tbuckley/cabot-search huggingface dataset:
MET amplification and exon 14 skipping in treatment naïve patients in lung cancer.
Authors: Yaqian Han, Ying Xu, Chunling Liu, Jun Zhao, Lingjun Zhu, Liren Li, Lin Gen, Lianke Liu, Yong Cheng, Ke Ye, Likun Chen, Longbo Zhang, Fenglei Yu, Kaiqi Du, Liyun Miao, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e14543 Background: Somatic mutations in MET are diverse and include MET amplification, exon 14 skipping and also some functional point mutations (H1094Y, Y1230H, D1228N, etc). Generally, amplification and ex14 skipping are the two main mutation types. Methods: MET mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of multi-mutation types of at least 59 genes (range 59-1021 genes). Results: Screening tens of thousands treatment naive patients, we found 319 patients with MET mutations, 56 patients (18%) with MET amplification, 55 patients (17%) with MET ex14 skipping, and 214 patients with other unknown functional point mutations. 39 cases with MET amplification and 52 cases with MET ex14 skipping in lung cancer. Patients with MET amplification or ex14 skipping had fewer mutations compared with patients with other MET mutations ( P &lt; 0.0001), while there were no differences in ctDNA abundance between two groups ( P = 0.58). Further compared the MET amplification and ex14 skipping groups, we found mutation numbers and ctDNA abundance were both significant lower in ex14 skipping group (mutation numbers: P = 0.0134; ctDNA abundance: P &lt; 0.0001). MET amplification range from 2 to 7 copies in these 39 patients, and patients with more than 3 copies had a higher ctDNA abundance than = &lt; 3 copies patients ( P &lt; 0.0005). Six patients with both amplification and ex 14 skipping, all of them with advanced age ( &gt; 70 years). Of the MET amplification group, 11 patients (28%) developed EGFR driver mutation concurrently, four patients with L858R, three with ex19 del, one with G719A, one with both L858R and EGFR amplification, one with both ex19 del and amplification and one with only amplification, while no patients were found to have any EGFR driver mutation in MET ex14 skipping group. Conclusions: The cfDNA from patients with EGFR amplification or ex14 skipping was only 18% or 17% in MET mutations. Both of these two mutation types were mainly found in lung cancer. Furthermore, MET amplification group patients had fewer mutations and lower ctDNA abundance. In treatment naïve patients, MET amplification concurrent with other EGFR drive mutations, rather than ex14 skipping.
Usefulness of molecular methods for the diagnosis of malignant pleural effusions
Authors: Leila Antonangelo, Debora Cristina Batista Rosolen, Vera Luiza Capelozzi, Francisco Suso Vargas, Giorgio Bottura, Ana Rosa N. Dutra, Vanessa Martins, Annelise C. W. Lopes, Lisete Ribeiro Teixeira
Journal: Journal of Thoracic Oncology (2014)
Clinical implication of inflammation-based serologic biomarkers and tissue biomarkers on hyperprogression in NSCLC patients receiving immune checkpoint blockers in real world.
Authors: Seoree KIM, Jin-Hyoung Kang, Sang Hoon Chun, Joori Kim
Journal: Journal of Clinical Oncology (2019)

e20633 Background: Although immune checkpoint blockades (ICBs) therapy can lead to favorable and durable results by reinvigorating the anti-tumor immune response in some patients, many other patients experience poor prognosis and even tumor overgrowth can be seen in real practice. We aimed to assess these hyperprogressive disease (HPD) in patients who underwent ICB therapy. Methods: We retrospectively reviewed medical records of non-small cell lung cancer patients (n = 243) treated with anti-PD-1 or anti-PD-L1 monotherapy. HPD was defined as a tumor growth kinetics ratio &gt; 2 during anti-PD-1/PD-L1 therapy and a time-to-failure of less than 2 months. We analyzed the association of Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and CRP-albumin ratio (CAR) with HPD and the difference of immune composition in TME by multiplex IHC. Results: Overall, 231 patients were included. The median age was 64.2 years; most patients were male (74.9%) and smokers (70.1%, n = 162). 25 patients (10.8%) met the criteria for HPD. Oncogenic drive mutant status was significantly associated with HPD (18.6% vs 9.04%; P = 0.001). Kaplan Meier overall survival estimates showed a clear trend toward worse outcomes for patients with HPD (median, 5.6 months; P &lt; 0.001) than for those without (median, 7.4 months). We also analyzed the association of NLR, PLR and CAR with HPD. Serologic markers at the time of first response evaluation (post 6 weeks, i.e.,) showed a prognostic value for HPD after ICB use ( P &lt; 0.001, 0.008, 0.017). In multiplex IHC, there was no difference in T cell related immune marker of CD 3/4/8/45RO and FOXP3, dendritic cell, NK cell and other co-inhibitory signal markers between two groups. However, the key point was the M2 polarized tendency in the HPD group when the macrophage M1 / 2 markers of CD68, CD163, CD206 and CCR7 were observed. This suggests that changes in the AXL pathway and EMT features associated with reinvigorating anti-tumor immunity in M2 polarized cells may lead to changes in poor prognosis to HPD. Conclusions: Despite improved recognition of HPD, its etiology and predisposing factors remain unclear, but it is clear that the prognosis becomes poor when it occurs. We observed that some serologic biomarkers (NLR, PLR and CAR. i.e.,) can be used to predict HPD. Multiplex IHC can be used not only to predict HPD, but also to validate its mechanism. Furthermore, we undergo whole exon sequencing and multiplex IHC to understand mechanism of Hyperprogression.
Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors.
Authors: Timothy A Yap, Jordi Rodon Ahnert, Sarina Anne Piha-Paul, Siqing Fu, Filip Janku, Daniel D. Karp, Aung Naing, Ecaterina Elena Ileana Dumbrava, Shubham Pant, Vivek Subbiah, Apostolia Maria Tsimberidou, David S. Hong, Kelsey Meagan Rose, Quanyun Xu, Christopher P. Vellano, Mikhila Mahendra, Philip Jones, Maria Emilia Di Francesco, Joseph R. Marszalek, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2019)

3014 Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T 1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.
Capacity to provide specialized care for older adults in community oncology practices: Results of the NCI Community Oncology Research Program (NCORP) Landscape survey.
Authors: Grant Richard Williams, Kathryn E. Weaver, Glenn Jay Lesser, Emily Van Meter Dressler, Karen Marie Winkfield, Heather B. Neuman, Anne Kazak, Ruth Carlos, Lucy Jean Gansauer, Charles Stewart Kamen, Joseph M. Unger, Supriya Gupta Mohile, Heidi D. Klepin
Journal: Journal of Clinical Oncology (2019)

6539 Background: American Society of Clinical Oncology guidelines recommend that patients ≥65 years of age starting chemotherapy undergo a geriatric assessment (GA) to inform and guide management; however, little is known about resources available in community oncology practices to facilitate geriatric specialty care and implement these guidelines. Methods: Community oncology practices were electronically surveyed in 2017 regarding the availability of various providers, supportive services, and practice characteristics, as part of a larger survey of cancer care delivery research (CCDR) capacity at NCORP sites. Designated CCDR leads provided information about their site. Descriptive statistics were used to report prevalence of resources available at each community practice. Results: Of the 925 NCORP practice locations, 504 (54%) responded to the survey, representing 227 practice groups. Of respondents, 58% included a free-standing clinic or private/group practice and 82% included inpatient services. The median number of new cancer cases per year ≥65 years of age was 443 (Interquartile range [IQR] 220-903). The median number of medical oncology providers was 5 (IQR 3-11). Only 1.8% of practices had a dual fellowship trained geriatric oncologist on staff. Geriatricians were available for consultation or co-management for 34% of sites, but only 13% of those had availability within the oncology clinic. Among those with access to geriatricians, consultations were primarily outpatient (90%) versus inpatient (54%). Ancillary services that could support GA were variably available onsite: social work (83%), nurse navigators (78%), pharmacist (77%), dietician (69%), supportive caregiver services (62%), rehabilitative medicine (57%), psychologist (41%), and psychiatrist (39%). Most sites utilized electronic health record systems (84%) and patient portals (89%). Conclusions: Availability of geriatric-trained providers is limited in community oncology practices. Use of primarily self-administered GA tools that direct referrals to available ancillary services may be an effective implementation strategy for guideline-based care.
A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Christos Kyriakopoulos, Channing Judith Paller, Ajit Verma, Karim Kader, Jeff Kittrelle, Per G Borgström, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2019)

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by &gt; 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.
Genomic landscape of FNAs positive for medullary thyroid cancer (MTC) and potential impact on systemic therapy.
Authors: Lori J. Wirth, Steven G. Waguespack, Naifa Lamki Busaidy, Mimi I-Nan Hu, Elizabeth Gardner Grubbs, Steven P Weitzman, Mark Zafereo, Joshua Babiarz, Yangyang Hao, Jing Huang, Giulia Kennedy, P. Sean Walsh, Richard Kloos
Journal: Journal of Clinical Oncology (2019)

6087 Background: Systemic therapies targeting specific genomic alterations in advanced MTC are available or under investigation. The Afirma Genomic Sequencing Classifier (GSC) uses RNA sequencing to assess FNA specimens from cytologically indeterminate thyroid nodules, which are also tested for specific molecular aberrations associated with thyroid cancer via a suite of highly accurate malignancy classifiers. This suite can be applied independently to Bethesda V/VI nodules. The Afirma Xpression Atlas (XA) is an additional test that can be combined with Afirma GSC to report nucleotide variants and fusions across 511 cancer-associated genes. Here we report the prevalence and genomic landscape of MTC classifier positive (MTC+) FNA samples. Methods: All Afirma GSC and malignancy classifier tests run in the Veracyte Clinical Laboratory between July 2017 and January 2019 were deidentified and examined for MTC+ cases. Afirma XA was run on all such cases, and all variants and fusions were tabulated. Results: Examination of 29,895 FNAs revealed 90 MTC cases. Of 22,793 Bethesda III cases, 32 (0.14%) were MTC+. Of 5,491 Bethesda IV cases, 33 (0.60%) were MTC+. Provider-ordered testing was done on an additional 16 and 9 MTC cases from Bethesda V and VI nodules, respectively. 58% of all MTC+ samples harbored a RET variant (+/- others), 9% contained a KRAS variant (+/- others), 6% included an HRAS variant, 1% had a BRAF fusion, 1% demonstrated other fusions, and 26% held no variant/fusion. Conclusions: In our cohort, Afirma XA identified a variant or fusion in 74% of MTC+ FNAs. Currently approved or investigational therapies exist for cancers with RET, BRAF and HRAS alterations, suggesting that 64% of our series might be eligible for treatment based on genomic information from FNA. In advanced MTC, noninvasive FNA sample collection at the time of diagnosis may ultimately impact on targeted therapy selection, with the option to repeat FNA testing should the disease progress. Future studies may investigate how finding a genomic alteration by FNA can inform the management of MTC and, in the case of progressive disease, improve our understanding of the mechanisms of disease progression and drug resistance.
Treatment and prognosis analysis of elderly patients with nonmetastatic triple-negative breast cancer.
Authors: Meng Xiu, Pin Zhang
Journal: Journal of Clinical Oncology (2019)

e12038 Background: Treatment of TNBC in elderly women is limited by declining functional status and life expectancy. The impact of providing less aggressive treatment remains controversial. Methods: Data from patients aged ≥65 years with non-metastatic TNBC treated at Cancer Hospital of CAMS from 2010 to 2016 were included. The clinicopathological characteristics, treatment details and long-term survival were analyzed. Results: A total of 183 patients were enrolled. The median age was 69 years, and those ≥75 years old accounted for 23.0%. Of all the patients, 75.0% had chronic comorbidities, and 88.0% were invasive ductal carcinoma pathologically. Patients in stage I, II, III were 37.7%, 41.9%, 20.8%. Stage and age influenced chemotherapy or not independently. 42.0%, 34.7%, and 10.5% of patients with stage I, II and III had no chemotherapy and the proportion of chemotherapy decreased with age. 45.3% of patients had dose reductions during the treatment. At a median follow-up of 45 months, 28 patients (15.3%) had relapsed. The median RFS of patients relapsed was 23.5 months, 71.4% occurred within 3 years after diagnosis. Kaplan-Meier survival analysis estimated that the 3-year RFS and OS were 88.8% and 96.6%, and the 5-year were 84.0% and 92.8%. Multivariate Cox regression analysis (Table) showed that ≥6 cycles of chemotherapy, clinical stage, and lymphovascular invasion influenced prognosis significantly. Most patients received chemotherapy as AC-T/AT, AC/TC/T, or PCb, and RFS of subgroups had no difference obviously, as 3-year RFS were 87.5%, 76.5%, 93.2%. Compared to patients received no or &lt;6 cycles of chemotherapy, the 3-year RFS of patients with stage I, II, and III who received ≥6 cycles of chemotherapy increased 4.4% (95.6% vs 100%), 1.3% (93.7% vs 95.0%) and 35.7% (34.3% vs 70.0%). Conclusions: There is insufficient treatment of non-metastatic TNBC in the elderly. The proportion of patients with stage I and II without chemotherapy is up to 40%, and the overall prognosis is not inferior obviously. We need more individualized treatment strategies for elderly TNBC.[Table: see text]
Multiplexed digital PCR for detection of HPV in tissue samples from oropharyngeal cancer patients.
Authors: Sunil Kumar, Bhishamjit S. Chera, Brian Beaty, David Marron, Stuart Jefferys, Robert Amdur, Nathan Sheets, Roi Dagan, David N. Hayes, Jared Weiss, Juneko E. Grilley-Olson, Adam M. Zanation, Trevor Hackman, Jeffrey Blumberg, Samip Patel, Mark Christian Weissler, Joel S. Parker, Xianming Tan, William M. Mendenhall, Gaorav Gupta
Journal: Journal of Clinical Oncology (2019)

e17552 Background: p16 immunohistochemistry (IHC) is a commonly used method for identifying HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, p16 overexpression in a minority of HPV negative OPSCC can give rise to false positive results. In contrast, HPV nucleic acid testing lacks adequate sensitivity for routine diagnostic testing. The goal of this study was to investigate whether a multiplexed digital PCR assay can detect and quantify HPV DNA in p16 positive OPSCC treated with definitive chemo-radiotherapy (CRT). Methods: Formalin-fixed paraffin embedded (FFPE) residual diagnostic biopsy specimens were collected from 57 patients. Macrodissection was performed to ensure tumor cellularity &gt; 70%. Extracted genomic DNA was analyzed by next generation sequencing (NGS) using a hybrid capture assay (UNCSeq) targeting &gt; 200 cellular genes and HPV 16/18 genomes. We also designed, validated, and implemented an multiplexed droplet digital PCR (dPCR) assay to detect and quantify HPV DNA (strains 16, 18, 31, 33 and 35) in tissue samples, relative to a genomic control locus (chromosome 6). Results: HPV strain 16 DNA was identified in 50 patients (87.7%), whereas 5 patients (8.8%) had HPV DNA from an alternative high-risk strain (18/31/33/35). HPV DNA was undetectable in 2 patients, indicating a false positive rate of 3.5% for p16 IHC testing in this cohort. HPV DNA copy number per diploid genome equivalent varied significantly across samples, with a median value of 19.7 (range 0.23-1712). A significant correlation was observed between the copies of HPV detected by dPCR and NGS (R 2 = 0.5853, p &lt; 0.0001). Evidence for HPV integration was detected by NGS in 23 out of 56 evaluable tumors (42%). There was a trend towards a higher prevalence of HPV integration in tumors with less than 10 HPV copies per diploid genome relative to cancers with &gt; / = 10 HPV copy number (63% versus 34%, p = 0.07). Conclusions: Multiplexed digital PCR demonstrates excellent sensitivity for detection and typing of HPV DNA in diagnostic FFPE specimens from patients with p16 positive oropharyngeal cancer. HPV copy number varies significantly across samples, with a possible association with HPV integration status. Future investigations of potential correlation between HPV copy number, integration status, and clinical outcomes are warranted. Clinical trial information: NCT02281955, NCT03077243.