tbuckley/cabot-search huggingface dataset:
Population-based assessment of disease-free survival (DFS) as a surrogate endpoint (SE) of 5-year overall survival (5Y OS) in stage I-III rectal (RC) and colon cancer (CC).
Authors: Richard M. Lee-Ying, Yaling Yin, Howard John Lim, Winson Y. Cheung, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2016)

3602 Background: 3Y DFS is a validated SE for 5Y OS in adjuvant chemotherapy (AC) CC trials, while no SE have been established for radiation (RT) in RC trials. The objective of this study was to validate 3Y DFS as a SE for 5Y OS in RC and CC. Methods: Patients diagnosed with stage I-III RC and CC referred to any 1 of 5 regional cancer centers in British Columbia between 1990 and 2009 were followed by the GI Cancer Outcomes Unit. Clinical, pathological, and treatment characteristics were prospectively collected, with DFS and OS measured from the date of definitive surgery until relapse or death. RC patients who received RT and CC patients who received AC were propensity-score matched to those who did not, within each cancer center, using an absolute standard difference of ≤0.2. Individual level associations between DFS and 5Y OS were calculated using Spearman’s rho . Propensity-score adjusted treatment effects, by center were calculated using R2. Results: Of 3153 patients with RC, 2564 received RT and 589 did not. Of 4638 patients with CC 2563 received AC and 2075 did not. Patients with AC and RT were younger and more likely to have grade 3, lymphovascular and perineural invasion, and stage III disease. RC patients also had higher CEA levels and received more CT. After matching, most patients at the extremes of age and with stage I-II disease were removed, resulting in 1544 RC and 2226 CC patients with no significant differences between treatment groups. There was a strong correlation between 2, 3 and 4Y DFS and 5Y OS by Spearman’s rho and R2. Crude recurrence rates for both RC and CC were similar, peaking in the first year and declining to zero after eight years. Conclusions: These data support 3 year DFS as a SE for 5Y OS, for RT in RC and AC in CC. Correlations remained significant at both individual and across-centers for both RC and CC. The recurrence rates for both RC and CC are similar. Association with 5Y OS. RC CC Rho (95% CI) R2 (95% CI) Rho (95% CI) R2 (95% CI) 2Y DFS 0.91 (0.89-0.92) 0.88 (0.67-1.10) 0.88 (0.86-0.90) 1.00 (0.99-1.01) 3Y DFS 0.92 (0.90-0.93) 0.98 (0.93-1.02) 0.90 (0.88-0.91) 0.96 (0.89-1.04) 4Y DFS 0.93 (0.92-0.94) 0.93 (0.80-1.06) 0.91 (0.90-0.93) 0.98 (0.95-1.02)
TCT-97 Preserving coronary access after Valve-in-TAVI: a glimpse into the future.
Authors: Nicola Buzzatti, Vittorio Romano, Ole De Backer, Lars Sondergaard, Liesbeth Rosseel, Pál Maurovich-Horvát, Julia Karady, Bela Merkely, Matteo Montorfano, Bernard Prendergast, Antonio Colombo, Azeem Latib
Journal: Journal of the American College of Cardiology (2018)
Use of panomic assessment to reveal DNA repair alterations and to predict potential therapeutic response to taxane-platinum combination therapy in prostate cancer.
Authors: Nancy Ann Dawson, Elisabeth I. Heath, Rebecca Feldman, Sandeep K. Reddy, David Spetzler, George H. Poste, Derek Raghavan
Journal: Journal of Clinical Oncology (2016)

5040 Background: Patients with PC have limited treatment options after failure of hormonal and taxane therapy. Androgen receptor (AR) signaling may exert therapeutic effects on the DNA repair pathway in PC. We have assessed the proteomic/genomic DNA repair aberrations in primary (P) and metastatic (M) PC and explored the therapeutic implications of these mutations using panomic next generation sequencing (NGS). We hypothesized that there is a differential in gene expression and mutation between P and M tumors. Methods: Molecular profiles of 437 PC tumor samples were defined. Protein expression (IHC), gene amplification (ISH) and sequencing (NGS) were performed. A panel of 30 DNA repair genes was used to define DNA repair intact (DRI) and DNA repair deficient (DRD) subgroups. Unclassified variants were included for analysis. Pearson’s chi-squared test was used to test for significant differences. Results: Biopsies from 437 PCs (median age 67) were studied. Specimens submitted for profiling included 158 P PCs (36%) and 279 M PCs (64% [18% bone; 37% visceral; 24% lymph nodes; 21% other sites]). The most frequently mutated DNA repair genes included TP53 (31%), ERCC5 (19%), FANCG (16%), MSH6 (13%), PMS1 (13%), POLE (10%) PTEN (9%) and BRCA2 (6%). Functional protein loss as measured by IHC was seen in ERCC1 (44%), MGMT (39%), and PTEN (43%). In a limited cohort of patients tested using a 592-gene hybrid-capture NGS, 26/31 (84%) had alterations in at least 1 DNA repair gene. DRD PC exhibited higher expression rates of AR (57% vs. 20%; p = .048) and TOPO1 (88% vs. 40%; p = .02) than DRI PC. An optimal taxane therapeutic response profile was observed in 20% of DRD tumors. Significant differences between P and M tumors were seen in ERCC1, AR, ATM and TP53. M tumors had significantly increased expression of TOP2A, TS and TUBB3. Conclusions: DNA repair defects are common in PC with a difference in gene expression and mutation between P and M tumors. Differential expression between African American and Caucasian patients and further classification of variants are currently being assessed. Taxane-platinum combination chemotherapy should be tested specifically in DRD PC.
Oncogenic activation of STAT3 pathway drives PD-L1 expression in natural killer/T cell lymphoma.
Authors: Soon Thye Lim, Tammy Song, Jing Quan Lim, Yurike Laurensia, Jane Wan Lu Pang, Sanjanaa Nagarajan, Giovanni Claresta, Tan Jing, Tiffany Pooi Ling Tang, Maarja-Liisa Nairismagi, Choon Kiat Ong
Journal: Journal of Clinical Oncology (2017)

7549 Background: Natural killer/T-cell lymphoma (NKTL) is a rare type of non-Hodgkin lymphoma that occurs more frequently in East Asia and Latin America and is associated with Epstein–Barr virus infection. Recent whole-exome sequencing studies in NKTL have reported recurrent somatic mutations in genes associated with JAK-STAT pathway, however the role of aberrant JAK-STAT signaling in tumor immune escape through PD-L1 regulation is unclear. Methods: To determine the prevalence of JAK-STAT pathway alteration in NKTL, we performed targeted sequencing of 188 genes associated with JAK-STAT pathway in 109 NKTL (22 Singapore cases, 79 China cases and 8 cell lines). Single nucleotide variants and micro-indels were called using Freebayes and candidate variants annotated using ANNOVAR. Ba/F3 model system was used to test the transformation capacity of identified variants. Cell lines were evaluated for PD-L1 expression by immunoblotting and flow cytometry. Tissue microarrays were examined for p-STAT3 and PD-L1 expression by immunohistochemistry. Results: We identified a total of 284 non-synonymous somatic mutations candidates in 114 genes, including 243 missense, 10 nonsense, 4 splice-site and 27 indel mutations. Recurrent mutations were most frequently located in STAT3 (25/109 cases, 23%) followed by TP53 (16/109 cases, 16%) and JAK3 (8/109 cases, 7%). A total of 18 STAT3 variants were identified including known hotspot mutations and novel mutations in the SH2, coiled coil and DNA-binding domains. Characterization of novel E616K mutant residing in the SH2 domain showed that E616K conferred IL3 independent growth to Ba/F3 cells, increased STAT3 phosphorylation and PD-L1 expression. Consistent with these findings, PD-L1 was over expressed in cell lines harboring STAT3 mutations. A positive correlation between PD-L1 and p-STAT3 expression was also observed in tumor tissue (R = 0.51, P = 0.02). Conclusions: We characterized a novel activating STAT3 mutant and demonstrated its ability to drive PD-L1 expression, which may promote tumor evasion from the antitumor immune response. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising and novel therapeutic approach for NKTL in the future.
Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL).
Authors: William G. Wierda, Tanya Siddiqi, Ian Flinn, Xavier C. Badoux, Thomas J. Kipps, John N. Allan, Alessandra Tedeschi, John M. Pagel, Bryone J. Kuss, Eva González Barca, Paolo Ghia, Karl Eckert, Cathy Zhou, Joi Ninomoto, James P. Dean, Danelle Frances James, Constantine Tam
Journal: Journal of Clinical Oncology (2018)

7502 Background: Ibr, a first-in-class, once-daily BTK inhibitor, is approved in the US and EU for CLL treatment, including del17p. Early studies support synergistic antitumor activity with combined ibr and ven, a BCL-2 inhibitor approved by FDA for relapsed del17p CLL. Single-agent ibr lead-in may lower tumor lysis syndrome (TLS) risk by debulking prior to adding ven. PCYC-1142 (CAPTIVATE) is a multicenter, phase 2 study of ibr + ven (I+V) in first-line CLL (NCT02910583) evaluating if remission with undetectable minimal residual disease (MRD(-)) after I+V can provide pts treatment holidays. Methods: Treatment-naïve pts <70 y with active CLL/SLL by IWCLL criteria receive single-agent ibr (420 mg/d PO) lead-in (3 x 28 d cycles) before initiating ven ramp-up to 400 mg/d PO. MRD (<0.01% by flow) is assessed in peripheral blood (PB) after 6 cycles I+V. MRD and response in bone marrow (BM) are assessed after 12 cycles I+V with planned randomization and intervention based on MRD status. Results: 163 pts were enrolled (median 58 y; 14% del17p; 15% del11q; 33% longest lymph node diameter [LDi] ≥5 cm). The first 14 pts enrolled for safety run-in completed ≥6 cycles I+V (median treatment duration, 9.9 mo ibr, 7.2 mo ven). No dose-limiting toxicities occurred during safety run-in; response was seen in 14/14 (CR confirmed in 1/5 early BM; 13/14 PR); PB was MRD(-) in 9/11 assessed pts. 97 pts (including 14 safety run-in pts) completed ibr lead-in plus ≥1 dose of ven (I+V Exposed). AEs in ≥20% of I+V Exposed pts were diarrhea (39%), fatigue (23%), nausea (23%) and arthralgia (21%); grade ≥3 AEs in ≥3% were neutropenia (10%), hypertension (3%) and thrombocytopenia (3%). No clinical TLS occurred; lab TLS was seen in 1/163 pts. In I+V Exposed pts with baseline LDi ≥5 cm, LDi decreased to <5 cm in 19/30 pts (63%) after ibr lead-in. TLS risk shifted from high to medium/low in 17/22 pts (77%); overall, proportion of high-risk TLS decreased from 23% at baseline to 3% after ibr lead-in. Conclusions: Early data show promising activity of I+V oral regimen with MRD(-) response in 82% in first-line CLL. Safety was consistent with AE profiles of single-agent ibr or ven. The protocol-specified efficacy analysis in the first 30 pts will be presented. Clinical trial information: NCT02910583.
Effectiveness and safety of LMWH treatment in patients with cancer diagnosed with nonhigh-risk venous thromboembolism (VTE): Results of the Turkish observational study (TREBECA).
Authors: Ersin Ozaslan, Metin Ozkan, Irfan Cicin, Mustafa Benekli, Murat Kocer, Mukremin Uysal, Berna Oksuzoglu, Abdurrahman Isikdogan, Erdem Cubukcu, Emin Tamer Elkiran, Faysal Dane, Mehmet Aliustaoglu, Alper Sevinc, Aziz Karaoglu, Arife Ulas, Gamze Gokoz Dogu
Journal: Journal of Clinical Oncology (2017)

e21656 Background: Venous thromboembolism (VTE) is one of the most important causes of death in cancer patients, with VTE risk being 4-7 times higher among these patients compared to normal population. TREBECA is an observational study on cancer outpatients with low risk VTE treated with LMWH. Methods: Patients were treated by medical oncologists in Turkey at 15 sites, where they were enrolled and followed-up for a period of 12 months. Each center used their own treatment protocol. Primary endpoints were efficacy and the time to a change inVTE status (dissolution of thrombosis). The doses of LMWHs have been calculated according to patients’ body weights based on the dosage scheme and administered subcutaneously once or twice daily. Results: Data for 250 patients who met the study inclusion criteria were examined and analyzed. Of the included patients; 239 patients (95.6%) completed their Day 15 visit, 176 (70.4%) completed their Month 3 visit, 130 (52.0%) completed their Month 6 visit, and 91 (36.4%) completed the entire study. The mean age of the patients was 60.2 ± 13.7, while 53.2% (n = 133) of the patients were women. Colorectal (21.2%), lung (16.8%) and breast (14.8%) cancers were the most common forms of cancer. One hundred thirty-three patients were treated with enoxaparin, 112 patients were treated with bemiparin and 5 patients were treated with tinzaparin. Bemiparin resulted thrombosis resolution in more patients than enoxaparin, during day 15, month 3 and month 6 visits (table 1; p &lt; 0.05). Conclusions: The observation that bemiparin is more effective in resolution of thrombosis was noteworthy. Thrombosis could not be effectively treated within the first 15 days in a significant number of patients, but could effectively be treated in most patients by Month 3. We can conclude that a treatment of at least 3 months is appropriate for cancer patients, even among those who are at low risk for venous thromboembolism. [Table: see text]
Evaluation of rucaparib in platinum-sensitive recurrent ovarian carcinoma (rOC) in patients (pts) with or without residual bulky disease at baseline in the ARIEL3 study.
Authors: Carol Aghajanian, Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Ana Oaknin, Andrew Peter Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew R. Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, Peter C.C. Fong, Jeffrey C. Goh, David M. O'Malley, Susana N. Banerjee, Kenton Wride, Teresa Cameron, Jonathan A. Ledermann
Journal: Journal of Clinical Oncology (2018)

5537 Background: In ARIEL3, pts were randomized 2:1 (oral rucaparib 600 mg or placebo). Rucaparib significantly improved progression-free survival (PFS) vs placebo in all primary analysis groups (Coleman et al. Lancet. 2017;390:1949-61). An exploratory subgroup analysis of ARIEL3 pts with or without bulky residual disease ( > 2 cm per blinded independent central review [BICR]) at baseline is reported. Methods: Pts were assigned to 2 analysis subgroups: with or without bulky residual disease at baseline. PFS was assessed in 3 predefined cohorts: BRCA mutant; homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/high loss of heterozygosity); and intent-to-treat (ITT) population. Results: PFS data for each subgroup (visit cutoff date 15 Apr 2017) by status of bulky disease at baseline are summarized in the Table. Safety data were consistent with data reported previously. In the rucaparib arm, the most common grade ≥3 treatment-emergent adverse event in pts with and pts without bulky disease was anemia (20.0% and 18.5%, respectively). Clinical trial information: NCT01968213. Conclusions: Rucaparib improved PFS vs placebo in all 3 predefined cohorts for both pts with and without bulky residual disease. PFS benefit with rucaparib was largest in pts with BRCA-mutant rOC. Cohort Rucaparib, n Placebo, n PFS (investigator review) PFS (BICR) HR (95% CI) Median PFS, mo; P value* HR (95% CI) Median PFS, mo; Pvalue* Rucaparib vs placebo Rucaparib vs placebo Bulky disease at baseline (per BICR) Yes BRCA mutant 21 10 0.09 (0.02–0.37) 11.1 vs 2.8; P= 0.0002 0.13 (0.03–0.55) 17.1 vs 2.9; P= 0.0028 HRD 39 18 0.30 (0.13–0.69) 8.3 vs 2.8; P= 0.0030 0.58 (0.25–1.34) 8.3 vs 2.9; P= 0.1994 ITT 71 29 0.40 (0.24–0.69) 8.2 vs 2.9; P= 0.0007 0.46 (0.26–0.81) 8.3 vs 3.0; P= 0.0057 No BRCA mutant 109 56 0.26 (0.17–0.40) 16.6 vs 5.6; P< 0.0001 0.22 (0.13–0.37) 26.8 vs 5.5; P< 0.0001 HRD 197 100 0.31 (0.23–0.43) 13.8 vs 5.5; P< 0.0001 0.32 (0.22–0.47) 24.7 vs 5.6; P< 0.0001 ITT 304 160 0.36 (0.29–0.46) 11.0 vs 5.4; P< 0.0001 0.34 (0.26–0.45) 16.2 vs 5.4; P< 0.0001 *Stratified log-rank P value.
Assessing delay and barriers to risk-reducing surgery in women with BRCA mutations.
Authors: Anne Olsen, Deanna Gerber, Olivia R Khouri, Jessica Lee, Julia Fehniger, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2018)

5564 Background: The NCCN recommends risk-reducing salpingo-oophorectomy (RRSO) for women with BRCA mutations by age 35-40 or upon completion of childbearing. We previously reported that RRSO was being performed at age 43-44; and age 46-47 when fertility considerations were excluded. Since these ages are past the NCCN guidelines, our objective was to elucidate the timing between genetic testing (GT) and risk-reducing surgery (RRS) and reasons for delay. Methods: We conducted a retrospective chart review to identify women with BRCA mutations who underwent RRSO between 2012-2017. We analyzed demographics, date of GT and RRS and reasons for delay in RRS. Results: We identified 187 patients with mutations who underwent RRS: 93 with BRCA1 and 94 with BRCA2. Median age at RRS was 44 (28-77); 43 (31-77) and 45 (28-71), for BRCA1 and BRCA2, respectively. The median time between GT and RRS was 9 (1-171) months (m). Fifty-six percent of patients (n = 105) had a documented reason for delay in RRS: 39 (37%) for future fertility; 25 (24%) for breast cancer (BC) treatment; 14 (13%) due to fear of surgical menopause; 10 (10%) to coordinate with simultaneous breast surgery; 17 (16%) miscellaneous. The median time of delay from mutation diagnosis to RRS among groups was: fertility, 29 (3-171) m; BC, 9 (2-36) m; menopause, 12 (4-76) m; and surgical coordination, 8 (4-13) m. Median age at RRS among groups was: fertility, 39 (31-46) years (y); BC, 45 (28-70) y; menopause, 42 (32-44) y; and surgical coordination, 52 (37-71) y. In patients undergoing RRS after diagnosis of BC, 30 of 36 (83%) had a family history that qualified them for earlier genetic testing by NCCN guidelines. Two of these BC patients had ovarian cancer at the time of RRS. Conclusions: Overall, patients underwent RRS within a year of mutation diagnosis. Patients comprised two distinct groups: those with fertility or menopause concerns who underwent RRS at 39-42 y, close to the NCCN recommended age; and those with BC who underwent RRS at 45-52 y. Over 80% of patients in the BC group qualified for earlier genetic screening. Obtaining a family history, referral for GT, and earlier diagnosis of mutations, prior to development of BC, will be an important step to better comply with NCCN guidelines and prevent ovarian cancer.
The practice patterns and outlook of gynecology oncologists in the treatment of pediatric, adolescent and young adults with gynecologic malignancies: A survey study.
Authors: Ira Seth Winer, Divya Patel, Vanessa Dalton, Carolyn Johnston, Elisabeth Quint, Melissa Zochowski, Adnan R. Munkarah, Robert Morris, Hope Haefner
Journal: Journal of Clinical Oncology (2016)

e18207 Background: While rare, therapy for pediatric gynecologic malignancy impacts development, fertility and self-image. Limited data examining the divide between pediatric and adult providers exists. Methods: 33-question survey was disseminated to practicing gynecologic oncologists (GYO) and fellows within the United States. Responses were analyzed in aggregate for descriptive statistics. Results: Total response was 14.2%. 70% were 30-50 years-old and equally distributed among male and female providers. 80% were Caucasian. 74% were faculty, with 50% in practice > 6 years. 60% desire to care for these children with 14% against. Academicians were more likely to desire this(p < 0.004). 43% felt they should be involved in care beginning at 6 years-old; > 65% were comfortable ≥ 11 years-old. Only 3.9% received formal fellowship training, while 50% felt this should be incorporated. Concerns regarding treatment in this population include comfort/knowledge of:surgery, chemotherapy/hormones, medication dosing, rare tumors, barriers allowing GYO involvement. 90% feel multidisciplinary teams (MDTs) should care for these patients, yet only 24% were confident their institution uses MDTs. In institutions that use MDTs, GYO providers are included. > 65% reported institutional GYO consultation is readily available. Finally, only 22% of institutions have clinics dedicated to the longitudinal care of pediatric/adolescent patients. Conclusions: Our survey demonstrates GYOs wish to be involved in pediatric care. Concerns regarding specialized treatment exist and few receive formal training. MDTs provide the ideal setting, but many institutions do not use these. Our results suggest an open dialogue between GYO and pediatric specialists is required to provide optimal, longitudinal care. Furthermore, formal training should be incorporated into fellowships.
Prognostic role of inflammatory index in head and neck squamous-cell carcinoma patients in first line chemotherapy.
Authors: Valentina Fausti, Federica Recine, Flavia Foca, Sebastiano Calpona, Davide Bruschi, Alberto Bongiovanni, Nada Riva, Laura Mercatali, Giacomo Miserocchi, Chiara Liverani, Alessandro De Vita, Chiara Spadazzi, Valentina Di Iorio, Greta Fabbri, Monia Dall'Agata, Venetia Zavoiu, Giovanni Martinelli, Dino Amadori, Toni Ibrahim
Journal: Journal of Clinical Oncology (2018)

e18054 Background: Hematologic markers of inflammation have been shown to be prognostic in different malignancies. Also in head and neck squamous-cell carcinoma (HNSCC) a prognostic role has been demonstrated in patients who were candidates for radical treatment. The purpose of this study is to evaluate retrospectively the prognostic role of these markers in patients receiving a first-line medical therapy. Methods: One hundred and fifty-eight HNSCC patients have been treated with first-line chemotherapy at our institute from 2003 to 2017. Among these, 54 patients were selected excluding patients that received concomitant radiotherapy, corticosteroid therapy for more than 10 days or GCSF. Patients characteristics for site and treatment are summarized in table 1. Information on blood counts were carried out the day before starting therapy and after the day before the last cycle of chemotherapy. NLR and PLR were computed as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively. Cut-off from literature for NLR and PLR were considered. Results: NLR and PLR showed a statistically significant reduction from beginning to end of therapy (p-values 0.006 and 0.059 respectively)but this reduction wasn’t correlated with an improvement in overall survival (OS) or progression-free survival (PFS). Patients with baseline NLR < 2.5 ( 11 patients) had a better OS respect to patients with baseline NLR≥2.5( 40 patients) (median OS 60 vs 26 months p-value 0.0296) but not a different PFS. Results for PLR values wasn’t statistically significant. Conclusions: For our knowledge this is the first study that tests the prognostic validity of NLR even in the advanced metastatic setting in HNSCC patients. Further analyses to correlate these data to the type of treatment, location of diseases and virus disease correlation status will be performed. Table 1 Characteristics Total - N (%) Age, Median ( iqr range) 61 (53-68) Gender Male 42 (77.8) Female 12 (22.8) Site of disease Oral cavity 24 (44.4) Larynx 10 (18.5) Nasopharynx 11 (20.4) Other 9 (16.7) Chemotherapy Cisplatin+Fluoruracil+CETUXIMAB 31 (57.4) Cisplatin+Fluoruracil 8 (14.8) Other 15 (27.8)