bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carboplatin (C) versus paclitaxel and carboplatin alone for the treatment of advanced non-small cell lung cancer (NSCLC).
Authors: Fidias P. , Ciuleanu T. A. , Gladkov O. , Manikhas G. M. , Bondarenko I. N. , Pluzanska A. , Ramlau R. , Lynch T. J.
Published: February 2017

LBA7007

Background: NOV-002 is a formulation of disodium glutathione disulfide (GSSG). GSSG is a naturally occurring substance that functions as a component of the glutathione (GSH) pathway, vital to the regulation of the intracellular redox state. A key function of the GSH/GSSG redox couple is to dynamically regulate protein functions, including cell signaling pathways, through the reversible formation of mixed disulfides between protein cysteines and GSH (S-glutathionylation). Based on positive results from a randomized, phase I/II study of carboplatin and paclitaxel (CP) with or without NOV-002, as well as positive results from 2 ex-U.S. phase II studies with cisplatin-based chemotherapy, an international phase III randomized trial was launched.

Methods: Patients with advanced NSCLC (stages wet IIIB and IV, inclusive of all histological subtypes) were eligible if they had a PS of 0-1 and adequate end-organ function. Patients with CNS metastases were excluded. Eligible patients were randomized to C (AUC 6), P (200 mg/m2), and NOV-002 (Group A) or C and P alone (Group B). NOV-002 was administered as two-60 mg IV boluses on day -1 of cycle 1 and as one IV bolus on day 1 of each cycle, followed by daily 60-mg subcutaneous injections. A total of 725 events were required to detect a difference in overall survival (OS) from 10.0 to 12.5 months with 85% power and a two-sided significance level of 0.05. No interim analysis was performed.

Results: From 11/06 until 9/09, 903 patients were randomized, with target enrollment reached in March 2008. Patient characteristics for Groups A and B were as follows: stage IV (91.5/90.8%), PS 1 (76.6/72.6%), male (69.9/72.4%), never smoker (22.3/19.1%) median age (59.6/59.5), and histology (adenocarcinoma [40.0/36.8%] squamous [41.2/40.8%]). The median overall survival for Groups A and B was 10.2/10.8 months (p = 0.375), median progression-free survival was 5.3/5.6 months, objective response rate was 26.6/26.0% and 54/53% of patients completed at least six cycles of chemotherapy. Major toxicities for Groups A and B included grade 3/4 neutropenia (29.7/26.3%), febrile neutropenia (2.2/1.8%), grade 3/4 thrombocytopenia (3.8/2.9%), and grade 3/4 neuropathy (2.9/2.4%). Adverse events resulting in death in Groups A and B were reported in 5.6 and 3.1%, respectively.

Conclusions: The addition of NOV-002 to CP does not improve overall survival in patients with advanced NSCLC. NOV002 does not appear to add to the overall toxicity of chemotherapy.

[Table: see text]
Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC).
Authors: Kris M. G. , Johnson B. E. , Kwiatkowski D. J. , Iafrate A. J. , Wistuba I. I. , Aronson S. L. , Engelman J. A. , Shyr Y. , Khuri F. R. , Rudin C. M. , Garon E. B. , Pao W. , Schiller J. H. , Haura E. B. , Shirai K. , Giaccone G. , Berry L. D. , Kugler K. , Minna J. D. , Bunn P. A.
Published: February 2017

CRA7506

Background: The ability to detect driver mutations like EGFR and EML4-ALK in tumor specimens from patients with lung cancer and administer agents targeting those molecular lesions has revolutionized the management of adenocarcinoma of the lung. The availability of multiplexed assays to detect mutations permits the identification of multiple driver mutations from tumors at diagnosis. The number of molecular lesions and new agents to target them continues to grow. To exploit this, we created the LCMC to determine 10 driver mutations in tumors from 1,000 patients and to give the results to clinicians for care and entry onto targeted therapeutic trials based on these findings. Methods: The 14 member LCMC is prospectively enrolling patients to test tumors from patients with lung adenocarcinoma in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS using standard multiplexed assays and fluorescence in situ hybridization (FISH) for ALK rearrangements and MET amplifications. All are stage IIIB/IV, PS 0-2, have available tissue, and signed consent. Results: 830 patients have been registered with 50 enrolling monthly. We detected a driver mutation in 60% (252/422, 95% CI 55 to 65%) of tumors thus far. Mutations found: KRAS 107 (25%, 95% CI 21 to 30%), EGFR 98 (23%, 95% CI 19 to 27%), ALK rearrangements 14 (6%, 95% CI 4 to11%), BRAF 12 (3%, 95% CI 1 to 5%), PIK3CA 11 (3%, 95% CI 1 to 5%), MET amplifications 4 (2%, 95% CI 0.5 to 5%), HER2 3, (1%, 95% CI 0.1 to 2%), MEK1 2 (0.4%, 95% CI 0.1 to 2%), NRAS 1 (0.2%, 95% CI 0.01 to 1%), AKT1 0 (0%, 95% CI 0 to 1%). 95% of molecular lesions were mutually exclusive. Conclusions: We detected an actionable driver mutation in 60% of tumors from prospectively studied patients with lung adenocarcinoma. Results of EGFR mutation testing are given to treating physicians to select erlotinib as initial treatment per NCCN and ASCO guidelines. Patients with other driver mutations are offered participation in LCMC-linked trials of agents targeting the mutation identified, e.g. crizotinib with EML4-ALK. At half of LCMC sites, multiplexed testing for all mutations is now routine practice in their pathology departments. Supported by 1RC2CA148394-01.
The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40.
Authors: Bear H. D. , Tang G. , Rastogi P. , Geyer C. E. , Robidoux A. , Atkins J. N. , Baez L. , Brufsky A. , Mehta R. S. , Fehrenbacher L. , Pajon E. R. , Senecal F. M. , Gaur R. , Margolese R. G. , Adams P. T. , Gross H. M. , Swain S. M. , Mamounas E. P. , Costantino J. P. , Wolmark N.
Published: February 2017

LBA1005

Background: The addition of capecitabine (X), gemcitabine (G), and bevacizumab (B) to taxanes have each improved PFS in metastatic breast cancer. The primary aims of this trial were to determine if adding X or G to docetaxel (T) → AC will increase breast pathologic complete response (pCR) rates in operable, HER2-negative breast cancer and if adding B to T-based regimens →AC will increase pCR rates. Secondary aims included assessment of clinical complete response (cCR) rates. Methods: Pts received one of 3 T-based regimens, with or without B, 15mg/kg, q3wks x 4: T 100 mg/m2 day 1; T 75 mg/m2 day 1 and X 825 mg/m2 BID days 1-14; or T 75 mg/m2 day 1 and G 1000 mg/m2 days 1 and 8. Pts then received preoperative AC x 4, with or without B for the initial 2 cycles of AC. Pts randomized to B resumed B for 10 postop doses. The primary endpoint was pCR in the breast. The maximum of the standardized pairwise differences between pCR rate for the T → AC regimen and for the other 2 T-based regimens was used as the test statistic to adjust for multiple comparisons. Fisher’s exact test was used to compare the arms with and without B. Results: The groups were balanced, with 47% clinically node+, 56% poorly differentiated, and 59% HR+. Assessments for pCR were available from 1180 of 1206 randomized patients. pCR for TX and TG were 29.7% and 32% vs. 32.7% for T. Neither TX nor TG increased cCR rates relative to T (58.3% and 60.4% vs. 61.5%). TX and TG increased toxicity. Addition of B increased the pCR rate (28.4 vs. 34.5%, p=0.027) and the cCR rate (55.8 vs. 64.3%, p=0.007). The effect of B was predominantly in the HR+ subset (15.2 vs. 23.3%, p=0.008) with minimal effect in the HR- subset (47.3% vs. 51.3%, p=0.44). Grades 2/3/4 toxicities increased with B were HTN (1/<1/0% vs. 13/9/<1%), HFS (11/7/0% vs. 15/11/0%), and mucositis (10/3/0% vs. 20/5/0%). Conclusions: The addition of B to neoadjuvant chemotherapy improved pCR and cCR rates, but the addition of X or G to T did not improve outcomes. Follow-up for wound healing issues and DFS will help define the role of B in the treatment of early breast cancer. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U10-CA-44066, and F. Hoffmann La-Roche, Ltd., Genentech, USA, and Eli Lilly.
Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF).
Authors: Harrison C. N. , Kiladjian J. , Al-Ali H. K. , Gisslinger H. , Waltzman R. J. , Stalbovskaya V. , McQuitty M. , Hunter D. S. , Levy R. S. , Cervantes F. , Vannucchi A. M. , Barbui T. , Barosi G.
Published: February 2017

LBA6501

Background: MF, a myeloproliferative neoplasm characterized by dysregulation of the JAK pathway, is associated with splenomegaly, constitutional symptoms and reduced lifespan. Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor. Methods: COMFORT-II, a randomized (2:1) phase III study, compared the efficacy and safety of ruxolitinib PO BID with BAT (other agents or no therapy) in adults with intermediate-2 or high-risk (Cervantes et al, Blood 2009) PMF, PPV-MF or PET-MF and palpable splenomegaly. The primary endpoint was the proportion of patients (pts), stratified by baseline risk category, achieving ≥ 35% reduction in spleen volume at week (wk) 48 determined by MRI or CT. The key secondary endpoint was the proportion achieving ≥ 35% reduction in spleen volume at wk 24. Results: 219 pts were randomized: 146 to ruxolitinib and 73 to BAT. Both arms included 49% high- and 51% intermediate-2 risk pts. The wk 48 response rate was 28.5% vs 0% (ruxolitinib vs BAT, P < .0001). The wk 24 response rate was 31.9% vs 0% (ruxolitinib vs BAT, P < .0001). Median duration of response to ruxolitinib was 48 wks. The most common (> 20%) adverse events (AEs) of any grade were (ruxolitinib vs BAT) thrombocytopenia (44.5% vs 9.6%), anemia (40.4% vs 12.3%), diarrhea (24.0% vs 11.0%), and peripheral edema (21.9% vs 26.0%). Grade 3-4 AEs occurring in ≥ 5% of pts in the ruxolitinib arm were: anemia (11%) and thrombocytopenia (7.5%). The most frequent grade 3-4 AEs in the BAT arm were anemia, thrombocytopenia, pneumonia and dyspnea (each 4.1%). Seven deaths occurred on treatment or within 28 days after end of treatment: 4 (2.7%) ruxolitinib and 3 (4.1%) BAT. Disposition of discontinuations were (ruxolitinib vs BAT) 8.2% vs 5.5% due to AEs and 1.4% vs 12.3% due to withdrawn consent. Conclusions: The COMFORT-II study demonstrates that ruxolitinib provides marked and sustained clinical benefit in spleen size and an acceptable safety profile relative to BAT, extends the positive results of COMFORT-I which compared ruxolitinib with placebo, and may result in a new standard of care for a large number of patients with MF.
A phase III study of receptor-targeted 99mTc-tilmanocept versus blue dye in the evaluation of SLNs in breast cancer and melanoma.
Authors: Cope F. O. , Sondak V. K. , Wallace A. M.
Published: February 2017

LBA8526^

Background: Intraoperative lymphatic mapping (ILM) evaluation is widely used for staging clinically node-negative breast CA and melanoma. [99mTc]Tilmanocept (TcT) is a novel CD206 receptor-targeted (intra-nodal CD206+ RE cells) radiopharmaceutical designed for ILM of nodes (LNs) with anatomic nexuses to the tumor bed. We report the results of a Phase III, multicenter trial designed to assess the ILM performance of TcT vs the approved standard, vital blue dye (VBD) in both melanoma and breast CA patients (pts). Methods: 8 centers provided 153 pts w/ 10 melanoma or breast CA (ECOG 0-2; T1-4, N0, M0). TcT (50 µg @ 0.5-1.0mC i 99mTc) and VBD (per label) were injected to each pt; ILM was performed w/ a hand held γ-detector (for TcT) and visual eval (for VBD); all γ+ and blue+ LNs were excised and histologically examined. TcT was injected per study center practice (subareolar and intradermal injection w/ >0.5 hr wait); VBD was injected at surgery. The 10 endpoints were concordance w/ TcT and VBD (% of LNs detected by VBD and identified by TcT) and reverse concordance (% LNs detected by TcT and identified by VBD); path +/- per localization of TcT and VBD were also assessed. Pts were assessed for lab safety and AEs. Results: (Table) VBD pts (standard ILM pt metric) who expressed ≥1 VBD+ LN equate to the intent-to-treat (ITT) group. Conversely, the reverse ITT (RITT) group consisted of pts expressing ≥1 γ+ node. The analyses of the 10 endpoints are estimates of the 95% CIs. The 10 hypothesis is H0: R ≤0.90 vs Ha: R >0.90; R = concordance rate (2-sided, α = 0.05). Additional contrasts include tests for Δ residual disease (path) and effect on pt staging. Conclusions: The receptor targeted ILM agent, TcT, provided clinically superior results compared to label-approved VBD. TcT localization of occult disease was significantly improved vs VBD. The results suggest that receptor targeting of the lymphatic RE cells is a key development in ILM of LN metastasis.

[Table: see text]
Association between bisphosphonate use in metastatic breast cancer (MBC) and overall survival.
Authors: Mathew A. , Rosenzweig M. Q. , Brufsky A.
Published: February 2017

102

Background: Preclinical studies on bisphosphonates in breast cancer have suggested an anti-tumor effect in addition to its bone protective role. However, randomized controlled trials of bisphosphonates versus placebo have found little evidence of increased overall survival (OS) in MBC. We conducted a retrospective single-institution cohort study of MBC patients to evaluate the association between bisphosphonate use and overall survival.

Methods: Baseline demographic and tumor specific data were collected on newly diagnosed MBC patients between January 1998 and December 2009. Other variables included the number and sites of each metastasis, use of baseline neoadjuvant and adjuvant chemotherapy, and use of hormone therapy. Bisphosphonate use was defined as present if it was administered for a period of at least 3 months in the metastatic setting. Overall survival was determined from the date of diagnosis of first metastatic disease. Survival analysis was performed using the Kaplan-Meier method and Cox proportional-hazards model.

Results: Data were available on 737 patients with MBC, of whom 434 died during a median follow-up of 2 years; median age was 50.3 years. 92% of patients were Caucasian; 32% were both ER and PR-negative; and 31% were HER2-positive. Over 67% of MBC patients had bone metastasis and nearly 80% received bisphosphonates. Multivariate analysis found an overall survival benefit for bisphosphonate use, with a hazard ratio of 0.63 (95% confidence interval: 0.48-0.84; p<0.002), when adjusted for variables with significant effect on survival on univariate analysis and other known prognostic variables. These variables include age, stage at diagnosis, race, hormone receptor status, HER2 status, and number of metastatic sites, presence of bone metastasis and the use of adjuvant therapy. The administration of adjuvant therapy did not yield a significant survival advantage in the analyses.

Conclusions: This retrospective cohort study provides evidence for an OS benefit with the use of bisphosphonates in MBC even after controlling for other significant prognostic factors.
Statin treatment use in diabetic patients with breast cancer: A potential C-reactive protein mediated benefit.
Authors: Ceacareanu A. C. , Hong C. , Brennan J. J. , Epstein M. , Kossoff E. , Nimako G. K. , Patel K. , Forrest A.
Published: February 2017

173

Background: Statin treatment has not yet been evaluated in relation to breast cancer (BC) prognosis in diabetes mellitus (DM) patients. Reported decreased survival following BC in women with metabolic syndrome, led us to investigate whether specific statin therapy may lead to improved BC survival. Reported associations between elevated C-reactive protein (CRP) levels at the time of diagnosis with worse cancer prognosis, and CRP-lowering properties of statin treatment in non-cancer patients, led us to investigate whether statin use is associated with lower CRP levels at the time of BC diagnosis and with improved BC outcomes.

Methods: All DM patients newly diagnosed with BC between 2003 and 2007 (Roswell Park Cancer Institute) were retrospectively reviewed (n = 225). BC pathology, outcomes, existing comorbidities and drug therapy were documented. Follow up began at BC diagnosis and ended with first confirmed recurrence and/or death, or last date of follow-up. Hazard ratios (HR) and 95% confidence intervals (CI)s representing the association between statins, BC and a defined event were computed with Cox proportional hazards model. CRP plasma levels were determined by enzyme-linked immunosorbent assay in specimens donated at the time of BC diagnosis. A total of 98 study patients, DM+BC, and their matched controls, BC only (n = 196) were analyzed.

Results: After a median follow up of 30 months, patients receiving statins for cholesterol management were found to have better disease-free survival (HR 0.27, 95% CI: 0.10, 0.71, X2 = 7.31, p = 0.06), and lower overall mortality (HR 0.23, 95% CI: 0.08, 0.66, X2 = 7.80, p = 0.05) compared to patients not receiving any cholesterol management medication. CRP levels have ranged between 0.2 and 21 mg/L and clinically relevant levels ( > 3mg/L) were noted in the study group.

Conclusions: This study explored for the first time the association between statin therapy and BC prognosis in DM. We observed improved outcomes in statin-treated patients. While we currently analyze statin therapy in relationship with baseline CRP levels and BC prognosis, our existing findings suggest that statins have the potential to improve BC outcomes potentially through lowering overall inflammation.
Demography and treatment outcomes of triple-negative breast cancer: A single institution study.
Authors: James S. E. , Vos P. , Biswas T.
Published: February 2017

179

Background: Triple negative breast cancer (TNBC) constitutes about 11-20% of all cases of breast cancer. TNBC has particularly aggressive clinical course and worse prognosis especially in African American (AA) women compared to white women. This retrospective study aims to investigate TNBC in the eastern North Carolina (NC) population, report treatment outcomes and determine the rate of recurrence.

Methods: 202 TNBC patients treated at our institution between 1/01 and 11/09 were included in this analysis. Eastern NC has an AA population higher than the national average (30.2% vs. 12.4%) which is reflected in our patient demographics with 111 (55%) AA, 84 (41.6%) White, 5 (2.5%) Hispanic and 2 (1%) Chinese patients. Stage distribution was 41 (20%) stage I, 97 (48%) stage II, 37 (18%) stage III, 16 (8%) stage IV disease. Six patients (3%) had a diagnosis of DCIS and 5 (3%) were unknown. Majority was (79%) poorly differentiated carcinoma followed by moderately differentiated (13%) carcinoma. Variables were compared between groups using two-sample t-tests. Kaplan Meier curves were generated for overall survival (OS). Group was compared by log rank test.

Results: The median FU time was 4.73 years (1.2–10.2). Median age at diagnosis was 53 (22-88) years overall, 51 years for AA and 57 years for White (p=0.01) patients. The overall median survival was 32.18 months with no difference between AA (32.39 months) and white (29.7 months) patients (p=0.785). 160 patients with stage I-III disease received chemotherapy with 96 patients (60%) receiving adjuvant and 64 (40%) receiving neoadjuvant therapy. The median survival for adjuvant patients was 37.08 months (6.87–113) vs 26.48 months (1.51–87.49) for neoadjuvant patients (p=0.001). 27 (14%) patients with stage I-III diseases experienced a local recurrence, 31 patients (15%) experienced distal recurrence with a median time to failure of 25.6 months.

Conclusions: This study demonstrated no significant difference in median survival between AA and white patients; however, AA women were diagnosed at a younger age compared to white women. Patients treated with adjuvant chemotherapy had a significantly greater median survival when compared to patients receiving neoadjuvant treatment.
Reasons for choosing contralateral prophylactic mastectomies in women who test negative for the BRCA mutation: A retrospective questionnaire.
Authors: Howard-McNatt M. M. , Hurt G. , Levine E. A. ,   Society Surgical Oncology
Published: February 2017

192

Background: Determination of BRCA1and 2 mutation carrier’s status has become increasingly important. BRCA1/2 carriers are offered bilateral mastectomy (BLM) and prophylactic oophorectomy. Those who test negative typically do not undergo such extensive surgery. However, there is a cohort of women who still decide to have BLM at the time of their breast cancer diagnosis despite testing negative for the mutation. A questionnaire was sent to women who had prophylactic mastectomies to determine the reasons for their surgical choice.

Methods: Women who received BRCA1 and 2 testing and tested negative but chose bilateral mastectomies between January 2005- May, 2010 were sent a questionnaire. For those who expressed an opinion, a two-sided Fisher exact test was used to compare responses. Patient demographics, family history, reasons for choosing mastectomy, and satisfaction were recorded.

Results: A total of 35 surveys were mailed, and 28 were returned (80%). The mean patient age at diagnosis was 41.9 years. The majority of women were Caucasian, had some college to postgraduate education, and had children. 64% had a relative with breast cancer. Fear was the main reason why these women choose BLM. The majority had breast reconstruction and overall 71% were very satisfied with their surgical choice.

Conclusions: Increased rates of contralateral prophylactic mastectomies have been observed in women with negative BRCA results. In our study Caucasian, educated, married women were more likely to choose BLM. The main reason women gave for choosing BLM was fear of recurrence. Prospective studies are needed to examine factors effecting patient decision-making.
What factors affect the place of end-of-life care for patients with metastatic breast cancer?
Authors: Harano K. , Yonemori K. , Hashimoto K. , Yunokawa M. , Shimizu C. , Tamura K. , Katsumata N. , Ando M. , Fujiwara Y.
Published: February 2017

218

Background: Despite the early detection and treatment, advanced breast cancer is still impossible to cure. Palliative care has become the standard of care at the time of end-of-life (EOL). However, there are limited data about the degree of access to such care and the factors that affect the choice of place to die. The purpose of this study is to identify factors that affect the place of EOL care in patients with metastatic breast cancer in Japan.

Methods: Our study included breast cancer patients who were diagnosed with recurrence or metastatic diseases between 2004 and 2010 at the National Cancer Center Hospital and received EOL care. The following data were obtained: treatments, place of EOL care, and social background such as age, whether patients had young children, whether patients had elderly family members who needed nursing care, whether patients had jobs at the time of recurrence, and where they lived in.

Results: Overall, 124 patients met our inclusion criteria. Among them, only 13% of patients received EOL care at home and 43.5% of patients at hospices, while 43.5% of patients died in acute care beds. Patients who had jobs at the time of recurrence were significantly more likely to receive EOL care in acute care beds (odds ratio 2.46; 95% CI 1.04−5.83). Other social backgrounds were not significantly related to the place of EOL care.

Conclusions: A sizable proportion of patients, especially patients who had jobs at the time of recurrence, received acute care at the EOL and did not have access to palliative care at home or hospices. Familial backgrounds were not the determinant to choose the place of EOL.
Purinergic mechanisms in breast cancer metastasis.
Authors: Buxton I. L.
Published: February 2017

229

Background: Breast cancers survive in patients in a dormant state only to grow as metastatic disease in the future. Surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. Many breast cancer deaths might be averted if we understand the cellular mechanisms underlying escape from dormancy. We have proposed that extracellular nucleotide signaling constitutes a pathological axis from the transformed tumor cell to the endothelium in the service of intravasation, dissemination, extravasation and angiogenesis. We demonstrate a role for the dinucleotide kinase NM23/NDPK in the generation of signals that stimulate angiogenesis and escape from latency.

Methods: We have employed protein purification and identification by Western blot, tubulogenesis, migration and proliferation assays in human endothelial cells, signaling assays of receptor activation, nucleotide and receptor transactivation/phosphorylation assays and tumor growth and metastasis imaging in immunocompromized mice (SCID) to establish a role of r nucleotides in breast cancer metastasis.

Results: A panel of breast cancer cell lines, but not normal breast cells, shed/secrete large amounts of NM23 that is active as an ADP transphosphorylase. NM23 stimulates tubulogenesis, proliferation and migration in cultures of human endothelial cells in a manner blocked by purinergic receptor antagonist, inhibitors of the nucleoside diphosphate kinase activity of NM23, or by VEGFR2 antagonists. In SCID mice carrying MDA-MB-231 luciferase over-expressing breast cancers, NM23 appears in the blood early in tumorigenesis. Treatment with the P2Y1 receptor antagonist MRS2179, or the NM23 antagonist ellagic acid slows the growth of primary breast tumors and prevents metastatic tumor formation.

Conclusions: NM23 secretion leading to nucleotide generation activates endothelial P2Y1 receptors resulting in transactivation of VEGFR2 and angiogenesis in support of metastasis. Identification of Nm23 as a marker of early of breast cancer development and blockade of the extracellular actions of NM23 offer a new approach to breast cancer detection and treatment.
Reproductive health algorithm.
Authors: Patel A. , Radeke E. K. , Uy A. , Zaren H. A.
Published: February 2017

263

Background: About 692,000 women are newly diagnosed with various cancers yearly in the US, with breast being the most common, and 10% within reproductive age group. When concerned about survival, reproductive health is overlooked. The objective of this study was to incorporate a reproductive health algorithm into oncologic care of reproductive aged women.

Methods: This prospective observational study was conducted at John H. Stroger, Jr. Hospital of Cook County. Eleven newly diagnosed patients were recruited. The algorithm was implemented for each participant and they were surveyed quarterly for 2 years.

Results: The mean age of participants was 39 and mean living children was 1.9. Of the 11 women, two (18%) were pregnant at the time of recruitment and nine were not. Both pregnant subjects had an obstetric consultation and chose to continue the pregnancies. They delivered without complications. One began chemotherapy in the second trimester, the other began postpartum. After completion of the pregnancies, these women went into the “not pregnant” cohort. Of the now 11 women in the “not pregnant” cohort, one (9%) had not completed childbearing and 10 (91%) had. The one woman interested in childbearing underwent REI consultation and fertility preservation counseling. Of the women who had completed childbearing, 70% had adopted a long term contraceptive method, 10% a short term method and 20% were abstinent. All 11 women had a family planning consultation. Eighteen percent had already undergone permanent sterilization and 27% had an IUD in place at the time of diagnosis. An additional 27% selected an IUD. Seventy-two percent continued or began long term contraception. Eighteen percent remained abstinent throughout study period.

Conclusions: Conclusions from this study demonstrate that with the intervention of the algorithm and referral system, 100% of patients had a basic management plan consistent with reproductive health goals. Most selected a form of long term contraception prior to or on study. All sexually active women had a contraceptive plan in place post diagnosis and during treatment of cancer consistent with long term reproductive health goals. A cluster-design, multicenter, randomized controlled trial has been developed to further investigate and validate our findings.
A multicenter, open-label phase II trial of dovitinib, a fibroblast growth factor receptor 1 (FGFR1) inhibitor, in FGFR1-amplified and nonamplified metastatic breast cancer (BC).
Authors: Andre F. , Bachelot T. D. , Campone M. , Dalenc F. , Perez-Garcia J. M. , Hurvitz S. A. , Turner N. C. , Rugo H. S. , Baselga J. , Zhang Y. ,   Novartis Oncology Clinical Group
Published: February 2017

289

Background: Amplification of the FGFR1 gene occurs in ≈ 10% of BC, correlates with FGFR1 overexpression, and is mainly observed in estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)- BCs. Dovitinib (TKI258) is a multitargeted tyrosine kinase inhibitor that demonstrated potent antitumor activities in FGFR1-amplified tumor cell lines. This phase 2 study evaluated the efficacy and safety of dovitinib in metastatic HER2- BC.

Methods: Patients were stratified into 4 groups based on FGFR1 and hormone receptor (HR) tumor subtype: 1) FGFR1+, HR+; 2) FGFR1+, HR-; 3) FGFR1-, HR+; 4) FGFR1-, HR-. Screening for FGFR1 status was performed by fluorescence/chromogenic in situ hybridization (cutoff ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day-on/ 2-day-off schedule. The primary endpoint was RECIST best overall response rate in patients with measurable disease per external radiology review.

Results: Data from 77 of 81 treated patients were available as of January 2011 (n=21, n=34, n=22 in groups 1, 3, 4, respectively). Median number of prior therapies in the metastatic setting was 2 chemotherapy lines (all patients) and 2 endocrine therapy lines (HR+ patients). Liver metastases were present in 58% of patients (81%, 50%, 50% in groups 1, 3, 4, respectively). Most common adverse events included vomiting (75%; grade 3 [g3]: 6%), diarrhea (72%; g3: 6%), nausea (62%; g3: 5%), and asthenia (61%; g3: 17%). Median dovitinib exposure was 1.7 (range, 0-8.2) months, including 8 patients with > 4 months of therapy. Of patients with measurable disease at baseline, in group 1, 13% had unconfirmed partial responses and 44% had stable disease ≥ 4 months (SD4). In groups 3 and 4, 29% and 11% had SD4.

Conclusions: This is the first trial reporting efficacy of an FGFR1 inhibitor in patients with FGFR1-amplified BC. Dovitinib showed antitumor activity in patients with HR+, FGFR1- amplified BC and disease stabilization in other subgroups. FGFR1 is likely a relevant target in BC, and FGFR1 amplification may define a segment of dovitinib-sensitive disease. Further evaluation of dovitinib in patients with HR+ BC is planned.
The effects of substance P fragments on breast cancer cells.
Authors: Oz E. , Aydemir E. , Korcum A. F. , Fiskin K.
Published: February 2017

295

Background: Substance P (SP), a neuropeptide, is known to induce tumor cell proliferation. In contrast with intact peptide, the fragments of SP are suggested to inhibit the growth of various cancer cells. The aim of the present study was to determine cytotoxic effects of physiological fragments of SP either alone or in combination with radiotherapy on mouse breast cancer cells.

Methods: In this study, we tested the physiological fragments of SP such as SP (4-11), SP (6-11) and SP (1-7). Dose-response and time-course studies were carried out with various concentrations (100-0.001 nM) of SP fragments and the intact peptide. 4T1 mouse breast cancer cell lines were used in this study. The cytotoxic effect of SP fragments alone or in combination with radiotherapy was determined via WST-1 assay. Changes in substance P amounts in cells and in mediums determined by SP EIA kit.

Results: SP(4-11) and SP(6-11), but not SP(1-7), inhibited the proliferation of breast cancer cells and potentiated antitumor effects of radiotherapy. Moreover, the intact peptide alone did not alter the proliferation rate of 4T1 cells and the cytotoxic effects of the fragments were not inhibited by SP.

Conclusions: These results demonstrate that combined treatment with 2 fragments of SP (4-11 and 6-11) and radiotherapy induce cytotoxic effects. These data may provide the basis for a strategy, in which it is possible to use SP fragments and radiotherapy together to improve the efficiency of the independent therapies.
Brain metastasis-free survival in patients with HER2-positive metastatic breast cancer.
Authors: Berghoff A. , Bago-Horvath Z. , Dubsky P. C. , Rudas M. , Pluschnig U. , Rottenfusser A. , Gnant M. , Steger G. G. , Zielinski C. , Bartsch R.
Published: February 2017

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Background: Brain metastases (BM) are diagnosed in up to 40% of patients with HER2-positive metastatic breast cancer (MBC). Since the introduction of trastuzumab in 1999, a rising incidence of BM was reported. We aimed to identify factors that prolong BM free survival (BMFS) in all HER2-positive patients (pts) treated for MBC at the Medical University of Vienna from 1999-2009.

Methods: BMFS was defined as primary study endpoint and measured as the interval from diagnosis of metastatic disease until diagnosis of brain metastases. 201 pts with HER2-positive MBC were identified from a breast cancer database. 82 pts (40.8%) were diagnosed with BM; 13 pts were excluded from this analysis as brain was the first site of disease progression. Complete data sets of 69 pts with pathologically verified HER2-positive MBC were available. HER2 status was analyzed by immunohistochemistry and reanalyzed by FISH if a score of 2= was gained. BMFS was estimated by using the Kaplan-Meier product-limit method; factors significantly associated with BMFS in the univariate analysis were included into a Cox proportional hazard model.

Results: Median BMFS was 25 months (m; 95%CI 13.37-36.63 m). Trastuzumab-based treatment significantly prolonged median BMFS (29 vs. 11 m; p<0.01); BMFS was further improved by trastuzumab treatment in multiple lines (30 vs. 17 m; p=0.045). Co-positivity for estrogen receptor (ER) and HER2 predicted for longer BMFS (30 vs. 15 m; p<0.05). Further variables such as prior exposure to capecitabine, presence of visceral metastasis, presence of lung metastasis, stage IV disease at primary diagnosis, as well as disease free interval from adjuvant therapy were not significantly associated with BMFS. In the Cox regression model, positive ER status (HR 2.03; 95%CI 1.22-3.36; p<0.05) and trastuzumab-based treatment (HR 2.72; 95%CI 1.20-6.17; p=0.017) remained independent predictors for longer BMFS.

Conclusions: Trastuzumab-based therapy significantly prolongs BMFS in HER2-positive pts with MBC, probably due to improved systemic disease control. In line with known better survival outcome, ER/HER2 co-positive disease appears to be a less aggressive subtype of HER2-positive breast cancer associated with longer BMFS.
Quantitative nuclease protection assay (qNPA) for gene expression analysis on breast cancer core biopsies.
Authors: Evangelist M. C. , Snider J. , Krushkal J. , Qu Y. , Kulkarni A. , Kerns B. , Seligmann B. , Sachdev J. C.
Published: February 2017

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Background: qNPA employs in situ hybridization of detection probes to cross linked mRNA, making it ideal for formalin fixed paraffin embedded (FFPE) tissue. It has been shown to measure gene expression in archived lymphoid and lung cancer tissue. We assessed the feasibility of qNPA to measure differentially expressed genes in pretreatment FFPE core breast biopsies among pathologic responders (pR) and nonresponders (pNR) to preoperative chemotherapy.

Methods: We included preoperative breast cancer patients treated at our institution from 2003-09 with FFPE core biopsies. mRNA expression of 170 genes, representing oncogenic pathways or associated with anthracycline and taxane response was measured by qNPA (HTG, Tucson, AZ). Data was normalized to 3 housekeeper genes and average of 3 biologic replicates reported. Seven genes below detection in > 50% samples were excluded. Expression values of 163 unique genes were analyzed for pR vs pNR with dChip software. Empirical FDR was estimated using 1,000 permutations of sample labels.

Results: Treatment and response: Sample failure: 6/57 (10%). pR vs pNR did not separate on hierarchical clustering. FLJ12650 and IGFBP2 showed lower expression in pR vs pNR with fold changes of 4.09 and 2.40, respectively (p < 0.01; median FDR: 1/163). FLJ12650 was significant (p < 0.01, median FDR: 0/163) when patients receiving anthracycline ± taxane were analyzed (groups 1-3) and showed a trend (p < 0.05) in group 1 alone.

Conclusions: qNPA for limited available FFPE tissue from core biopsies is feasible with acceptable sample failure rates. Small sample size and number of analyzed genes limited definitive conclusion about informative genes in our study. Our FLJ12650 results, a gene coding for membrane Na+/K+ ATPase interacting protein, are consistent with previous findings of overexpression in pNR to anthracyclines + taxanes (Hess et al, JCO 2006, Vol 24; 4236) using fresh tissue. Future qNPA validation of predictive markers, identified by whole transcriptome analysis in a homogenous cohort may provide more definitive results.

[Table: see text]
Impact of chemotherapy timing on local-regional failures in patients with breast cancer undergoing breast-conserving therapy.
Authors: Mittendorf E. A. , Buchholz T. A. , Tucker S. L. , Meric-Bernstam F. , Kuerer H. M. , Gonzalez-Angulo A. M. , Bedrosian I. , Babiera G. , Yi M. , Ross M. I. , Hortobagyi G. N. , Hunt K.
Published: February 2017

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Background: Debate continues as to whether BCT after neoadjuvant chemotherapy (chemo) can achieve long-term local control rates similar to those experienced by patients undergoing surgery first, especially in those presenting with large tumors. This study was performed to evaluate long-term results of BCT for patients undergoing surgery first versus chemotherapy.

Methods: 2,984 patients underwent BCT with whole breast irradiation from 1987 to 2005. Clinicopathologic and outcomes data were reviewed and comparisons made between surgery first and chemotherapy patients.

Results: 2,331 (78%) patients underwent surgery first; 653 (22%) received chemotherapy first. Overall, chemotherapy patients had more adverse clinicopathologic features (Table). 5 and 10-yr local-regional recurrence (LRR)-free survival rates were 97% (95% CI: 96%-98%) and 94% (93%-95%) for surgery first patients. Chemotherapy downstaged patients presenting with clinical stage II/III disease (608/653; 93%) allowing for BCT, and pathologic findings revealed stage II/III disease in only 305/653 (46%) (p<.001). 5 and 10-yr LRR-free survival rates were 93% (91%-95%) and 90% (87%-93%) after chemotherapy. After adjusting for clinical stage at presentation, there were no differences in LRR between surgery first and chemotherapy patients. On multivariate analysis, age<50, clinical stage III, grade 3, ER neg status, associated DCIS on final pathology, and close/positive margins were associated with LRR.

Conclusions: LRR after BCT is driven by biologic factors and not the timing of chemotherapy. Chemotherapy downstages a significant number of patients with stage II/III disease allowing appropriately selected patients to achieve high rates of local-regional control with BCT.

[Table: see text]
Can locoregional treatment of the primary tumor improve outcomes for women with stage IV breast cancer at diagnosis?
Authors: Nguyen D. H. A. , Truong P. T. , Lesperance M. , Alexander C. , Walter C. V. , Hayashi E. , Christie J. , Olivotto I. A.
Published: February 2017

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Background: To determine whether locoregional treatment (LRT) of the primary tumor improves outcomes in patients with stage IV breast cancer at diagnosis.

Methods: The study cohort comprised 733 women referred from 1996 to 2005 to a population-based cancer institution with clinical or pathologic M1 breast cancer at diagnosis. Patient, tumor, and treatment characteristics were compared between women who were treated with (n=378) and without LRT (n=355) of the primary tumor. Five-year Kaplan-Meier overall survival (OS) and locoregional progression-free survival (LRPFS) were compared between groups. Multivariable analysis to control for potential confounding factors was performed using Cox regression modeling.

Results: LRT consisted of surgery alone in 67%, radiotherapy alone in 22%, and both in 11% of patients. LRT use was significantly associated with age <50 years, ECOG performance status 0-1, T1-2 tumors, and N0-1 disease, (all p<0.05). Subjects with less metastatic disease burden and those asymptomatic from the M1 disease were more likely to undergo LRT (p<0.001). Systemic therapy was used in 92% and 85% of patients treated with vs. without LRT, respectively. Five-year OS rates in the LRT and no LRT cohorts were 21% vs 14% (p<0.001). The 5-year LRPFS rates were 72% vs 46% (p<0.001). Among 378 patients who underwent LRT, 5-year OS rates were higher in patients with age <50, ECOG 0-1, ER positive disease, clear surgical margins, single M1 subsite, bone only metastases, and 1-3 metastatic lesions (all p<0.003). Type of LRT (surgery vs radiotherapy vs both) and type of surgery (lumpectomy vs mastectomy) were not associated with 5-year OS (all p>0.05). On multivariable analysis, LRT was associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.64-0.94, p=0.009).

Conclusions: LRT of the primary disease was associated with improved survival in women with stage IV breast cancer at diagnosis. Among subjects treated with LRT, the most favorable survival rates were observed in patients with young age, good performance status, ER-positive disease, clear resection margins and in those with distant disease limited to one subsite, bone only, or fewer than 4 metastatic lesions.
Use of perioperative therapy in gastric cancer: A retrospective comparison of ECF and chemoradiation.
Authors: Siripurapu V. , Watson J. C. , Hoffman J. P.
Published: February 2017

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Background: Gastric Cancer (GC) remains a major cause of cancer related morbidity and mortality in Western Countries with five year survival rates between 30%-40%. Preoperative therapy has been championed by groups extrapolating data from the Intergroup 0116 and the MAGIC trials, with a view to enhancing completion of therapy and improving survival in locally advanced tumors.

Methods: Patients with preoperative treatment of GC were reviewed from our tumor registry. Stages were assigned by AJCC 7th edition. A comparison between the ECF regimen and non-ECF chemoradiation regimens was performed to view patterns of pathologic complete response (pCR), recurrence, toxicity and overall survival.

Results: Forty-two patients were identified and stratified into two groups; Group 1 ECF treatment arm (n = 16) compared to group 2 non-ECF chemo-radiation arm (n = 26). No statistical difference was noted in age, ethnicity or stage stratification. All of Group 1 received their chemotherapy regimen after 2005. In contrast, 60% of Group 2 patients received their treatment pre-2005. Only 56% the ECF group completed their treatment course (19% received other postoperative therapy). Seventy percent of group 2 received adjuvant chemotherapy. A grade 2 or higher toxicity was noted in 16% of Group 1 compared to 60% in Group 2 (p = 0.035). Seven complications were noted in the group 1 compared to 10 in group 2 (p = NS). The differentiation of tumor between groups was not significant (p = 0.97). Length of stay was significant (Group 1:9 days, Group 2:12 days, p = 0.02). More nodes were retrieved from group 1 versus group 2 (20.2 versus 15.2, p = 0.03). Group 1 had 3 recurrences (19%) while Group 2 had 11 recurrences (42%, p = 0.94). In both groups 80% of recurrences were distant. Group 1 had a 19% pCR versus 23% in group 2 (p = 0.79). Two-year survival was 70% in both groups, with a median survival of 51 months for group 2. Median survival was not reached for group 1.

Conclusions: No difference was noted in pCR, recurrences, or survival between these two regimens. If this can be confirmed in larger, prospective, randomized trials, use of radiation and its potential morbidity may be avoided.

No significant financial relationships to disclose.
Pharmacokinetic and pharmacodynamic analysis of gastric cancer patients treated with telatinib.
Authors: Burd A. , Castillo J. , Whiteside M. , White M. , Ajani J. A. , Fattaey A. , Kunkel L. A.
Published: February 2017

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Background: The soluble form of the VEGFR2 receptor (sVEGFR2) neutralizes circulating VEGF, and functions as a negative feedback mechanism to enable partial inhibition of VEGF-stimulated endothelial cell migration and proliferation. In response to inhibition of VEGFR2 tyrosine kinase activity, up-regulation of VEGF expression and down-regulation of sVEGFR2 expression levels have been observed (Murukesh et al., 2010). Telatinib (tel) is a novel orally available kinase inhibitor that is highly selective for the VEGFR, PDGFR, and KIT tyrosine kinases at nanomolar concentrations with potent antiangiogenic activity. Correlation between telatinib exposure and reduction in plasma sVEGFR2 levels from baseline has previously been demonstrated in patient serum samples in phase I studies.

Methods: TEL0805, a phase II study administered tel with capecitabine (X) and cisplatin (P) in previously untreated metastatic or unresectable gastric or GEJ adenocarcinoma pts. Patient serum samples were obtained on day -7, [6 plasma samples (pre-dose, and at 30 min, 1, 2, 3 and 4 hours)] and on day 1, [4 plasma samples (pre-dose and at 1, 2 and 3 hours)] and evaluated for the levels of telatinib and its M2 metabolite (M2). Additional serum samples were collected every 42 days and evaluated for VEGF and sVEGFR2 levels.

Results: Measurement of tel and M2 levels confirmed previous pharmacokinetic findings and demonstrated no drug accumulation following continuous daily dosing. Baseline plasma sVEGFR2 levels have previously not been reported for advanced gastric cancer patients and displayed a wide range at disease presentation. Reduction in sVEGFR2 levels were noted for nearly all treated patients and correlated with the duration of stay on tel therapy.

Conclusions: Telatinib continuous dosing is possible in combination with XP with little effect on tel exposure or accumulation. Reduction in sVEGFR2 levels may be useful in identifying patients who may benefit from tel treatment in this combination setting.

[Table: see text]