tbuckley/cabot-search huggingface dataset:
Perioperative therapy in patients with metastatic colorectal cancer.
Authors: Olatunji B. Alese, Katerina Mary Zakka, Xingyue Huo, Renjian Jiang, Walid Labib Shaib, Christina Wu, Mehmet Akce, Patrick S. Sullivan, Madhusmita Behera, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2019)

e18231 Background: Knowledge about perioperative systemic therapy in metastatic colorectal cancer (mCRC) is limited. We aim to describe the nationwide pattern of use and survival outcomes of patients with mCRC treated with surgical resection. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate analyses was done to identify factors associated with patient outcome. Results: A total of 61,940 patients with stage IV CRC older than 18 years were identified. Mean age was 63.4 years (SD±14), with a male preponderance (54.8%). About 80% were Caucasian and 69.9% had colon cancer. Compared to medical treatment only, resection of both primary and metastatic sites (13.5%; HR 0.40; 0.37-0.44; p &lt; 0.001), or primary site resection alone (49.2%; HR 0.52; 0.48-0.56; p &lt; 0.001) were associated with improved overall survival (OS). Other co-variates associated with improved survival included younger age group, year of diagnosis (2009-2013), colon tumor location, and &lt; 3 metastatic sites (Table). Five-year OS for resection of primary and metastatic site (28.2%) was higher than for primary site resection alone (14.9%) or no surgical treatment (4.7%). Conclusions: Resection of metastatic sites or primary tumor was associated with improved survival in patients with stage IV CRC.[Table: see text]
Satellite alpha transcript levels to predict risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer who lack <i>BRCA</i>-related clinical features.
Authors: Nao Kakizawa, Koichi Suzuki, Sawako Tamaki, Hideki Ishikawa, Kosuke Ichida, Kazushige Futsuhara, Toshiki Rikiyama, Fumiaki Watanabe
Journal: Journal of Clinical Oncology (2019)

e12575 Background: Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We have reported that the overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. Methods: In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression SAT (rSAT) level was calculated in normal and tumor tissues from 167 patients. Twenty-seven patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC). We detected that 71 patients had factors associated with inherited breast cancer; age under 50yo, harboring family history of breast cancer, pathological diagnosis of TNBC, and history of ovarian cancer and we determined these factors as BRCA-related clinical factors. Results: We excluded 71 patients with BRCA-related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues ( P = 0.0121) and normal tissues ( P = 0.00586). A univariate analysis indicated significant predictors including rSAT &gt; 1.5 in tumor tissues, rSAT &gt; 2.4 in normal tissues. In a multivariate analysis, rSAT &gt; 2.4 in normal tissues was a significant predictor of BBC (HR, 22.7; P = 0.00120) and MPC (HR, 11.1; P = 0.00885). Conclusions: Our data indicated that patients with breast cancer with high rSAT levels in their breast tissues have a 10- to 20-fold increased risk for the development of multiple cancers when they harbored no BRCA-related clinical features. These patients had been excluded from the high-risk group for BBC, however, our results shed light on these patients and we detected another risk factor which could predict multiple cancers.
Best supportive care (BSC) with or without low-dose chemotherapy (chemo) in frail elderly patients with advanced gastroesophageal cancer (aGOAC): The uncertain randomization of the GO2 phase III trial.
Authors: Daniel Swinson, Mohan Hingorani, Zuzana Stokes, Jo Dent, Kamalnayan Guptal, Anirban Chatterjee, Konstantinos Kamposioras, Simon Aird Grumett, Mohammad Khan, Helen Marshall, Sharon Ruddock, Christine Allmark, Eszter Katona, Helen C Howard, Galina Velikova, Simon Lord, Peter S Hall, Matthew T. Seymour
Journal: Journal of Clinical Oncology (2019)

4051 Background: Before 2000, trials comparing BSC +/- chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using low-dose chemo in a frail population, with comprehensive baseline health and frailty assessment. Methods: In the GO2 trial, elderly and/or frail aGOAC pts with a “certain” indication for chemo were randomised between 3 chemo doses. In this GO2 substudy, pts with an “uncertain” indication for chemo were instead randomised to BSC ± the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR ≥30 and bili &lt; 2xULN were required. Baseline assessment included global QL, symptom &amp; functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d1-21 (modified if eGFR 30-50 ml/min or bili 1.5-2.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not pre-set, but around 60 pts were anticipated. Results: 558 pts entered GO2 at 61 centres 2014-17, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2-tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p&lt;0.01) or distant mets (p&lt;0.05). OS was not significantly improved with chemo; however we cannot exclude HR &gt;0.32. QL deteriorated less with BSC+chemo than with BSC alone. Conclusions: In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty. Clinical trial information: 44687907. [Table: see text]
Does the innovative 4R Cancer Care Delivery Model improve patient self-management in safety net and non-safety net centers?
Authors: Julia Rachel Trosman, Christine B. Weldon, Della F. Makower, Bruce D. Rapkin, Moreen Bozier, Eileen Knightly, Cathleen M. Schaeffer, Kent Hoskins, Christopher Gallagher, Shelly S. Lo, Cathy Grace-Louthen, Alyssa Throckmorton, Lindi Vanderwalde, Editha A. Krueger, Jennifer Van Horn, Lidia Schapira, Cesar Augusto Santa-Maria, Arliene Ravelo, Al Bowen Benson, William John Gradishar
Journal: Journal of Clinical Oncology (2019)

6601 Background: Under the NCI ASCO Teams Project, we proposed a 4R Model of teamwork and patient self-management (pSM) (Trosman JOP ’16). 4R (Right Info / Care / Patient / Time) enables patient (pt) and care team to manage complex care continuum with an innovative multimodality 4R Care Project Plan. 4R includes a novel “project” feature – a graphical description of care interdependencies. 4R was previously piloted at 3 Chicago centers (Trosman ASCO ‘18). Methods: In this new study, we improved and tested 4R for impact on pSM at 4 safety net and 3 non safety net centers across the US. 4R Plans were provided to stage 0-III breast cancer pts Jan - Nov’18 (4R cohort). We surveyed the 4R cohort and a historical control cohort of pts who received care at same centers pre-4R, Jan - Dec ’17. Results: Survey response rates: 65%, 105/162 (4R cohort); 44%, 190/432 (control). 4R markedly improved 4 of 5 pSM metrics vs control (Table). Additional analyses showed that safety net pts had a significant increase in 4R vs control cohort in “seldom overwhelmed” (84%, 49/58 vs 64%, 67/104 respectively, p = .007), while non safety net pts had nonsignificant increase. Other metrics improved to a similar extent for safety net vs non safety net pts. Within the 4R cohort, 85% found 4R useful in organizing their care and 73% found 4R’s novel “project” feature useful in understanding care interdependencies. Safety net pts reported similar usefulness of 4R in organizing their care as non safety net pts (88%, 51/58 vs 81%, 38/47, NS) and similar usefulness of the “project’ feature in understanding care interdependencies as non safety net pts (74% vs. 72%, NS). Conclusions: 4R significantly improved patient self-management, but further efforts are needed to expand the benefit to as close to a 100% of pts as feasible. Safety net pts benefited from 4R at similar or higher rates than non safety net pts, indicating that 4R may reduce care disparities. An expansion of 4R across the US continues this work. [Table: see text]
Patterns of mutation enrichment in metastatic triple-negative breast cancer.
Authors: Cesar H. Saravia, Claudio J. Flores, Luis Jesus Schwarz, Leny Bravo, Jenny Zavaleta, Jhajaira M Araujo, Silvia P. Neciosup, Joseph A. Pinto
Journal: Journal of Clinical Oncology (2019)

e12596 Background: Triple-Negative breast cancer (TNBC) is a group of heterogeneous tumors with aggressive biology. The purpose of this research was to evaluate enrichment patterns of genomic alterations in metastatic TNBC (mTNBC). Methods: We retrieved genomic data (mutations and copy number variation) from 550 primaries TNBC (pTNBC) from the projects METABRIC and TCGA and 58 mTNBC from the projects “Mutational Profile of Metastatic Breast Cancers” and “The metastatic Breast Cancer Project”. Differences in the proportions of mutations between primary vs. metastatic tumors were evaluated by the Chisquare test and the percentage of enrichment in mTNBC was estimated. Pvalues were adjusted for multiple testing with the Benjamini-Hochberg method with and a FDR &lt; 0.05. In addition we conducted an analysis of the hallmarks of cancers enriched in mTNBC. Results: In total, mutations in eight genes were significantly enriched in mTNBC after correcting for multiple testing. These genes included TTN, HMCN1, RELN, PKHD1L1, DMD, FRAS1 and RYR3. In the other hand, only amplification of RPS6KB2 was enriched in mTNBC. Deletions were enriched more frequently in the genes TET1, RHOA, EPHA5, SET, KCNJ5, ABCG4, NKX3-1, SDHB, IGF2, BRCA1, among others. The hallmark of “genetic instability and mutation” was over represented while the hallmark “activating immune destruction” was the least represented between the enriched genetic alterations in mTNBC. Conclusions: Despite the study limitations, we identified that deletions are the aberrations more commonly enriched in mTNBC while some biological processes could be targetable in order to improve the therapeutic opportunities in TNBC.
A phase I/Ib multicenter study to evaluate the humanized anti-CD73 antibody, CPI-006, as a single agent, in combination with CPI-444, and in combination with pembrolizumab in adult patients with advanced cancers.
Authors: Mehrdad Mobasher, Richard A. Miller, Long Kwei, Deborah Strahs, Vaijayanti Das, Gabriel Luciano, John D. Powderly, Jaime R. Merchan, Minal A. Barve, Patricia LoRusso, Abhishek Tripathi, Jason J. Luke
Journal: Journal of Clinical Oncology (2019)

TPS2646 Background: CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. CPI-006 is a humanized IgG1 FcγR binding-deficient anti-CD73 antibody now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA) or combination with CPI-444, an oral, small molecule, selective A2aR antagonist or in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods: Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients must have: non-small cell lung, renal cell carcinoma, urothelial bladder, cervical, colorectal, ovarian, pancreatic, prostate, head and neck, triple-negative breast, endometrial, select sarcomas and non-Hodgkin lymphoma malignancies relapsed, refractory or intolerant to 1 to 5 standard therapies; aged ≥ 18 yo; adequate organ function and measurable disease. The objectives of the study are 1) evaluate the safety and tolerability of SA CPI-006, in combination with CPI-444 and in combination with pembrolizumab, 2) evaluate the pharmacokinetics of each regimen and 3) identify potential biomarker signals predictive of response. Study design in table. Study Design. Clinical trial information: NCT03454451. [Table: see text]
The effect of metformin on sex hormones in non-diabetic breast cancer patients in CCTG MA.32: A Phase III randomized adjuvant trial of metformin versus placebo in addition to standard therapy.
Authors: Isabel Pimentel, Bingshu E. Chen, Ana Elisa Lohmann, Marguerite Ennis, Jennifer A. Ligibel, Lois E. Shepherd, Dawn L. Hershman, Vuk Stambolic, Ingrid A. Mayer, Timothy J. Hobday, Julie Lemieux, Alastair Mark Thompson, Priya Rastogi, Karen A. Gelmon, Timothy Joseph Whelan, Manuela Rabaglio-Poretti, Ryan JO Dowling, Wendy R. Parulekar, Pamela Jean Goodwin
Journal: Journal of Clinical Oncology (2019)

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or &gt; 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m 2 , median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = &lt; 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = &lt; 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.
Screening of differentially expressed genes of esophageal squamous cell carcinoma with cDNA microarray.
Authors: Si Fuchun, Yue Jingyu, Si Gao
Journal: Journal of Clinical Oncology (2019)

e13005 Background: Esophageal Carcinoma (EC) is one of the most common malignant tumors in digestive system and is the sixth leading cause of cancer-related mortality worldwide. To find out the genes related with the occurrence and development of EC can help to elucidate the pathogenesis and molecular mechanism of it. The aim of the present study was to find out differentially expressed genes of EC in different stages(cancerous tissue, paraneoplastic tissue, normal mucosa tissue) by cDNA microarray technique, so that to provide new molecular biomarker and approach for the treatment and diagnosis of EC, and contribute to comprehensively knowing the mechanism of EC occurrence and development. Methods: The whole RNA of 21 cases of EC cancerous tissue, paraneoplastic tissue and normal mucosa tissue were extracted, then using agarose gel electrophoresis to make quality control, Agilent human genome 4*44K gene chip was applied to screen differentially expressed genes. Results: 2659 differential expression genes between cancerous tissue and normal mucosa tissue were screened, included 1328 up-regulated genes and 1331 down-regulated genes; 2505 differential expression genes between cancerous tissue and paraneoplastic tissue were screened, included 1286 up-regulated genes and 1218 down-regulated genes. 48 significant up-regulation genes and 11 significant down-regulation genes were reported in association with EC for the first time. Through GO classification, screened differentially expressed genes mainly were involved in the following function and process: catalytic activity, signal transduction, molecular transport and combination, enzymatic activity regulation, transcription activity regulation, protein transportation function, cell growth and apoptosis, and so on. Conclusions: The screened differential expression genes of EC in different stages may provide experimental basis for further illuminating the occurrence mechanism of esophageal squamous carcinoma.
Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial.
Authors: Michael Friedlander, Kathleen N. Moore, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Alla Sergeevna Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Susana N. Banerjee, Amit M. Oza, Antonio González-Martín, Carol Aghajanian, William Hampton Bradley, Elizabeth S. Lowe, Ralph Bloomfield, Paul Disilvestro
Journal: Journal of Clinical Oncology (2019)

5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]
Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: Safety and preliminary efficacy in combination with anti-PD-1 agent.
Authors: Prasad S. Adusumilli, Marjorie Glass Zauderer, Valerie W. Rusch, Roisin O'Cearbhaill, Amy Zhu, Daniel Ngai, Erin McGee, Navin Chintala, John Messinger, Waseem Cheema, Elizabeth Halton, Claudia Diamonte, John Pineda, Alain Vincent, Shanu Modi, Stephen Barnett Solomon, David Randolph Jones, Renier J. Brentjens, Isabelle Riviere, Michel Sadelain
Journal: Journal of Clinical Oncology (2019)

2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 &lt; 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.