tbuckley/cabot-search huggingface dataset:
Efficacy of immune checkpoint inhibitors (ICIs) for in-transit melanoma.
Authors: Emilia Nan Tie, Julia Elizabeth Lai-Kwon, Lumine Na, Michael Alexander Rtshiladze, James Bozzi, Tavis Read, Victoria Atkinson, George Au-Yeung, Georgina V. Long, Grant A. McArthur, Shahneen Kaur Sandhu, Robyn Saw, Euan Thomas Walpole, Alexander M. Menzies, B. Mark Smithers, David E. Gyorki
Journal: Journal of Clinical Oncology (2019)

9583 Background: The efficacy of ICIs in metastatic melanoma is well-established. However, there is limited data regarding their efficacy in in-transit melanoma metastases (ITM). This study assessed the efficacy of ICI in patients with ITM. Methods: A multisite, retrospective review of patients with ITM treated with ICI from 2004-2018. Demographic and clinicopathological factors (age, sex, primary site, AJCC version 8 stage, BRAF status, prior locoregional therapies) were collected. Objective response rate (ORR) based on a clinician-assessed best overall response, progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Results: Fifty-four patients were included: 27 (50%) female; median age 69 (range 19-89); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10(19%) BRAF mutant. Forty (74%) received single agent PD-1 inhibitor (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PDL-1/MEK inhibitor (atezolizumab and cobimetinib). ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single agent anti PD-1, 38% for single agent anti-CTLA4, and 40% for anti-PD-1/anti-CTLA-4 (Table). The median follow-up was 15 months (2-46). The median PFS was 11.7 months (6.6-N/A). PFS at 1 and 2 years were 48% and 39%. Fourteen (56%) progressed locoregionally and 11 (44%) progressed distantly. OS at 1 and 2 years were 85% and 63%; the median OS was not reached. No clinicopathological features were associated with ORR. Conclusions: ICI produces objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence despite locoregional therapies. [Table: see text]
Perioperative (P) UGT1A1 genotype guided irinotecan (iri) dosing ‘gFOLFIRINOX’ for gastroesophageal adenocarcinoma (GEA).
Authors: Daniel V.T. Catenacci, Leah Chase, Samantha Lomnicki, Theodore Karrison, Robert de Wilton Marsh, Murtuza M. Rampurwala, Sunil Narula, Lindsay Alpert, Namrata Setia, Shu-Yuan Xiao, John Hart, Uzma Siddiqui, Chih-Yi Liao, Blase N. Polite, Hedy L. Kindler, Kiran Turaga, Vivek N. Prachand, Kevin K. Roggin, Mark K. Ferguson, Mitchell C. Posner
Journal: Journal of Clinical Oncology (2019)

4050 Background: Complete resection (R0) and pathologic response grade (PRG) correlate with long-term GEA outcome. FOLFIRINOX demonstrated efficacy in advanced GEA; gFOLFIRINOX improved tolerability. We evaluated R0, PRG and tolerability in this pilot P study. Methods: Gastric body (GB) + esophagogastric (EGJ) GEA patients (pts) with ≥T3Nx or TxN+ were enrolled &amp; treated with 4 pre + 4 postoperative biweekly cycles of gFOLFIRINOX (5-FU 2400mg/m2 over 46 hrs; oxaliplatin 85mg/m2; iri: 180mg/m2 for UGT1A1 genotype 6/6, 135mg/m2 for 6/7, 90mg/m2 for 7/7) (+ trastuzumab (T) 6mg/kg then 4mg/kg for HER2+) with prophylactic peg-filgastrim. 1°endpoint R0 resection required 36 pts to assess for a 90% R0 rate (intention to treat (ITT)) with 90% power + 0.05 alpha; ≥30/36 R0 considered positive. Co-1°endpoint was PRG (Becker); 36 pts provided 85% power with 0.05 alpha for a complete (pCR G1a) rate of 16%. 2°endpoints were safety/toxicity, PET response, &amp; R0/PRG by tumor site, histologic subtype, HER2 status, &amp; UGT1A1 genotype. We report efficacy and toxicity data from the neoadjuvant (Neo) portion of the study; postop data &amp; survival outcomes will be presented at the meeting. Results: 4 sites enrolled 36 ITT pts between 2/2014-8/2018; 75% male, median age 66 (range 27-85). All pts completed all 4 cycles of Neo therapy: 10% had any dose reduction of iri (16%/0%/25% by genotype 6/6, 6/7, 7/7); any G3+ toxicity occurred in 35% of pts (32% 6/6, 29% 6/7, 75% 7/7). G3+ toxicity in ≥5% of pts: diarrhea (17.5%; 6/6 21%, 6/7 11%, 7/7 25%), anemia (5%), vomiting (5%). Efficacy is shown in the Table. Of pts going to surgery, both R1 resections were GB linitus. PRG1(a+b) was achieved in 36% of ITT pts, 46% of intestinal type histology. Conclusions: Neo gFOLFIRINOX was tolerable with surrogate efficacy comparable to FLOT. Clinical trial information: NCT02366819. [Table: see text]
Study of the expression of programmed death ligand 1 (PD-L1) on non-small cell lung cancers (NSCLCs) at Bach Mai Hospital, Vietnam.
Authors: NGO Thuy TRANG, Van Tuyen Pham, Minh Khuy Doan, Anh Tuan Hoang, Long-Sheng Lu
Journal: Journal of Clinical Oncology (2019)

e13107 Background: Programmed death ligand 1 (PD-L1) expressions is a known predictor for anti-PD1 therapy outcomes. This study is the first study that describe the status of PD-L1 status on Vietnamese non-small cell lung cancers (NSLCs) patients. Methods: Patients who were diagnosed with advanced NSCLCs and PD-L1 testing from 14 Dec 2017 to 14 Dec 2018 at The Pathology Center, Bach Mai Hospital, Hanoi, Vietnam. Study team collected data of age, gender, histopathological types, biopsy sites and PD-L1 expressions. Qualified pathologists interpret levels of PD-L1 via immunohistochemical (IHC) assays Ventana PD-L1 (SP263) with archive formalin-fixed, paraffin-embedded (FFPE) NSCLCs tissues (primary lung tumor or metastases) on VENTANA BenchMark XT. Results: In total 166 patients, the majority were male (73.49%) with male/female ratio is 2.77. Age range from 29 to 85 with median age was 61 years old. The most common histopathological type was adenocarcinoma (n = 143, 86.14%). Other patients including 19 squamous cell carcinoma (11.45%) and 3 patients with “not otherwise specified” (NOS) tissues (2.41%). Overall 127/166 (76.51%) specimens were taken from lung tumors while 39 (23.49%) samples were from lymph node (10), pleura (20), liver (2), pericardia (2), brain (3) and bone (2). Rates of high expression (≥50%), expression (≥1% and ≤49%) and no expression (&lt;1%) of PD-L1 were 26.51%, 31.32% and 42.17%, respectively. In multivariable regression analysis, we did not observe correlation between PD-L1 expression and age (p = 0.25, CI 95%), type of histopathological tissues (p = 0.41, CI 95%), biopsy sites (compare between lung vs non-lung samples, p = 0.89, CI 95%). Male gender has higher chance to have high expression ò PD-L1 with p = 0.0044, CI 95%. In female patients only, age has negative correlation with PD-L1 expression (p = 0.014, CI 95%). Conclusions: We found that male Vietnamese or younger female NSCLCs are likely to have higher PD-L1 expression. Further data on sequential anti PD-L1 treatment after PD-L1 testing is needed for validation the benefit of Ventana PD-L1 (SP263) IHC assay in Vietnamese NSCLC patients.
Real-world cardiovascular outcomes with novel anti-androgen agents in prostate cancer patients.
Authors: Amit Kulkarni, Nathan Rubin, Tony Tholkes, Anna Prizment, Charles J. Ryan, Arpit Rao
Journal: Journal of Clinical Oncology (2019)

e16510 Background: Abiraterone use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude of this morbidity in contemporary US prostate cancer (PC) population remains unknown. We examined a large medical claims database to answer this important question. Methods: We retrospectively reviewed Marketscan claims database (1/1/2013 to 9/30/2015) to identify adults with diagnosis of localized PC, recurrent localized PC, biochemically recurrent non-metastatic PC and metastatic PC who received treatment with androgen deprivation therapy (ADT) alone or ADT with novel antiandrogen agents (abiraterone or enzalutamide). The primary outcome measure was composite severe CV outcome of acute myocardial infarction (MI), stroke or heart failure (HF). We used Cox regression model with time dependent covariates to estimate the CV risk of various therapies. Results: A total of 7030 patients of PC were identified- 1285 received ADT for localized PC, 424 received ADT for recurrent localized PC, 554 received ADT for biochemically recurrent non-metastatic PC, 256 received ADT alone for metastatic PC and 1366 received abiraterone or enzalutamide with ADT for metastatic PC. During the study period, 143 severe CV events occurred, resulting in an incidence rate of 0.74 per 100 patient-years. In multivariate analysis, abiraterone use was associated with a trend towards increased risk of severe CV compared to non-abiraterone users (HR = 1.58; 95% CI: 0.98-2.59, p= 0.06). No such increased risk was detected for ADT (HR = 1.35; 95% CI: 0.92-2.00, p= 0.12) or enzalutamide (HR = 0.84 95% CI: 0.34-2.11, p= 0.71). Conclusions: To our knowledge, this is the first study to present real-world data on CV outcomes of PC patients receiving novel anti-androgens. Our findings support the trend towards increased severe CV risk seen in abiraterone trials. No such association was seen for enzalutamide. Additional analyses with a longer follow-up duration are planned.
Case 25-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Edward J. O'Rourke, Atul K. Bhan
Journal: New England Journal of Medicine (1988)

Presentation of CaseA five-year-old boy was admitted to the hospital because of lumbar and abdominal pain and fever.He was well until two years earlier, when symptoms of a persistent respiratory tract infection led to the discovery of pancytopenia, and microscopical examination of an aspirated specimen of bone marrow showed acute lymphocytic leukemia of the non-B, non-T cell type. Treatment was initiated with vincristine, prednisone, and intrathecal methotrexate, cytarabine, and hydrocortisone. Four weeks later a repeated bone marrow aspiration confirmed that there had been complete remission. Consolidation treatment was then begun with asparaginase and cyclophosphamide for two weeks, and . . .
Abstract 14872: Utility of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Variants of Uncertain Significance
Authors: John R Giudicessi, Ram K Rohatgi, David J Tester, Martijn J Bos, Arthur A Wilde, Michael J Ackerman
Journal: Circulation (2017)

Introduction: Pathogenic RYR2 variants underlie 60% of catecholaminergic polymorphic ventricular tachycardia (CPVT). However, due to a three percent rate of background genetic noise, cumbersome fun...
Clinical relevance of 21-gene recurrence score with lymph node involvement in HR+HER2- early breast cancer: A tumor size-match paired cohort study.
Authors: Xingfei Yu, Chen Wang, Bo Chen, Xiaodan Pan, Hongjian Yang
Journal: Journal of Clinical Oncology (2019)

e12059 Background: Axillary lymph node (LN) involvement is significantly related with high recurrent risk and influenced by tumor size, histologic grade and subtype in early breast cancer. For hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer without LN involvement, 21-gene recurrence score (RS) provides an effective method evaluating the risk of recurrence and metastasis. But the correlation between RS and LN involvement is not clear currently. To investigate the effect of RS on LN involvement, we designed a retrospective cohort study based on the data of tumor size-match LN+/- HR+HER2- breast cancer. Methods: The luminal type (ER+, PR+ and HER2-) early breast cancer (cT 1-2 ) patients with 1~3 LN+ were enrolled and were tumor size-match paired (1:3) with those LN- during the same period. We compared the 21-gene RS between the LN+ and LN- group by univariate and multivariate analyses. Results: From April 2016 to May 2018, there were 65 LN+ cases undergoing 21-gene test included and 195 LN- cases were paired. With tumor size matched, the LN+ group had significantly younger age, more positive family history, higher histologic grade and higher RS than LN- group. All those factors, excepted histologic grade, were further confirmed in multivariate analysis (Table). Conclusions: After adjusted by tumor size, RS may have a significantly independent correlation with LN involvement in HR+HER2- early breast cancer. Total HR+HER2- cases’ tumor size-match paired (1:3) clinic pathologic and RS data. Clinical trial information: NCT03638648. [Table: see text]
The role of miR200c in leptin-mediated triple-negative breast cancer progression to an epithelial-to-mesenchymal transition.
Authors: Lucas Wang, Brittany Harlow, Laura Bowers, Stephen Hursting, Linda A deGraffenried, Andrew Jacob Brenner
Journal: Journal of Clinical Oncology (2019)

e12548 Background: Almost 40% of women with breast cancer are obese at diagnosis. Obesity is associated with a worse prognosis in triple negative breast cancer (TNBC). Preclinical studies have shown that leptin is an important factor associated with TNBC by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). Transcription factors SNAIL, TWIST and ZEB are critical components in enhancing EMT in cancer cells. The specific mechanism(s) by leptin regulates SNAIL, TWIST and ZEB expression remain unclear, limiting the development of effective interventions to improve outcomes in obese TNBC patients. Recent studies have demonstrated that miR200c, downstream of leptin receptor signaling, regulates the expression of SNAIL1, TWIST and ZEB. We will test the hypothesis that leptin contributes to obesity-induced EMT/CSC in TNBC through modulation of miR200c. Methods: Ob-R (leptin receptor) expression was suppressed in TNBC MDA-MB-231 and E-Wnt cells using shRNA (Ob-R null). Ob-R and Ob-R null cells were exposed to sera pooled from lean or obese women, as well as lean sera supplemented with leptin, after which expression of SNAIL, TWIST, ZEB and miR200c was measured by qPCR, while activation of the JAK-STAT pathway was assessed by Western blotting. Results: TNBC cells exposed to obese and high leptin conditions demonstrated increased expression of EMT markers compared to levels expressed under lean conditions. The Ob-R WT and null cells were used to determine the specific role of leptin signaling in regulating expression of SNAIL, TWIST and ZEB through miR200c. Conclusions: Both obese and high leptin conditions result in increased expression of EMT regulators, suggesting that effective targeting of this pathway may provide clinical benefit in the obese breast cancer patient. Elucidating the specific mediators of this pathway will guide development of novel and more potent medical therapies.
Upper extremity deep venous thrombosis in 10 common malignancies: Analysis of incidence, risk factors, and effect on mortality from the California Cancer Registry.
Authors: Christina Poh, Ann Brunson, Anjlee Mahajan, Theresa Keegan, Ted Wun
Journal: Journal of Clinical Oncology (2019)

e18190 Background: Upper extremity deep venous thrombosis (UE DVT) is a known complication in patients with cancer. However, the cumulative incidence by cancer type, risk factors associated with UE DVT and impact on survival is not well-described. Methods: Using the California Cancer Registry , we identified patients with 10 common malignancies (2005-2014) and linked this to the California hospitalization and emergency department databases to find patients with an incident UE DVT event using specific ICD-9-CM codes. We determined cumulative incidence of UE DVT adjusted for the competing risk of death. Using Cox proportional hazards regression, stratified by tumor type and adjusted for other prognostic covariates including central venous catheters (CVC), we identified risk factors for developing UE DVT and the impact of UE DVT on overall survival. Patients with venous thromboembolism prior to malignancy diagnosis were excluded. Results: Among 785,444 patients with malignancy, 6,099 (0.8%) had an incident UE DVT. The 24-month cumulative incidence of UE DVT varied by cancer type (Table). Most UE DVT (62.2%) occurred in patients with CVC. VTE after cancer diagnosis and CVC substantially increased the risk for UE DVT across all cancers. UE DVT was also associated with worse overall survival for all malignancies with hazard ratios ranging from 1.52 to 3.72. Conclusions: UE DVT is a rare but important complication among patients with malignancy, with incidence highest in leukemia and lowest in prostate cancer. Although uncommon, UE DVT may affect prognosis in patients with malignancy as it is associated with an increased hazard of death. Table: 24-month cumulative incidence of UE DVT, adjusted for the competing risk of death, in 10 common malignancies among California cancer patients, 2005-2014. [Table: see text]
The genomic landscape and its prognostic significance for stage III colorectal cancer in Japan: An ancillary study of JCOG0910 trial—JCOG1506A1.
Authors: Dai Shida, Aya Kuchiba, Tatsuhiro Shibata, Tetsuya Hamaguchi, Satoshi Yamasaki, Masaaki Ito, Takaya Kobatake, Nobuhiro Takiguchi, Tadahiko Masaki, Manabu Shiozawa, Yasumasa Takii, Hiroyuki Uetake, Shu Okamura, Hitoshi Ojima, Yusuke Nishizawa, Hiroshi Takeyama, Keisuke Kanato, Yasuhiro Shimada, Yoshinori Murakami, Yukihide Kanemitsu
Journal: Journal of Clinical Oncology (2019)

3607 Background: To date, large-scale genomic sequencings of colorectal cancers (CRC) have been reported mainly from Western countries. However, ethnic diversities, differences by stage, and the prognostic impact of the genomic landscape in CRC remain poorly identified. Methods: The subjects were 534 patients (pts) with stage III CRC from the JCOG0910 study—a randomized phase-III trial conducted in Japan on 1564 pts to assess the efficacy of S-1 versus capecitabine as adjuvant chemotherapy. Targeted-capture sequencing of 171 potentially CRC-associated genes was performed on both normal tissue and tumor samples, and somatic single-nucleotide variants and insertion/deletions were determined. Tumors with MSIsensor scores &gt; 7 and ultra-mutated tumors with POLE mutations were grouped as hypermutated tumors. Genes whose alterations were associated with recurrence-free survival (RFS) were evaluated using multivariable Cox regression models. Results: Of the 534 pts (right-sided: 184, left-sided: 350), 109 pts had recurrences or died during the study. Mutation frequencies were as follows: TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%) (right: 14.1%, left: 1.4%). None of the 49 genes with mutation frequencies &gt; 3% showed a significant association with RFS based on Bonferroni’s adjustment for multiple testing. The following modest associations were observed: mutant KRAS [HR, 1.66; p=0.011] and mutant RNF43 [HR, 2.17; p=0.055] had poorer RFS, whereas mutant COL6A3 [HR, 0.35; p=0.040] and mutant NOTCH3 [HR, 0.18; p=0.093] had better RFS. RFS tended to be better for hypermutated than for non-hypermutated tumors [HR, 0.53; p=0.229]. Conclusions: The overall mutation spectrum of our stage III CRC cohort was generally similar to that of the Cancer Genome Atlas (TCGA). However, the mutation frequencies of TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations seemed to impact RFS, indicating that tumor genomic profiling has a high potential to support precision medicine for pts with CRC.
Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC.
Authors: Chaitali Singh Nangia, Mira Kistler, Leonard S. Sender, John H. Lee, Frank R. Jones, Omid Jafari, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2019)

e12566 Background: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 8 subjects with 3 rd -line or greater TNBC have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.