bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast cancer control in Iran: Specialized breast unit/national screening: Which one is the urgent priority?
Authors: Kalantari Mojgan , Joulaee Azadeh , Kadivar Maryam , Joolaee Soodabeh , Bahrani Naser
Published: February 2017

29

Background: Rapid correct diagnosis and treatment is the key point in breast cancer control worldwide. Though screening decreases mortality, due to high cost, the need for enough imaging centers and radiologists actually is not affordable for many populated low resource countries. Specialized Breast Unit is a cost-effective program. While increasing the accuracy and quality, the total cost of diagnosis and treatment is significantly decreased. The more there is limitation of budget, the more it is important to go through this program as an urgent act for breast cancer control. In this study we try to show the actual problems of breast cancer in Iran and the efficacy of Specialized Breast Unit to solve them. Methods: All published data about breast cancer in Iran are reviewed since 2001 to 2012 to list the problems. Then the workflow and outcome of our unit between 2003 to 2012 with total 60, 021 visits are analyzed to show how does it help to solve these problems. Results: Younger age, late presentation, delayed diagnosis, and small numbers of nonpalpable lesions are the major features. Diagnosis is based on excisional/incisional biopsy or frozen section. Mastectomy and axillary dissection is the dominant approach. Sentinel node biopsy, reconstruction and screening are offered in few centers. Multidisciplinary approach in specialized breast unit provides rapid assessment of breast symptoms with correct pre-operative imaging and trucut biopsy for diagnosis. This results in tailored surgery (conservative, mastectomy with or without immediate reconstruction) and sentinel node biopsy for all eligible cases. Team work has decreased the number of visits and surgeries. Conclusions: If screening as the standard for early detection in asymptomatic women is considered as an option, Specialized Breast Unit is an obligation for correct diagnosis and treatment of both symptomatic and asymptomatic breast cancers as a life threatening disease. It is cost effective and helps to shift from dominant Halstead concept through international standards even in low resource countries. Without these referral units no attempt can be done for breast awareness programs, training, and further screening.
Impact of the U.S. Preventive Services Task Force update for breast cancer screening on mammography utilization in women age 40 to 49.
Authors: Wang Amy T. , Fan Jiaquan , Van Houten Holly K. , Shah Nilay D.
Published: February 2017

5

Background: The 11/2009 USPSTF breast cancer screening update recommended against routine screening mammography for women age 40-49, created confusion and prompted organizations to release opposing statements. We aimed to determine if the USPSTF update for breast cancer screening impacted screening mammography utilization in women age 40-49. Methods: We conducted a time-series analysis utilizing administrative claims data from over 100 health plans. Women ages 40-64 with at least one month of enrollment from 01/2006-12/2010 were included. Medicare claims are not included and thus women ≥65 were excluded. The start date of 01/2006 was chosen to account for possible effects of the recent recession. We developed claims-based algorithms to identify the number of monthly screening mammograms. Time series models were fit using SAS PROC AUTOREG; strong seasonal fluctuations were adjusted by including an autoregressive error of order 12. Results: Over 7.9 million women were included. Prior to the intervention, the baseline monthly mammography rate was 40.9/1,000 women for the 40-49 group and 47.4/1,000 women for the 50-64 group. Based on projections from pre-intervention trends, the update was associated with a 5.72% (1.27,10.18) and 4.97% (1.11,8.84) decrease in mammography rate at 3 and 10 months post-intervention, respectively in the 40-49 group. The intervention had no effect on mammography rates in the 50-64 group. This translates to 53,969 fewer mammograms performed in the year following the update for women ages 40-49 in this dataset. Conclusions: We present the first estimates of the impact of the USPSTF breast cancer screening update using a large nationally representative database. The update was associated with a small but significant decrease in mammography rates for women ages 40-49, while no change was seen for women ages 50-64, which is consistent with the context of the guideline change. A modest effect is also in line with public backlash and the release of numerous conflicting guidelines. These findings underscore the need for further research on benefits and risks of screening mammography as it is difficult to act on numerous sources of contradictory information.
ACE inhibitors/ARB and the risk of breast cancer recurrence after surgery in Japanese population: A pilot study.
Authors: Fujii Takeo , Takahashi Osamu , Yamauchi Teruo
Published: February 2017

52

Background: Angiotensin II can work as a growth promoter via angiotensin II type1 receptor (AT1R). In an in vivo study, Angiotensin Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor Blocker (ARB) down regulates vascular endothelial growth factor and activates apoptosis pathway through AT1R. In some clinical studies, the efficacy of ACEI/ARB to cancer patients has been investigated; however, the results are various. This has not been examined in Asian population. We investigated breast cancer patients in a single institution if the recurrence rate is related to ACEI/ARB use. Methods: This retrospective study will evaluate disease-free survival (DFS) for Japanese patients who were diagnosed with invasive breast cancer and had curative surgery between January 2004 and December 2006 at St Luke’s International Hospital. We will compare DFS of two groups with and without ACEI/ARB use. DFS is defined as the interval between curative surgery and the recurrence of breast cancer. Recurrence of disease was confirmed by radiographically or pathologically. Patients who took ACEI/ARB are defined as those who had taken them for at least 6 months after initial diagnosis. The following patient data will be extracted from their medical records; age, stage, body mass index, menopausal status, biomarker status (ER, PgR, and HER2), usage of bisphosphonate, usage of statin, diabetes, surgical procedure. Results: A total of 1,163 patients were analyzed. 76 were ACEI/ARB user and 1,087 were non-user. The recurrence rate of ACEI/ARB users was 17.1% (13/76). In comparison, that of non-users was 12.2% (133/1,087). The odds ratio (OR) was 1.480 (95 % CI: 0.793-2.762 p=0.218). Kaplan-Meier analysis did not show a significant difference between them (log-rank test p=0.194). Conclusions: Our study is the first one to evaluate the efficacy of ACEI/ARB in breast cancer recurrence among Asian population. Recurrence rate did not differ in the two groups although molecular biology suggested antitumor effect of ACEI/ARB. We will further explore if any confounding factors lie between the two groups, and plan to conduct a prospective study if ACEI/ARB exhibits antiproliferative effect in postoperative cancer patients.
Does atypical ductal hyperplasia require 6 months of postoperative surveillance?
Authors: Plichta Jennifer Kay , Rumas Natalia , Godellas Constantine V. , Perez Claudia Beth
Published: February 2017

60

Background: Standard follow-up imaging for women with a history of breast cancer is well defined, but the appropriate screening guidelines for other high risk breast lesions, such as atypical ductal hyperplasia (ADH), remain unclear. Current practices often parallel those of cancer patients and include a 6 month interval mammogram prior to resuming annual screening, which may be unnecessary. As such, it is critical to evaluate the utility of the current standard practice of additional screening beyond a routine annual mammogram. Methods: Our pathology database was queried for the phrase "atypical ductal hyperplasia" from 2008 to 2010, and patients who underwent surgical excision were identified. Those who did not have subsequent follow up at our institution were excluded. Results: There were 44 patients who underwent excisional biopsies that were diagnosed with ADH and proceeded with follow up. In addition to a routine clinical exam, a short-term follow up diagnostic mammogram was performed in 24 patients. The median age was 56.5 years, and the median breast cancer risk assessment scores were 2.8% at 5 years and 13.4% lifetime. Of the 24 interval mammograms, 21 yielded benign findings on initial imaging (BIRADS 2), while 3 patients (12.5%) required additional imaging that ultimately resulted in benign findings. There were only 4 patients with a lifetime risk ≥25%, and all of these patients had benign findings on their initial imaging and resumed routine follow up. To date, 22 patients have received at least one additional mammogram, and all subsequent findings have been benign. No additional biopsies or surgeries have been performed. Conclusions: In sum, a clinical exam is still recommended at 6 months following surgical excision for a diagnosis of ADH. In the post-surgical breast, imaging may be misleading and result in psychological distress for patients and possibly unnecessary procedures. Based on our findings, a 6-month follow up mammogram is not recommended and patients should resume annual surveillance.
Accrual of under-represented minority women to breast cancer clinical trials in Inland Empire, California.
Authors: Yuan Yuan , Uppala Padma Tadi , Lum Sharon S. , Morgan John W. , Garberoglio Carlos
Published: February 2017

64

Background: Ethnic minority women are currently underrepresented in breast cancer clinical trials. The age-adjusted incidence and mortality rates for breast cancer are higher in Riverside and San Bernardino Counties (Inland Empire), California, than the statewide average. During the 10 years of enrollment at Loma Linda University Cancer Center (LLUCC) between 1999 and 2009, a total of 151 patients were enrolled to breast cancer clinical trials. Among the enrolled patients, only 26.7% were ethnic minority women in contrast with the 59% of ethnic minority women living in Inland Empire. Methods: A countywide breast cancer awareness campaign using billboard, print ads, and newsletters, combined with direct mailing sent to regional physician offices and breast imaging centers was launched. We specifically addressed previously identified barriers to participation in clinical trials, such as lack of medical insurance, time, invitation, awareness of available studies, access to the institution or doctors conducting the trial, and coordination among clinics. In addition, we utilized a culturally sensitive multidisciplinary team to address the breast cancer care for minority women. Results: During the two year period since implementation of the regional culturally sensitive breast cancer awareness campaign, we successfully enrolled 32 patients into breast cancer clinical trials. Minority breast cancer patient accrual increased from a 10-year average of 26.7% to 46.9% in comparison with non-Hispanic white patients (p=0.02). The accrual rate of Hispanic population increased from 10% to 21.9%. The accrual rate of black patients increased from 5.3% to 12.5%. Conclusions: The use of materials specifically targeting known barriers to participation in clinical trials successfully improved accrual of minority women, and has the potential to improve the cure rate, decrease disparities in breast cancer care, and eventually decrease the breast cancer burden particularly in underserved minority groups in Inland Empire, California.
Stratification of 5-year cancer detection rate in an organized breast screening program based on Gail model risk factors.
Authors: Rajapakshe Rasika , Parker Brent , Araujo Cynthia , Ruscheinsky Stephanie , McAvoy Steven , Hoegg Tanja , Coldman Andy , Wilson Christine
Published: February 2017

7

Background: The Gail model has been validated in the United States and several European countries, but to our knowledge, it has not been validated in organized breast screening programs in Canada. The Screening Mammography Program of British Columbia (SMPBC) records participant data from a questionnaire based on Gail model parameters (which include family and personal medical history). This study investigates whether the Gail model is a valid tool to predict the breast cancer risk for the population undergoing screening mammography in the province of BC. Methods: Client information of the 223,349 British Columbian women who participated in the year 2000, along with their tumor status from 2000-2004, was extracted from the provincial database. A software program was developed to rapidly calculate the absolute 5-year Gail score from questionnaire data. Participant data was separated into .5% risk intervals and also into quintiles based on increasing Gail scores, and the mean absolute risks were compared to the actual five year rate of cancer as detected by the SMPBC. Results: Overall, goodness of fit between Gail score and SMPBC detection (E/O) across the categories can be rejected (χ2=247.9, df=9, p value < .001). The Gail model significantly underpredicts the cancer detection for risk categories up to 2%, however it provides a sufficient fit for categories 2%-4% as the E/O ratio is not significantly different from 1.0 in these intervals. For the highest risk interval, categorized as greater than 4% risk, the model significantly overpredicts cancer detection. Additionally, when presented in quintiles, the Gail model under-predicts risk in all but the highest quintile (1.77-11.43% risk range). Conclusions: Our results, based on participants of SMPBC, suggest that the Gail model significantly under-predicts cancer detection. Although this model provides a sufficient fit for women with a Gail score between 1.51-4%, it does not predict breast cancer risk accurately for low and high risk women in the Screening Mammography Program of BC.
The effect of a varied exercise program (VEP) on shoulder function and lymphedema (LE) in breast cancer survivors (BCs): A pilot study.
Authors: Hanssens Sophie , Fontaine Christel , Decoster Lore , Schallier Denis C. C. , Luyten Rik , Watthy Christiaan , Van Hemelrijck Roxane , De Greve Jacques
Published: February 2017

82

Background: A common physical sequel after adjuvant therapy is a decrease in shoulder movement of the upper-limb of the affected side and the development of LE. Resistance exercise is known to be safe and does not increase the risk of LE. The objective of this study is to evaluate the effect of a VEP on shoulder range of motion and upper-limb LE after adjuvant therapy in BCs. Methods: 22 BCs treated with surgery and adjuvant therapy were randomly assigned to the VEP (n=12) or the control (n=10). The VEP aimed at improving aerobic endurance, joint mobility and muscle strength. The frequency of the VEP was 2 times a week, during 3 months, with a total of 30 sessions. Primary endpoints included the range shoulder motion and arm volumes of both arms. The secondary outcome was quality of life (QoL) as measured by the EORTC QLQ-C30. All outcome measures were assessed at baseline and after 3 months. Results: After ending the VEP, in the exercise group, the movements such as abduction (p=0.04), external rotation (p=0.02), extension (p=0.03) and flexion (p=0.01) of the affected arm increased significantly but there was no change for internal rotation (0.27). No significant changes in arm volume (p=0.06) were found after 3 months compared to baseline, whereas the quality of life did improve significantly (p=0.01). After 3 months the range of motion of the shoulder of the affected arm (sum of abduction, external rotation, extension and flexion) in the exercise group tended to be better although this was not significant (p=0.50). The arm volume difference between the two groups was not significant (p=0.10) but it was for the QoL (p=0.02). Conclusions: A VEP lead to significant specific improvements in arm mobility compared to baseline. These BCs also compared favourably to the control cohort, but this was not significant. The study confirms that exercising the ipsilateral arm and shoulder has no detrimental effect on LE and has a positive impact on the QoL. Standard guidelines concerning physical therapy to ameliorate shoulder function and LE are not available. Additional patients will be enrolled to develop standard recommendations for physical therapy to improve shoulder and limb function in BCs.
Evaluation of a breast cancer survivorship clinic that uses a group medical appointment model: Patient program evaluation and financial analysis.
Authors: Trotter Kathy , Schneider Susan M.
Published: February 2017

90

Background: Group medical appointments have been shown to improve access, health outcomes and health care utilization rates, as well as self-management skills. A new model of breast cancer survivor care was designed and piloted at Duke Cancer Center. Survivors attended the clinic together in groups of six. An interdisciplinary group visit format in the initial part of the appointment provided surveillance, education and support, as well as formation of an individualized survivorship care plan. The first hour included review of their personal care plan and a 45-minute facilitated discussion. Afterwards, individual visits with the nurse practitioner, and dietitian, physical therapist, or social worker occurred. Methods: A 22-item Likert-type questionnaire sought opinions regarding logistics and the style and function of care delivered. 122 surveys were collected. Descriptive statistics (via SPSS v19) using ANOVA type regression were accomplished. Secondly, a retrospective two-group study of clinic financial data for follow-up patients was done. Revenues from the group medical visit by the NP were compared to those seen traditionally by the MD (N=300). Review of time to third available appointment for each clinician was also recorded. Results: 122 surveys were collected with a 86% response rate. Mean scores for all questions rated at least 4.4 of 5, with the highest score given for the confidence felt in the nurse practitioner (4.93) and the lowest for the acceptability of the wait time in the breast imaging area (4.4). Overall, 98% felt the program provided quality care and 97% were likely to recommend the clinic to other breast cancer survivors. What participants liked most about the program was sharing with other survivors. Cost benefit analysis revealed that revenues and direct costs were nearly equal between delivery models. Time to third available appointment for the primary referring oncologist, dropped from 29.4 to 26.7 days, while the NPs time remained stable at 8.7 days. Conclusions: The group visit model applied to survivor care appears feasible and highly satisfactory to participants.
Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane.
Authors: Pegram Mark D. , Blackwell Kimberly , Miles David , Bianchi Giulia Valeria , Krop Ian E. , Welslau Manfred , Baselga José , Oh Do-Youn , Dieras Veronique , Guardino Ellie , Olsen Steven R. , Fang Liang , Lu Michael , Verma Sunil
Published: February 2017

98

Background: T-DM1 is an antibody-drug conjugate comprising T, a stable linker, and the potent cytotoxic agent DM1; it incorporates the antitumor activities of T and the HER2-targeted delivery of DM1. Methods: EMILIA is a randomized study of T-DM1 vs XL, the only approved combination for T-refractory HER2+ MBC. Patients (pts) received T-DM1 (3.6 mg/kg IV q3w) or X (1,000 mg/m2PO bid, days 1–14 q3w) + L (1,250 mg PO daily) until progressive disease (PD) or unmanageable toxicity. Pts had confirmed HER2+ MBC (IHC3+ and/or FISH+), and prior therapy with T and a taxane. Primary end points were PFS by independent review, OS and safety. An interim OS analysis was planned at the time of the final PFS analysis. Results: 991 pts were enrolled; 978 received treatment. Median (med) durations of follow-up were 12.9 (T-DM1) and 12.4 (XL) months (mo). Baseline demographics, prior therapy and disease characteristics were balanced. There was a significant improvement in PFS favoring T-DM1 (med 9.6 vs 6.4 mo; HR=0.650 [95% CI, 0.549–0.771]; p < .0001). The med T-DM1 OS was not reached vs 23.3 mo (HR=0.621 [95% CI, 0.475–0.813]; p =.0005); the interim efficacy boundary was not crossed (HR= 0.617; p =.0003). T-DM1 was well tolerated with no unexpected safety signals. The most common Grade ≥3 adverse events (AEs) per treatment were for T-DM1: thrombocytopenia (12.9% vs 0.2%), increased AST (4.3% vs 0.8%), and increased ALT (2.9% vs 1.4%); for XL: diarrhea (20.7% vs 1.6%), palmar plantar erythrodysesthesia (16.4% vs 0) and vomiting (4.5% vs 0.8%). The table lists other end points. Conclusions: T-DM1 conferred a significant and clinically meaningful improvement in PFS compared with XL. Other end points support T-DM1 as an active and well-tolerated novel therapy for HER2+ advanced BC. [Table: see text]
KOC (K homology domain containing protein overexpressed in cancer) overexpression and progression-free survival after curative intent resection of pancreatic ductal adenocarcinoma.
Authors: Johnson Benny , Khalil Maged F. , Lin Fan , Zhu Shaobo , Kirchner Lester
Published: February 2017

48

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. Unfortunately, effective screening and early detection mechanisms are currently unavailable, thereby 80% of patients present with distant metastasis. Of the subset of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Negative surgical margins, tumor size, stage, and node negative disease are traditional prognostic indicators. However, these can be limited in their ability to predict patient specific prognosis. KOC is an oncofetal RNA-binding protein involved in RNA stabilization and cell growth during embryogenesis. Previous studies have revealed that KOC mRNA is inappropriately overexpressed in pancreatic cancer and that increased expression correlates with tumor stage. In this study, we attempt to identify whether KOC expression in patients who undergo curative intent surgery correlates with progression free survival. Methods: Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of patients with PDAC who underwent curative intent surgery were assessed by immunohistochemistry. Results: A total of 35 patients were included. Comparisons between groups on progression free survival are estimated using the Kaplan-Meier method and the log-rank test. KOC was overexpressed in 23.6% of tumors. It was found that there were zero patients with a high KOC expression and no distant metastasis. Patients with a high KOC expression were more than 3 times more likely to progress compared to those with a low KOC expression (HR=3.54, 95% CI: 1.34, 9.36, p=0.011). Conclusions: KOC is a useful prognostic biomarker for predicting those patients with PDAC who have a high risk for early progression and distant metastasis. Identifying patients with high KOC expression upon initial diagnosis can serve as a way to risk stratify patients to aggressive treatment regimens upfront and early exposure to clinical trials.
A comparative study of a monoclonal antibody against EGFR (nimotuzumab) used in combination with chemoradiation versus chemoradiation alone in the treatment of locally advanced inoperable squamous cell carcinoma of the head and neck.
Authors: Bhatnagar Aseem Rai , Singh Dharam Pal
Published: February 2017

51

Background: To determine the efficacy, safety and tolerability of concurrent nimotuzumab (monoclonal antibody against epidermal growth factor receptor) used in combination with chemoradiation versus chemoradiation (CRT) alone in advanced inoperable squamous cell carcinoma of the head and neck (SCCHN). Methods: 56 patients were randomly assigned to either of the two treatment arms, nimotuzumab + CRT arm and CRT alone arm. Both arms received concurrent Cisplatin 30 mg/m2 repeated weekly for 6-7 cycles along with external beam radiotherapy 64-70 Gy (200cGy/day for 5 days a week for 6-7 weeks). Nimotuzumab arm additionally received nimotuzumab 200 mg weekly for 6-7 cycles. The patients were followed for 6 months after completion of CRT. The study end points were tumor response evaluation according to the RECIST Criteria version 1.1 and safety analysis using RTOG Acute Radiation Morbidity Scoring Criteria. Patients were evaluated weekly with hematologic tests and for adverse events like mucositis and dermatitis during the CRT. Tumor assessment was performed with clinical and endoscopic methods regularly during the CRT and then at 1 month, 3 months, and 6 months intervals after CRT. One MR imaging was done before starting the CRT to evaluate the baseline tumor characteristics, and another was done after the completion of CRT either at 3 months or 6 months or at both the intervals. Results: 25 patients each were evaluable in both the arms who completed the 6-month study. The overall response rate (complete response + partial response) was 96% in nimotuzumab + CRT arm, whereas it was only 72% in CRT alone arm after 6 months of completion of CRT, which is statistically significant (p value = 0.0206 by Chi Square test). Additionally, nimotuzumab did not potentiate toxicities of CRT, and there was no significant difference in the acute radiation mucositis, dermatitis, or hematological toxicities in both the groups (p value>>0.05). Conclusions: Nimotuzumab can be safely added to the standard CRT treatment for advanced inoperable SCCHN, to achieve better tumor response without potentiating toxicity.
Methylation of MGMT in paired primary and recurrent GBMs.
Authors: Bie Li , Zhang Feng Xian
Published: February 2017

65

Background: Epigenetic sliencing of the MGMT gene promoter in primary glioblastomas of patients subsequently treated with TMZ is associated with prolonged survival. Further, several studies have observed a change in MGMT silencing in paired primary and recurrent glioblastoma. However, the relationship between this “MGMT switch” and patients outcome is largely unknown. Methods: The study involved primary and recurrent tumor tissue samples from 53 glioblastoma patients diagnosed and treated within the First Hospital of Jilin University from January 2003 to November 2010. After surgical treatment, all patients were subjected to radiotherapy with concomitant administration of TMZ. Patients that experienced recurrent tumors received TMZ. 53 patients underwent 58 further operations after recurrence (5 pats received a third surgery). MGMT promoter methylation levels were determined using qMSP. The relationship between “MGMT switch” and clinical outcome was investigated. Results: 53 (M/F=33/20; median age: 49.2±3.6, 19.5-72.3 ys) underwent a first operation for GBM. qMSP analysis revealed MGMT promoter methylation in 19 pats (35.8%, A, OS 31.5 ms); no methylation in 34 pats (64.2%, B, OS 7.9 ms). In the recurrent tumors, MGMT promoter methylation was detected in 25 pats (47.2%); and no methylation in 28 pats (52.8%). Comparison of individual pairs of primary and recurrent GBMs revealed a changed methylation status in 10 (18.9%), including 8 changed from unmethylated to methylated tumors (15.1%, C, OS 29.4 ms), 2 changed from methylated to unmethylated tumors (3.8%, D, OS 10.5 ms). Median overall survival (OS) was 12.1 months. MGMT promoter methylation was significantly associated with a favorable clinical outcome (A vs B, p=0.0027). The outcome of patients were not significant different between group A and group C (p>0.01). Conclusions: The methylation status of the MGMT promoter was altered in 10 (18.9%) of 53 recurrent GBM after chemoradiotherapy. 8 patients the promoter changed from unmethylated to methylated and these patients had a median overall survival similar to the better prognosis of patients who had a methylated promoter in their primary tumor. 2 pats where a change from methylated to unmethylated was observed had a poorer outcome.
Biopsy-driven study to identify biomarkers of drug resistance in patients with triple-negative breast cancer.
Authors: Aguilar-Mahecha Adriana , Lafleur Josiane , Ahmadzadeh Elaheh , Przybytkowski Ewa , Seguin Carole , Mihalcioiu Catalin Liviu Dragos , Roy Josee-Anne , Desbiens Christine , Robidoux Andre , Marcus Elizabeth A. , Diaz Zuanel , Pelmus Manuela , Batist Gerald , Basik Mark ,   Quebec Clinical Research Organization in Cancer
Published: February 2017

87

Background: Resistance to chemotherapy is the underlying cause of death in most patients dying of breast cancer. Patients with early stages of breast cancer whose tumor is or becomes resistant to chemotherapy have a poor prognosis, while women with advanced breast cancer live as long as their tumors respond to chemotherapy. Because of the great difficulty of obtaining clinical samples from drug resistant tumors in patients, there is scant information about molecular factors from actual drug resistant tumors. This project aims to systematically profile resistant triple negative breast cancers (TNBCs) in order to discover molecular “resistance” genes/proteins as a first step to develop strategies to overcome drug resistance. Methods: Paired biopsies are collected from TNBC patients (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Results: We have currently enrolled 28 patients in the neoadjuvant setting and 3 metastatic patients. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. In parallel, we have generated acquired resistance to paclitaxel in a panel of TNBC cell lines. These cell lines will also undergo genomic profiling and exome sequencing to identify molecular markers of resistance that will be correlated with the markers found in patient samples. Conclusions: This project will allow us to identify the molecular factors responsible for drug resistance in TNBCs and enable the elaboration of strategies to overcome resistance.
Eradication of experimental brain metastases of human non-small cell lung cancer by macitentan, a dual antagonist of the endothelin A and B receptor, combined with paclitaxel.
Authors: Hanibuchi Masaki , Kim Sun-Jin , Otsuka Kenji , Tabata Sho , Kuramoto Takuya , Goto Hisatsugu , Nishioka Yasuhiko , Fidler Isaiah Josh
Published: February 2017

92

Background: Treatment of patients with lung cancer brain metastases remains a major challenge because of the limited availability of standard therapy. Thus, the development of successful treatment options for these patients is mandatory. Recently, the endothelin axis was reported to be involved in cancer progression through its pleiotropic biological effects on cell survival, proliferation, invasion, and metastasis. Methods: In this study, we evaluated both the in vitro and in vivoeffects of macitentan, an orally bioavailable, dual endothelin A receptor and endothelin B receptor antagonist, as monotherapy, and in combination with paclitaxel. Results: In human non-small cell lung cancer PC-14 cells, macitentan treatment inhibited cell proliferation, corresponding with inhibition of Akt and p42/44 mitogen-activated protein kinase phosphorylation, and increased apoptosis. The combination of macitentan and paclitaxel resulted in the potentiation of all of these effects, suggesting that macitentan could enhance sensitivity to paclitaxel. Moreover, macitentan completely abrogated astrocyte-mediated protection of tumor cells against paclitaxel. In an experimental brain metastasis model of human lung cancer, the combination of macitentan and paclitaxel significantly inhibited the growth of brain metastasis and produced a striking survival prolongation of tumor-bearing mice. Conclusions: The endothelin A and B receptor blockade by macitentan could be a promising therapeutic strategy for brain metastases of non-small cell lung cancer.
Clinical assay development program.
Authors: Conley Barbara A. , Cavenagh Margaret M. , Rohan JoyAnn Phillips , Lively Tracy G. , Lih Chih-Jian , Williams P. Mickey
Published: February 2017

98

Background: Discoverers of predictive or prognostic molecular features often do not have the resources to analytically validate findings into a “locked down” assay. Methods: The Clinical Assay Development Program (CADP) was created to provide resources to transition promising markers/signatures into validated assays for use in clinical trials. The CADP is composed of the Clinical Assay Development Network of 8 contracted CLIA-accredited labs and research lab soon to be CLIA accredited (at Frederick National Laboratory for Clinical Research), and Tissue Resources. Applicants from industry, academia, and government are eligible to apply. Applicants must specify one intended clinical use, a prototype assay that performs in human tissues, and relevant prevalence information. Applicants must also describe the clinical need, the current state of the assay and future plans for assay development (such as use in clinical trial) and request the services required for analytical validation (e.g. platform migration, etc.). The applications are evaluated by outside experts. Recommended applications are reviewed internally to ensure availability of appropriate resources and consistency of the application with NCI strategic directions. The successful application is then overseen by a project management team: project manager, subject matter experts from NCI, expertise from contracted resources, and the assay submitter. Intellectual Property remains with the submitter. After validation, the specifics of assay performance and standard operating procedures are returned to the assay submitter. Results: Of 16 applications in year 1, 2 projects are near completion and 2 are beginning. Common problems of the applications were lack of definition of single intended use, specimen availability, and marker still in discovery. Several applicants have used the advice of the CADP team to improve development strategy. Conclusions: Continued education on assay development strategy, particularly intended use and clinical context, is necessary to encourage development of potential molecular assays from the research lab into clinical use. Creativity is needed in finding appropriate specimens. Initial results of CADP are promising; interest from potential applicants is increasing. http://cadp.cancer.gov .
Differential receipt of sentinel lymph node biopsy within practice-based research networks.
Authors: Meyer Anne-Marie , Reeder-Hayes Katherine Elizabeth , Liu Huan , Wheeler Stephanie B. , Penn Dolly , Weiner Bryan , Stitzenberg Karyn Beth , Carpenter William Ruffin
Published: February 2017

102

Background: Sentinel lymph node biopsy (SLNB) is a quality indicator for breast cancer care. Provider-based research networks (PBRNs) promote diffusion of innovations like SLNB into clinical practice; however, evidence is limited. We examined the diffusion of SLNB for early-stage breast cancer through the Community Clinical Oncology Program (CCOP), a community-based PBRN and its interaction with medical school affiliation. Methods: We identified women undergoing breast conserving surgery with axillary staging for stage I or II breast cancer between January 2000 and December 2003 using Surveillance Epidemiology and End Results-Medicare data (n=6,226). The primary outcome was receipt of SLNB vs. ALND. Exposure was constructed by combining information on the CCOP affiliation of the preforming physician with the medical school affiliation of the hospital. Covariates included race, age, marital status, education, Medicaid eligibility, comorbidity, tumor grade, stage, estrogen receptor status, year of diagnosis, SEER region, and NCI cancer center designation. Multivariable generalized linear modeling with generalized estimating equations was used to measure association between CCOP exposure and receipt of SLNB. Results: Women who saw a CCOP physician at a hospital affiliated with a medical school had a three-fold increase in odds of receiving SLNB compared to non-CCOP women. In contrast, the odds of SLNB were equivalent when looking in women who were seen by a CCOP physician but differed only by their hospital affiliation. Conclusions: Women seen by CCOP-affiliated physicians were more likely to receive SLNB; while medical school affiliation did appear to significantly impact receipt. Innovative, high-quality cancer care can be facilitated PBRNs such as the NCI CCOP program. There must be mechanisms by which providers are exposed to advances in clinical practice outside of organizational affiliations. [Table: see text]
Quality oversight for specialized cancer services.
Authors: Hertz Sherrie , Ross Jillian , Kaizer Leonard , Sawka Carol Anne
Published: February 2017

103

Background: Cancer Care Ontario (CCO), a provincial agency responsible for continually improving cancer services in Ontario, Canada, reviews selected services with a view to understanding and resolving issues of access, quality, innovation, and funding. Specialized cancer services are low-volume, high-complexity, high-cost, and are not available in every region. They tend to be high-risk, involve a rapidly evolving scientific knowledge base, and a high degree of specialization. A specialized services oversight (SSO) approach has been implemented to address the challenge for optimization of service delivery while providing equitable access to safe, high-quality, best practice care. Methods: The SSO approach involves 1) establishing a provincial forum for expert clinical advice; 2) A regular and systematic process for literature and jurisdictional reviews; 3) provincial-level demand and capacity forecasting; 4) provincial funding linked to evidenced-based eligibility/quality criteria; 5) communication/awareness strategies for appropriate and equitable access. Enablers are CCO structures for performance management, stakeholder engagement, service planning, data management, and CCO’s guiding principles of "transparency, equity, evidence, performance-oriented, active engagement, and value for money." Results: The SSO approach has been implemented in full for PET scanning services, and in part for stem cell transplant (SCT), sarcoma, molecular oncology, prostate brachytherapy, and selected neuroendocrine cancer care. Stakeholder acceptance of the approach has been high. Outputs include provincial guidelines on indications for SCT, performance metrics and benchmarks, multicentre sharing of information, and inter-regional referral processes. Conclusions: Implementation of the SSO approach has introduced provincial-level system planning, formal evidence scanning, sharing of best practices, and performance measurement for high-complexity services where there was no such oversight in the past. The approach is anticipated to avoid access crises and support timely and equitable access to services of high quality, which make optimal use of resources.
Use of predictive models (PMs) in colorectal cancer (CRC) for diagnosis of Lynch syndrome (LS): A process measure for quality of care.
Authors: Sadeghi Sarmad , Barzi Afsaneh , Kattan Michael W. , Meropol Neal J.
Published: February 2017

116

Background: LS diagnosis (Dx) in CRC patients (probands or Pds) and their first degree relatives (FDRs) impacts the management, outcomes and quality of care. Lack of a uniform approach to screening in academic and community centers is an impediment. Recent studies advocate universal immunohistochemistry (IHC) testing for Pds; however, these analyses exclude clinical criteria e.g., Amsterdam (Ams), Bethesda (Beth), and PMs, e.g., MMRpro (Mpro), MMRpredict (Mpre), and PREMM (PRE) due to concerns for reliability. This comprehensive comparison of all LS screening strategies (STs) aims to identify a cost effective process measure that addresses this need. Methods: We performed a cost effectiveness analysis with a societal viewpoint using TreeAge software. 21 STs for Pd and general population (GP) screening in a population of 100,000 were examined assuming a 3% LS prevalence (Prev) in Pd and 0.23% in GP, 5 FDRs per LS (Dx), 50% LS Prev in FDRs, and 90% germline testing (GT) compliance in Pds and GP and 52% in FDRs. Sensitivity, life years gained (LYG), and incremental cost effectiveness ratios (ICERs) were calculated. Results: See table. Conclusions: This study suggests that Mpro is a cost-effective first step in screening for LS in Pds, and its routine use may be considered as a possible process measure for quality of care in CRC patients. Up-front IHC +/- BRAF, GT could be reserved for Pds where history is incomplete. [Table: see text]
Doctor, what are my options? A prospective cohort study of an individualized care plan for patients with gastrointestinal cancer.
Authors: Hird Amanda E. , Lemke Madeline , Turovsky Miriam , DeAngelis Carlo , Chow Edward , Ko Yoo-Joung
Published: February 2017

12

Background: For new cancer patients, information about the complexity of the disease, treatment schedule and potential side effects is often delivered during an emotional, stressful visit which can lead to misunderstanding. Appropriate informational support can improve informed decision making, adherence to treatment, and reduce anxiety and cancer morbidity. This is a 3-part clinical study investigating the utility of a patient-centered individualized care plan for patients with gastrointestinal (GI) cancer starting a new treatment. Methods: Part 1: Items identified in a comprehensive literature search were formatted into a questionnaire. For each item, participants ranked its importance. Part 2: MDs and RNs involved in the care of patients with GI cancer provided comments about the content of the care plan. Part 3: A prospective cohort study was conducted. During the first 10-weeks, patients received the standard of care. During the subsequent 10-weeks, patients received the intervention, a written individualized care plan. Outcomes were assessed at baseline and 2-4 weeks: QOL (FACT-G), anxiety and depression (HADS), treatment compliance and patient satisfaction (FACT-TS-PS). Results: Part 1: 73 items were included in the questionnaire. 20 patients completed the interview. Part 2: A long and short version of the care plan were created. The majority of MDs and RNs preferred the long version. Based on the comments, the final version was created. Part 3: 54 and 41 patients have been enrolled in the control and intervention cohorts, respectively. Analysis of the baseline data revealed fewer self-reported anxious (p=0.008) and depressive symptoms (p=0.002) in the intervention group. The nursing satisfaction score was significantly higher in the intervention group (7.09 vs. 4.80, p=0.018). Overall QOL and satisfaction scores were higher in the intervention group, but not statistically significant (81.30 vs. 76.25, 79.70 vs. 76.27). Conclusions: The care plan resulted in fewer anxious and depressive symptoms. There was a trend towards improved QOL and satisfaction in the intervention group, although not significant. We are continuing to enroll patients and analyze follow-up data.
Cancer therapy and heart failure: Successful management through collaborative interdisciplinary practice.
Authors: Fadol Anecita P. , Durand Jean-Bernard , Summers Barbara L. , Woods Myrshia L. , Lewis Katie , Johnston Patty , Tomczak Nancy , Estrella Joylynn Mae , Kidin Lisa M. , Browning Douglas
Published: February 2017

123

Background: Heart failure (HF) is a clinical problem of emerging importance in cancer care. The advances in cancer detection and complex treatment regimens have resulted in increased cancer treatment induced HF. The literature indicates that more than 50% of all patients exposed to anthracyclines will show some degree of cardiac dysfunction either acutely or 10 to 20 years after treatment, and 5% of those patients will develop overt HF. Successful management requires a collaborative, interdisciplinary approach. The purpose of this presentation is to discuss how the “Heart Success Program” (HSP) resulted in cost effective and clinical quality outcomes in patients with cancer and HF. Methods: The HSP was piloted in the emergency center and telemetry units with high volume admission of HF patients. The HSP includes comprehensive education of patients, families, and health care providers regarding HF management in cancer patients. HSP implementation includes a HF order set, patient education booklet, and educational videotape specific for patients with cancer and HF. Weekly interdisciplinary clinical rounds provide a forum for discussion of identified patient’s problems and formulation of solutions. Endpoint outcomes include compliance with the Center for Medicare and Medicaid Services (CMS) core measures for HF, as well as decreasing HF readmissions. Results: The pilot implementation of the HSP resulted in decreased hospital length of stay by 57%, and average hospital admission cost by 60%. Despite multiple co morbid conditions, patients were discharged with improved functional status and compliance with CMS HF core measures. Conclusions: The findings from this quality improvement project showed significant impact in clinical and cost outcomes for patients with cancer and HF. The multidisciplinary team approach that provided support to patients and their families and allowed for patients to continue their cancer treatment resulting in improved outcomes. As we move toward value-based purchasing, the HSP provides an example of how collaboration and standardized process improvement impacts cost and quality in the oncology population.