bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene methylation in random FNA samples as biomarkers for breast cancer.
Authors: Stearns Vered , Khan Seema Ahsan , Fackler Mary Jo , Chatterton Robert T. , Jacobs Lisa K. , Khouri Nagi , Kenney Kara , Shehata Christina , Jeter Stacie , Ivancic David , Wolfman Judith , Zalles Carola M. , Huang Peng , Sukumar Saraswati
Published: March 2020

518

Background: Current methods to determine breast cancer risk are insufficiently sensitive to select women most likely to benefit from preventive strategies. We hypothesized that candidate gene promoter hypermethylation may provide an individualized risk profile. We performed a prospective study to determine whether DNA cumulative methylation index (CMI) varies by menstrual phase or menopausal status, and to correlate CMI with established risk factors. Methods: We obtained random fine needle aspiration (rFNA) samples from healthy women age 35-60 and determined their menopausal and menstrual status, lifetime Gail risk, mammographic breast density, and cytologic atypia assessed as the Masood score. We evaluated CMI of 11 candidate genes in rFNA cells using the Quantitative Multiplex Methylation-Specific PCR (QM-MSP) technique. We used Wilcoxon test and ANOVA model to compare CMI across menopausal and menstrual (follicular, mid-cycle, luteal) categories, respectively. We used linear regression model to adjust for age and BMI. Methylation scores were log-transformed in the analysis. Results: We enrolled 390 women at the Avon Breast Centers at Johns Hopkins and Northwestern, the majority through the Love/Avon Army of Women, and 380 completed study procedures. Median age 50 (36-60), mean BMI 28 (18.7-50.8), 52% were postmenopausal. Mean life-time Gail risk 14.6 (5.6-54.1), mean percent mammographic density 19.6 (2.5-72.8), and mean Masood score (N=354) 13.6 (7-18). QM-MSP analysis was completed on 229 samples. We did not observe differences in CMI among menopausal (P=0.4895) or menstrual categories (P=0.2333). There was no association between CMI and life-time Gail risk (P=0.706) or breast density (P=0.4116). We observed a significant correlation between CMI and Masood score (P=0.0167). Conclusions: CMI correlates with degree of cytologic atypia and is potentially a robust indicator of breast cancer risk since it does not vary with menstrual or menopausal status. Next, we will select genes that best reflect changes in the clinical parameters to create a gene methylation signature that will be validated in other studies and correlated with breast cancer risk.
Reacquisition of RAI uptake in RAI-refractory metastatic thyroid cancers by pretreatment with the MEK inhibitor selumetinib.
Authors: Ho Alan Loh , Leboeuf Rebecca , Grewal Ravinder K. , Sherman Eric Jeffrey , Deandreis Desiree , Pentlow Keith S. , Tuttle Robert Michael , Fury Matthew G. , Ricarte-Filho Julio Cezar M. , Pfister David G. , Larson Steven M. , Fagin James A.
Published: March 2020

5509^

Background: Therapies for radioactive iodine (RAI)-refractory thyroid cancers of follicular origin (TC-FCO) are desperately needed. TC-FCO mouse models show that blocking mitogen-activated protein kinase (MAPK) signaling with a MAP kinase kinase 1/2 (MEK1/2) inhibitor increases sodium iodide symporter expression and iodine incorporation. This 20 patient (pt) pilot study aimed to evaluate if the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142866) can reverse RAI-refractoriness in TC-FCO pts (NCT00970359). Methods: RAI-refractory TC-FCO disease was defined as: 1) non-RAI-avid lesion/s on a diagnostic or post-therapy RAI scan, 2) RAI-avid lesion/s that was stable or increased in size after RAI therapy, or 3) fluorodeoxyglucose (FDG)-avid lesion/s by positron emission tomography (PET) scan. rhTSH-stimulated lesional dosimetry with 124I PET was performed prior to and after 4 weeks of treatment with selumetinib (75 mg orally bid). If the second 124I PET scan predicted a lesional RAI dose of > 2000 cGy, therapeutic RAI was administered while on the drug. Primary endpoints were to evaluate changes in tumor iodine uptake and RECIST response after RAI therapy; changes in serum thyroglobulin (TG) after RAI was a secondary endpoint. Results: 24 pts were enrolled, 22 eligible, and 20 evaluable. For the 20 evaluable pts, median age was 61 (range 44-77 yrs), 11 were men. 19 pts had tumors analyzed for BRAF and N-,K- RAS mutations. 8 pts had BRAF mutant (MUT), 11 BRAF wild-type (WT) tumors; 1 pt to be analyzed. Selumetinib increased 124I uptake in 12 of the 20 pts (4 of 8 BRAF MUT; 8 of the 12 other pts). The 8 of those 12 pts achieving sufficient iodine avidity to warrant RAI therapy included all 5 pts known to be NRAS MUT to date and 1 BRAF MUT pt. Of the 7 pts who have received RAI, 5 had partial responses (PRs); 2 stable disease (SD). Mean percent reduction in TG in this group (pre- vs 2 months post- RAI) was 91%. No > grade 2 CTCAE toxicities attributable to selumetinib were observed. 1 pt was diagnosed with myelodysplastic syndrome > 51 weeks after RAI (unrelated to selumetinib). Conclusions: Selumetinib can enhance iodine uptake in a subset of RAI-refractory TC-FCO and may be particularly effective for RAS MUT tumors.
Acetylated tubulin and risk of nodal metastases in squamous cell carcinoma of the head and neck (SCCHN).
Authors: Saba Nabil F. , Magliocca Kelly R. , Kim Sungjin , Muller Susan , Chen Zhengjia , Eggers Carrie , Phelan Vanessa H , Kono Scott A. , Owonikoko Taofeek Kunle , Ramalingam Suresh S , Grist William , Chen Amy Y. , Beitler Jonathan Jay , Shin Dong M , Marcus Adam , Khuri Fadlo Raja
Published: March 2020

5560

Background: We previously established that AT expression predicts for response to chemotherapy in SCCHN (Saba et al, AACR 2010 meeting abstr 3744). We wanted to further examine the relation of AT expression and nodal metastases in SCCHN. Methods: We assessed AT expression in archival tissue specimens from primary SCCHN cases with (50 cases) and without (53 cases) lymph node metastases (NM) using standard immunohistochemistry (IHC). Clinical characteristics of patients were retrieved from the department of pathology under the guidelines of the institutional review board (IRB). IHC staining for AT was scored based on intensity and percentage of tumor cells stained: 0 = no staining, 1+ = weak, 2+ = moderate, 3+ = moderate to high, 4+ = high and a weighted index (WI) was calculated as percent stain x stain intensity. Wilcoxon two-sample test and Kruskal-Wallis test were used to estimate the relationships of the WI with nodal metastasis, node status, primary tumor location, grade, and stage. Log-rank test was used to examine the difference in OS and DFS among four groups based on quartiles of the WI. A Cox proportional hazard model was employed to estimate the adjusted effect of WI on OS and DFS. Results: A higher AT expression was associated with nodal metastasis (p=0.0155) and higher stage (p=0.0311). A lower AT expression was associated with oral cavity primary (p=0.0107). After adjusting for age, gender, race, and smoking status, a lower AT expression was significantly associated with better DFS in the subset of patients with NM by multivariate analysis (HR=1.008; 95% CI=1.002- 1.014; p=0.0123). Among patients with no NM there was a marginally significant difference in OS among four different groups based on quartiles of AT expression (p=0.0765). Conclusions: High AT expression is associated with nodal metastases in SCCHN and may be a marker of poor prognosis in patients with node positive disease. The value of AT as a prognostic marker in SCCHN needs to be better defined. This work is supported by a SPORE CDP Grant P50 CA128613-03 to NFS.
P16 and cyclin D1 (CYD1) as prognostic markers in hypopharyngeal (HSC) and oropharyngeal squamous cell carcinoma (OSC).
Authors: Ang Siok Hoon , Haaland Benjamin , Thu Minn Minn Myint , Krishna Sai Sakktee , Chen Wallace , Hwang Siok Gek Jacqueline , Tan Puay Hoon , Tai Wai Meng David , Tan Eng Huat , Lim Wan-Teck , Ang Mei-Kim
Published: March 2020

5580

Background: In head and neck cancer (HNC), dysregulation of cell cycle proteins p16 and CYD1 are common. Variable associations of p16 over- and under- expression and CYD1 overexpression with overall survival (OS) have been described in different HNC sites. We evaluated the relationship of p16 and CYD1 expression with clinical characteristics and OS in OSC and HSC. Methods: p16 and CYD1 expression was evaluated by immunohistochemistry in 77 HSC and 103 OSC patients (pts) and recorded as p16N (0% tumor cells stained), p16L (5-69%) and p16H (≥70%), CYD1-(<10%) and CYD1+ (≥10%). OS between groups was evaluated by Kaplan-Meier method and compared by log rank test. Hazard ratio (HR) for death was estimated using multivariable Cox models. Results: Pts were predominantly Chinese (83.6% v 85.4%) with locally advanced HNC (91.4% v 92.2%). Compared to OSC, HSC pts were older (median age 67 v 61 yrs), more likely male (89.3% v 74.0%), current or ex-smokers (83.3% v 63.6%) with higher comorbidity-age combined risk score (ageCCI), less likely p16H (6.5% v 30.1%)(all p<0.001) and had similar CYD+. p16H pts were younger (median age 58 (p16H) v 65 (p16L) v 66 (p16N) yrs, p=0.002), more likely non-smoker (51.4% v 23.4% v 13% p<0.001) with lowest ageCCI (p<0.001). Clinical characteristics did not differ by CYD1 status. At median f/u of 50mths, median OS was 33 mths. Median OS was poor in HSC compared to OSC (23.9 v 72.1, p<0.001). Multivariate analysis showed associations of N2/N3 disease (HR 1.57, p=0.036), ageCCI (HR 1.22 per 1 pt increase, p<0.001), p16 (p16H: ref; p16L: HR 2.34, p=0.045; p16N: HR 2.74, p=0.013) and CYD1+ (HR 1.94, p=0.015) with death, independent of gender, smoking and site. Association of p16 with OS was seen mainly in OSC (median OS p16H: not reached (NR), p16L: 62, p16N: 22 mths, p<0.001) compared with median OS (HSC) (27 v 28 v 21, p=0.609). Similarly the association of CYD1 with OS was mainly in OSC (median OS CYD1-: NR v 23 mths, p<0.001 v HSC: 25 v 25 mths, p=0.19). Conclusions: In OSC, p16 expression correlates with OS, with p16N associated with worst OS. CYD1 has an independent association with OS. Poorer OS in HSC may be due to adverse clinical characteristics. Assessment of p16 and CYD1 status in HSC did not predict for OS.
Characterization of the overall survival benefit in ENCORE 301, a randomized placebo-controlled phase II study of exemestane with and without entinostat in ER+ postmenopausal women with metastatic breast cancer.
Authors: Klein Pamela , Ordentlich Peter , McCulloch William , Cruickshank Scott , Rees Miranda , Yardley Denise Aysel
Published: March 2020

567

Background: Histone deacetylase inhibitors (HDACi) prevent the emergence of drug tolerant clones and sensitize cells to a variety of anti-cancer therapies. We previously reported ENCORE 301, a randomized placebo controlled phase 2 study comparing exemestane with (EE) and without (EP) the HDACi entinostat met its primary endpoint of prolonging progression free survival (PFS) (4.3 months vs 2.3 months) and extending overall survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and better understand the OS benefit, exploratory analyses were conducted. Methods: Hazard ratios (HR) for treatment were estimated from the Cox proportional hazards model, with EP serving as the reference treatment in the calculations. Inferential comparisons between treatment groups were made using the log-rank test. Results: Analysis of OS across multiple subsets of interest demonstrated a consistent benefit in EE group versus EP. Sensitivity analysis of baseline characteristics potentially impacting OS did not identify any factors that influenced the effect of EE on OS. Examination of treatments received during follow-up after discontinuation of EE and EP demonstrated balance between treatment group for patients receiving chemotherapy (48% EE: 44% EP), hormone therapy (37% EE: 35% EP), bisphosphonates (2% EE; 0% EP), radiation (6% EE; 5%EP), and surgery (0% EE: 2% EP). Compared to EP, OS was longer in EE group for patients whose first subsequent treatment was a hormone therapy (EE median not reached vs EP median 20.5 months; HR 0.65 [95% CI 0.26, 1.58]) or chemotherapy (EE median 26.9 months vs EP median 17.6 months; HR 0.51 [95% CI 0.25, 1.04]). Updated PFS and OS data will also be presented along with correlation analysis of PFS and OS. Conclusions: Analyses of baseline characteristics, subsequent treatment and subsets of prognostic factors in ENCORE 301 did not identify any contributing factors that account for the extended OS benefit in the EE treatment group. Long lasting effects of entinostat on progenitor cells, emergence of drug tolerant cells and or priming to subsequent therapies cannot be ruled out.
Treatment pattern by hormone receptors and HER2 status in patients with metastatic breast cancer in the United Kingdom, Germany, France, Spain, and Italy (EU-5): Results from a physician survey.
Authors: DeKoven Mitch , Bonthapally Vijayveer , Lee Won Chan , Pathak Prathamesh , Jiao Xiaolong , Ray Saurabh
Published: March 2020

570

Background: The differences in country-specific treatment patterns across Europe for Stage IV metastatic breast cancer (mBC) patients have not been extensively studied. This study compared treatment choices, by biomarker status, between various lines of therapy (LOT) in clinical practice in the EU-5 countries among newly diagnosed stage IV mBC patients. Methods: The IMS LifeLink Oncology Analyzer (OA) database, based upon practicing oncologist surveys, was used to identify mBC patients aged ≥21 and surveyed between July 2008 – June 2010. The database encompasses over 100,000 unique patients per year, treated by nearly 3,000 physicians, including nearly 60,000 patients and 800 physicians in the EU5. Results: A total of 152,311 mBC patients were included in the study. In Italy, 30.8% of HER2+/HR+ patients received chemotherapy following mBC diagnosis, as compared to only 8.6% in France. The majority of these patients in France received chemotherapy plus a HER2 targeted therapy (58.2%) as their first treatment. For HER2+/ HR- patients, chemotherapy plus a HER2 targeted therapy was provided to the majority of the patients in France (70.8%), with the UK providing this regimen to the fewest patients with this biomarker status (44.9%). Monotherapy hormonal regimens were given as a first LOT for HER2-/HR+ patients (UK 64.7%, Spain 52.8%). Triple negative patients received chemotherapy (UK 84.1% as compared to France 57.3%) or chemotherapy plus bevacizumab (France 36.6% as compared to UK 0.9%) as a first treatment. Conclusions: Thisstudy confirmed that chemotherapy combined with HER2-targeted therapy was the most frequent initial treatment option for HER2+ patients, while the vast majority of ER/PR+ patients were initially treated by hormonal therapy, suggesting that a personalized medicine approach has been accepted in the EU-5. However, the use of HER2-targeted therapy and bevacizumab greatly varied; while they were most frequently used in France, they were least frequently opted for in the UK. Also, fewer treatment options existed for triple negative patients and patients with HER2+ disease following trastuzumab treatment.
An international study of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different cancer sites.
Authors: Quinten Chantal , Zikos Efstathios , Sprangers Miriam , Greimel Eva , Martinelli Francesca , Reeve Bryce B. , Ringash Jolie , Gotay Carolyn , Maringwa John T , Coens Corneel , Ediebah Divine Ewane , King Madeleine , Osoba David , Cleeland Charles S. , Flechtner Henning , Schmucker-Von Koch Jospeh , Taphoorn Martin J. B. , Weis Joachim , Bjordal Kristin , Bottomley Andrew
Published: March 2020

6002

Background: The prognostic value for survival of HRQOL data derived from self-report questionnaires, has been well documented in cancer research. The objective of this study was to examine the prognostic value of HRQOL parameters for different cancer sites using one standardized and validated patient self-assessment tool. Methods: A total of 11 different cancer sites, pooled from 30 European Organisation for Research and Treatment of Cancer (EORTC) Randomized Controlled Trials (RCTs), were selected for this study. For each cancer site, univariate and multivariate Cox proportional hazard modeling was used to assess the prognostic value (p<0.05) of 15 HRQOL parameters, assessed with the EORTC QLQ-C30 at baseline before randomization, for overall survival. Models were adjusted for the parameters age, gender, distant metastasis, World Health Organization performance status and stratified by clinical study. Results: A total of 7,417 patients completed the EORTC QLQ-C30 before randomization. For brain cancer cognitive functioning (CF) (hazard ratio (HR) =0.95; p<.0001) was prognostic. For breast cancer nausea and vomiting (NV) (HR=1.17; p=0.0011) was a prognostic indicator. For colorectal cancer physical functioning (PF) (HR=0.93; p<.0001), NV (HR=1.07; p<.0001), and appetite loss (AP) (HR=1.07; p<.0001) predicted survival. For esophageal cancer PF (HR=0.88; p=0.0072) and for head and neck cancer NV (HR=1.14; p=0.0097) were prognostic. For lung cancer PF (HR=0.94; p=0.0006) and pain (HR=1.08; p<0.0001), for melanoma dyspnea (HR=1.06; p<.0001), for ovarian cancer NV (HR=1.2; p<.0001), for pancreatic cancer global QOL (HR=0.83; p=0.0073), for prostate cancer role functioning (RF) (HR=0.96; p=0.006) and AP (HR=1.07; p<.0001), and for testis cancer RF (HR=0.81; p=0.0144) were predictors of survival. Conclusions: Our findings show that different HRQOL parameters provide prognostic information for survival for patients with different tumor sites and that no single HRQOL scale can predict survival in all cancer patients. Thus, each cancer site needs careful examination and no single QOL paramenter can predict survival in all cancer diseases.
Refused versus recommended adjuvant chemotherapy in the United States: A reason for concern.
Authors: Habermann Elizabeth Butzer , Abraham Anasooya A , Zhu Yanrong , Markin Abraham , Rothenberger David A. , Kuntz Karen M , Vickers Selwyn M. , Al-Refaie Waddah B.
Published: March 2020

6016

Background: We designed this study to identify factors driving treatment recommendations and refusal in surgically treated patients with gastrointestinal (GI) cancers eligible for adjuvant chemotherapy. Methods: Using the 2001-2008 California Cancer Registry (CCR), we constructed a cohort of 22,469 patients surgically treated for three GI cancers and eligible for adjuvant chemotherapy (stage III colon cancer in patients < 80 years, Ib-IVM0 gastric cancer, or nonmetastatic resected pancreatic adenocarcinoma). Information on chemotherapy receipt, recommendation, and refusal was utilized to construct our outcome measures. Multivariate logistic regression models identified predictors of recommendation and refusal of adjuvant chemotherapy across three GI cancer sites, adjusting for potential confounders. Results: Of those eligible for adjuvant therapy, only 61.4% were recommended treatment and 54.3% received it. Refusal rate was 3.5%. Persons who were older, black, publicly insured or uninsured, or with gastric cancers were less likely to have adjuvant chemotherapy recommended. Yet, older, Medicaid-insured, and those treated for gastric cancer were more likely to refuse adjuvant therapies. Women were as likely as men to be recommended adjuvant therapies but more likely to refuse them (Table). Conclusions: Many patients eligible for adjuvant chemotherapy after GI cancer surgery have not been so advised. Striking variations exist between recipients of treatment recommendations versus those who refuse them. These results demonstrate a wide implementation gap between the recommendations arising from cancer clinical trials versus actual clinical practice. [Table: see text]
Endocrine therapy use among Medicaid-insured breast cancer survivors with hormone receptor-positive tumors.
Authors: Kohler Racquel Elizabeth , Wheeler Stephanie B. , Reeder-Hayes Katherine Elizabeth , Goyal Ravi K. , Lich Kristen Hassmiller , Smith Timothy , Melvin Cathy , Moore Alexis , Muss Hyman Bernard
Published: March 2020

6017

Background: Estrogen receptor positive (ER+) and progesterone receptor positive (PR+) cancers account for the majority of breast cancer diagnoses and deaths. Among women with ER+ or PR+ breast cancers, endocrine therapy (ET) is the cornerstone of adjuvant therapy and reduces 5-year risk of recurrence by as much as 40%. Observational studies in Medicare and privately-insured populations suggest that ET is underutilized. We sought to characterize ET use in a low-income Medicaid-insured population in North Carolina. Methods: We used Medicaid claims data matched to NC Central Cancer Registry records for women ages 18-64 diagnosed with in situ, stage I or II breast cancer from 2003-2007. We excluded dual eligibles and included only cases enrolled in Medicaid for at least 12 of the 15 months following the index diagnosis. We defined our outcome as receipt of any ET medication (tamoxifen, letrozole, exemestane, or anastroxole) in prescription claims during the 15-month period post-diagnosis, among women with ER+ or PR+ disease. In multivariate logistic regressions, independent variables included age, race, tumor characteristics, receipt of other breast cancer treatments, co-morbidity, rural/urban residence, reason for Medicaid eligibility, involvement in the Breast and Cervical Cancer Control Program (BCCCP), patient-centered medical home enrollment, and diagnosis year. Results: Of the 269 women who met inclusion/exclusion criteria and were ER+ or PR+, only 45% filled a prescription for ET during the study period. In multivariate analyses, being involved in the CDC-affiliated BCCCP was significantly associated with higher likelihood of receipt of guideline-recommended endocrine therapy (Marginal Effect: 0.299, p<0.01), but other independent variables were not significantly correlated with receipt of ET. Conclusions: Results suggest that ET is substantially underutilized in this low-income, vulnerable population and that intervention efforts to improve ET use may be important. Qualitative research is needed to understand the more nuanced, behavioral reasons for ET underuse, which may be related to symptom burden, cost, and patient-provider communication.
Neoadjuvant bevacizumab (B) and trastuzumab (T) in combination with weekly paclitaxel (P) as neoadjuvant treatment in HER2-positive breast cancer: Results from a phase II trial (AVANTHER).
Authors: Fernandez Abad Maria , Calvo Isabel , Martinez Noelia , Herrero Mercedes , Quijano Yolanda , Duran Hipolito , Garcia Aranda Mariola , Suárez Ana , López-Ríos Fernando , Perez Diego , Perea Sofia , Hidalgo Manuel , García-Estevez Laura
Published: March 2020

602

Background: B in combination with T has showed meaningful activity in patients (pts) with metastatic HER2-positive breast cancer. AVANTHER is a Phase II trial of preoperative systemic therapy combining B with T and P in a weekly regimen in HER2 positive breast cancer to assess safety and efficacy of the combination. Methods: Pts with centrally-confirmed HER2-positive (IHC 3+ or FISH positive) breast cancer (stage II or III including locally advanced) received neoadjuvant chemotherapy (NC) with weekly P (80mg/m2/week) for 12 weeks in combination with weekly T (4mg/kg loading dose and 2 mg/kg maintenance) and B (15mg/kg every 3 weeks) for 4 cycles. After surgery all pts received T (1 year) and liposomal doxorubicin plus cyclophosphamide every 3 weeks (4 cycles); primary endpoint was rate of pathological complete response (pCR) in breast and axilla. For all patients, a tissue sample at baseline as well as at surgery was collected for biomarker analyses. Results: A total of 44 pts have been enrolled. Median tumor size: 3.9 cm. Seven (19.4%) pts had stage IIA; 17 (47.2%) stage IIB; 8 (22.2%) stage IIIA and 4 (11.1%) stage IIIB. Twenty-one (58.3%) pts had both positive-hormonal receptors and 10 (27.8%) were hormone receptor negative. Eight (22.2%) pts had sentinel biopsy before NC, being negative in 6 (16.7%) cases. Data from surgery (only from 36 pts): pCR was achieved in 16 (44.4%) pts. Safety and tolerability were good, with rare adverse events of grade ≥3 [1 (2.8%) episode of severe hypertension]. Conclusions: These data show that the combination of P with T and B without an anthracycline for 12 weeks is very effective as NC in HER2 positive breast cancer pts with a high rate of pCR and minimal side effects.
Cancer patients’ trade-offs for efficacy, toxicity, and cost.
Authors: Wong Yu-Ning , Egleston Brian , Sachdeva Kush , Hamilton Olivia , Eghan Naa , Pirollo Melanie , Stump Tammy K , Beck J Robert , Meropol Neal J.
Published: March 2020

6021

Background: When making treatment decisions, cancer patients (pts) must make trade-offs between efficacy, toxicity (tox) and cost. However, little is known about how individual characteristics influence these decisions, particularly as many face high out of pocket costs. Methods: We presented cancer pts with hypothetical scenarios that asked them to choose between 2 treatments of varying levels of efficacy, tox and cost. Each scenario included 9 choice pairs. Pts were given 2 of 3 scenarios described in the Table. Tox was also varied. Demographics, cost concerns and numeracy were assessed. Within each scenario, we used latent class methods to distinguish pt groups with discrete preferences. We then used regressions with group membership probabilities as covariates to identify associations. Results: We enrolled 400 pts. Median age was 61 years (range 27-90). 63% were female. 41% were college educated. 51% had an annual income ≥$60K. 25% were enrolled at a community hospital. 98% were insured. Within each of the 3 scenarios, we identified 3 pt classes with preferences for survival or aversion to high cost or toxicity. Across each of the scenarios, <6% of pts in the group averse to high cost chose the costlier treatment. >92% of pts in the group that favored survival chose the highest efficacy treatment. >65% of pts in the group with aversion to tox chose the lower tox treatment. Within each of the scenarios, pts in the group with preference for survival were more likely to have an income of >$60K (p<.05) and greater numeracy skills (p<.05). In scenarios 2 and 3, pts with concerns about treatment costs were more likely to be in the class that was averse to high cost (p<.05 for both). Conclusions: Even in hypothetical scenarios presented to insured pts, socioeconomic status was predictive of treatment choice. Higher income pts may be more likely to focus on survival when making decisions while those with greater cost concerns may be more likely to avoid costly treatment, regardless of survival or tox. This raises the possibility that health plans with greater cost-sharing may have the unintended consequence of increasing disparities in care. [Table: see text]
The involvement of partners in breast cancer treatment decision making.
Authors: Hawley Sarah T. , Janz Nancy K. , Lillie Sarah E , Schwartz Kendra L. , Graff John , Hamilton Ann S. , Katz Steven J.
Published: March 2020

6023

Background: Incorporating partners into treatment decision making is an important element of patient-centered care, yet little is known about the role of partners in the decision process. Methods: We surveyed 503 partners of a population-based sample of breast cancer survivor 4 years after diagnosis (RR= 76%, N=382).The outcome was partners’ reports of decision regret. Independent variables included decision making process measures (partners’ reports of sufficient treatment information receipt and sufficient involvement in decision making), race/ethnicity, age, education and income. Multivariable logistic regression was used to assess associations between decision regret and race/ethnicity, controlling for other variables. Results: 49% of partners were white, 14% African American, 15% more-acculturated Latino, and 18% less-acculturated Latino. One quarter (26%) of partners reported that they received insufficient information and one third (35%) desired more involvement in decision-making. Compared to whites, less-acculturated Latino partners more often reported that they received insufficient information (41% vs. 18%, p<0.05) and desired more involvement in decision-making (49% vs. 14%, p<0.001). Overall 30% of partners reported high decision regret. Multivariate analyses showed factors associated with high decision regret were less-acculturated Latinos, insufficient information receipt and desire for more involvement (Table). Conclusions: Most partners of breast cancer survivors reported low decision regret and positively appraised their involvement in the decision process. Less acculturated Latinos reported more dissatisfaction with the decision process. Findings suggest the need for culturally appropriate treatment decision support interventions that include partners. [Table: see text]
Conflict of interest disclosure in off-label oncology clinical trials.
Authors: Irwin Blair Billings , Abernethy Amy Pickar , Hirsch Bradford Richard
Published: March 2020

6041

Background: Off-label prescribing of anti-cancer targeted therapies is increasingly prevalent. Post-regulatory evidence and reporting requirements for reimbursement for off-label oncologic indications are less stringent than the threshold for United States Food and Drug Administration registration. What are the prevalence, reliability, and predictors of conflict of interest (COI) and funding disclosure statements in published reports of studies of cancer targeted therapies conducted in the post-regulatory setting? Methods: As a part of a federally-funded systematic review, manuscripts were included in the analysis if they were used to support one of 19 indications for cancer targeted therapies that were off-label but reimbursable according to authoritative compendia in 2006 or before. Studies were categorized according to trial design, trial results, average impact factor of journals, and the presence of COI and funding disclosure statements. Results: Sixty-nine studies were included in the systematic review. Prevalence of COI and funding disclosures was low, at 33% and 58%, respectively; time trends showed some improvement between 2002 to 2007, but only 60% of studies had disclosures by 2007. Predictors of COI disclosure were publication in high impact factor journals (p<0.001), large study sample size (p=0.001), enrollment exclusively in the US (p=0.04), and study of the targeted therapy in combination with other agents as opposed to the study drug alone (p=0.03). Studies with multiple sites were more likely to include a funding disclosure statement (p=0.01). Conclusions: There is need for more consistent disclosure of potential sources of bias in COI and funding statements in studies of off-label indications for anti-cancer targeted therapies.
Cost-effectiveness of biomarker-directed bevacizumab for first-line therapy of persons with metastatic colorectal cancer.
Authors: Berry Kristin , Bensink Mark Eliot , Musa Zahra , Shankaran Veena , Lin Edward H. , Ladabaum Uri , Bodnar Carolyn , Birt Michael , Ramsey Scott David
Published: March 2020

6077

Background: When added to first-line chemotherapy for metastatic colorectal cancer, bevacizumab provides a moderate survival increase, but is associated with significant adverse events and high cost. As only a minority of patients respond to antiangiogenic therapy, a diagnostic that identifies potential responders ex ante could potentially change the benefit to risk profile of bevacizumab and likely improve cost-effectiveness. Since efforts to identify a predictive test have so far been unsuccessful, a novel strategy may be to measure tumor response after bevacizumab treatment initiation using an in vivo biomarker test to guide decisions on whether patients should continue treatment. The objective is to estimate the cost-effectiveness of biomarker-directed use of bevacizumab in first-line treatment of metastatic colorectal cancer compared to standard care. Methods: The analysis takes the perspective of the US healthcare system. A decision model was built to estimate the incremental effect of adding bevacizumab to IFL, FOLFIRI, 5FU/LV and FOLOFOX/XELOX regimens. Survival data, estimated through a meta-analysis of four clinical trials, combined with utilities from the literature were used to calculate quality-adjusted life years (QALYs). Costs were based on Medicare reimbursement and expert opinion. Assumed performance characteristics of the biomarker technology (sensitivity, specificity – provided by our industry partner) were 75% and 95% 10 days after commencement of bevacizumab. Results: The biomarker-directed bevacizumab strategy dominated usual care, providing both an average per patient gain of 0.015 QALYs and a cost-savings of $21,038. The cost-effectiveness of the biomarker technology was most influenced by the cost of the test and colorectal cancer utilities. Variations in biomarker specificity and sensitivity changed the magnitude of cost-savings and benefit gain but did not change the overall result of dominance. Conclusions: Modeling predicts that a validated marker which could identify responders to bevacizumab will save money and improve quality-adjusted life years. The results support additional investment in identifying such a diagnostic.
Quality of life of elderly patients undergoing concomitant chemoradiation therapy for head and neck cancers, including assessment of geriatric parameters.
Authors: Extermann Martine , Fulp William J , Lee Ji-Hyun , Kish Julie Ann , Sehovic Marina , Poon Donald , Gwede Clement
Published: March 2020

6100

Background: Data on the quality of life of older patients undergoing concomitant chemoradiation therapy (CCRT) for head and neck (H&N) cancer are very scarce and no study has focused specifically on them. Furthermore, no study has assessed the contribution of geriatric symptoms to their quality of life. Methods: We prospectively assessed patients aged 65 and older undergoing curative intent CCRT for H&N cancers, either alone or adjuvantly after surgery. We used the Quality of life-Radiation Therapy Instrument (QOL-RTI), with its H&N module (Trotti et al., 1998). In addition we created a 12-items senior adult questionnaire (SAQ). Patients were assessed at baseline, at 4 weeks, at the end of treatment (EOT), and 2 months after EOT (recovery). Results: Fifty patients were enrolled. Median age was 69 years (range 65-87). Eighty-two percent of patients had locally advanced stage IV disease. Twenty-eight percent had prior surgery. All patients were treated with IMRT, 92% at 70 Gy. The most frequent chemotherapy regimen was cisplatin q3wks (58%), followed by weekly carboplatin (24%). Patients had on average 4 comorbidities (CIRS-G), 54% of them a grade 3 or 4 disease. Forty-four percent were independent in IADL, and 98% were ECOG PS 0 or 1. The baseline scores were QOL-RTI: 7.72 (SD 1.36), H&N module 7.7 (SD 2.16), SAQ 8.21 (SD 1.54). At EOT, the scores were 6.22 (1.26), 4.59 (1.82), 7.38 (1.38) respectively, and at recovery 7.17 (1.25), 6.06 (1.66), 7.96 (1.16). The scores paralleled functional evolution, as 24% of patients had an ECOG PS 2 and 76% were IADL dependent at EOT; 16% ECOG 2-3 and 55% IADL dependent at recovery. Cronbach alphas for the 3 QOL measures were 0.88, 0.89, and 0.81, suggesting adequate internal consistency reliability. The SAQ was low-to-moderately correlated with the other two QOL measures (r=0.22 to 0.59) at different points of assessment. Conclusions: Older H&N cancer patients experience significant impact of CCRT on their function, and on their quality of life on all three measures. Most recover after two months, although some may take longer. A geriatric module adds significant information to the general QOL-RTI and H&N questionnaires.
A phase I dose-escalation study evaluating weekly paclitaxel with neratinib and trastuzumab in women with metastatic HER2-positive breast cancer, NSABP FB-8.
Authors: Jankowitz Rachel Catherine , Abraham Jame , Tan Antoinette R. , Limentani Steven A. , Adamson Laura M , Buyse Marc E. , Jacobs Samuel A. , Wolmark Norman
Published: March 2020

611

Background: Dual blockade of ErbB receptors combined with chemotherapy compared with single-agent blockade improves efficacy in HER2-positive disease. FB-8 is single arm, Phase I dose-escalation study to determine safety and tolerability of weekly paclitaxel (P), the irreversible tyrosine kinase inhibitor, neratinib (N) and trastuzumab (T) in women with metastatic, HER2-positive breast cancer (MBC). Methods: Women with measurable or non-measurable MBC (ECOG PS 0 - 2) received P (80 mg/m2 IV days 1, 8, 15 of 28-day cycle), T (4 mg/kg IV, then 2 mg/kg IV weekly), and N (oral, daily). N was dose-escalated using 3+3 design at 120 mg, 160 mg, and 240 mg, dose-limiting toxicity (DLT) determined in cycle 1. All patients (pts) received prophylactic anti-diarrheals. Results: All pts were taxane and trastuzumab pre-treated, with mean of 4 prior regimens. At N=120 mg, there was 1 DLT, grade (gr) 3 diarrhea with dehydration. Three more pts were enrolled; none experienced DLT. At N=160 mg, there were no DLTs. At N=240 mg, 2 of 3 pts had DLTs: one gr 3 diarrhea and dehydration, one gr 3 diarrhea, dehydration, and gr 3 mucositis. After de-escalation to N=160 mg, 3 more pts were added. If N=160 mg is well tolerated, a 200 mg cohort is planned. 12 pts completed cycle 1. Efficacy data are available on 10: CR 1, PR 3, SD 1 (8+months). One pt* had resolution of non-target disease (skin and breast mass). 4 pts were off-study before the first scan (DLT 3 and progressive disease 1) and are considered non-responders (NR). The most frequent grade 3-4 adverse event was diarrhea, 3 pts. Conclusions: Dual anti-HER blockade with N, T combined with P is tolerable and highly active in pts pre-treated with anti-HER2 agents and chemotherapy. This combination will be studied in a phase II neoadjuvant breast cancer trial (NSABP FB-7). We thank Pfizer, Inc and Puma Biotechnology, Inc for their support. [Table: see text]
Financial relationships with commercial interests (COI) among abstracts at the ASCO Annual Meeting.
Authors: Bradbury Angela R. , Moy Beverly , Peppercorn Jeffrey M. , Egleston Brian , Sands Colleen B. , Sheikh-Salah Moktar , Storm Courtney D. , Helft Paul R.
Published: March 2020

6128

Background: ASCO has a formal policy that requires disclosure of COI with entities having a commercial interest in research. There are limited data describing the frequency and type of COI reported in cancer research and how these have changed over time. Methods: We reviewed author-reported COI for abstracts submitted for the ASCO Annual Meeting in 2006 and 2008–2011. COI are classified as employment, stock, consultant, honoraria, research, expert witness, and other. Logistic regression models were used to evaluate the association between COI and acceptance at the annual meeting and change over time. Results: 37% of all abstracts reported at least one author with a COI. Any COI increased significantly from 33% in 2006 to 39% in 2011 (p<0.001). Any COI and all categories of COI were significantly more prevalent among abstracts accepted for presentation compared to those accepted for publication only (Table). Among abstracts accepted for presentation, any COI increased from 39% in 2006 to 48% in 2011 (p<0.001) Increases by year were statistically significant for overall (p<0.001), honoraria (p=0.045), and research (p=0.002) COI. Conclusions: Many authors submitting abstracts accepted for presentation at the ASCO Annual Meeting disclose COI. Reported COI have increased over time and are significantly more frequent among abstracts accepted for presentation than for publication only. These data suggest either that cancer research increasingly involves relationships with industry or that COI reporting has become more common. Policies to manage and foster these relationships will continue to be required and revised. [Table: see text]
Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to calecheamicin, given weekly, for refractory-relapse acute lymphocytic leukemia (R-R ALL).
Authors: Jabbour Elias , O'Brien Susan Mary , Thomas Deborah A. , Jorgensen Jeffrey L. , Kebriaei Partow , Rytting Michael E. , York Sergernne , Ravandi Farhad , Kwari Monica , Faderl Stefan , Rios Mary Beth , Cortes Jorge E. , Fayad Luis , Tarnai Robert , Wang Sa , Champlin Richard E. , Advani Anjali S. , Kantarjian Hagop
Published: March 2020

6501

Background: Patients (pts) with R-R ALL have a poor prognosis. CD22 is highly expressed in ALL. We have previously reported on 49 pts with R-R ALL treated with IO at the dose of 1.8 mg/m2 every 3-4 weeks; the overall response rate was 57%. From preclinical studies, lower dose more frequent exposure schedules to IO may offer better anti-ALL activity. Methods: Pts with R-R ALL received IO 0.8 mg/m2 on Day 1, 0.5 mg/m2 on Day 8, and 0.5 mg/m2 on Day 15. The total dose per course remained the same 1.8 mg/m2. Courses were given every 3-4 weeks. Early stopping rules were implemented for an overall response rate < 40%. Results: 20 pts were treated so far. Median age was 57 yrs (range 22–84). Cytogenetics were: Ph+ in 7 (35%), t(4:11) in 2 (10%) , diploid in 3 (15%), and other in 8 (40%). CD22 was expressed in > 50% blasts in all pts and in > 90% in 14 (70%). Median number of courses so far was 2 (1–4). 9 (45%) pts received IO as salvage 1 (S1), 5 (25%) as salvage 2 (S2), 6 (30%) as salvage 3 (S3). one pt had allo SCT before IO. Median follow-up is 22 weeks (range, 7-43). Overall, 2/20 pts (10%) achieved CR, 6 had CRp (30%), 2 had marrow CR (10%), 8 were resistant, 2 died within 4 wks. Overall, CR+CRp+mCR (OR) was 50%: S1 6/9 (67%); S2 2/5 (40%); S3 2/6 (33%). Of the 10 responders, 7 pts (70%) became MRD negative. There were no clear correlations between OR and pts/ALL characteristics or with CD22 expression vs. < 90%. In 16 pts with evaluable pharmacokinetics studies, the median end of the infusion levels of IO were 117 ng/ml and 77 ng/ml in responders and non-responders, respectively. Median survival was 7+ months. Median OR duration was 5+ months. Median survival in 10 responders has not been reached. Liver function abnormalities (LFA) were noted as IO related in 7 (35%) pts, severe and reversible in 2 (10%). 4 pts were able to proceed to allo SCT (1 in CR, 3 in CRp) after a median of 4 weeks from the last infusion of IO; No cases of veno-occlusive disease were observed. Conclusions: IO given weekly is active in R-R ALL with an OR of 50%. LFAs occur and are reversible. This study of IO weekly schedule is ongoing. IO and chemotherapy combinations are being pursued.
PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation.
Authors: Cortes Jorge E. , Kim Dong-Wook , Pinilla-Ibarz Javier , Paquette Ronald , le Coutre Philipp D. , Chuah Charles , Nicolini Franck E. , Apperley Jane , Khoury Hanna Jean , Talpaz Moshe , DiPersio John F , DeAngelo Daniel J , Rea Delphine , Abruzzese Elisabetta , Müller Martin C , Baccarani Michele , Gambacorti-Passerini Carlo , Turner Christopher D. , Haluska Frank G. , Kantarjian Hagop
Published: March 2020

6503

Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Methods: The PACE (Ponatinib Ph+ALL and CML Evaluation) trial started Sept 2010. Pts with refractory CML (CP, AP or BP) or Ph+ALL resistant or intolerant (R/I) to dasatinib or nilotinib or with T315I received 45 mg ponatinib once daily. The trial is ongoing; enrollment completed Sept 2011. Data as of 17 Jan 2012 are reported. Results: 449 pts were enrolled, 5 of whom were ineligible (post-imatinib, non-T315I) but treated. Median age was 59 (18-94) yrs; 53% male. Diagnoses were: 271 CP-CML (R/I=207; T315I=64); 79 AP-CML (R/I=60; T315I=19); 94 BP/ALL (R/I=48; T315I=46). Median time from diagnosis to ponatinib was 6 yrs. Prior TKIs included imatinib (96%), dasatinib (85%), nilotinib (66%), bosutinib (7%); 94% failed ≥2 prior TKIs, 59% failed ≥3 prior TKIs. 83% had a history of resistance to dasatinib or nilotinib; 12% were purely intolerant. In CP, best response to most recent dasatinib or nilotinib was MCyR 25%. Frequent mutations confirmed at entry: 29% T315I, 8% F317L, 4% E255K, 4 % F359V, 3% G250E. Median follow-up was 6.6 months. Response rates are presented in the table. Overall, 64% remained on therapy (77% CP). Most frequent reasons for discontinuation were progression (12%) and AE (10%). Most common drug‑related AEs were thrombocytopenia (33%), rash (33%), dry skin (26%). Conclusions: Ponatinib has substantial activity in heavily pretreated pts and those with refractory T315I. Response rates continue to improve with longer follow-up. Multivariate analyses of predictors of outcome will be presented. [Table: see text]
Subcutaneous omacetaxine mepesuccinate in patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/intolerant to two or three approved tyrosine-kinase inhibitors (TKIs).
Authors: Nicolini Franck E. , Lipton Jeffrey Howard , Kantarjian Hagop , Wetzler Meir , Akard Luke Paul , Baccarani Michele , Craig Adam , Nanda Nisha , Brown Peter D. , Cortes Jorge E.
Published: March 2020

6513

Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class, reversible, transient inhibitor of protein elongation that facilitates tumor cell death without depending on BCR-ABL signaling. Clinical activity was shown in two phase 2, open-label, multicenter studies in treatment-resistant CML. Methods: A subset from the phase 2 studies included patients in CP or AP who were resistant/intolerant to ≥2 approved TKIs. Omacetaxine 1.25 mg/m2 was given SC twice daily: ≤14 consecutive days/28-day cycle for induction, ≤7 days/cycle as maintenance. Secondary results were calculated for responses by number of prior TKIs. Results: Of 122 patients (median age, 60 years), 62 had received 2 TKIs (100% imatinib; 76% dasatinib; 24% nilotinib) and 60 had received all 3 approved TKIs. Prior non-TKI therapies (eg, 52% hydroxyurea, 34% interferon) were common. Of 45 CP patients in the 2 TKI group, 12 (27%) had major cytogenetic response (MCyR; median duration of 17.7 mo), and of 36 in the 3 TKI group, 4 (11%) had MCyR (median duration not reached). Of 17 AP patients in the 2 TKI group, 6 (35%) had major hematologic response (MaHR; median duration, 13.4 mo), and of 24 in the 3 TKI group, 5 (21%) had MaHR (median duration, 6.4 mo). Median months of survival in the 2 and 3 TKI groups were 30.1 and not reached for CP and 12.0 and 24.6 for AP. Treatment-related grade 3/4 adverse events (AEs) occurred in 52 (84%) patients in the 2 TKI group and 42 (70%) in the 3 TKI group (most common: thrombocytopenia [71%, 48%]). Fifteen (24%) and 16 (27%) had an AE leading to discontinuation, primarily disease progression. There were 20 deaths (primarily disease progression), 11 in the 2 TKI group and 9 in the 3 TKI group; 4 were considered related to treatment (sepsis in 2, pancytopenia, febrile neutropenia). Conclusions: In patients with heavily pretreated CML, response to omacetaxine therapy occurred whether they had received 2 or 3 prior TKIs. The drug was well tolerated. Tolerability was similar across the TKI groups in both CP and AP patients. Support: Teva Pharmaceutical Industries Ltd.