford , Urban Renata , Hitchcock-Bernhardt Katie , Coveler Andrew L. , Higgins Doreen , Childs Jennifer S , Shakalia Hania , Stanton Sasha E. , Tinker Anna , Wahl Tanya A. , Ancheta Richard G. , McGonigle Kathryn F. , Dai James , Disis Mary L. , Goff Barbara Ann 
Published: May 2019

5519 Background: Pembrolizumab has shown activity in advanced recurrent ovarian cancer (AOC) with an 8% response rate and median progression-free survival (PFS) of 2.1 months reported in KEYNOTE-100. Because platinum chemotherapies also induce T cell proliferation and enhance tumor cell recognition through PD-1/PD-L, we assessed the safety and activity of pembrolizumab with carboplatin in platinum resistant AOC. Methods: Key eligibility criteria for this Phase 1/2 single arm trial were platinum resistant AOC, fallopian tube, or peritoneal cancer, progression after subsequent systemic therapy, and ECOG PS 0-1. Pembrolizumab 200mg was given on Day 1 and carboplatin AUC 2 on Day 8 and 15 of a 3 week cycle until progression, unacceptable toxicity, or consent withdrawal. Imaging was done before cycles 4 and 8, then every 3 months and unconfirmed objective response assessed by blinded independent review per RECIST 1.1. Adverse events (AEs) were reported per Common Terminology for Adverse Events v5.0. PD-L1 expression was assessed by immunohistochemistry. Results: 27 patients (median age: 64) had received a median of 5 (range: 2-9) prior lines of systemic therapy, which included bevacizumab in 74% of patients. The most common treatment related (TR) AEs were lymphopenia (18%) and anemia (9%). The majority of TR AEs were grade 1 or 2 (93%). 6% of AEs were grade 3 with lymphopenia the most common. Two grade 4 AEs were neutropenia and lymphopenia. Of 23 patients evaluable for best objective response, 13.0% (95% CI, 2.7-33.6) had partial response (PR), 65.2% (95% CI, 42.7-83.6) had stable disease (SD), and 21.7% (95% CI, 7.4-43.7) had progression. 7 of the 23 evaluable patients (30.4%) had archival tumor with modified percent scoring ≥5 for PD-L1 and all achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Overall median PFS was 4.6 months (95% CI, 2.7-6.2). Rate of PFS at 6 months was 40.4% (95% CI, 25.5-65.5). Median follow-up is 6.2 months and PFS is based on current data, but 8 patients remain on study and estimates will be updated. Conclusions: Pembrolizumab with low dose carboplatin was well tolerated and showed activity in heavily pretreated platinum resistant AOC. Survival and biomarker analyses are ongoing. Clinical trial information: NCT03029598.
Evolve: A post PARP inhibitor clinical translational phase II trial of cediranib-olaparib in ovarian cancer—A Princess Margaret Consortium – GCIG Phase II Trial.
Authors: Lheureux Stephanie , Oaknin Ana , Garg Swati , Bruce Jeffrey , Dhani Neesha C. , Madariaga Ainhoa , Bonilla Luisa , Lee Yeh Chen , Colombo Ilaria , Bhat Gita , Bowering Valerie , White Justin , Accardi Sarah , Tan Susie , Braunstein Marsela , Karakasis Katherine , Liu Zhihui (Amy) , Pugh Trevor John , Oza Amit M. 
Published: May 2019

5521 Background: PARP inhibitors (PARPi) are approved therapies in high grade serous ovarian cancer (HGSOC). There are few studies after PARPi progression and correlation with dynamic changes in resistance. We hypothesized that PARPi resistance could be overcome by adding an anti-angiogenic. Methods: We report the first phase 2 trial assessing the combination of olaparib and cediranib after PARPi failure in HGSOC. This investigator initiated study included three cohorts of 10 evaluable patients (pts): i) platinum sensitive post PARPi (PS), ii) platinum resistant post PARPi (PR) and iii) exploratory cohort of pts re-challenged with chemotherapy post PARPi progression (PE) (NCT02681237). The primary objective was to determine objective response rate by RECIST v1.1 and progression free survival (PFS) at 16 weeks. Secondary objectives were to evaluate safety, PFS, overall survival (OS) and mechanisms of PARPi resistance. Pts who had radiographic progression on any PARPi were eligible. Archival tumor at initial diagnosis and baseline tumor biopsy at PARPi progression were mandatory. Pts received olaparib tablets 150mg BID with cediranib 20mg QD until progression or unacceptable toxicity. CT scans were performed every 8 weeks. Whole exome and RNA sequencing were performed on paired tumors tissues. Results: Thirty-four pts were enrolled. BRCA1/2 mutations were found in 9/11 PS, 8/10 PR and 7/13 PE pts. By RECIST1.1, four partial responses were observed (2 in PR and 2 in PE cohorts) and 18 stable disease. The 16−week PFS was 54.5% (31.8−93.6) in PS, 50% (26.9−92.9) in PR and 36% (15.6−82.8) in PE, respectively. OS at 1 year was 81.8% (61.9−100) in PS, 64.8% (39.3−100) in PR and 39.1% (14.7−100) in PE. Main related adverse events were anemia, hypertension, diarrhea and fatigue, grade 3 < 10%. Molecular analyses identified different mechanisms of PARPi resistance in ~77% of evaluable pts with matched pre-post PARPi progression biopsies such as reversion mutations in BRCA1/2 and other homologous repair (HR) genes; BRCA, HR and MDR upregulation, CCNE amplification and RIG-I like receptor downregulation. Conclusions: Treatment with olaparib-cediranib after PARPi failure was feasible and met the predefined bar for efficacy in each cohort. This is the largest clinical trial prospectively evaluating PARPi failure and correlating tissue genomic mechanisms of resistance. Clinical trial information: NCT02681237.
Tailored dose-dense chemotherapy in combination with trastuzumab as adjuvant therapy for HER2-positive breast cancer: A secondary analysis of the phase III PANTHER trial.
Authors: Foukakis Theodoros , Papakonstantinou Antroula , Matikas Alexios , Bengtsson Nils-Olof , Malmström Per , Hedayati Elham , Steger Guenther G. , Untch Michael , Hübbert Laila , Johansson Hemming , Hellstrom Mats , Gnant Michael , Loibl Sibylle , Greil Richard , Moebus Volker , Bergh Jonas C. S. 
Published: May 2019

553 Background: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no data to inform on the combination of DD chemotherapy with trastuzumab for patients with HER2-positive disease. Methods: This is a protocol predefined secondary analysis of the randomized phase 3 PANTER trial. Women 65 years old or younger with node-positive or high-risk node negative BC were randomized 1:1 to either tailored according to hematologic nadirs and DD epirubicin/cyclophosphamide (4 cycles) followed by 4 cycles of docetaxel (tDD EC/D) or standard 3-weekly 5-fluorouracil/E/C (3 cycles) and D (3 cycles); Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. In addition, HER2-positive and an equal number of matched for age, treatment group and institution, HER2-negative patients that were enrolled in Swedish sites were enrolled in a predefined study of cardiac safety and underwent echocardiography or MUGA and electrocardiography at baseline and at four and six years of follow-up. The primary endpoint was BC relapse-free survival (BCRFS). Results: There were 342 HER2-positive patients; 335 received at least one dose of trastuzumab, while 29 patients discontinued trastuzumab prematurely. BCRFS was not statistically significantly in favor of tDD EC/D (HR = 0.68, 95% CI 0.37 – 1.27, P= 0.231). Cardiac outcomes after four and six years of follow-up did not differ significantly between HER2-positive and HER2-negative patients, nor between tDD and standard treatment. Conclusions: To our knowledge, these are the only data on combining DD adjuvant chemotherapy and trastuzumab in BC. The combination decreased the risk for BC relapse by 32% compared to standard treatment, a statistically non-significant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies. Clinical trial information: NCT00798070.