tbuckley/cabot-search huggingface dataset:
ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.
Authors: Maria Bassanelli, Alessandra Felici, Michele Milella, Diana Giannarelli, Silvana Giacinti, Giovanna Gentile, Paolo Carlini, Francesco Cognetti, Michela Roberto, Giulia Poti, Serena Macrini, Anna Maria Aschelter, Maurizio Simmaco, Paolo Marchetti
Journal: Journal of Clinical Oncology (2017)

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C&gt;T, 3435C&gt;T], CYP3A5*3 6986A&gt;G, CYP3A4*1B-392A&gt;G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C&gt;T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C&gt;T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.
Efficacy of INK128, an mTORC1/mTORC2 kinase inhibitor, in breast cancer models driven by HER2-PI3K-AKT-mTOR pathway.
Authors: Pradip De, Yuliang Sun, Hui Wu, Christian Rommel, Yi Liu, Nandini Dey, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2012)

626 Background: Downstream of the PI3K-AKT pathway, the mTOR has been shown to be essential effector in promoting cell proliferation, survival, mRNA translation and tumor susceptibility. Aberrant activation of the PI3K-AKT-mTOR pathway occurs frequently in breast tumor (BT) and contributes to resistance to trastuzumab (T). Using a HER2 amplified BT model; we investigated the antitumor efficacy of the dual mTORC1/mTORC2 kinase inhibitor INK128 alone and in combination with T. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of INK128 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with INK128 and T (alone and in combination). Results: (1)INK128 exhibited excellent in vitro cell killing activity in MTT assay with IC50’s below 50nM. INK128 was more potent when combined with T, (2) INK128 blocked mTORC1, mTORC2 and thus did not cause the mTORC2 activation of AKT observed with rapalogues, (3) inhibition of phosphorylation of AKT(S473), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following INK128 treatment, and the combination of INK128 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) INK128 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of INK128 and T has strongly enhanced anti-tumor effect in both sensitive and resistant models, something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, 2) INK128 mitigates the feedback activation of AKT caused by selective inhibition of mTORC1 and 3) targeting both the HER2 and the mTORC1/2 signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.
Correlation of insurance status, ethnicity, and race with pathologic risk in retinoblastoma: A Children's Oncology Group (COG) study.
Authors: Adam L. Green, Bryan Langholz, Murali M. Chintagumpala, Myles Cockburn, Patricia Chevez-Barrios, Daniel Albert, Ralph Eagle, Carlos Rodriguez-Galindo
Journal: Journal of Clinical Oncology (2013)

e17573 Background: Insurance status affects cancer diagnosis and outcome in adults, but the impact has not been well studied in pediatric cancer. In children with retinoblastoma, time to diagnosis correlates with tumor invasiveness and patient survival, and therefore the disease can be a model to study the effect of demographic variables on delays in diagnosis. Methods: Our patient population consisted of all 203 patients from the United States enrolled on Children’s Oncology Group ARET0332, a study of patients with unilateral retinoblastoma requiring enucleation. All surgical specimens underwent central review by three pathologists to determine the presence of well-defined histopathologic features that correlate with a higher risk of disease progression. Data on insurance status, ethnicity, and race were collected for each patient. For variables not collected, including English proficiency, income, and educational attainment, analyses were conducted indirectly by matching patient zip code with census data for each variable. Results: On univariate analysis, a higher rate of high-risk pathologic findings was found in patients of Hispanic ethnicity (p=0.021) and non-white race (p=0.037), and in those with Medicaid or no insurance (p=0.035). On multivariate analysis, although no one variable correlated with high-risk features independently from the others, Hispanic ethnicity had the greatest impact on risk. Zip code-based analysis did not show significant differences in rates of high-risk findings based on English proficiency, income, or education. Conclusions: Hispanic ethnicity, non-white race, and Medicaid or no insurance all correlated with high-risk pathologic features in a large group of retinoblastoma patients who had central pathology review, and we believe these findings are due to delays in diagnosis for these groups. Future work should use direct methods to study the impact of other variables, including English proficiency, since indirect, zip code-based analysis may be inadequately powered to do so. Further effort should also focus on where in the diagnostic process delays exist, so that interventions can be designed to overcome barriers to care for these groups.
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation phase I study.
Authors: Christian K. Kollmannsberger, Herbert Hurwitz, James M. Cleary, John H. Strickler, Michel A. Drouin, Manuela Juretic, Wendy Hunt, Gregory K. Reid, Christiane R. Maroun, Claire Bonfils, James Wang, Andre Karam, Jeffrey M. Besterman, Mariam Mehran, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2012)

3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC 50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m 2 QD to 235 mg/m 2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured were: grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation, grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily doses ≥ 250 mg/m 2 . Additional ≥ grade 3 drug-related adverse events (observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and elevated alkaline phosphatase (n=1 for each event). Two schedules of MGCD265 were tested sequentially: once (QD) and twice daily (BID), respectively. Increasing the dose frequency to BID increased the exposure of MGCD265 by ~ 2 fold at steady state. To date, the exposure (C max ) attained at steady state with the BID schedule was ~20 fold higher than the IC 50 for Met and VEGFR inhibition and was also above the plasma exposures associated with efficacy in the Met-sensitive xenograft model (MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles). Conclusions: The safety profile of MGCD265 continues to be favorable in this Phase I dose escalating study. While no evidence of objective responses have been noted to date, several pts have had prolonged SD. Dose escalation is ongoing.
SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients with stage IV melanoma.
Authors: Christopher D. Lao, James Moon, John P. Fruehauf, Lawrence E. Flaherty, Martin J. Bury, Antoni Ribas, Vernon K. Sondak
Journal: Journal of Clinical Oncology (2012)

8521 Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle control and agents that can target cdks in malignant progression remain viable therapeutic strategies. Selective inhibition of cdk2, in particular, may be of therapeutic value in a subset of patients with melanoma. Methods: 60 patients with metastatic melanoma of cutaneous or mucosal origin were planned to be recruited to a multicenter, single-arm phase II trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were potentially eligible if they had 0-1 previous treatments, PS of 0-1, and adequate organ function. Ocular melanoma patients and patients with a history of brain metastases were excluded. SCH 727965 50 mg IV every 3 weeks was given until progression with disease assessment occurring every 2 cycles. Co-primary endpoints were 1-year overall survival (OS) and 6-month progression free survival (PFS). Results: 72 patients were enrolled from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of patients had M1c disease and 43% had LDH elevation. 19% had prior therapy for metastatic disease. 28 patients (39%) experienced Grade 4 adverse events, including 20 cases of neutropenia, one case each of cardiac ischemia/infarction, cardiac troponin I elevation, dehydration, abdominal pain, leukopenia, muscle weakness, headache, syncope, and anterior ischemic optic neuropathy. 65 patients are currently evaluable for response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease was observed in 22%. The estimated median PFS was 1.5 months (95% CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%). Median OS was 8 months (95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null hypothesis of 1-year overall survival=25% was rejected (p=0.04) but 6-month PFS=11% was not (p=0.8). Data Analysis will be updated when missing data are received. Correlative studies of Rb phosphorylation and cyclin expression will be pursued. Conclusions: SCH 727965 appears to be reasonably well tolerated although grade 4 events were relatively common, particularly near the time of infusion. There were no responses but few patients had prolonged disease stabilization that may have resulted in improvement in the 1-year OS rate.
Predicting sensitivity to azacytidine in non-small cell cancer lines by absence of activating mutations.
Authors: John Wrangle, Helai P Mohammad, Abde Abukhdeir, Rosalyn A. Juergens, Kirsten Harbom, Kristen Rodgers, James Shin, Cynthia A. Zahnow, Stephen Baylin, James Gordon Herman, Charles M. Rudin, Malcolm Brock
Journal: Journal of Clinical Oncology (2012)

e18147 Background: A completed clinical trial has demonstrated activity of a combination of epigenetic therapies: entinostat, a histone deacetylase inhibitor, and azacytidine (AZA), a hypomethylating agent. A plasma-based biomarker assaying methylation status of key gene promoters from circulating DNA was developed. In order to test the relationship of activating mutations to sensitivity to epigenetic therapy, we treated non-small cell lung cancer (NSCLC) lines with AZA and assessed tumor growth in xenografts. Tumor from patients on trial was analyzed for mutational status. Methods: Nine NSCLC lines were treated in vitro for 72 hours with 500 nM AZA and injected to form flank tumors in NOG mice. Four lines contain no activating mutations. Of the five mutant lines, three were KRAS and two were EGFR mutations. Lines with no activating mutations are termed “mutation-negative” for known oncogenic drivers. Growth of mock versus treated tumors was compared over time to determine treatment phenotypes. Lines were grouped into four categories: augmented growth compared to mock, no treatment effect, mild inhibition of tumor growth, and marked inhibition. Seventeen tumors from the clinical trial were analyzed by SNaPshot multiplex PCR. Results: Among mutation negative lines three showed marked tumor growth inhibition and one showed mild inhibition. Among cell lines with activating mutations, one showed mild inhibition, three showed no effect, and one showed augmented tumor growth. Among 17 tumor samples from patients on study, four driver mutations were identified: 3 KRAS and one PTEN mutation. All four patients experienced progressive disease on study. Among thirteen patients with mutation negative tumors, three had stable disease and one had a complete response. Conclusions: The association between driver mutation negative status and treatment outcome in NSCLC cell lines in patients receiving AZA and entinostat merits further exploration. Future trials of epigenetic therapy in NSCLC may benefit from a biomarker enrichment strategy and the data presented here represents a potential way forward.
A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma
Authors: B. H. O'Neil, L. W. Williams-Goff, J. Kauh, T. Bekaii-Saab, J. R. Strosberg, R. Lee, A. M. Deal, D. Sullivan, S. M. Sebti
Journal: Journal of Clinical Oncology (2009)

e15574 Background: HCC is a deadly disease with few effective treatments. It is characterized by frequent MEK/ERK activation in the absence of RAS or RAF mutation. AZD6244 is a specific inhibitor of MEK that can be administered orally. Methods: Multi-center, single-arm study with a two-stage design utilizing RR as primary endpoint. Patients had advanced or metastatic HCC not amenable to surgical therapy or who failed locoregional therapy. Pts with Childs-Pugh A and compensated B were eligible. No prior systemic therapy was allowed. A pre-treatment biopsy was performed for p-ERK analysis. AZD6244 was administered orally at a dose of 100 mg bid. Results: 19 patients were enrolled, completing the first planned stage. One patient withdrew during cycle 1 with grade 2 AEs and is not evaluable. One patient is too early for evaluation. Another was removed from study for toxicity prior to evaluation. Two patients exhibited clinical progression and were removed from study without imaging (both assigned response of PD). Of 16 evaluable patients, PR + CR was 0%, SD 37.5%, PD 62.5%. Toxicities were generally low grade and included nausea (75%), transaminitis (63%), Alkaline phosphatase (50%), vomiting (50%), fatigue (44%), diarrhea (44%) and skin rash (44%). Grade 3–4 toxicity included transaminitis (38%), hyperbilirubinema (25%), and hypokalemia (13%). Median TTP was 8 weeks (95% CI: 6.6, 11.1). Conclusions: The study has been stopped at the interim analysis due to lack of radiographic response. Time to progression is not suggestive of significant prolonged stable disease. AZD6244 is well tolerated, but appears to have minimal activity in advanced HCC. Analysis of ERK phosphorylation status in biopsy samples is ongoing. No significant financial relationships to disclose.
Ongoing needs in 625 women living beyond early breast cancer.
Authors: Marta Capelan, Nicolo Matteo Luca Battisti, Anne McLoughlin, Nikki Snuggs, Vivienne Maidens, Patrycia Slyk, Clare Peckitt, Susannah Jane Stanway, Natalie Doyle, Theresa Wiseman, Alistair E. Ring
Journal: Journal of Clinical Oncology (2017)

139 Background: In some healthcare systems people with a diagnosis of early invasive breast cancer (BC) are discharged from hospital-based follow-up after completion of initial treatment. However there are limited data on the prevalence of specific ongoing physical and psychological needs in such people. Methods: We conducted a retrospective study involving survivors of BC who entered into the Open Access Follow-Up (OAFU) program at The Royal Marsden Hospital (UK) from January to December 2015. The ongoing needs were assessed using the Holistic Needs Assessment (HNA) (a checklist questionnaire regarding physical, emotional, family, practical and spiritual needs) or extracted directly from the Electronic Patient Record (EPR). Results: Six hundred and twenty-five invasive survivors of BC were seen for the first time in the OAFU program after completing their initial treatment. Ongoing needs were identified in 214 (34%) from their returned HNA and in 411 (66%) direct from EPR. Demographic and treatment characteristics were not significantly different between the two groups. The median age was 59 year-old. Median time from diagnosis to assessment was 8.9 months. Ongoing needs were categorized in 3 different groups: 0, 1-4 and ≥ 5 needs. 513 (82%) survivors of BC had 0-4 ongoing needs and 18% had ≥ 5 needs. Physical and emotional needs were the most frequently reported (55% and 24% respectively). Rates of ongoing needs were more frequently identified using formal HNA assessment than extraction from EPR: overall physical needs: 79% vs. 43% (p &lt; 0.001) and emotional needs 50% vs. 10% (p &lt; 0.001). The most frequent specific ongoing needs were: hot flushes (23%), fatigue (21%), pain (19%), worry, fear and anxiety (16%), sleep problems (14%), tingling in hands/feet (11%), dry, itchy or sore skin (11%) sadness and depression (10%), changes in weight (10%) and memory or concentration problems (10%). Conclusions: Fifty-five percent survivors of BC reported at least one physical need and 24% an emotional need. Consistently higher levels of ongoing needs were identified using the HNA formalized checklist. The HNA enables people self-reflection and promotes discussion with the health professional in order to identify ongoing needs and provide on-going supportive care.
Pegylated liposomal doxorubicin plus paclitaxel as an individualized chemosensitivity-directed treatment in advanced metastatic melanoma
Authors: S. Ugurel, K. Neuber, C. Pfoehler, C. Mauch, J. Ulrich, D. Schadendorf
Journal: Journal of Clinical Oncology (2007)

8551 Background: Melanoma is a cutaneous neoplasm known for its high agressiveness and its poor prognosis once metastasized. Dacarbacine chemotherapy is actually considered standard first-line treatment of metastatic melanoma, with reported response rates of 6–7%. Due to this unsatisfactory situation, a number of non-standard anti-cancer drugs have been tested for improved efficacy. The present study was aimed to test doxorubicin plus paclitaxel in metastatic melanoma patients based on in-vitro chemosensitivity of this drug combination in fresh tumor samples. Methods: The primary study endpoint was objective response, secondary endpoints were safety and overall survival. Patients with histologically confirmed metastatic melanoma (AJCC stage IV), measurable tumor parameters, and an in-vitro chemosensitivity to doxorubicin plus paclitaxel which is superior to other test drugs determined by an ATP-based luminescence viability assay, were eligible. Patients received paclitaxel 175 mg/m 2 i.v. followed by pegylated liposomal doxorubicin 30 mg/m 2 i.v. at d1 every 28 days. Tumor assessment was performed every 8 weeks and evaluated according to RECIST. Treatment was continued at a tumor response of stable disease (SD) or better, and stopped in case of disease progression (PD) or intolerable side effects. Results: Out of 14 patients enrolled into this study, 12 received study treatment as first-line, and two as second-line therapy. Objective response was 14.3% (1 CR, 1 PR); progression arrest was 28.6% (1 CR, 1 PR, 2 SD). Median overall survival was 9.7 months. Common slight to moderate side effects were myelosuppression and neurotoxicity. Severe toxicities (CTC grade 3/4) were experienced by three patients (21.4%), with two of them presenting severe myelosuppression, and one experiencing myocardial infarction. Conclusions: Pegylated liposomal doxorubicin combined with paclitaxel shows significant efficacy in advanced metastatic melanoma if applied in an individualized, sensitivity- directed regimen. The observed side effects were comparable to other combination chemotherapies. This treatment regimen needs further evaluation in larger clinical trials containing standard therapy control groups. No significant financial relationships to disclose.