bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported toxicity after treatment for cancers of the head and neck.
Authors: Hill-Kayser Christine E. , Vachani Carolyn , Hampshire Margaret K. , Di Lullo Gloria A. , Metz James M. 
Published: March 2020

6135 Background: Patients with cancers of the head and neck (HNC) may be at risk for significant late effects after treatment. Quality of life may be altered significantly as a result. This Internet based study evaluates patient perceptions of toxicity after treatment for HNC. Methods: Patient-reported data were gathered via a convenience sample frame from HNC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLinkwebsite, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, HNC survivors are queried regarding late effects associated with specific treatments. All data have been maintained with IRB approval. Results: Of 3866 survivors using this tool between 4/2010 and 10/2011, 140 (4%) had undergone primary treatment for HNC. Median diagnosis age was 52y and median current age 56y. When queried regarding treatment received, 88% reported having undergone radiation, 73% surgery, and 67% chemotherapy. Many patient-reported late effects were associated with local tumor control, and included difficulty swallowing/speaking (83%), decreased saliva production (88%), dental problems (49%), thyroid problems (33%), decreased neck mobility (60%), eye and vision deficits (9%), and tinnitus (40%). In addition, 53% noted concerns regarding cognitive function. Users of the tool reported that they would share it with their healthcare team in 55% of cases. The most common reasons for not sharing it were “I did not think they would care,” and “ I did not want to upset or anger them.” Conclusions: Survivors using this tool anonymously and voluntarily report significant toxicity after treatment for HNC. Not all survivors appear comfortable discussing these issues with healthcare providers, despite major potential impact on quality of life. The data reported here may be of significant impact in future study of outcomes after HNC, as well as patient counseling and survivor care.
Prognostic role of HER2 loss after neoadjuvant therapy in patients with HER2-positive operable breast cancer.
Authors: Guarneri Valentina , Barbieri Elena , Piacentini Federico , Dieci Maria Vittoria , Omarini Claudia , Ficarra Guido , Bettelli Stefania Raffaella , Conte Pier Franco 
Published: March 2020

631 Background: Emerging literature data are consistently showing that a change in HER2 status adversely affect the prognosis of breast cancer patients. Aim of the present analysis is to evaluate the prognostic impact of HER2 loss in breast cancer patients with HER2 positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. Methods: A total of 94 HER2 positive patients were identified from a prospectively maintained database. The first cohort (A) includes 40 patients treated with chemotherapy alone (enrolled before 2005). The second cohort (B) includes 54 patients treated with neoadjuvant chemotherapy in combination with anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by IHC or FISH on pre-treatment core biopsy and on surgical specimen after neoadjuvant therapy. Patients were considered as having HER2 positive disease in case of IHC 3+ or FISH amplification. Results: No imbalance in terms of age, stage at diagnosis, tumor grade and expression of hormone receptor was observed in the two cohorts. In detail, 67% and 61% of the patients have a co-expression of HER2 and hormone receptor in cohort A and B, respectively. The rate of breast conservation was significantly higher in cohort B (chemotherapy+anti-HER2 agents) as compared to cohort A (chemotherapy alone) (59% vs 38%, p=0.048). Similarly, the rate of pathologic complete response (pCR) was significantly higher in cohort B (42.6% vs 7.5% in cohort A, p<0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 35% of the patients in cohort A vs 9% of the patients in cohort B (p=0.04). No patients achieving a pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (47% vs 15% in patients with no change, p=0.007). At 5 years, 53% of the patients with Her2 change and 75% of the patients without Her2 change were alive and free of recurrence (log rank test: p=0.03). Conclusions: The rate of HER2 loss was significantly higher in patients not receiving anti-HER2 agents as a part of the neoadjuvant therapy. In this series, the change in HER2 status has a negative prognostic impact.
Effect of neratinib (N) alone and in combination with trastuzumab (T) in HER2-positive breast cancer (BC) cell lines.
Authors: Canonici Alexandra , Pedersen Kasper , Walsh Naomi , Crown John , O'Donovan Norma 
Published: March 2020

632 Background: HER-2, a member of the transmembrane receptor tyrosine kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2 targeted therapies, in particular, T, a monoclonal antibody targeting HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have been shown to significantly improve the prognosis for HER-2 positive BC patients. However, resistance to T and/or L is a significant clinical problem. The aim of this study is to assess the activity of N (HKI-272), an irreversible HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines, including T and/or L resistant cells. Methods: Using proliferation assays, the effect of N was assessed alone and in combination with T in HER-2 positive BC cell lines, including T and/or L resistant cell lines. The effect of N on HER-2 and downstream signalling molecules, Erk and Akt, was determined by immunoblotting. Results: HER-2 positive BC cell lines, including T and/or L resistant cells, are sensitive to N alone with IC50 values (concentration which inhibits 50% of growth) ranging from 1 to 280 nM. The combination of N and T has additive effects in SkBR3 and BT474 which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL which are resistant to T, combined treatment with T and N showed no enhancement compared to N alone. Finally, N decreased phosphorylation of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results suggest that N should be studied in patients with HER-2 positive BC, including patients with T and/or L resistant BC. We also demonstrate that N in combination with T may be more effective than either agent alone in T sensitive cells.
Adjuvant treatment of early-stage HER2+ elderly breast cancer patients: A retrospective, multicenter French study.
Authors: Barthelemy Philippe , Bassot Karine , Joly Florence , Ray Coquard Isabelle , Freyer Gilles , Dufour Patrick Regis , Campos France , Kurtz Jean Emmanuel 
Published: March 2020

636 Background: Trastuzumab (T) is the standard of care for the adjuvant treatment of early stage, HER2+ breast cancer (BC). However, few data are available for elderly HER2+ breast cancer patients in this setting. In this current study, the patterns of care for elderly HER2+ early stage BC in 7 French cancer centres was evaluated. Methods: Medical records of all consecutive early stage HER2+ BC patients over 70 years old treated between 2006 and 2011 among participating centres were retrospectively reviewed. Specific factors such as age, comorbidities, tumor stage, grade, ER/PR and HER2 status, treatment characteristics, follow-up and cardiotoxicity data were analysed. Results: One hundred and two patients were identified, median age 75.4 (range 70-95). Elderly patients presented mostly (57%) large tumors (pT ≥2), and positive lymph node involvement (n=61). Trastuzumab-based adjuvant treatment was administered in 62% of patients (n=63). 54% of patients (n=55) received adjuvant chemotherapy whereas five patients received neoadjuvant chemotherapy. Chemotherapy without T was administered in 2 additional patients. Anthracyclines (A)-Taxanes (Ta) combination-based chemotherapy was given in 27% of patients (n=16), whereas 38% received a Ta-based chemotherapy (n=23), 35% (n=19) an A-based chemotherapy. Five patients received single-agent T. Treatment delays for T were required in 37% of patients (n=23) among whom 15 and 8 permanently or temporarily stopped T, respectively. The most frequent reason for interrupting or delaying therapy was cardiotoxicity (n=12) as well as patients refusal (n=7). A ≥ 10% decrease in LVEF was observed in 18/63 (29%) of patients, among whom T was stopped in 12. After a median 33 months follow-up, the median progression-free survival was not reached in patients receiving T-based therapy. The 2 and 3-year PFS rate were 94 and 89.5%, respectively. Conclusions: In routine practice only 62% of elderly early stage HER2+ BC patients are treated with a neoadjuvant or adjuvant T-based regimen. However, less than 50% of all patients completed their therapy. A-based chemotherapy was administered in around 60% of treated patients, and could explain cardiotoxicity in this setting.
The effects of lapatinib and neratinib on HER2 protein levels in breast cancer cell lines.
Authors: Collins Denis , O'Donovan Norma , Walsh Naomi , Gately Kathy , Edwards Connla , Davies Anthony , O'Byrne Kenneth John , Crown John ,   Molecular Therapeutics for Cancer Ireland (MTCI)
Published: March 2020

637 Background: HER2, a member of the c-erbB receptor tyrosine kinase family, is over-expressed (HER2 gene amplification/IHC 3+, >30% cells) in approx. 25% of breast cancers. Pre-clinical studies have shown that the HER2-targeted small molecule tyrosine kinase inhibitor (TKI) lapatinib (LAP) can increase HER2 levels in cell line models and can potentiate trastuzumab-mediated antibody dependent cell-mediated cytotoxicity. To assess the potential effects of the next generation TKI neratinib (NER) on expression of HER2 in breast cancer, this study compares the effects of LAP and NER on HER2 protein levels in the HER2-amplified SKBR3 and HER2-non-amplified T47D cell lines in vitro. Methods: SKBR3 and T47D were treated with LAP or NER (0.2, 1 and 2 µM) for 12, 24 and 48 hours.HER2 protein levels were determined by ELISA, immunoblotting and high content analysis (HCA). HER2 protein was examined using two antibodies targeting the extracellular domain (ECD) and the intracellular domain (ICD) of HER2. pHER2, EGFR/pEGFR, MAPK/pMAPK and AKT/pAKT levels were determined by immunoblotting. Proliferation studies utilized an acid phosphatase-based assay. Results: ELISA analysis confirmedsignificantly lower HER2 expression in T47D (44 +/- 17 pg/µg) compared to SKBR3 (748 +/- 296 pg/µg), p = 0.015. NER proved a more potent inhibitor of pHER2 and pEGFR as analyzed by immunoblotting and in proliferation studies (NER IC50 - SKBR3 0.03 +/- 0.01 nM, T47D 199 +/- 70 nM, LAP IC50 - SKBR3 20 +/- 1 nM, T47D 1.2 +/- 0.2 µM). LAP induced an increase in both ECD and ICD-containing HER2 protein levels in SKBR3 and T47D cells. No increase in HER-2 levels was observed with NER treatment, as determined by HCA and immunoblotting. EGFR protein levels increased in response to lapatinib in both cell lines. Conclusions: Our results suggest that LAP and NER have differing effects on HER2 protein levels in the models examined. NER provides greater inhibition of HER2 signaling activity but does not increase HER2 protein levels as was observed with LAP. Further pre-clinical assessment of combinations of LAP and NER with HER2 and EGFR monoclonal antibody therapies is warranted in HER2-amplified, HER2-non-amplified and EGFR-expressing breast cancer models.
Time to brain metastasis (TTBM) from initial diagnosis of distant metastasis in breast cancer: Prediction of TTBM according to breast cancer subtypes and treatment effect.
Authors: Park Yeon Hee , Ahn Hee Kyung , Park Silvia , Maeng Chi Hoon , Lee Su Jin , Ahn Jin Seok , Im Young-Hyuck 
Published: March 2020

644 Background: Brain metastasis (BM) from breast cancer (BC) is a growing problem. About 10-15% patients with metastatic breast cancer (MBC) developed BM, with a 1 year survival of 20%. Currently, one-third of MBC patients with either HER2+ve tumors or triple negative BC (TNBC) tumors develop brain metastases. We hypothesized that MBC patients may predispose to BM differently during the disease courses according to BC subtype and treatment. We analyzed TTBM from initial diagnosis of distant metastasis how BC subtypes and treatment affect on TTBM. Methods: We retrospectively investigated 189 consecutive patients who were diagnosed with BM from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM according to BC subtypes and treatment effect. Results: The median age of 189 BM patients from BC was 48 (range 26-87) years. The numbers of patients with hormone receptor (HR)+ve and HER2-ve, HER2+ve irrespective of HR status, and TNBC were 43 (22.8%), 88 (46.6%), and 58 (30.7%), respectively. Median TTBM of all 189 patients was 10.4 (95% CI, 7.7-13.1) months. We analyzed TTBC into four groups considering BC subtypes and treatment; HR+ve/HER2-ve (n=43), HER2+ve with trastuzumab (T) (n=59), HER2+ve without T (n=29), and TNBC patients (n=58). The median TTBMs for each group were 17.7 months, 13.8 months, 4.3 months, and 2.9 months, respectively (p=0.002). BM as an initial site of distant metastasis was much more common in HER2+ve without T and TNBC patients than in the other patients’ groups (40.2% vs 20.6%, p= 0.003). Conclusions: TTBMs were much shorter in patients with HER2+ve without T and TNBCs than in other BC patients. Different approaches for evaluation and therapeutic strategy for BM at the time of distant metastasis may be considered for these populations.
Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib.
Authors: Shah Neil P. , Kantarjian Hagop , Kim Dong-Wook , Hochhaus Andreas , Saglio Giuseppe , Guilhot Francois , Schiffer Charles Alan , Steegmann Juan Luis , Mohamed Hesham , Dejardin David , Healey Diane I. , Cortes Jorge E. 
Published: March 2020

6506 Background: Dasatinib, a potent BCR-ABL inhibitor, is approved for use as 1st- and 2nd-line therapy for CML pts with newly diagnosed disease or resistance/intolerance to imatinib. This ongoing study in pts with imatinib-resistant/-intolerant CML provides the longest follow-up of a second-generation BCR-ABL inhibitor. Methods: Study design has been described (Shah, J Clin Oncol 2008). Pts with imatinib-resistant/-intolerant CML (N=670) were randomized to dasatinib 100 mg once daily (QD), 50 mg twice daily (BID), 140 mg QD, or 70 mg BID. Results: Five-yr data are reported here; 6-yr data will be presented. After a minimum of 5 yrs, 151 pts (74%) remain on QD dosing, 85 of whom (56%) are on ≥100 mg QD dosing. Overall, 205 pts (31%) remain on study therapy with 55 pts (53%) originally randomized to BID dosing having switched to QD dosing. For pts randomized to the 100 mg QD arm (n=167), progression-free survival (PFS) at 5 yrs is 57%, overall survival (OS) is 78% with an overall 5% rate of transformation to advanced disease. In exploratory analyses, 42% and 60% of pts had BCR-ABL levels ≤10% (International Scale) at 1 and 3 months (mos), respectively. In a landmark analysis, BCR-ABL ≤10% at 1 or 3 mos was associated with higher 5-yr PFS. For dasatinib 100 mg QD, nonhematologic adverse events (AEs; all grades) generally first occurred in <24 mos. Cumulative rates of AEs in the 100 mg QD arm were headache (33%), diarrhea (28%), fatigue (26%), and pleural effusion (24%). For dasatinib 100 mg QD, cytopenias (grades 3/4) generally first occurred in <12 mos. The most common hematologic AEs (grades 3/4) in the 100 mg QD arm were neutropenia (36%) and thrombocytopenia (24%). AEs were managed by dose/schedule modifications. Conclusions: Five-yr follow-up of pts who switched to dasatinib 100 mg QD after imatinib-resistance/intolerance shows high rates of PFS, and OS with an overall low rate of transformation. Exploratory analyses suggest that achievement of a fast and deep response (≤10% BCR-ABL) at 1 or 3 mos after initiation of dasatinib 100 mg QD may be associated with a higher PFS. Dasatinib 100 mg QD was generally well tolerated over 5 yrs. Six-yr data will be presented.
A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases.
Authors: Jaglowski Samantha Mary , Jones Jeffrey Alan , Flynn Joseph M. , Andritsos Leslie A. , Maddocks Kami J. , Blum Kristie A. , Grever Michael R. , Geyer Susan Michelle , Woyach Jennifer Ann , Johnson Amy J , Heerema Nyla A. , Molnar Erin , Stefanos Mona , Devlin Susan , Navarro Tasheda , James Danelle Frances , Lowe Ann M. , Hedrick Eric , Byrd John C. 
Published: March 2020

6508 Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is critical for B-cell receptor (BCR) signaling in normal and malignant B lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, antagonizes BCR signaling in CLL cells and abrogates protective features of the microenvironment. P is highly active as a single agent in CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent experience by combining P with ofatumumab (O), an anti-CD20 monoclonal antibody. We present initial safety and efficacy data from cohort 1. Methods: Pts with relapsed/refractory (R/R) CLL/SLL following ≥2 prior therapies (Tx), including a purine-nucleoside analog (PA), are treated with 420 mg P daily, in 28-day cycles, until disease progression. O is added at a dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. Results: As of November 2011, 27 patients with either CLL/SLL/PLL (n=24) or Richter’s transformation (RT, n=3) have been enrolled and have received at least 6 cycles of treatment. The median age is 66 (range 51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 2-10), 15 pts had bulky disease (> 5 cm); 11 pts were PA refractory. Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia have been observed. The majority of adverse events (AE) were G1/2. G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia (7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: PCI-32765 combined with ofatumumab is well tolerated and highly active (100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of response, low relapse rate, and favorable safety profile make this combination worthy of further study. Cohorts evaluating other Tx sequences are currently underway.
Combination of the Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase Ib/II study.
Authors: O'Brien Susan Mary , Barrientos Jacqueline Claudia , Flinn Ian W. , Barr Paul M. , Burger Jan Andreas , Navarro Tasheda , James Danelle Frances , Hedrick Eric , Friedberg Jonathan W. , Brown Jennifer R. 
Published: March 2020

6515^ Background: BTK is an essential mediator of B cell receptor signaling and a critical kinase for lymphoma cell survival. PCI-32765 (P), an oral, selective, irreversible inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells, and is highly active as a single agent for the treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report interim data on P combined with BR. Methods: R/R CLL pts received P 420 mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of 6 cycles. Response was evaluated according to IWCLL criteria. Results: 30 pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4). 37% and 13% were considered refractory (treatment free interval <12 mo) to a purine analog containing regimen or BR, respectively. Bulky disease was present in 52%. Adverse events (AE) have been consistent with that expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been noted in 47% and 10% of pts, respectively. Grade >3 non-hematologic AEs potentially related to P included rash (3 pts) and fatigue and tumor lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There have been no discontinuations (D/C) due to AE and no deaths on study. At a median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%, PR 80%). 2 additional pts achieved a nodal response with residual lymphocytosis. Responses appear independent of high-risk clinical or genomic features. 90% of pts remain on study; reasons for D/C include PD (n=2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination with BR, is highly active. The high ORR, low rate of PD, and good tolerability compares very favorably with historical controls, warranting additional investigation of this combination.