bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial of MK 2206 in children with refractory solid tumors: A Children’s Oncology Group study.
Authors: Phillips Christine L. , Fouladi Maryam , Perentesis John Peter , Leary Sarah , McGovern Renee M. , Reid Joel M. , Ingle Ashish M , Ahern Charlotte H , Ames Matthew M. , Houghton Peter , Doyle L. Austin , Weigel Brenda , Blaney Susan 
Published: March 2020

9581 Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.
Psychological study of adolescent and young adult (AYA) cancer patients and their parents throughout and beyond their cancer treatment: A pilot study.
Authors: Hatcher Helen , Lack Carole , Walsh Cathy , Abbas Laura , Fretwell Jo , Moss Wendy , Dobson Nicky , Goodyer Ian , Alam Salma 
Published: March 2020

9589 Background: The cancer journey for an AYA is often complicated by diagnostic delays, poor prognosis and negative physical and psycho-social consequences. Distress of young patients and survivors is often overlooked and the real incidence of psychopathology remaining hidden. We aimed to understand the psychological impact and identify which factors most affect the patient experience. Methods: 172 patients on the Cambridge AYA register were invited to take part. Patients were asked to complete 2 questionnaires, SCL90 and RSQ, measuring psychological symptoms and response styles respectively, and to take part in a semi-structured interview. Parents were asked to complete the York Survey and be interviewed. Results: 33 patients and 45 parents/others were recruited. Questionnaires completed: 33 SCL90 and RSQ; 42 York Survey. Interview data from: 23 patients, 26 parents, 3 others. Patient sample: 16 male, 17 female; mean age (recruitment) = 20.76 (16-26); age (diagnosis) = 17.26 (12-24). Diagnoses evenly distributed across solid and haematological malignancies. All patients had experienced significant levels of psychological distress at some point in their cancer journey. 51% reached caseness on the SCL90 (showed a symptom profile consistent with a high risk of a disorder). Caseness increased with age and was correlated with higher rumination scores. Positive influences included family, friend and peer support, good communication and support from the AYA service and specialist nurses. Negative influences included delayed diagnosis, poor communication styles, anxiety about long term effects and lack of appropriate psychological support. Conclusions: We have shown evidence of elevated psychological symptoms in this population. Patients and their families have prioritized clear needs; early diagnosis, high quality of information and communication, access to psychological help at each stage and post treatment help in gaining independence and planning for a positive future. We should work towards meeting these needs for this vulnerable group.
The value of personalizing medicine: Medical oncologists’ and patients’ perspectives on genomic testing of breast tumors in chemotherapy treatment decisions.
Authors: Trudeau Maureen E. , Bombard Yvonne , Rozmovits Linda , Leighl Natasha B. , Deal Ken , Marshall Deborah 
Published: March 2020

e11000 Background: Benefits of adjuvant chemotherapy for early-stage breast cancer patients (pts) depend on baseline recurrence risks. Gene expression profiling (GEP) of tumours informs baseline risk prediction, potentially reducing unnecessary treatment and healthcare costs. Limited evidence exists on its clinical utility; we explored pts and medical oncologists (MO) perspectives on GEP in chemotherapy decisions. Methods: We used a qualitative design of individual interviews with MO (n=10), focus groups and individual interviews with pts (n=20) from Ontario. Pts who underwent genomic testing of their tumours (‘OncotypeDx’), were recruited through clinics from two academic hospitals in Toronto. MO were recruited through clinics, advertisements and referrals from the research team. Data were analyzed using interpretative qualitative methods, including content analysis, qualitative description and constant comparison techniques. Results: Pts and MO valued GEP as an additional decision-support tool, complementing existing clinical indicators. Its perceived utility varied between pts and MO. Pts valued the test highly, suggesting it was one of the primary determinants of their treatment decision. All pts followed the course of action their results suggested. Pts with intermediate scores often used the results to reinforce their pre-existing treatment preferences. MO were mixed about the test’s utility. Some considered it another tool supporting their approach to risk assessments, while others used it more definitively to resolve their uncertainty. MO explained the test’s contribution to decision-making but remained uncertain about pts understanding and expectations of the test. Some raised concerns about the variability of its use and interpretation within their medical community. Conclusions: Pts and MO valued the test, often using it as a primary determinant in their treatment decision, despite MO concerns about its technical limitations and pts limited understanding. Results identify a need for informational decision aids and practice guidelines to support pts understanding and standardized application of the test.
Characterization of patients who received further adjuvant endocrine therapy after 5 years of aromatase inhibitors (AIs): NCIC CTG MA 27.
Authors: Vogl Steven E. , Altwairgi Abdullah Khalaf , Chapman Judy-Anne W. , Zhu Liting , Shepherd Lois E. , Goss Paul Edward ,   NCIC Clinical Trials Group
Published: March 2020

e11005 Background: MA.27 examined the efficacy of 5 yrs of adjuvant aromatase inhibitors (AI), exemestane and anastrozole. Long term outcomes of AI trials may be influenced by unspecified subsequent hormonal therapy so we enquired about its frequency. Methods: Clinical trials (NCIC CTG MA.17R, NSABP B-43) are exploring >5 yrs AI; neither efficacy nor toxicities are known. MA.27 enrolled 7,576 patients June 2003 to July 2008: 5526 (73% in US), 1301 (17% in Canada), 749 (10% outside North America). Clinical cut-off for final follow-up and analysis was April 15 2010: median 4.1 yrs follow-up. Receipt of concomitant medications was routinely reported throughout the trial. Only 345 patients (median age, 64.2 years) completed protocol-specified 5 yrs AI, without breast cancer (BC) relapse, development of contralateral BC, or other second malignancies. Patients were classified by extended endocrine therapy: off trial, physician prescribed specific endocrine therapy; randomized trial endocrine therapy; or no endocrine therapy. Differences in baseline patient and tumor characteristics for these classifications were compared with Fisher’s exact test. Results: From the total group of 345 patients, 320 (93%) received no further endocrine therapy, and 25 (7%) received subsequent therapy. Among the 25, 18 (72%) entered trials and were assigned to endocrine therapy or placebo. Physicians prescribed endocrine therapy to the other 7 (28%). Fourteen (78%) of those who received trial assigned and 7 (100%) of those who received specific additional endocrine therapy were below 70 years of age. Of the 25 patients who received subsequent therapy, only 2 (8%) had >2 cm tumor, and 6 (24%) had node positive tumors. None of the characteristics were significantly different for women who did or did not receive additional therapy. Conclusions: MA.27 is closed to further follow-up, so these results represent the totality of trial information about further endocrine therapy from clinical practices of those who enrolled MA.27 patients. It appears that subsequent hormonal therapy was uncommon (7% of women) after 5 yrs of an AI.
Combination treatment with aromatase inhibitor and capecitabine as first- or second-line treatment in metastatic breast cancer.
Authors: Alvarado Miranda Alberto , Limon Jesus , Medina Fernando Lara , Arce Claudia , Zinser Juan Wolfgang , Bargallo Rocha Enrique , Villarreal-Garza Cynthia Mayte 
Published: March 2020

e11016 Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and oral fluoropyrimidines in estrogen receptor (ER)-positive cell lines enhance antitumor efficacy. This might be explained by reduction of ER-induced growth signaling in addition to decrease in estrogen production. This retrospective analysis of a cohort of patients with metastatic breast cancer (MBC) evaluates the efficacy and safety of combined AI with capecitabine. Methods: Patients with hormone receptor-positive MBC treated with this combination were evaluated and outcomes were compared to women treated with capecitabine (conventional dose) or AI as monotherapy. The administered total dose of capecitabine was 2000 mg. per day in combination with AI. Results: Of 93 patients evaluated, 37 received the combination treatment, 27 capecitabine and 29 an AI. Combination was used in 26 patients as first-line treatment and 11 as second-line. At the time of progression, 92% had a performance status of ≤2 and 58% of patients had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow-up was 23 months (m). The median PFS of first-line treatment was significantly better for the combination (PFS not-reached vs.3.0 m for capecitabine and 13.0 m for AI, p<0.0001). For second-line treatment, the PFS was longer in the combination compared to capecitabine and AI (PFS not reached vs. 6.0 m vs.13.0 m, respectively, p=0-041). For the entire cohort, OS was not reached. The most common adverse events for the combination group were grade 1 and 2 hand-foot syndrome (65%), grade 1 fatigue (52%) and grade 1 diarrhea (5%). Only one grade 3 hand-foot syndrome event was reported. Conclusions: Combination treatment with capecitabine and AI used as first-line treatment or second-line improved PFS compared to treatment with either single agent. The combination was safe and rendered dismal toxicity. Prospective randomized clinical trials should evaluate the use of the combination of capecitabine and an AI in advanced breast cancer in order to confirm our findings.
Evaluation of the prognostic value and phenotypic determinants of Bcl-2 expression in breast invasive carcinoma.
Authors: Luengo Maria Isabel , Garcia-Garre Elisa , Martinez-Diaz Francisco , de la Morena Pilar , Garcia-Martinez Elena , Castaño Patricia , Luengo-Gil Gines , Vicente Angeles , Ortuño-Pacheco Guzman , Vicente Vicente , Ayala Francisco 
Published: March 2020

e11024 Background: Bcl-2 expression has been related to hormonal dependence and better prognosis of breast cancer. Although some reports suggest that its expression has an independent prognostic value, especially in N positive patients, the clinical relevance of determining Bcl-2 is unclear. The aim of this work was to analyze which other tumor markers predict Bcl-2 expression in breast cancer and explore its prognostic value. Methods: Immunohistochemical expression of ER, PR, Her2-neu, Ki-67, p53, cathepsin-D and Bcl-2 was prospectively examined in a series of 87 consecutive invasive BC patients. Bcl-2 was semiquantitavely scored according to a validated system (Treré, 2007). Correlation between variables was analyzed with Chi-square test; disease free (DFS) and overall survival (OS) were analyzed by log-rank test and Cox models. Results: Patient characteristics: median age 57 yrs (31-86), 64.5% postmenopausal; treatment: 49.5% breast-preserving surgery, 71.6% adjuvant-neoadjuvant chemotherapy, 72.1% adjuvant radiotherapy ; tumor histology: 83.9% ductal invasive carcinoma, 28.2% grade 3; stage: T1:57%, T2:31.2%, T3-4:8.6%, 48.9% nodal metastasis (pN1:36.7%; pN2:12.2%); tumor phenotype: 77.2% ER+ , 78.3% PgR+ , 9.7% Her2-neu+, 50.6% high Ki-67 (>13%). Immunohistochemical evaluation for Bcl-2: 41/87 (47.1%) positive cases. No expression of Bcl-2 was observed in ER/PgR negative tumors (p< 0.001). Bcl-2 expression was associated to histological grade 1-2 (p=0.009), absence of Her2-neu amplification (p=0.03), p53+ status (p=0.008) and lower cathepsin-D expression (p<0.001), but no association was found for proliferation (Ki-67) or stage (pT or pN). A significant effect of Bcl-2 on overall (p=0.27) or disease free survival (p=0.28) was found neither in the whole group nor in pN+ or pN- subgroups. The only independent prognostic factors for DFS were hormone-sensitivity (OR: 0.10; p=0.009) and pN (OR=2.77; p=0.05). Conclusions: Expression of Bcl-2 in invasive breast cancer seems to be dependent on hormonal sensitivity, p53 status and Her2 expression; no independent prognostic value for recurrence or survival was found in our series.
Outcomes for elderly breast cancer patients in Louisiana.
Authors: Ruiz Marco A , Reske Tom 
Published: March 2020

e11030 Background: Elderly breast cancer patients, compared to younger breast cancer patients, are diagnosed with a higher stage of disease. They are also found to undergo less surgery, receive more frequently hormonal treatment and have decreased relative survival. The interest of this study was to examine if differences in treatment and survival between >65 year old and <65 year old patients in Louisiana. Methods: The SEER database was searched and all cases of female breast cancer in the state of Louisiana between 2000 and 2008 were analyzed. Data was stratified by age group and year of occurrence. SEER definitions for breast cancer, surgery, chemotherapy, elderly, young populations, radiation therapy, breast conservative surgery were applied. Results: The state prevalence of localized breast cancer is lower compared to the national rate (128.5 vs. 144 p <0.001). The rate of regional breast disease is much higher in Louisiana patients than national average rate (69.7 vs. 57.9 p <0.001). There is no difference in disseminated disease. When the elderly group is compared to non-elderly group there was a difference in localized disease (non-elderly 59.9% vs. elderly 64.98 P<0.001). There was a difference also in regional disease (non-elderly 33.75% vs. elderly 25.02%). No difference was noted in rates of disseminated disease (non-elderly 5.03% vs. elderly 5.77%). The elderly group was offered less surgery compared to the young group (11.39% vs. 6.68% in the young group, p<0.005). In terms of radiation therapy the elderly group receive more general radiation interventions than the young group (65.97% vs. 53.86 p <0.005). In relation to type of radiotherapy (beam radiation and radioactive implants) there were no differences between the two groups. Mortality rates for the elderly group was higher in Louisiana compared to the national average. This difference was more remarkable in the >85 age group (127.8 vs. 118.5, p<0.001) Conclusions: Differences in treatment modalities and management interventions between young and elderly breast cancer in Louisiana patients were observed. Mortality is higher among elderly breast cancer patients in Louisiana compared to national average. Further studies are needed to review the these regional differences.
A multicenter, open-label phase II trial of liposomal doxorubicin (LD) and docetaxel (DX), followed by concurrent chemotherapy and radiation therapy in locally advanced high-risk, early breast cancer (HRBC).
Authors: Recchia Francesco , Candeloro Giampiero , Cesta Alisia , Desideri Giovambattista , Necozione Stefano , Rea Silvio 
Published: March 2020

e11041 Background: Taxanes and anthracyclines (ANs) are among the most active agents in the treatment of breast cancer. However, ANs are associated with dose-related cardiac toxicity, which can lead to progressive myocardial damage. Non-pegylated liposome-encapsulated doxorubicin (Myocet®), has been shown to significantly reduce cardiac toxicity even though providing comparable antitumor efficacy. Primary endpoint of this phase II study was the assessment of early and late cardiac toxicity of young patients with HRBC treated with LD and DX. Secondary end-points were the incidence of hematological toxicity, time to progression and overall survival in this cohort of patients. Methods: From 05-2006 to 10-2009, 60 HRBC patients were entered into the study. They were treated with LD 60 mg/m2 and DX 75 mg/m2 every three weeks for six courses. Hematological growth factors were given when indicated. Cyclophosphamide 600 mg/m2, methotrexate 60 mg/m2 and 5-fluorouracil 600 mg/m2 were given for six courses concomitantly with radiation therapy to the breast, axilla and supraclavicular nodes. After chemo-radiation therapy, a hormonal therapy was given to estrogen receptors positive (ER+) patients and trastuzumab to Herb-2 positive patients. LVEF was evaluated at baseline and after 6 months, thereafter, up to 5 years. Results: Median age was 49 years. Mean number of positive axillary nodes was 4.9 (range 0-20). 70% were ER+, 30% were ER - and progesterone receptor (PGR) negative. Median Ki-67 was 30% (range 20%-100%), 18% of patients were Herb-2 positive and 18% of patients had pre-existing hypertension. Delivered dose was 95.7% of the planned dose. No patient showed neither a decrease of EF > 10%, nor congestive heart failure. Febrile neutropenia was observed in 12% of patients. At 44 months of median follow-up, 86% of patients were disease-free and 94% were alive. Conclusions: Chemotherapy with LD and DX has shown low cardiac toxicity and high activity in this group of HRBC patients.
Overexpression of Notch-1 induced tamoxifen resistance through down regulation of ESR1 in positive estrogen receptor breast cancer.
Authors: Yousif Nasser Ghaly , Al-Matwari Majid 
Published: March 2020

e11046 Background: Tamoxifen is one of the most widely used drugs in the treatment of estrogen-receptor positive breast cancer, and acquired resistance to tamoxifen during treatment are largely unknown and recent research showed that lower levels of ESR1 associated with tamoxifen resistance in ER-positive breast tumors, from other hand highly expression of Notch-1 and/or Jagged-1 has negative prognostic significance in breast cancer, in this study we show the cross-talk between Notch and the lower levels of ESR1 estrogen receptor positive breast cancer. Methods: A retrospective study with clinico-pathological analysis of 195 patients had ER-positive breast cancer used tamoxifen as an adjuvant systemic therapy, gene expression profiling of paraffin-embedded tumors for ESR1, Real-time PCR and Western blot analysis were performed to detect Notch-1/Jagged-1. Results: From 195 patients 32% had tamoxifen resistance which related with lower levels of ESR1 expression (P=0.019) and there was, a highly significant association of over expression Notch1 protein with the lower levels of ESR1 (P=0.006). Conclusions: The results from this study demonstrate for the first time that Notch-1 regulate levels of ESR1 in ER-positive breast cancer, and partly responsible for tamoxifen resistance, the Notch signaling pathway may be a potential therapeutic target beside current breast cancer therapy and need further investigation to know the mechanism of this pathway.
Concordance between independently and investigator-assessed progression-free survival in CLEOPATRA.
Authors: Miles David , Swain Sandra M. , Im Young-Hyuck , Knott Adam , Ross Graham , Clark Emma , Benyunes Mark , Baselga José 
Published: March 2020

e11055^ Background: In CLEOPATRA, pertuzumab (P) + trastuzumab (T) + docetaxel (D) was compared to placebo (Pla)+T+D in HER2-positive 1st-line MBC. In MBC trials, PFS rather than overall survival is often defined as the primary endpoint as PFS data are available earlier and later-line therapy does not impact results. The primary endpoint in CLEOPATRA, PFS, was assessed by an Independent Review Facility (IRF), with investigator (inv)-assessed PFS as a secondary endpoint. As a measure of consistency and robustness, concordance between IRF- and inv-assessed PFS was analyzed. Methods: PFS was defined as time from randomization to first documented radiographic evidence of progressive disease (PD) or death from any cause within 18 wk of the last IRF tumor assessment. Tumor assessments took place every 9 wk and continued until IRF-confirmed PD. Treatment decisions were solely based on the inv’s assessment of PD. Indicators of concordance between IRF- and inv-assessed PFS included: PFS event by IRF only; PFS event by inv only; PFS event by IRF and inv; no PFS event by IRF and inv. These indicators were assessed at any time on study, within 30 d or within 9 wk. Several pre-specified sensitivity analyses for PFS were also performed. Results: 808 pt were enrolled and central tumor assessments performed for 781 pt. Compliance with the schedule of tumor assessments was generally high and comparable between arms, with >78% of pt undergoing assessments within 7 d of the scheduled visit over the 1st yr. At any time on study, concordance between IRF- and inv-assessed PFS was 85%. Of the 15% discordant cases, an equal proportion was assessed by the IRF as a PFS event but not by the inv and vice versa. Estimates of the median time to PFS event based on IRF and inv assessments were identical, Pla+T+D: 12.4 mo, P+T+D: 18.5 mo (IRF: HR 0.62, P < .0001; inv: HR 0.65, P < .0001). Conclusions: Concordance between IRF- and inv-assessed PFS was high, supporting consistency and robustness of the PFS analyses. The subjective nature of PD and potential for bias were reduced by the double-blind, placebo-controlled study design; RECIST 1.0 criteria; identical schedule of assessments in both arms; IRF review and continuation of tumor assessments until IRF confirmation of PD.