tbuckley/cabot-search huggingface dataset:
MGMT gene promoter methylation in plasma of glioma patients receiving temozolomide.
Authors: Riccardo Soffietti, Luca Bertero, Elisa Trevisan, Anna Castiglione, Valentina Fiano, Morena Trevisan, Paola Cassoni, Franco Merletti, Roberta Ruda
Journal: Journal of Clinical Oncology (2014)

2016 Background: MGMT gene promoter methylation in tumor tissue of gliomas is now recognized as a predictive biomarker for response to temozolomide. Up to date there is lack of studies investigating MGMT methylation status in the circulating DNA of glioma patients undergoing chemotherapy with temozolomide. In this prospective study on a cohort of patients with gliomas of different grades of malignancy we aimed to: (1) evaluate the concordance between MGMT methylation status in tumor tissue and plasma; (2) monitor MGMT methylation status in plasma before and during temozolomide, and explore its value as a predictive biomarker. Methods: We enrolled 58 patients who underwent surgical resection, followed by radiotherapy and/or temozolomide. Blood samples were collected at baseline and every 3 cycles of temozolomide up to 12 months. MGMT promoter methylation status was assessed in both paraffin-embedded tumor tissue and plasma by real-time PCR. Results: MGMT promoter methylation status was concordant in tumor tissue and plasma at baseline in 42 out of 48 patients (87.5%, Kappa=0.75, 95%CI: 0.57-0.93). When considering glioblastomas only we obtained a 93.7% concordance and a Kappa of 0.87 (95%CI: 0.70-1.00). Mortality was higher for patients with MGMT unmethylated promoter both in tumor tissue (HR=2.21, 95%CI: 0.99-4-95) and plasma (HR=2.19, 95%CI: 1.02-4.68). Progression-free survival was shorter for patients with unmethylated MGMT promoter both in tumor tissue (HR=2.30, 95%CI: 1.19-4.45) and plasma (HR=1.77, 95%CI: 0.95-3.30). The cumulative incidence of unmethylated MGMT promoter in plasma was 58% at baseline and reached virtually 100% at 12 months. Conclusions: The assessment of MGMT promoter methylation in plasma can be useful when adequate tumor tissue (i.e. in stereotactic biopsy or in inoperable tumors) is not available. Moreover, the analysis of MGMT promoter methylation in plasma could be particularly useful to monitor methylated patients, helping to establish when the tumor switches from a methylated to an unmethylated status, thus predicting the emerging of a treatment resistance.
Tobacco use among lymphoma survivors.
Authors: Guadalupe R. Palos, Frances Ann Zandstra, Kristin A. Simar, Ludivine Russell, Delrose Ozeri, Weiqi Bi, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2014)

e20608 Background: There is a growing body of literature establishing the risks associated with tobacco use among cancer survivors and benefits from discontinuing this behavior. Smoking behavior among lymphoma survivors is of interest due to the wide differences among the subtypes’ demographic characteristics and treatment regimens, i.e. Hodgkin’s lymphoma (HL) vs. diffuse large B-cell lymphoma (DLBCL). We reviewed tobacco use as reported by HL and DLBCL post-treatment survivors. Methods: Data were abstracted from the electronic medical records (EMRs) of 154 survivors treated for DLBCL or HL and seen in the Lymphoma Survivorship Clinic between 10/1/2012 to 7/31/2013. Thirty-three records with diagnoses other than DLBCL or HL were excluded. Information on smoking patterns, demographic, and clinical characteristics was collected from EMRs. Data were analyzed by “never” smoked, “former” smoker, or “current smoker” status. Descriptive statistics summarized these data. The Institutional Quality Improvement Assessment Board approved this project. Results: A total of 121 patients' records were included in this review. Of these 54.2% survivors were diagnosed with DLBCL and 45.8% with HL. The majority of DLBCL (64%) and HL survivors (77.7%) reported never having smoked. Overall, survivors in the DLBCL group, regardless of smoking status, were mostly white (85.9%), men (51.5%), married (79.9%), 9.6 (SD 4.3) years since diagnosis, and with a mean age of 63.3 (13.2 SD) years. In the HL group, the majority were white (79.6%), married (74.1), similar in gender (50%), 13.3 (SD 6.8) years since diagnosis, and with a mean age of 46.0 (SD 12.0) years. In the DLBCL group, more men (73.9%) than women quit smoking and more women (61.0%) than men reported never smoking. Current smokers (2.5%) were all white, varied in sex, and with a mean age of 69.7 (SD 7.6) years. Conclusions: Overall, survivors of HL and DLBCL predominantly reported not ever engaging in smoking or stopping their tobacco use. Further investigation is needed to identify factors that may have motivated this group of lymphoma survivors to never smoke and/or to quit smoking. This information can then be used to personalize smoking cessation interventions for other cancer survivors.
Efficacy and safety data from elderly patients with pretreated advanced melanoma in the Italian cohort of ipilimumab expanded access programme (EAP).
Authors: Vanna Chiarion-Sileni, Jacopo Pigozzo, Paolo Antonio Ascierto, Michele Maio, Riccardo Danielli, Michele Del Vecchio, Laura Ridolfi, Federica De Galitiis, Alessandro Testori, Emilia Cocorocchio, Francesco Cognetti, Virginia Ferraresi, Maria Grazia Bernengo, Michele Guida, Andrea Antonuzzo, Mario Mandala, Giorgio Parmiani, Vito Vanella, Massimo Aglietta, Paola Queirolo
Journal: Journal of Clinical Oncology (2013)

9548 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Here we evaluate the safety and efficacy of ipilimumab treatment outside of clinical trials in elderly (&gt;70 years old) patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Disease evaluation was performed at baseline and after completion of induction therapy using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: Out of 855 Italian pts participating in the EAP from June 2010 to January 2012 across 55 centres, 193 (22.6%) were over 70 years old (median 75; 70-88). Of these, 132 pts (68.4%) received all 4 doses of ipilimumab, 24 (12.4%) 3 doses, 17 (8.8%) 2 doses and 20 pts (10.4%) received 1 dose. With a median follow-up of 7.6 months (range 1-26), the disease control rate among 188 pts evaluable for response was 38.3%, including 4 pts (2.1%) with a complete response, 24 (12.8%) with a partial response and 44 (23.4%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.7 months and 8.9 months respectively, with 1-year survival rate of 38%. In total, 96 pts (49.7%) reported an AE of any grade, which were considered treatment-related in 69 pts (35.7%), with a safety profile comparable to the general population. Grade 3/4 AEs were reported by 19 pts (9.8%) and drug-related in 11 pts (5.7%). AEs were generally reversible with treatment as per protocol-specific guidelines with a median time to resolution of 2.0 weeks. Conclusions: Based on the data from EAP, ipilimumab is a feasible treatment in the elderly population; efficacy and safety results were similar to those observed in the general population.
Multigene hereditary cancer panel testing for patients with pancreatic cancer.
Authors: Anna K McGill, Sheila R Solomon, Megan L Marshall, Lisa Susswein, Corrine Fillman, Katherine A Skora, Kristen J Vogel Postula, Rachel Klein, Kathleen S. Hruska, Zhixiong Xu
Journal: Journal of Clinical Oncology (2017)

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.
A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated <i>CDKN2A</i>.
Authors: Priya Kadambi Gopalan, Mary Colleen Pinder, Alberto Chiappori, Alison Marguerite Ivey, Andres Gordillo Villegas, Frederic J. Kaye
Journal: Journal of Clinical Oncology (2014)

8077 Background: The Retinoblastoma pathway is targeted for mutational or epigenetic inactivation in more than 70% of NSCLC. The most common event is loss of CDKN2A expression (p16 protein), usually by hypermethylation, resulting in deregulated CDK4/6 activity and cell cycle progression. Palbociclib is a highly specific CDK4/6 inhibitor and has been shown to inhibit cell cycle progression and promote cellular senescence. Methods: We conducted a phase II, single arm trial of palbociclib in 19 previously-treated patients with recurrent or metastatic NSCLC. Only patients whose tumors were negative for p16 expression by immunohistochemistry were eligible. The primary endpoint was response rate. A Simon's 2-stage design was employed, with 2 or more responses required to proceed to the second stage. Palbociclib at 125 mg daily was given orally on days 1-21 of a 28-day cycle. Tumors were assessed by RECIST every 2 cycles. Secondary endpoints included overall survival, progression-free survival, toxicity and biomarker analysis. Results: Of the 16 evaluable patients who received at least one month of therapy, there were no responses, and the trial was closed to accrual. However, 8 patients with previously progressive NSCLC had stable disease (SD) lasting 16, 17, 20, 24, 35, 38, 41 and 42 weeks. The remaining 8 patients had progressive disease within 8 weeks. The median PFS was 12.5 weeks. There was no correlation between SD and histology or EGFR mutation status. One patient experienced grade 3 and 4 toxicities as a result of transaminitis and rhabdomyolysis (generalized muscle weakness and increased CPK) thought to be due to concomitant use of high-dose (80 mg) simvastatin. Three patients developed grade 3 or 4 neutropenia, and one patient developed grade 3 thrombocytopenia. All other toxicities were grade 1 or 2. Conclusions: Palbociclib therapy alone was well-tolerated, and stable disease (SD) was achieved in 50% of evaluable patients, suggesting the induction of cellular senescence. PFS was comparable to other second-line chemotherapeutic agents. Molecular predictors of clinical benefit (SD) are currently under investigation. Clinical trial information: NCT01291017.
Long-term population-based outcomes of adjuvant trastuzumab in HER2-positive early breast cancer: The British Columbia experience.
Authors: Stephen K. L. Chia, Caroline Speers, Melanie Dawn Seal, Sheridan Marie Wilson, Scott Tyldesley, Caroline A. Lohrisch
Journal: Journal of Clinical Oncology (2014)

611 Background: The use of adjuvant trastuzumab in women with HER2 positive early breast cancer also receiving adjuvant chemotherapy became standard of care in British Columbia in 2005. As the randomized clinical trials continue to update on the long-term efficacy of adjuvant trastuzumab, we have also recently updated our longer term outcomes from a population based publicly funded health care perspective. Methods: The British Columbia Cancer Agency (BCCA) Breast Cancer Outcomes Unit database includes all referred patients to the BCCA since 1989. Only patients with stage I-III HER-2 positive breast cancer diagnosed from July 2004 – Dec 2008 were included in the analysis. Demographic, pathologic and treatment data were reviewed. 5 year relapse free survival (RFS), distant relapse free survival (DRFS) and overall survival (OS) rates were calculated by Kaplan-Meir method. Results: 1,413 patients were identified, of which 953 were treated with adjuvant trastuzumab with a median follow-up of 5.4 years. 226 Stage I HER-2 positive breast cancers were treated with chemotherapy and trastuzumab. Of the 64 T1a-bN0 cases, 63% were ER-; while in the 162 T1cN0 cases, only 37% were ER-. Conclusions: 5-year population based clinical outcomes in the era of adjuvant trastuzumab are favorable, especially in node negative disease. Our 5 year RFS in T1cN0 HER2+ breast cancers treated with chemotherapy and trastuzumab is 100%. Future adjuvant clinical trials with new or multiple anti-HER 2 agents should only focus on node positive patients. No. of patients 5-year RFS (95% CI) 5-year DRFS (95% CI) 5-year OS (95% CI) Node- 400 95.1% (92-97%) 95.6% (93-97%) 95.1% (93-97%) Node+ 552 82.6% (79-86%) 83.9% (81-87%) 86.3% (83-89%) T1a-bN0 64 92.2% (82-97%) 93.7% (84-98%) 94.6% (84-98%) T1c N0 162 100% (100%) 100% (100%) 98.1% (94-99%)
FLT3 mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).
Authors: Pavan Kumar Bhamidipati, Naval Guastad Daver, Hagop Kantarjian, Sherry Pierce, Roshni Daver, Jorge E. Cortes, Farhad Ravandi, Michael Mathisen, Naveen Pemmaraju, Aziz Nazha, Tapan M. Kadia, Elias Jabbour, Gautam Borthakur, Stefan Faderl, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2012)

6597 Background: FLT3 mutations occur in one third of acute myeloid leukemia (AML) patients (pts) and predict poor outcome. The incidence and impact of FLT3 in MDS/ CMML is unknown. Methods: We conducted a retrospective review at MDACC to identify FAB MDS/ CMML pts with FLT3 mutations at diagnosis. Results: From 1996 to 2010; 2052 MDS/ CMML pts had mutation analysis. 45 (2.2%) had FLT3 mutations (internal tandem duplication-ITD or D835) at diagnosis. 29 pts had MDS and 16 had CMML. Median (Med) age was 64 years (21 to 83) and 69% were males. FAB groups: 3 pts with refractory anemia (RA), 11 pts with refractory anemia-excess blasts (RAEB), 18 pts with refractory anemia-excess blasts in transformation (RAEB-T) and 13 pts with CMML. IPSS: 3 in Low (7%), 16 in Int-1 (36%), 11 in Int-2 (24%), and 15 in High (33%). Med white count, hemoglobin, platelet count and marrow blast percent at diagnosis were 5.2 x 10 9 /l (1.2 to 211), 10.0 g/l (6.8 to 14.9), 78 x 10 9 /l (8 to 429), and 14% (1 to 28), respectively. FLT3 ITD and FLT3 D835 mutations were present in 32 (71%) and 13 pts (29%), respectively. Karyotype was diploid in 30 (66%); -5/-7 in 5 (11%), 11q in 1 (2%), and others in 9 pts (19%). All 5 pts with -5/ -7 had the ITD mutation. Concurrent mutations were identified in RAS, NPM1 and C-Kit in 6 (13%), 3 (7%) and 1 (2%) pt, respectively. Med overall survival (OS) for FLT3 pts was 15 months compared to 17 months for non FLT3 pts (P=0.9). 18 pts had RAEB-T: 13 (72%) received AraC-based therapy and 3 (17%) received hypomethylating therapy (HMT) with complete remission (CR) in 14 pts (78%). 14 pts had RA/ RAEB: 5 (36%) received AraC-based therapy and 7 (50%) received HMT with CR in 5 (37%) and hematological improvement (HI) in 4 (28%). 13 pts had CMML: 4 (31%) received AraC-based therapy and 6 (46%) received HMT with CR in 3 (23%) and HI in 3 (23%). Repeat FLT3 was available on 16 pts achieving any response and was absent/ decreased in 14 (88%), stable in 1 (6%) and increased in 1 (6%). Notably, the 14 pts with absent/ decreased FLT3 had med OS of 27 months versus 12 months for remaining group (P=0.004). Conclusions: FLT3 occurs in MDS/ CMML at a lower frequency than AML and does not predict poor outcome. Pts who achieve absent/ decreased FLT3 seem to have significantly improved overall survival.
Immune profiling in elderly cancer patients for predicting immune senescence.
Authors: Hye Ryun Kim, Soo Jung Kim, Sang Joon Shin, Woo Sun Kwon, Tae Soo Kim, Joong Bae Ahn, Jaewoo Song, Chang Oh, Sun Young Rha
Journal: Journal of Clinical Oncology (2015)

e22117 Background:Cancers are increasing with aging and thus the number of elderly cancer patient is expected to increase significantly in years to come. The aims were to evaluate and determine the immune profiling associated with immune-senescence, which could be important in deciding the treatment of elderly cancer patients. Methods: We prospectively enrolled patients, who were treated and followed-up in the department of Geriatrics and Medical oncology. Key inclusion criteria were follows; radically resected stage I-III, gastric and colorectal cancer patients who were disease-free over 3 years, or non-cancer elderly patients ≥ 65 years old (yo) with chronic diseases. PBMC were stained with following antibodies: anti-CD4, anti-CD8, anti-CD27, anti-CD28, anti-CD34, anti-CD44, anti-CD25, anti-FOXP3 and anti-CD133, and analyzed by four-color flow cytometry on a FACS Beckman Coulter. We analyzed the immune profiling depending on aging ( > 65 vs. ≤ 65) and the prior presence of cancer, respectively. Results: We enrolled 118 patients and the median age was 73 yo (range 34-90) and the male were 57.6%. Eighty-four (71.1%) patients were more than 65 yo and 45 (38.1%) had experienced the surgery for cancer. At first, we observed there was no difference in various immune markers depending on the previous presence of cancer. Then, we compared various immune markers based on the age groups. Each percentage of CD4+ and CD8+ lymphocytes and the ratio of CD4:CD8 were comparable. By contrast, the mean percentage of CD27+, CD28+, CD27+CD28+ and CD27-CD28+ in CD8 T cells gated population were significantly lower in patients > 65 than ≤ 65 yo, respectively (14.1 vs. 11.6 %, P= 0.008; 12.2 vs. 10.3%, P= 0.009; 35.0 vs.27.6%, and P= 0.009; 2.8 vs. 3.4%, P= 0.036). There were no significant differences in Treg, CD34+, CD133+, and CD133+CD44+ subsets. Conclusions: This pilot study elucidated the profiling for immune-senescence in elderly patients. We observed that immune subsets of T cells with increased expression of immune stimulatory molecules were decreased in elderly patients, suggesting decreased immune function in elderly patients. In addition, these could be explored as an immune-senescence marker to assist the treatment decision of elderly cancer patients.
Radiologic signs of adipocytic maturation (AM) in dedifferentiated liposarcoma (ddLPS) patients (pts) treated with trabectedin (T): Correlation with disease control.
Authors: Sree Harsha Tirumani, Andrew J. Wagner, Harika Tirumani, Atul B. Shinagare, Jyothi Priya Jagannathan, Jeffrey A. Morgan, James E. Butrynski, Suzanne George, George D. Demetri, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2014)

10561 Background: T has been shown to induce histological AM in myxoid liposarcoma (mLPS), but this has not previously been described in ddLPS. In this retrospective analysis, we analyzed the imaging studies in pts with various LPS subtypes (ddLPS, mLPS, pleomorphic LPS (pLPS), unclassified LPS (uLPS)) treated with T to see whether radiologic AM is detectable in clinical assessments. Methods: This single institution study, which enrolled 55 pts with LPS, was conducted as part of an expanded access trial of T (NCT00210665). Assessable pre- and post-T imaging studies were available for 48 pts (33M, 15F), including 24 ddLPS, 16 mLPS, 4 pLPS, and 4 uLPS. Mean age at diagnosis was 50 yr (range 24 – 74 yr). T was administered until disease progression, and restaging scans were performed approximately every 6 weeks. Radiologic evidence of AM (change of tumor to fat density), changes in lesion density and size, and best response per RECIST 1.1 were assessed at final T cycle. Clinical benefit and rate (CBR) was based upon CR, PR or prolonged SD (≥ 6 months). Results: Median T treatment duration was 11 mos (range, 1-44 mos). T was discontinued in 3 pts (5%) due to adverse events. Best response was PR in 8 (15%; 7 mLPS, 1 ddLPS), SD in 31 (56%; 9 mLPS, 14 ddLPS, 4 uLPS, 2 pLPS) and PD in 11 (20%; 9 ddLPS, 2 pLPS) pts. Radiologic evidence of AM was noted in 8 pts (15%; 6 ddLPS, 2 mLPS), all of whom had SD as best response. Decrease in tumor density was noted in 13 pts (27%; 9 mLPS, 4 ddLPS). Median T treatment duration was 6 months (1-44 mos) in all ddLPS and 13 mos (6-44 mos) in ddLPS with AM. There was a statistically significant correlation between radiologic AM and SD in ddLPS (p=0.0481; Fisher’s exact test). Median progression-free survival was 6.5 mos (1 – 44 mos) for all patients and 6 mos for ddLPS. CBR was 60% in all pts and 50% in ddLPS. Conclusions: Radiologic AM in ddLPS pts treated with T is seen more often in patients receiving the drug for ≥6 mos, and is correlated with objective disease control.