bluuebunny/crossref_metadata_2025 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.
Association of detection of aflatoxin in plasma of Kenyan women with increased detection of oncogenic HPV.
Authors: Zhiang Jianjun , Omenge Elkanah , Maina Titus , Muthoka Kapten , Kiptoo Stephen , Groopman John , Tong Yan , Ermel Aaron , Loehrer Patrick J. , Brown Darron
Published: May 2019

5530

Background: Cervical cancer is the leading cause of cancer-related deaths among women living in Africa. Only a small proportion of HPV-infected women develop cervical cancer and other cofactors may increase a woman’s risk of developing cervical cancer. Aflatoxin, a potent carcinogen and immunosuppressive agent, is produced by fungi that contaminate corn and other staple foods in sub-Saharan Africa. Women who ingest aflatoxin may be more likely to have persistent infections with oncogenic HPV type. Methods: Demographics, behavioral data, plasma, and cervical swabs were collected from HIV-uninfected women 18 and 45 years of age who presented for cervical cancer screening at Moi Referral and Teaching Hospital (Eldoret, Kenya) and had normal VIA examination. HPV testing was performed on cervical swabs using the Roche Linear Array Assay. Aflatoxin-albumin adduct (AFB1-lys) was detected and quantified in plasma. The association of plasma AFB1-lys detection and concentration and the detection of HPV was examined. Results: Sufficient plasma was available from 88 HIV-uninfected women and was transported to the U.S. for aflatoxin testing. Valid HPV testing results were available for 86 of these women (mean age 34.0 years); 49 women (57.0%) had detectable AFB1-lys and 37 (43.0%) had no detection. Substantial variation existed in plasma AFB1-lys concentrations among the 49 women (range 0.02 to 0.21 pg/µL). Detection of AFB1-lys was not associated with age, and other behavioral factors such as number of lifetime partners, marital status and age at first sex. AFB1-lys detection was associated with detection of A9 HPV types (HPV 16, 31, 33, 35, 52, and 58) as a group in cervical swabs (p = 0.029) as well as A9 types excluding HPV 16 (p = 0.020), but not with individual A9 types, A7 HPV types (such as HPV 18), or low-risk HPV types. A concentration dependent association of AFB1-lys was seen with detection of A9 HPV types as a group (p = 0.009), non-HPV 16 A9 types (p = 0.005), and HPV 52 (p = 0.042), but not with the A7 HPV types. Conclusions: AFB1-lys was detected in 57% of HIV-uninfected Kenyan women without cervical dysplasia. AFB1-lys-positive women were more likely than AFB1-lys-negative women to have oncogenic HPV A9 types detected. Higher plasma AFB1-lys concentrations were associated with increased likelihood of oncogenic HPV A9 type detection. Further studies are needed to determine if chronic exposure to aflatoxin interacts with HPV infection (and possibly HIV co-infection) to modulate the risk of cervical cancer in women in Kenya and other developing countries.
A randomized, double-blind, placebo-controlled phase Ib/II study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine (G) and carboplatin (C) versus GC for women with recurrent platinum-sensitive ovarian cancer.
Authors: Vergote Ignace , Heitz Florian , Buderath Paul , Powell Matthew A. , Sehouli Jalid , Lee Christine M. , Hamilton Anne L. , Fiorica James , Moore Kathleen N. , Teneriello Michael , Golden Lisa , Zhang Wei , Pitou Celine , Farrington Daphne L. , Bell-McGuinn Katherine M , Wenham Robert Michael
Published: May 2019

5537

Background: p38 mitogen-activated protein kinase (MAPK) regulates cytokine production in the tumor microenvironment and enables therapeutic resistance of cancer cells. Ralimetinib (R) is a selective small-molecule inhibitor of p38α and p38β MAPKs. Methods: Main inclusion criteria: ≥18 y; recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal, cancer after first-line treatment. Phase (Ph)1b was to determine the recommended Ph2 dose (RP2D) of R administered 12-hourly (Q12H) on Days 1-10 (21-day cycle [Q21D]) in combination with gemcitabine (G: 1000 mg/m2 on Days 3 and 10) and carboplatin (C: AUC 4 on Day 3) for 6 cycles. In Ph2, patients (pts) were randomized double-blind, 1:1 to RP2D R+GC or placebo (P)+GC, for 6 cycles, followed by R 300 mg Q12H or P on Days 1-14, Q28D until disease progression. The stratified log-rank test compared progression-free survival (PFS; primary endpoint) between treatment groups in Ph2, at a 1-sided α level of 0.2. ClinicalTrials.gov, NCT01663857. Results: 118 pts received ≥1 dose of R or P (safety population); 8 in Ph1b and 110 in Ph2 (R+GC N = 58; P+GC N = 52). The RP2D for R in combination with GC was 200 mg Q12H. The study met its primary objective (median PFS: R+GC 10.3 mo vs P+GC 7.9 mo; HR = 0.773, 2-sided p = 0.246). The secondary objectives of median overall survival (R+GC 29.2 mo vs P+GC 25.1 mo; HR = 0.827, p = 0.469) or overall response rate (R+GC 46.6% vs P+GC 46.2%; p = 0.967) were not statistically significant, and 32.4% vs 25.0% of pts had normalized CA125 at the end of cycle 6. Most pts (safety population) experienced ≥1 Grade 3/4 treatment-emergent adverse event (TEAE: R+GC 63/66 [95.5%]; P+GC 48/52 [92.3%]). Decreased neutrophil count (60.6% vs 76.9%), platelet count (43.9% vs 38.5%), and white blood cell count, (30.3% vs 26.9%), anemia (22.7% vs 25.0%), and increased alanine aminotransferase (ALT) (19.7% vs 3.8%) were the Grade 3/4 TEAEs in ≥10% of pts in the R+GC and P+GC arms, respectively. Conclusions: Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857.
Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial.
Authors: Mathews Cara Amanda , Moore Kathleen N. , Colombo Nicoletta , Scambia Giovanni , Kim Byoung-Gie , Oaknin Ana , Friedlander Michael , Lisyanskaya Alla Sergeevna , Floquet Anne , Leary Alexandra , Sonke Gabe S. , Gourley Charlie , Banerjee Susana N. , Oza Amit M. , González-Martín Antonio , Aghajanian Carol , Bradley William Hampton , Lowe Elizabeth S. , Bloomfield Ralph , Disilvestro Paul
Published: May 2019

5541

Background: In SOLO1 (NCT01844986), maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. N Engl J Med 2018) in pts with newly diagnosed advanced OC and a BRCAm. This analysis evaluates olaparib efficacy by timing of surgery, presence of residual tumor following surgery and response status after completion of chemotherapy in SOLO1. Methods: Pts underwent cytoreductive surgery and were in clinical complete response (CR) or partial response (PR) after platinum-based chemotherapy. Pts were stratified by response and received olaparib tablets 300 mg twice daily or placebo. Investigator-assessed PFS and objective response were assessed using modified RECIST v1.1. Results: 260 pts were randomized to olaparib and 131 to placebo; one pt did not receive placebo. Median follow-up was 41 months in both arms. 63% and 35% of pts underwent upfront and interval surgery, 21% and 76% had residual and no residual macroscopic disease after surgery, and 74% and 26% entered the study in clinical CR and PR (based on electronic case report form [eCRF] data). PFS was significantly improved regardless of the timing of surgery, residual disease status after surgery or response after platinum-based chemotherapy (Table). In pts with baseline radiologic evidence of disease (n=80; eCRF), the objective response rate was 43% for olaparib (CR, 28%) and 23% for placebo (CR, 12%). Conclusions: Maintenance olaparib improved outcomes compared with placebo in pts with newly diagnosed advanced OC and a BRCAm, regardless of surgical or tumor status. Clinical trial information: NCT01844986. [Table: see text]
Modeled CA-125 kinetics during neoadjuvant chemotherapy for predicting the likelihood of optimal interval debulking surgery in ovarian cancer patients: Data from CHIVA trial (a GINECO study).
Authors: Robelin Patrick , Tod Michel , Colomban Olivier , Louvet Christophe , Lotz Jean-Pierre , Abadie Lacourtoisie Sophie , Fabbro Michel , Desauw Christophe , Bonichon Nathalie , Kurtz Jean Emmanuel , Follana Philippe , Leheurteur Marianne , Del Piano Francesco , Alliot Carol René , De Rauglaudre Gaetan , Ray-Coquard Isabelle Laure , Combe Pierre , Chevalier Annick , Joly Florence , You Benoit
Published: May 2019

5546

Background: A pre-operative predictive biomarker of CC0 interval debulking surgery (IDS) likelihood would be helpful. The modeled CA125 elimination rate constant KELIM predicts OS in 1st line setting (You et al. Clin Cancer Res 2019). The predictive/prognostic values of KELIM regarding CC scores at IDS, and survivals, during neo-adjuvant chemotherapy were assessed. Methods: The data of the CHIVA randomized phase II trial, comparing carboplatin-paclitaxel +/- nintedanib before IDS (NCT01583322), were used. A semi-mechanistic model was built to describe CA125 longitudinal kinetics during the first 100 treatment days. The relationships between KELIM and IDS CC scores, PFS & OS, were assessed with other major prognostic factors (grade, histology, GCIG CA125 response, FIGO stage, and arm) using multivariate logistic regression (logit), C-index & survival tests. Results: The longitudinal kinetics of 529 CA125 values, assessed every 3 weeks during neo-adj chemotherapy, were modeled in 133 patients (out of 188). KELIM (as a continuous covariate) was the only significant predictive factor of CC0 IDS likelihood using multivariate analyses (OR = 12.37, 95% CI [4.32-39.67]). CC0 IDS probability can be estimated with patient KELIM: ≥ 90 % if standardized KELIM ≥ 0.12. Non-parametric survival models confirmed the independent predictive values of KELIM categorized by terciles regarding PFS & OS (Table). The parametric model linking KELIM (as a continuous covariate) with OS allows to predict the patient survivals (months) based on their estimated KELIM (HR = 0.20, [0.10-0.39]). Conclusions: The prognostic & predictive values of the modeled CA125 KELIM are also confirmed regarding CC0 IDS likelihood, PFS and OS with neo-adjuvant chemotherapy. Patient KELIM is calculable online, based on observed CA125 values, on http://www.biomarker-kinetics.org/ . Clinical trial information: 2011-006288-23. [Table: see text]
Randomized phase III trial comparing pegylated liposomal doxorubicin (PLD) 50 mg/m2 and 40 mg/m2 in patients with platinum-resistant Müllerian carcinoma (JGOG3018).
Authors: Yabuno Akira , Tabata Tsutomu , Michimae Hirofumi , Oishi Tetsuro , Nonaka Miwa , Takano Masashi , Hirata Toru , Fujiwara Keiichi , Sugiyama Toru
Published: May 2019

5550

Background: The standard dose of single-agent pegylated liposomal doxorubicin (PLD) is 50 mg/m2 every 4 weeks, but 40 mg/m2 has recently been used in clinical practice, though there is no evidence available to support its use. Methods: A Phase III, randomized, multicenter, non-inferiority study comparing progression-free survival (PFS) of patients with platinum-resistant Mullerian carcinoma (epithelial ovarian, fallopian tube, or primary peritoneal carcinoma) treated with an experimental arm (40 mg/m2 PLD) versus a standard arm (50 mg/m2 PLD) until 10 courses, disease progression, or unacceptable toxicity was conducted. Eligible patients had ≤ 2 prior lines. Stratification was by performance status (PS) and PFS of prior chemotherapy (<3 months versus ≥3 months). The primary endpoint was PFS, and secondary endpoints were overall survival (OS), toxicity profile, clinical response, and tolerability. The target total number of patients was 412. Results: The trial was closed due to accrual futility as patient recruitment was slow , with 272 patients randomized to the experimental arm (n=137) and the standard arm (n=135). The final analysis was performed with 234 deaths and 269 events for PFS. Median patient age was 62 years; 58% of patients had a treatment-free interval less than 3 months, and 81% of patients had PS 0. In the experimental versus standard arm, median PFS was 4.0 months versus 4.0 months (HR 1.065, 95.8%CI: 0.830-1.366), and median OS was 14.0 months versus 14.0 months (HR 1.078, 95%CI: 0.831-1.397). Adverse events ≥Grade 2 including oral cavity mucositis were more frequent in the standard arm than in the experimental arm (26.7% vs. 13.5%, respectively; p=0.0089), but there was no difference in ≥Grade 2 hand-foot-skin reactions (19.8% vs. 15.0%, respectively; p=0.333). Conclusions: The non-inferiority of PFS with the reduced dosing schedule was not confirmed because the trial was closed prematurely, but PFS and OS were similar. These results suggest a reduction of the standard dose of PLD because of the low rate of oral mucositis in patients with platinum-resistant ovarian cancer treated with the lower dose regimen. Clinical trial information: UMIN000003130.
Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA).
Authors: Bartoletti Michele , Pelizzari Giacomo , Gerratana Lorenzo , Garattini Silvio Ken , Basile Debora , Lisanti Camilla , Bortot Lucia , Corvaja Carla , Garutti Mattia , Scalone Simona , Nicoloso Milena , Bolzonello Silvia , Torrisi Elena , Da Ros Lucia , Di Nardo Paola , Lombardi Davide , Giorda Giorgio , Baldassarre Gustavo , Sorio Roberto , Puglisi Fabio
Published: May 2019

5564

Background: Patients (pts) experiencing a PS rOC are generally re-exposed to a platinum based-chemotherapy (CT). In this setting, the addition of a targeted agent like bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparison in randomized trials (RCTs), we have performed a NMA to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS rOC, according to BRCA status. Methods: We searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n = 3, 1563 pts) or PARPi (n = 5, 1839 pts). Only trials with PFS as primary endpoint were included. Trials in first line setting were excluded. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied. Results: In AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR] = 0.70, 95% CI 0.54-0.91, test of heterogeneity [I2] = 40.5%). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR = 0.46, 95% CI 0.36-0.59, I2= 17.2%). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR = 0.87, 95% CI 0.63-1.20, I2= 35.7%) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV). Hazard ratio for PFS between PARPi, BEV and CT in the three cohorts are reported in the table. Conclusions: According to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts. [Table: see text]
Rethinking breast cancer surveillance in women with BRCA-associated ovarian cancer in the post-solo trial era.
Authors: John Catherine S. , Amersi Farin F. , Fong Abigail , Gillen Jessica , Moore Kathleen N. , Walsh Christine S. , Li Andrew John , Rimel Bj , Cass Ilana
Published: May 2019

5565

Background: Patients with BRCA mutations are at increased risk of developing both breast (BC) and epithelial ovarian cancer (EOC). Optimal breast cancer surveillance guidelines for BRCA mutation carriers following EOC has not been defined due to high risk of EOC recurrence. The recent SOLO-1 trial demonstrated a survival benefit of olaparib maintenance therapy for newly diagnosed women with advanced stage EOC. Olaparib reduced the risk of disease-progression or death by 70% compared to placebo with a median progression-free survival (PFS) of 36 months. Methods: An IRB-approved, multi-institutional study retrospective chart review was performed. Patients had BRCA-associated EOC diagnosed between 1990-2015 without a history of prior BC or mastectomy. All women received combination chemotherapy for EOC. The observed breast cancer free survival was adjusted to reflect the enhanced 3-year PFS observed in olaparib-treated women from the SOLO-1 trial. Kaplan-Meier survival curves were performed. Results: 191 patients with BRCA-associated EOC were included (135 BRCA1, 55 BRCA2, 1 BRCA1 and BRCA2). Median age was 53 years. Most women had advanced stage, high-grade serous EOC (75%). The median overall survival was 7.7 years for BRCA 1, and 9.7 years for BRCA2 mutation carriers. Annual mammography and MRI were performed in 43% and 34% of women, respectively, with a median of 4 mammograms and 3 MRI per patient. 16 women (8.3%) were diagnosed with BC over a median follow up of 80 months: 7 (44%) DCIS and 9 (56%) invasive ductal carcinoma. 14 (88%) women had early stage (0-2) BC. 28 (15%) of women had risk-reducing mastectomy performed an average of 2.1 years following their EOC diagnosis. The incidence of BC increased from 5.6% to 11% at 5- and 10-years post EOC, and in the predicted model with olaparib, from 10% to 17% at 5- and 10-years, assuming olaparib does not impact breast cancer incidence. Conclusions: The risk of metachronous BC following BRCA-associated EOC increases over time. In the post SOLO trial era, BC surveillance strategies in women with EOC should be optimized to reflect improved outcome. [Table: see text]
Multi-parametric FDG PET/MRI as an early predictor of response to neoadjuvant chemotherapy in patients with epithelial ovarian cancer.
Authors: Frey Melissa Kristen , Sawaged Zacharia , Franceschi Ana M , Friedman Kent P , Lutz Kathleen , Curtin John Patrick , Blank Stephanie V. , Pothuri Bhavana
Published: May 2019

5569

Background: For patients with ovarian cancer undergoing neoadjuvant chemotherapy, the effectiveness of treatment is not evaluable by conventional methods until all or much of the treatment has been given. The purpose of this study is to investigate the performance of FDG PET, dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR as early predictors of treatment response. Methods: Subjects with a new diagnosis of epithelial ovarian cancer underwent 3 cycles of standardized chemotherapy followed by cytoreduction. FDG PET/MR including DCE and IVIM was performed at baseline (T0), after cycle 1 (T1) and after cycle 3 (T2) of chemotherapy. Final responses were categorized at T2 by RECIST 1.1. Image volumes at T1 were analyzed as predictors of final response. Parametric images of molecular diffusion restriction (D), tissue perfusion (D*), vascular volume fraction (F), blood- > interstitium constant of transfer (Ktrans), interstitum- > plasma constant of transfer (Kep), extravascular/extracellular volume % (Ve) and plasma volume % (Ve) were investigated along with routine measures of SUV and ADC. Results: Nine subjects were enrolled, 8 were responders by RECIST at T2 and one had stable disease. At T0 the mean, min, and max SUVmax of dominant tumor deposits was 11.5, 6.3, 19.0, respectively. Mean, min, and max values were 1.0, 0.75 and 1.63 for ADCmean and 0.62, 0.30, 0.96 for ADCmin. At T1, ADCmean increased in 8 subjects by +0.22% (s.d. +/- 13%) and decreased by -3% in one subject. ADCmin increased in 8 subjects by +21% (s.d. +/-11%) and decreased by -23% in one subject. D increased for 8 subjects (average +29% s.d. +/- 13%) and decreased by -10% in one. D*, F, Kep, Ktrans, Ve and Vp had no recognizable pattern. At T2, SUVmax, SUVmin, and ADCmean maintained their change direction across all subjects with measurable lesions. The only subject with a complete response at T2 had the highest ADCmin and ADCmean change at +45% after one cycle of chemotherapy (T1). The subject with stable disease at T2 had no significant difference in changes amongst all metrics. Conclusions: FDG PET/MR SUVmax and ADCmean values obtained after one cycle of neoadjuvant chemotherapy were consistently associated with partial anatomical treatment responses after three cycles. Molecular diffusion restriction also was reliably associated with treatment response. Future studies evaluating FDG PET/MR in platinum-resistant patients may allow for early discontinuation of ineffective and toxic treatment.
A phase II trial of durvalumab with or without tremelimumab in patients with persistent or recurrent endometrial carcinoma and endometrial carcinosarcoma.
Authors: Rubinstein Maria M , Caird Imogen , Zhou Qin , Iasonos Alexia , Friedman Claire Frances , Cadoo Karen Anne , Konner Jason A. , O'Cearbhaill Roisin Eilish , Tew William P. , Zamarin Dmitriy , Grisham Rachel N. , Kyi Chrisann , Soldan Krysten , Lichtman Stuart M. , Ligresti Louise , Schweber Sarah J. , Singh Jasmeet Chadha , Troso-Sandoval Tiffany A. , Aghajanian Carol , Makker Vicky
Published: May 2019

5582

Background: Monoclonal antibodies Durvalumab (D) and Tremelimumab (T) inhibit binding of programmed cell death ligand 1 (PDL1) to PD1 and inhibit activation of cytotoxic T-lymphocyte-associated protein 4 (CTLA4), respectively, resulting in improved tumor immunosurveillance. There is rationale to study D and DT based on recent genomic and tumor microenvironment evaluation of endometrial cancer (EC). Methods: Eligible patients (pts) were randomized to D or DT. Pts received D 1500 mg intravenously (IV) every 4 weeks (wks). DT therapy pts received D 1500 mg IV every 4 wks and T 75 mg IV every 4 wks for 4 cycles, followed by D 1500 mg IV every 4 wks until progression or unacceptable toxicities. Pts were stratified by histology with 10 carcinosarcoma or MSI-H EC pts per arm. Efficacy assessments were every 8 wks and treatment related adverse events (TRAEs) were assessed per CTCAE v.4.03. The primary endpoint was overall response rate (ORR) by RECIST v1.1. Descriptive statistics and 90% one sided CI are reported. Progression free survival (PFS) rate at 24 wks (PFS24wks) was estimated by Kaplan Meier method. Results: At planned interim analysis, 56 pts were enrolled (28 per arm). 15 pts: carcinosarcoma, 15 pts: endometrioid (3: Gr1), 14 pts: serous, and 12 pts: other histology. 5(9%) pts: MSI-H, 48(86%) pts: microsatellite stable (MSS), 3(5%): unknown. 2 pts were excluded due to early death. 27 pts per arm were evaluable for efficacy. In the D arm: 1 pt had complete response (CR)(MSS) and 3 pts had a partial response (PR) (2:MSS, 1:MSI-H) with an ORR of 14.8% (CI: 6.6-100%). The median PFS was 7.6 wks and PFS24wks was 13.3% (CI 6.1-100%). Median duration of response (DOR) was 16 wks in the D arm. In the DT arm, 2 pts achieved CR (1:MSI-H, 1:MSS) and 1 had PR (MSS). The ORR was 11.1% (CI: 4.2-100%). Median PFS was 8.1 wks, PFS24wks was 18.5% (CI 10.1-100%) and DOR was 8 wks. Grade 3 TRAEs occurred in 2 (7%) pts in D and 9 (32%) pts in DT. Grade 4 TRAEs occurred 1 (4%) pt in D and 3 (11%) pts in DT. 2 pts discontinued due to a TRAE. Most common TRAEs in total were fatigue (23%), diarrhea (20%), nausea (14%), vomiting (13%) and pruritis (11%). Conclusions: D and DT show modest activity in EC. No new safety signals were identified. Second stage accrual is ongoing. Clinical trial information: NCT03015129.
A prospective validation cohort study of a prediction model on non-sentinel lymph node involvement in early breast cancer.
Authors: Yu Xingfei , Zhou Linyan , Yang Chen , Yu Yang , Chen Daobao , Huang Jian , Yang Hongjian , Wang Chen
Published: May 2019

559

Background: Early breast cancer (cT1-2N0) with one or two sentinel lymph node (SLN) involved may avoid axillary lymph node dissection (ALND) if follow by radiotherapy supported by Z0011 and AMAROS trials. However, only less than one-third of those patients have positive non-sentinel lymph node (nSLN) and can truly benefit from radiotherapy or ALND in those two trials. It is necessary to identify the risk of nSLN metastasis before local treatment decision. We previously developed a predictive model for nSLN involvement using circulating CK19 mRNA level combined with contrast-enhanced ultrasound (CEUS) score (ASCO2017 poster 239, NCT02992067) in a training set. To evaluate the predict effect of this model, we designed a further study using the model prospectively in a validation set (NCT03280134). Methods: We identified early breast cancer cases in Zhejiang Cancer Hospital from July 2017 to June 2018. The level of circulating CK19 mRNA tested by qRT-PCR and CEUS scores were collected before surgery in each case. Patients with 1~2 SLN involved were enrolled and continued for ALND. The estimated percentage of nSLN-involved were calculated both by our model formula and the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram. The predictive accuracy and false negative rates (FNR) were evaluated and the area under curve (AUC) was compared between two predictive models. Results: Totally, 235 patients diagnosed as early breast cancer with 1~2 SLN involved were enrolled and 35.36% of them were nSLN involved after ALND. The total accuracy and FNR by our model for nSLN-involved prediction was 94.89% and 6.02%, respectively. The AUC was 0.952 (95%CI, 0.922~0.982), significantly higher than that in MSKCC model 0.880 (95%CI, 0.833~0.927). Furthermore, only CK19 mRNA level (HR = 40.091, 95%CI, 13.663~117.635) and CEUS score (HR = 2.009, 95%CI 1.158~3.485) are significantly related to nSLN involvement in both univariate and multivariate analysis, adjusted by age, menopause statue, tumor size, histological grade, estrogen receptor, progesterone receptor and human epidermalgrowth factor receptor-2 expression. Conclusions: Our model using CK19 mRNA and CEUS score showed potential predictive value of nSLN before surgery in early breast cancer patients. Further validation in larger multicenter cohort is warranted before changing clinical practice.