tbuckley/cabot-search huggingface dataset:
Effect of chemotherapy and trastuzumab as adjuvant treatment for small HER2-positive breast cancer: A single-institution experience.
Authors: I. Ghanem, E. M. Ciruelos, G. De Velasco, C. A. Castaneda, L. Manso, C. Mendiola, N. Valdivieso, M. Dorta, H. Cortes-Funes
Journal: Journal of Clinical Oncology (2011)

e11031 Background: The addition of trastuzumab as adjuvant treatment has allowed 50% reduction for relapse in >1cm size tumor, early-stage HER2-positive breast cancer (BC). However, it is not clear if this benefit is present as well in smaller, node-negative (N0) tumors. We retrospectively reviewed our experience in a single institution. Methods: From 1997 to 2007, BC patients (pts) with HER2-positive, T1a-b N0, early BC were included. Epidemiologic, clinical and characteristic tumor data were collected from patients at 12 de Octubre University Hospital (Madrid) Results: 35 pts with a median age of 55 years (range 35-82) were included. Six pts (17%) had T1a (≤ 0,5 cm) tumors and 29 (83%) T1b (0,5-1 cm). All cases had no lymph node involvement, tested by lymphadenectomy (30 pts, 86%) or sentinel-node biopsy (5 pts, 14%). Eighteen pts (51%) underwent mastectomy and 17 pts (49%) conservative surgery. Most frequent histology was infiltrating ductal carcinoma (31pts, 89 %). HER2 testing was performed by IHC in all cases and by FISH in 6 cases (17%). Twenty three pts (66%) did not receive any adjuvant chemotherapy or trastuzumab (Group N). Twelve pts (34%) received chemotherapy (anthracycline-based=8pts; methotrexate-based=3pts) and/or trastuzumab (6 pts) (Group A). Mastectomy, lymphadenectomy rate, T1b tumors and negative hormonal receptors were similar between both groups, while the median age (59y vs 49y, p=0.01) and nuclear grade (G1=43%vs0%, G2=33%vs18%, G3=24%vs82%; p=0.01) were significantly different for Groups N and A, respectively. After 106 and 80 months of follow up for N and A, there was one tumor relapse and one contralateral breast cancer in every group. Conclusions: Efficient adjuvant treatment with trastuzumab has become the gold standard for HER2-positive BC. Nevertheless, longer follow-up in bigger series is needed to test the benefit of such therapy in T1a-b, N0 tumors. Prospective randomized clinical trials should be considered in this population.
A phase II, open-label study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy in patients (pts) with metastatic colorectal cancer (mCRC): CP12-0709/NCT00862784.
Authors: Rocio Garcia-Carbonero, Fernando Rivera, Juan Maurel, Jean-Pierre M. Ayoub, Malcolm J. Moore, Andres Cervantes-Ruiperez, Timothy R. Asmis, Jonathan D. Schwartz, Shaila Ballal, Josep Tabernero
Journal: Journal of Clinical Oncology (2012)

533^ Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) are overexpressed in CRC and mediate angiogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 MAb that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In preclinical CRC models VEGFR-2 inhibition confers antitumor activity. RAM was administered with mFOLFOX-6 as 1st-line therapy (rx) in mCRC. Methods: Eligible pts had mCRC with no prior chemo Rx (prior adjuvant rx was allowed), at least 1 measurable target lesion by RECIST v1.0, ECOG PS 0-1, and adequate organ function. Pts received RAM (8 mg/kg IV on D1), oxaliplatin (85 mg/m² IV on D1), folinic acid (400 mg/m² IV on D1), fluorouracil (5-FU, 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours on D1). Rx cycles were q2w and tumor assessments were q8w. Endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics/immunogenicity. Sample size was based on an improved median (medn) PFS from 8 to 11 months (m). Results: 48 pts received therapy. All were white; 25 M/23 F; median age 60.5 y. ECOG PS was 0/1 in 30/18 pts. 42 pts (88%) had metastatic disease, with liver (79%) and lung (35%) as most frequent sites. 13 (27%) pts had liver-only mCRC. The most frequently observed RAM-related adverse events (AEs) included hypertension 46% (15% Grade [G] ≥3); diarrhea 31% (2% G≥3); and nausea and infusion-related reactions, each 19% (0% G≥3). 2 pts died on study due to acute MI or cardiopulmonary arrest. Medn PFS was 11.5 m (9-13 m 95% CI) with 1-yr PFS of 48% (32-62% 95% CI). ORR: 67% (52-80% 95% CI); disease control rate (DCR: CR+PR+SD): 94% (83-99% 95% CI; 5 pts had CR, 27 had PR and 13 had SD). Medn duration of response was 11.0 m (7-12 m 95% CI). One-year OS was 85% (72-93% 95% CI). As of 4/15/2011, 2 pts continued to receive rx, 20 had died and 28 (58.3%) remained alive. Conclusions: RAM combined with mFOLFOX-6 was reasonably tolerated in pts with mCRC. Median PFS exceeds 11 m. PFS, ORR, and DCR are encouraging and favor investigation of this regimen and of RAM in mCRC.
Safety of first-line bevacizumab-based therapy with concomitant cardiovascular or anticoagulation medication in advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) in MO19390 (SAiL)
Authors: F. Griesinger, J. J. Laskin, N. Pavlakis
Journal: Journal of Clinical Oncology (2008)

8049 Background: Bevacizumab (Bev) based therapy prolongs survival of NSCLC patients beyond 1 year. MO19390 (SAiL) is an open-label study assessing the safety of Bev with a wide range of standard first-line chemotherapy in approximately 2000 patients (pts). We report an interim analysis of the effect of concomitant medication on Bev treatment and vice versa, with a focus on cardiovascular therapy, which is widely used in this patient population, and on anticoagulation treatment to assess if the risk of bleeding is increased. Methods: Pts with locally advanced, metastatic or recurrent non-squamous NSCLC, receive Bev plus standard first-line chemotherapy for up to 6 cycles followed by Bev monotherapy until disease progression or unacceptable toxicity. Pts with a history of hemoptysis, evidence of tumor invading major blood vessels, CNS metastases, current or recent use of ASS >325mg/day, full-dose anticoagulation, or uncontrolled hypertension are excluded. Results: Here we present preliminary data as documented in the EDC in November 2007. 1065 pts completed ≥1 cycle of treatment and are evaluable for safety analysis. Median age is 60 years; ECOG PS 0/1/2 is 39.9%/53.3%/6.8%. At baseline, 796 pts (74.7%) were on concomitant medication: of these 338 (31.7%) on cardiovascular drugs and 36 (3.4%) on anticoagulants (86% on heparin). A total of 153 (14.4%) pts reported 181 hypertensive events (31 grade [g] 3, 2 g4 and 0 g5): 92.3% of these started during Bev treatment and 68.0% ended during Bev treatment; 140 pts (13.1%) received antihypertensive treatment. 140 pts (13.1%) received antihypertensive treatment. 68.9% of all events were resolved and 11.1% improved at data cut off. A total of 227 bleeding events occurred in 181 pts (17.0%; 12 g3; 0 g4; 2 g5), versus 19 bleeding events in 15 of 87 pts (17.2%; 0 g≥3) receiving anticoagulants. Conclusions: Over 1000 pts had been treated in MO19390 at data cut off; 74.4% were on concomitant medication at baseline. There is no evidence that management of antihypertensive treatment is impaired in Bev treated pts. To date, no safety risk has been identified in patients receiving anticoagulants. Updated results will be discussed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly, Roche, sanofi-aventis AstraZeneca Oncology, Eli Lilly, Roche, sanofi-aventis
Detection of breast cancer metastasis in sentinel lymph nodes using intra-operative real time PCR assay
Authors: R. E. Mansel Professor, A. Goyal, A. Douglas-Jones, V. Woods, B. Jasani
Journal: Journal of Clinical Oncology (2008)

11050 Background: Patients with sentinel lymph node (SLN) metastases will need delayed completion axillary lymph node dissection, if intra-operative assessment is not employed. Intra-operative assessment is not routinely performed in the UK due to poor sensitivity of available methods and overburdened pathology resources. A real-time PCR assay can be performed in ∼40 minutes and has high sensitivity and specificity when compared to permanent section H&E histology. We conducted a prospective clinical validation study of the GeneSearch™ Breast Lymph Node (BLN) Assay (Veridex, LLC) to confirm its potential usefulness within the UK healthcare system. Methods: The assay utilizes 50% of the lymph node to detect the presence of ck-19 and mammaglobin mRNA. Internal and external controls confirm a valid result. The assay has been calibrated to detect metastases > 0.2 mm. Assay results are compared to H&E performed on each face of ∼2 mm alternating node slabs. Results: Results on 124 SLNs from 83 subjects confirm the excellent performance of the assay: sensitivity 80% (22 SLNs, 10 patients) & specificity 94.4% (102 SLNs, 72 subjects). Five of the assay & histology positive SLNs contained macrometastases (>2.0 mm), 2 contained a micrometastasis (0.2 - 2.0 mm), and 1 contained a focus of undetermined size > 0.2 mm. Four assay positive/histology negative SLNs from were obtained. Two had isolated tumor cells seen by histology. Two assay negative/histology positive SLNs were both micrometastases. Conclusions: Intra- operative assessment of the SLN can be rapidly and accurately performed using the GeneSearch™ BLN Assay. Our results confirm the assay’s high sensitivity and specificity. The assay is being carried out and the results interpreted without difficulty by a trained biomedical scientist in our pathology laboratory within the operating theatre complex and does not require an expert histopathologist. The assay allows more thorough node analysis, reducing sampling error and improves intra-operative surgical management of breast cancer patients. Additionally the UK cost model presented at the San Antonio Breast Cancer Symposium (abstract #3012) indicates that the assay costs slightly less than overall cost of current methods, specifically in the area of preventing second surgeries. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Veridex Veridex
A phase I dose-escalation, pharmacokinetic (PK), and pharmacodynamic (PD) evaluation of intravenous LY2090314 a GSK3 inhibitor administered in combination with pemetrexed and carboplatin.
Authors: L. H. Brail, J. E. Gray, H. Burris, G. R. Simon, J. Cooksey, S. F. Jones, D. Farrington, T. Lam, K. Jackson, K. Chow, J. T. Brandt, J. R. Infante
Journal: Journal of Clinical Oncology (2011)

3030 Background: LY2090314 (LY) is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) which plays an important role in many pathways, including initiation of protein synthesis, cell proliferation, cell differentiation, and apoptosis. Pre-clinically LY stabilizes β-catenin and enhances the efficacy of platinum based regimens. With limited predicted efficacy as monotherapy, this first in human study was conducted in combination with pemetrexed + carboplatin (PC). Methods: In advanced solid tumor patients (pts), LY was dosed intravenously as a lead-in 7 days prior to the first administration of the triplet combination with PC (500 mg/m2 and AUC 5 or 6, respectively). PBMCs were collected to determine effects on β-catenin. The objectives of this first in human study were to investigate the safety, PK, and PD of LY in pts with advanced solid tumors in combination with PC. Results: Thus far, 40 pts were treated with LY at 10 mg (n=10), 20 mg (n=5), 40 mg (n=11), 60 mg (n=5), 80 mg (n=5), and 120 mg (n=4). The maximum tolerated dose (MTD) is LY 40 mg in combination with PC (500 mg/m2 and AUC 6). DLTs were visual disturbance, back pain, and chest pain at 120 mg and chest pain at 80 mg. At these doses above the MTD, this transient non-cardiac chest pain was frequently reported after a single dose of LY. Zantac prior to infusion seemed to help but did not eliminate this adverse effect. Other frequently (≥ 10%) reported toxicities attributed to LY were nausea (18.9%), fatigue (16.2%), and vomiting (13.5%). Preliminary PK analysis results show that exposure increased as dose increased over the dose range studied with a short terminal elimination half-life calculated in the majority of patients. Exposures at the MTD resulted in a significant, transient up regulation of β-catenin in PBMCs. 16 pts received ≥ 4 cycles of therapy and 7 patients received ≥ 6 cycles of therapy. Conclusions: LY at 40 mg can be safely combined with PC. At these exposures, β-catenin is up-regulated and the adverse event profile is acceptable. The large number of pretreated patients that experienced stable disease suggests continued evaluation of LY in NSCLC may be warranted.
A multicenter exploratory study of irinotecan-based chemotherapy on UGT1A1 polymorphisms for patients with colorectal cancer.
Authors: Motoya Chikakiyo, Hirohiko Sato, Nobuhiro Kurita, Takashi Iwata, Kozo Yoshikawa, Hideya Kashihara, Chie Mikami, Noriko Matsumoto, Shohei Eto, Mitsuo Shimada, Masanori Hotchi, Hiroshi Okitsu, Yasuhide Sonaka, Sadahiro Yoshida
Journal: Journal of Clinical Oncology (2014)

563 Background: Recent pharmacogenetic studies have revealed a significant association between uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6 and toxicities such as severe diarrhea and neutropenia under treatment with irinotecan. Moreover, the latter of these two polymorphisms is specifically detected in East Asian populations. We performed a prospective study to determine the optimal dose of this drug depending on which polymorphism is present in order to maximize the effectiveness of therapy while avoiding side effects. Methods: 59 patients from 11 institutions were enrolled in this study. Patients were assigned to one of the following three groups: wild type (*1/*1), heterozygous (*28/*1, *6/*1), or homozygous (*28/*28, *6/*6*, *28/*6*). The double heterozygous state (*28/*6) was included within the homozygous group. Second-line FOLFIRI was administered, with the dose of irinotecan at 150 mg/m2, in the wild type and heterozygous groups and at 100 mg/m2 in the homozygous group. The incidences of severe toxicities according to UGT1A1 gene type, response rate, and progression-free survival were investigated. Results: 26 (44.1%) were assigned to the wild type group, 28 (47.4%) to the heterozygous group, and 5 (8.5%) to the homozygous group. Grade 3 or higher severe toxicities were observed in 8 patients (30.8%) in the wild type group, 5 (17.9%) in the heterozygous group, and 1 (20.0%) in the homozygous group. No significant difference was observed among the three groups. The most frequently observed severe toxicities were neutropenia, nausea, vomiting, and diarrhea. The overall response rate (complete response + partial response) was 2 patients (7.7%) in the wild type group, 2 (7.1%) in the heterozygous group, and none (0.0%) in the homozygous group. Conclusions: In terms of tolerability and safety, the present results suggest that irinotecan should be administered at a dose of 150mg/m2 in heterozygous patients and 100 mg/m2 in homozygous patients receiving second-line FOLFIRI.
The host inflammatory responses, tumor stroma percentage, and survival in colorectal cancer.
Authors: James Hugh Park, Colin H. Richards, Donald C. Mcmillan, Paul G. Horgan, Campbell S. D. Roxburgh
Journal: Journal of Clinical Oncology (2014)

549 Background: The role of host inflammatory responses in determining colorectal cancer (CRC) outcome is increasingly recognised. In particular, a marked local inflammatory response is associated with improved survival. However, determinants of this response are not clear. A plausible factor in the density, location and type of the inflammatory cell infiltrate is the extent of tumor stroma. The aim of the present study was to examine the relationship between tumor stroma percentage (TSP), tumor inflammatory infiltrate and survival in patients undergoing elective CRC resection. Methods: 335 patients who had undergone elective resection for stage I-III CRC at a single institution between 1997-2008 were included. TSP at the invasive margin (IM) was assessed on H and E sections and grouped as low (≤50%) or high (&gt;50%). Local inflammatory response was assessed at the IM using Klintrup-Mäkinen (K-M) score and at the IM, tumor stroma and cancer cell nests (CCNs) using the following T-cell markers: CD3, CD8, CD45R0, FOXP3. Systemic inflammatory response was assessed using modified Glasgow Prognostic Score (mGPS). Results: Eighty-three patients (25%) had high TSP. High TSP was associated with increased T stage, N stage (both p &lt; 0.01), margin and serosal involvement (both p &lt; 0.05), an infiltrative invasive margin (p &lt; 0.001) and tumor necrosis (p = 0.001). TSP was associated with decreased infiltration by CD3 + and CD8 + cells at the CCNs (p &lt; 0.01 and p &lt; 0.05 respectively) but not at the IM or stroma. K-M score showed a trend towards an inverse association with TSP (p = 0.067). CD45R0 + and FOXP3 + cell infiltration and mGPS were not associated with TSP. On multivariate analysis, TSP was associated with poorer cancer-specific survival (HR 1.93, 95% CI 1.15-3.23, p = 0.012), independent of N stage, VI (both p &lt; 0.05), low CD8 at the IM and CCNs (both p &lt; 0.01) and mGPS (p = 0.001). Conclusions: TSP was associated with the presence of high risk pathological characteristics and down-regulation of host intra-tumoral immune responses and was independently associated with poorer cancer survival. The extent of tumor stroma is an important factor in the nature of the tumor inflammatory cell infiltrate and outcome in patients undergoing elective surgery for CRC.
Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes.
Authors: G. Cancello, P. Maisonneuve, N. Rotmensz, G. Viale, M. G. Mastropasqua, G. Pruneri, E. Montagna, S. Dellapasqua, M. Iorfida, A. Cardillo, P. Veronesi, A. Luini, M. Intra, O. D. Gentilini, E. Scarano, D. Pastrello, A. Goldhirsch, M. Colleoni
Journal: Journal of Clinical Oncology (2011)

546 Background: Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumors. Methods: We explored patterns of recurrence in 1,715 patients with pT1mic/T1a/T1b, node-negative operable breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67<14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67≥14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) triple negative. Results: At multivariate analysis, patients with the triple-negative subtype showed an increased risk of loco-regional relapse (HR 3.37; 95%CI: 1.31-8.70) and breast cancer related events (HR 2.17; 95%CI: 1.04-4.53). Overall, Luminal B was not associated with a significant higher risk of recurrence compared with Luminal A, while the subgroup of Lumimal B with HER2-positive has a 2-fold risk of reduced breast cancer survival compared with Luminal A subtype. HER2 was the only subtype with a statistically significant increased risk of loco-regional relapse (HR, 4.77; 95%CI: 1.65-13.8), distant metastases, and reduced breast cancer related event-free survival and overall survival (HR, 2.95; 95%CI: 1.07-8.10) if compared with the Luminal A subtype, at multivariate analysis. Conclusions: Patients with small size, node-negative breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or triple-negative disease. Multivariate analysis. Immunohistochemical subtype Locoregional relapse Distant metastasis Local + distant metastasis Breast cancer survival Overall survival Luminal A 1.00 1.00 1.00 1.00 1.00 Luminal B (HER2-negative) 1.30 (0.60-2.79) 1.69 (0.65-4.42) 1.48 (0.81-2.73) 1.29 (0.77-2.15) 0.52 (0.22-1.22) Luminal B (HER2-positive) 2.73 (0.98-7.62) 3.02 (0.78-11.7) 3.13 (1.38-7.13) 2.18 (1.03-4.60) 1.30 (0.38-4.38) HER2-positive 4.77 (1.65-13.8) 4.41 (1.08-18.1) 5.36 (2.29-12.5) 3.35 (1.50-7.47) 2.95 (1.07-8.10) Triple-negative 3.37 (1.31-8.70) 2.50 (0.62-10.1) 2.94 (1.30-6.64) 2.17 (1.04-4.53) 2.01 (0.73-5.49)
Developing innovative strategies to meet ACGME requirements and promote learning in a hematology/oncology fellowship program
Authors: L. J. Lyckholm, K. O. Kreutzer, T. J. Smith, M. B. Edmond
Journal: Journal of Clinical Oncology (2005)

6124 Background: The ACGME has developed 6 core competencies (medical knowledge, professionalism, interpersonal and communication skills, patient care, systems-based practice, and practice-based learning and improvement) to evaluate fellows and to measure outcomes and improvement. Fellowship programs are required to formally demonstrate how these competencies are implemented and measured effective July 1, 2005. Methods: We brainstormed with fellows, faculty and educational leaders, and reviewed educational literature, to develop educational and experiential strategies to meet the competency requirements, while promoting creative and dynamic educational experiences. Results: Examples of innovative strategies include: (1) a tumor-type based core curriculum by the fellows, with faculty mentoring, to be updated on an ongoing basis,(2) interactive, group-based use of the ASCO Cancer Genetics curriculum to teach Cancer Genetics, (3) interactive, interdisciplinary conferences prior to clinic, with particular focus on new clinical research protocols and attendance by cancer research nurses, (4) development of buddy systems for new fellows, (5) “Chemotherapy Day”, when fellows spend the day in the chemotherapy suite, administer chemo, access ports, give injections, etc, (6) a rotation in the palliative care unit, during which the fellow shares primary patient care and teaching responsibilities with the palliative care fellow, (7) “designer electives” during which the senior fellow spends time with a particular expert in an area in which he/she chooses to specialize or needs more experience, (8) responsibility of each fellow to teach 1–2 topics to the inpatient team each month, (9) supervised attending rounds by senior fellows with formal evaluation of their teaching and decision making. Conclusions: Innovations designed to meet the ACGME Core Competencies requirement, have improved the fellowship program and greatly enhanced learning, professionalism, clinical care and esprit de corps. Sharing these innovations will be helpful to other fellowship programs. No significant financial relationships to disclose.