tbuckley/cabot-search huggingface dataset:
Factors associated with 21-gene assay receipt among women with lymph node positive breast cancer.
Authors: Megan Roberts, Allison W. Kurian, Valentina I. Petkov
Journal: Journal of Clinical Oncology (2017)

6554 Background: The 21-gene Breast Recurrence Score (RS) assay predicts breast cancer (BC) recurrence and adjuvant chemotherapy benefit in select patients with lymph node-positive (LN+), hormone receptor-positive (HR+), HER2 negative BC. This study examines factors associated with assay uptake among women with LN+ BC in SEER databases. Methods: In this population-based study, incident BC cases in SEER registries (2010-2013) were linked to RS results from assays performed by Genomic Health. Our study sample included women with non-metastatic, LN+ (≥1 positive LN), HER2-, HR+, BC. We use logistic regression to identify demographic, SES, and tumor characteristics associated with having the 21-gene assay ordered. Results: A total of 4428 (14.0%) of 31520 women with LN+, HR+, HER2-, BC had the assay ordered. Uni- and multi-variate analyses identified key factors that were significantly associated with the proportion of women tested. In the multivariable analysis, age (aOR: 2.23, p&lt;0.001, 65-74 v &lt;45 years) and BC diagnosis year (aOR:1.75, P&lt;0.001 2013 vs 2010) were positively associated with assay receipt; whereas number of positive LN (aOR: 0.14, p&lt;0.001, 4+ positive LN vs 1 positive LN), tumor grade and size, low SES, being black, and being widowed were negatively associated with assay uptake (p&lt;0.001). Having Medicaid was associated with lower odds of test receipt (p=0.01). Finally, we identified geographic variation in assay ordering. See univariate results (Table). Conclusions: Important demographic and SES variables were associated with test receipt in LN+ disease, and differed from those previously reported in node negative disease. Moving forward, increased awareness of these disparities, particularly among low SES, Medicaid, Black and widowed patients, along with targeted interventions may help to improve quality of care and equity in test receipt. [Table: see text]
Pathogenic somatic mutation (SM) of mismatch repair (MMR) genes and associations with microsatellite instability (MSI), tumor mutational burden (TMB) and SM in other DNA repair pathways in 24,223 tumor genomic profiles.
Authors: Joseph Nicholas Bodor, Elizabeth A. Handorf, Rebecca Feldman, Michael J. Hall
Journal: Journal of Clinical Oncology (2018)

1505 Background: SM disabling DNA repair mechanisms is common in cancer. SM in MMR genes (MLH1, MSH2, MSH6, PMS2) contribute to MMR deficiency and the MSI phenotype. Biallelic SM (bSM) of an MMR gene can cause MMR deficiency in colorectal (CRC) and endometrial cancers (EC), but the frequency of monoallelic SM (mSM) and bSM of MMR genes in other tumors is unknown. Clinical/molecular correlates of MMR gene mSM/bSM are not well described. Methods: The Caris Life Sciences database was queried for tumors with ≥1 SM of an MMR gene by NGS (Illumina NextSeq 592 gene panel). Association of mSM or bSM with clinical factors, MSI, TMB, and SM in non-MMR DNA repair pathways was examined. Associations were tested by Fisher's exact test and logistic regression. Results: Of 24,223 tumors queried, 470 had ≥1 SM, of which 80 had bSM in an MMR gene. MSH6 had the highest frequency of bSM (n = 46) primarily due to recurrent SM at F1088fs, a coding microsatellite. Tumors with bSM were more common in younger pts, median age 57.5 yrs bSM vs. 63 yrs mSM (p = 0.003). bSM was associated with high TMB (p < 0.001), and with SM in nucleotide excision repair (NER) genes (p = 0.003), and homologous recombination (HR) genes (p = 0.01), e.g. ATM (62/470, 13.2%) and BRCA1/2 (n = 91/470, 19.4%). At the single gene level, mSM in MSH2 (p = 0.001) and MSH6 (p = 0.01) were positively associated with TMB, but inversely with PMS2 (p < 0.001). MSI was only associated with mSM in MLH1 (p < 0.001). Further, SMs in HR genes were associated with mSM in MLH1, MSH2, and MSH6 (all p < 0.01), but SM in NER were associated only with mSM in MSH6 (p = 0.004). By tumor type, mSM were common in EC (n = 84), CRC (n = 80) and lung (n = 45), but nearly all bSM (98%) were in LS-spectrum tumors. Differences in bSM frequency in left vs. right CRC (30.0% vs 12.5%) were not seen (p = 0.10). Conclusions: MMR gene mSM occur in diverse tumors, but bSM occur almost exclusively in LS-spectrum tumors. Younger age suggests germ-line mutations may precede some bSM events. Association of MMR mSM/bSM to high TMB, MSI, and SM in other DNA repair pathways suggests cascade effects of DNA repair deficiency and reveals possible treatment targets.
Perioperative outcomes in elderly patients undergoing hepatic resection for hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Elinor Tan, Charbel Sandroussi
Journal: Journal of Clinical Oncology (2018)

e16130 Background: Hepatocellular carcinoma is a disease of the elderly. The median ages of diagnosis were 63-65 in western countries. Surgical resection remains as an important curative treatment option available to patients. However, there is limited clinical data on the complications and survival associated with liver resection in the elderly. Methods: Medline, Embase and Cochrane Library were searched for original published studies comparing short and long-term postoperative outcomes between elderly patients (≥70,≥75,≥80 years) versus younger patients ( < 70, < 75, < 80 years) for hepatocellular carcinoma. Studies published before 2000 were excluded. Pooled estimates were measured using the fixed or random effect model. Subgroup analyses were performed. Heterogeneity was tested by the Cochrane Q statistic. Results: Twenty-seven studies (n = 10,064) were included. Older patients had higher ASA grade, lower albumin level and more cardiovascular and pulmonary co-morbidities than younger patients (p < 0.05). Liver cirrhosis was less common in the elderly group (p = 0.03); nonetheless, HCV associated HCC was more likely in this population (p < 0.01). Older patients experienced shorter operative time (p = 0.001), lesser intraoperative blood loss (p = 0.03) with no difference in postoperative complications (OR[95%CI], 1.19[0.95,1.48], p = 0.140), in-hospital mortality (OR[95%CI],1.37[0.83,2.26],p = 0.21), 30-day mortality (OR[95%CI], 1.34[0.60,2.98], p = 0.47) and 90-day mortality (OR[95%CI], 1.23[0.66,2.30], p = 0.52) between both groups. Complications that were more common with age included delirium (p < 0.01) and pneumonia (p < 0.01). There was a significant difference in overall survival (HR[95%CI], 1.24[1.09,1.41], p < 0.01) but disease free survival (HR[95%CI], 1.08[0.99,1.18], p = 0.08) was comparable between older and younger patients. Conclusions: Postoperative complication, postoperative mortality and disease free survival were comparable between the older and younger age groups. Age alone should not be the only determinant for the selection of patients for surgical treatment of hepatocellular carcinoma.
A phase 1 dose escalation study of the <i>IDH1</i>m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Authors: Justin M. Watts, Maria R. Baer, Sangmin Lee, Jay Yang, Shira Naomi Dinner, Thomas Prebet, Gary J. Schiller, Karen Seiter, Paul Brent Ferrell, Patrick Francis Kelly, Ping Li, Jennifer Sweeney, Courtney Watson, Hesham Mohamed, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2018)

7009 Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and 3% of MDS pts. FT-2102 is a highly potent, selective small molecule inhibitor of IDH1m without anticipated CYP or QTc liabilities at the recommended phase 2 dose. Methods: A Phase 1/2 study was initiated to evaluate the safety, PK/PD, and clinical activity of FT-2102 alone or in combination with azacitidine (AZA) or cytarabine in IDH1m AML/MDS pts. Safety for all pts and efficacy for evaluable pts are reported. Results: At the data cutoff, 35 pts with a median of 2 prior regimens (range 1-9) had received FT-2102 in dose-escalation, including 22 single-agent (SA) and 13 AZA combination (CO) pts. Sixteen pts remain on treatment (SA, n = 10; CO, n = 6) with a median of 2 treatment cycles (range 1-16); 4 pts discontinued for transplant. FT-2102 has been well tolerated both as SA and in combination with AZA. Overall, regardless of causality, most treatment emergent AEs (TEAEs) were grade (gr) 1/2; most common ( > 20%) TEAEs were fatigue (34%), nausea (29%), and febrile neutropenia (23%). The most common ( > 15%) gr 3/4 TEAEs were febrile neutropenia (23%), anemia (20%), and pneumonia (17%). Five (14%) pts had gr 3 differentiation syndrome that was manageable and did not result in discontinuation. Steady-state exposure that exceeded the target IC90 of IDH1m was achieved at 150 mg BID, resulting in a reduction of 2-HG to normal levels in the majority of pts. Best response in all evaluable SA pts (n = 16) included: 2 (13%) complete remissions (CR), 4 (25%) complete remissions with incomplete hematologic recovery (CRi), and 5 (31%) clinical benefit (CB; stable disease lasting ≥8 weeks), including 2 with > 50% reduction of marrow blasts (MB). Best response in evaluable CO pts (n = 11) included: 2 (18%) CR, 1 (9%) CRi, and 5 (45%) CB, including 2 with > 50% reduction of MB. Conclusions: FT-2102 has shown favorable safety, PK/PD, and clinical activity in IDH1m AML/MDS with a single agent complete response rate (CR/CRi) of 38% and a complete response rate of 27% in combination with AZA. Current data support the continued evaluation of 150 mg BID in the expansion and Phase 2 stages of the study. Clinical trial information: NCT02719574.
Non-AIDS defining malignancies among HIV-infected patients in a tertiary referral center in Hong Kong.
Authors: Daisy Wing-san Mak, Eugenie Ka Hui, Lawrence Chan, Wilson Lam, Man Po Lee, Sze Man June Lau
Journal: Journal of Clinical Oncology (2018)

1576 Background: Non-AIDS defining malignancy (NADM) is increasingly recognized as an important cause of death among human immunodeficiency virus (HIV)-infected individuals. This study describes the details and survival trend of NADM in this group of patients in a tertiary center in Hong Kong. Methods: We have investigated the occurrence of NADM in a retrospective observational study of 1,523 HIV-infected patients. Baseline demographics, immunological data, the use of highly-active anti-retroviral therapy (HAART), details of malignancy and their treatment were analyzed. Survival was analyzed by Kaplan-Meier and Cox proportional hazards model. Results: From November 1993 to March 2013, a total of 41 NADM was diagnosed in 39 HIV-positive patients. Lung cancer, anogenital cancer, head and neck cancer, and hepatocellular carcinoma were the most common malignancies among the NADM. Compared with the 65 patients diagnosed with AIDS-defining malignancy (ADM), patients with NADM were significantly older at cancer diagnosis (age 53 vs. 47, p = 0.01), had a significantly longer duration of HIV infection (94 vs. 2 months, p < 0.0001), were more likely to be recipients of HAART (92% of patients with NADM vs. 77% of patients with ADM, p = 0.028), and had a significantly higher CD4 count at cancer diagnosis (257 vs. 76 cells/ul, p = < 0.0001). Median survival of patients with NADM was 9 months (95% CI, 4.3-13.8 months), and was not dependent on age, CD4 count at diagnosis of malignancy, and treatment with HAART. Conclusions: This retrospective, observational study describes the pattern of NADM in a tertiary institution in Hong Kong. Together with the emerging body of literature on NADM, we have known that the general trend of NADM is rising in HIV-infected population, and the risk of these cancers is much beyond than seen in the general population. Frontline clinicians must recognize that these diseases strike a population at an age which still permits high functional capacity. The oncology community should add to the knowledge of how the immune system interplays with environmental factors and oncogenesis, work towards the goals of reducing the morbidity in these patients, and ultimately, prevent these diseases and revert the mortality.
A phase 1 study of MDM2 inhibitor DS-3032b in patients with well/de-differentiated liposarcoma (WD/DD LPS), solid tumors (ST) and lymphomas (L).
Authors: Todd Michael Bauer, Mrinal M. Gounder, Amy M. Weise, Gary K. Schwartz, Richard D. Carvajal, Prasanna Kumar, Oleg Zernovak, Alida Beck, Jana Doyle, Jeanne Mendell-Harary, Jarema Peter Kochan, Shuquan Chen, Patricia LoRusso, William D. Tap, Neeta Somaiah, David Michael Hyman, Funda Meric-Bernstam, David S. Hong
Journal: Journal of Clinical Oncology (2018)

11514 Background: Inactivation of p53 is the most frequent event in cancer driven by mutations in TP53 or overexpression of MDM2, a negative regulator of p53. DS-3032b is an oral small molecule that disrupts the MDM2-p53 interaction, resulting in reactivation of wild type p53 and causing growth arrest/apoptosis. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) and preliminary efficacy of DS-3032b. Methods: Patients (pts) received DS-3032b orally in 28 days cycle as per Table. TP53 status was confirmed post-enrollment. Results: 94 pts were enrolled with ST (50, 53%), WD/DD LPS (40, 43%), L (4, 4%). Doses, schedules (Sch), MTDs and responses are tabulated below. Median age was 60.5 years, 50% male, 63% had ≥ 3 prior therapies. 73/84 (87%) pts tested had WT TP53. The most common ( > 10%) TEAEs were nausea 71%, vomiting 31%, diarrhea 40%, decreased appetite 37%, abdominal pain 16%, dry mouth 11%, thrombocytopenia 61%, neutropenia 28%, anemia 43%, fatigue 55%, dysgeusia 18%, headache 19%, cough 19% and peripheral edema 14%. There were 8 dose limiting toxicities (DLT): six Gr 2-4 thrombocytopenia +/- neutropenia; 3 events resolved, 3 unresolved. One Gr 3 nausea, vomiting and anorexia and another Gr 2 fatigue. Sch D (3/14 days) had the best safety profile. In 79 efficacy-evaluable pts, 47 (60 %) achieved stable disease (SD). Median duration of SD was 6.7 (1.6 to 36.4) months. Partial responses (PR) were seen in DDLPS, synovial sarcoma and lung ca (SC).PK parameters AUC0-24h and Cmax were dose proportional with median Tmax 3 hours. PD biomarker MIC-1 correlated with drug exposure. In paired biopsies, MDM2 inhibition resulted in increase of nuclear p53 levels (IHC) in 5/6 pts (83%). Conclusions: DS-3032b has acceptable safety profile with intermittent dosing. Objective responses and durable SD were seen in MDM2 amplified ST and DDLPS warranting further studies Clinical trial information: NCT01877382.Schedule, days Doses, mg N = 94 pts Histology MTD, mg Best Response A – 21/28 15 – 240 40 ST/L 120 SD A – 21/28 120 20 120 B – 28/28 90 9 90 C – 7/28 120, 200 9 Progressing WD/DD LPS and MDM2 amp ST Not achieved 1 PR DDLPS D – 3/14 – 3/14 120, 200, 260, 340 16 260 2 PR: synovial sarcoma & SCLC
Rapid Track for Publication
Authors: James T. Willerson
Journal: Circulation (2001)

ThisSection will be clinically oriented and directed to the practicing physician.Articles will be contributed by experts recognized for their ability to describe in practical terms the implementation of therapeutic advances and the optimal use of new diagnostic modalities.The second Section is entitled "The Cardiology Patient Page," and was introduced in the June 26, 2001, issue.This Section will include articles on various topics in cardiovascular medicine that will be written in lay language by healthcare professionals and is designed to provide descriptions of critical concepts in cardiovascular diagnosis, testing methods, and therapeutics.
Sequencing of advanced breast cancers to reveal an evolving genetic landscape.
Authors: Matthew J. Rioth, Carlos L. Arteaga, Jeremy Warner
Journal: Journal of Clinical Oncology (2016)

11514 Background: Metastatic breast cancers are difficult to treat and generally fatal. Uncovering the genetic landscape of these cancers could reveal the mechanisms of those behaviors. Large sequencing projects, such as The Cancer Genome Atlas (TCGA), have predominantly used early stage, untreated, and non-metastatic specimens. We hypothesize that a pragmatically aggregated cohort of advanced breast cancers would present a landscape enriched in genetic mechanisms associated with treatment resistance and aggressive phenotypes compared to TCGA. Methods: Targeted exome sequencing data of 315 genes from a cohort of 230 breast cancers who underwent molecular profiling for clinical use was reviewed. Sequencing was performed on formalin fixed paraffin embedded specimens according to specifications by the FoundationOne assay (Foundation Medicine, Cambridge MA). Data for 925 breast cancers sequenced by TCGA was obtained using the cgsdr package (v1.2.5) in R (v3.2.2) which was also used for Mann-Whitney U and Chi-square analysis. Results: In comparison to TCGA, patients in the pragmatic clinical cohort were younger (median 52 vs 58 years, p = 6.5x10-7), more advanced stage (median 4 vs 2 p = 2.2x10-16), and had higher mutational rates (median 7.41 vs 2.77 mutation/megabase, p = 2.2x10-7). In the pragmatic vs TCGA cohorts, 98.2% were stage IV versus 2.1%; 33%, 17% and 50% of samples were from metastatic, nodal, and primary sites versus 0.5%, 8.9%, and 90% for TCGA. Mutations in genes implicated in treatment resistance in pragmatic vs TCGA: ESR1 (7.0% vs 0.11% p = 4.9x10-8), PIK3CA (42.1% vs 34.2% p = 0.036), ERBB2 (7.4% vs 2.5% p = 5.4x10-4), TP53 (59.1% vs 34.8% p = 1.0x10-12). Conclusions: Patients who undergo panel exome sequencing in the context of clinical care were younger, have more advanced disease, higher mutational burden and higher rates of mutations that are likely to convey resistance to therapy as compared to TCGA. Additionally the pragmatic cohort can be linked to clinical data such as pathology and treatment response. Pragmatically collected data from clinical specimens illustrates the important evolving genetic landscapes of advanced breast cancers that is not captured in genetic data of archival TCGA samples.
A randomized trial: Comparing the use of iPad versus scantron to collect breast cancer risk information in an underserved population.
Authors: Zhuoer Xie, Arash Naeim, Liliana Johansen, Neil Wenger, David Elashoff, Jacqueline Trent, Lori Viveros, Kristina Lee, Antonia Petruse, Guita Rahbar
Journal: Journal of Clinical Oncology (2018)

e18621 Background: The best way to collect data to ascertain breast cancer risk is not well understood in underserved population. One approach to better stratify patients' risk for breast cancer is to use mobile technology to improve data collection. Our aim was to assess the feasibility of using mobile technology to collect data in underserved populations. We developed a novel strategy to collect data via iPad and compared it with traditional Scantron data collection. Methods: A randomized control study was conducted in Olive View-UCLA Medical Center as a pilot within the University of California Athena Breast Health Network. A total of 340 Individuals agreed to undergo randomization to answer breast health survey via either iPad app (170) or Scantron (170). Metrics evaluated included: number and type of questions arising during the survey, satisfaction score, and completion time. These were compared between iPad and Scantron groups. All results were based on intention-to-treat analysis. Chi square tests and T tests were conducted to compare baseline demographic differences; multivariable linear regression was used to evaluate covariates of completion time; Poisson regression was conducted to examine differences of questions arising during survey and satisfaction score between groups. Results: All subjects completed the survey. Subjects in iPad group asked more questions about technology than Scantron group (p < 0.001), but there was no significant difference of questionnaire completion time between iPad and Scantron groups (12.5 mins vs. 12.1 mins, p = 0.07). Moreover, the iPad group was more satisfied with the experience (p < 0.001). Low health literacy and Spanish speaking subjects asked more questions and took longer time to finish the questionnaire regardless of survey method (p < 0.05 for all comparison). Conclusions: Using iPad survey is feasible in underserved, ethnically diverse and older populations. Subjects were more satisfied with iPad than Scantron. Future health care questionnaire application should focus on an intuitive design and accessibility improvements for low health literacy subjects and non-English speaking populations.
A phase 2 study of poziotinib in patients with EGFR or HER2 exon 20 mutation-positive non-small cell lung cancer.
Authors: Zandong Yang, Nishan Tchekmedyian, David T. Chu, Guru Reddy, Gajanan Bhat, Mark A. Socinski
Journal: Journal of Clinical Oncology (2018)

TPS9106 Background: Poziotinib is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the EGFR family of tyrosine-kinase receptors, including human epidermal growth factor receptor (HER1/ErbB1/EGFR), HER2 (ErbB2), and HER4 (ErbB4), which leads to inhibition of the proliferation of tumor cells that overexpress these receptors or activated by EGFR or HER2 exon 20 mutations. There is no FDA approved targeted therapy for EGFR or HER2 exon 20 insertion mutant NSCLC. Chemotherapy remains the standard of care for metastatic disease with severe side effects and modest efficacy. Preclinical testing indicates that poziotinib is more active than currently approved tyrosine kinase inhibitors against cell lines with a range of EGFR exon 20 mutations in vitro when using the standard Ba/F3 model. An ongoing investigator-initiated study at MD Anderson is showing that poziotinib is effective at reducing tumor size in patients with EGFR or HER2 exon 20 mutations. The primary endpoint of this Phase 2 study is to evaluate the Objective Response Rate (ORR) to poziotinib in patients with EGFR or HER2 positive non-small cell lung cancer (NSCLC). Secondary endpoints are to evaluate the Disease Control Rate (DCR) and Duration of Response (DoR) in this group of patients. Methods: This is an open-label, multicenter study evaluating the efficacy and safety of poziotinib in patients with histologically or cytologically confirmed NSCLC with a documented EGFR or HER2 exon 20 insertion mutation. Patients with T790M point mutations will be excluded. Patients will be enrolled into one of two cohorts based on documented EGFR (Cohort 1; n = 87) or HER2 (Cohort 2; n = 87) exon 20 mutations. Both cohorts are enrolling simultaneously. Patients must be 18 years of age, have an ECOG score ≤2, and have adequate tumor tissue from biopsy or surgical procedure to enable molecular profiling. The starting dose of poziotinib is 16 mg PO daily with possible dose reductions to 14 mg and 12 mg for tolerability issues. Patients will be treated until either progression or intolerable adverse events. Response will be assessed by an Independent Image Review. Study enrollment began in October 2017. Clinical trial information: NCT 03318939.