tbuckley/cabot-search huggingface dataset:
A phase 1 biomarker-directed multi-arm study evaluating the co-administration of MM-151 with MM-121, MM-141, or trametinib in EGFR-driven cancers.
Authors: Biljana Bazdar-Vinovrski, Marisa Wainszelbaum, Gavin MacBeath
Journal: Journal of Clinical Oncology (2016)

TPS11619 Background: The Epidermal Growth Factor Receptor (EGFR) is a key driver of tumor growth in colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). Although EGFR inhibitors prolong overall survival in many patients, resistance inevitably develops. Resistance usually arises through alterations in the EGFR pathway itself or through upregulation of alternative signaling pathways. In CRC in particular, mutations in KRAS and NRAS are strong predictors of resistance to EGFR inhibitors. Such resistance may potentially be overcome by combining MM-151, a potent EGFR inhibitor, with trametinib, a MEK inhibitor. In KRAS/NRAS wild-type tumors, resistance may arise through activation of parallel signaling pathways. Emerging data suggest that heregulin (HRG)-driven signaling through ErbB3 and insulin-like growth factor-1 (IGF-1)-driven signaling through IGF-1R may confer resistance to EGFR inhibitors by activating pro-survival signaling through the PI3K/Akt pathway. If HRG-mediated signaling is active, resistance may potentially be overcome through the combined administration of MM-151 and the ErbB3-targeting antibody MM-121. Similarly, if IGF-1-mediated signaling is active, resistance may be overcome by combining MM-151 with the IGF-1R-targeting antibody MM-141. The rationale underlying this trial is that mechanisms of resistance may be identified through biomarker analyses, allowing patients to be prospectively assigned to an appropriate investigational regimen. Methods: This is a Phase 1, biomarker-directed open-label study evaluating the safety, pharmacology and preliminary activity of MM-151 in combination with trametinib, MM-121, or MM-141. Patients are evaluated for KRAS/NRAS status and tumoral expression of HRG and IGF-1 and are then assigned to the study arm matching their biomarker profile. A modified “3 + 3” design is used to establish a recommended Phase 2 dose. Expansion cohorts in CRC and SCCHN will then be opened to further evaluate safety and preliminary signs of efficacy. Key exploratory analyses include evaluations of PK, PD, and biomarkers of additional resistance pathways. Clinical trial information: NCT02538627.
Preliminary results from the first in human study of activin-A inhibitor, STM434, in patients with granulosa cell ovarian cancer and other advanced solid tumors.
Authors: David Michael Hyman, Drew W. Rasco, Jeffrey R. Infante, Joyce F. Liu, Esther Welkowsky, Dung Luong Thai, Christopher M. Haqq
Journal: Journal of Clinical Oncology (2016)

5536 Background: STM 434 is an ACVR2B soluble receptor ligand trap that inhibits activin-A, a protein in the TGF-beta superfamily implicated in tumor growth, angiogenesis and immune modulation. Mutant FOXL2 drives activin A signaling and is present in ~97% of adult-type granulosa cell tumors. Methods: Using a 3+3 dose escalation design, the safety and pharmacokinetics (PK) of STM 434 IV every 2-4 weeks was evaluated. All patients (pts) continued until disease progression or unacceptable toxicity. CT scans were performed every 8-12 weeks. Results: We report interim January 2016 data in 22 pts who received STM 434 at doses of 0.25, 0.5, 0.75, and 1 mg/kg. Tumor types included ovarian cancer (n = 14; 9 granulosa cell, 3 serous, and 2 clear cell), colon (n = 2), and other solid tumors (n = 6). The most common treatment-emergent adverse events (AEs) were fatigue (n = 8), abdominal pain (n = 6), headache (n = 4), rash (n = 4), and epistaxis (n = 4); AEs were generally Grade 1-2. One DLT of self-limited peritoneal bleeding in a patient with clear cell ovarian cancer and peritoneal metastases was observed at the 0.5 mg/kg dose. At 0.75 mg/kg Grade 1 spider angioma was observed in one pt. The mean T1/2 was 5-7 days, and PK was linear between 0.25 mg/kg and 1 mg/kg. STM 434 administration resulted in the expected pharmacodynamic response to activin A inhibition with follicle stimulating hormone levels decreasing in a majority of patients. Stable disease (SD) up to 7 months in duration has been observed in 5/22 (23%) of pts including four granulosa cell tumor pts. The pt with spider angioma, who had a granulosa cell tumor, had a 20% reduction in tumor linear diameter. The SD rate in granulosa tumors was 4/9 (44%). Conclusions: Single agent STM 434 showed an acceptable safety profile in patients with advanced solid tumors and early evidence of clinical activity, particularly in patients with granulosa cell ovarian cancer. The MTD has not been determined and dose escalation is ongoing to determine the recommended phase 2 dose. Clinical trial information: NCT02262455.
Ten-year follow-up of pentostatin combined with cyclophosphamide, and rituximab in previously untreated indolent B-cell lymphoma.
Authors: Tamer Khashab, Muhammad Obaid Niaz, Fredrick B. Hagemeister, Jorge Enrique Romaguera, Michelle A. Fanale, Barbara Pro, Peter McLaughlin, Maria Alma Rodriguez, Sattva Swarup Neelapu, Luis Fayad, Anas Younes, Lei Feng, Zuzana Berkova, Neeraj Jain, Lalit Sehgal, Francisco Vega, Larry W. Kwak, Felipe Samaniego
Journal: Journal of Clinical Oncology (2017)

e19040 Background: Frontline regimens for indolent lymphoma are effective, but patients still suffer from relapse. From 2005 to 2007 we enrolled previously untreated patients on a phase II trial to investigate response rate and efficacy of pentostatin combined with cyclophosphamide and rituximab (PCR). PCR is an effective frontline therapy in chronic lymphocytic leukemia. We report the final analysis with a median follow up of nearly ten years. Methods: Patients were treated with 6 cycles of therapy with additional 3 cycles in case of not attaining a CR/CRu. All patients received Pentostatin (4 mg/m 2 ), Cyclophosphamide (600 mg/m 2 ), and Rituximab (375 mg/m 2 ) on day one and every 21 days. Results: Of the 83 patients, five were considered unevaluable for response, but are included as non-responders in our intent-to-treat analysis. Diagnoses included FL (43.4%), SLL (38.5%), and MZL (18.1%). 78.3% had Ann Arbor stage IV lymphoma and 63.9% had bone marrow (BM) involvement. For all 83 patients, the overall response was 92%, and most toxicity events were hematologic, with grade ≥3 neutropenia in 68 of 509 cycles of chemotherapy administered. Long term toxicity includes secondary malignancies in 14 patients. Two patients developed treatment related MDS/AML and both occurred after additional lines of therapy. PFS at 10 years for FL, MZL, and SLL was 71%, 67% and 15%, respectively. PFS was affected by clinicopathologic characteristics. 10-year PFS rates for those with pretreatment β2M &lt; 2.2 and &gt; 2.2 mg/l were 71 % and 21 % respectively. Patients without BM involvement had 10-year PFS of 72% versus 29% for those with BM involvement. The median OS has not been reached. The overall survival rate was 87% at 5 years and 64% at 10 years. The difference in OS rate was statistically significant based on histology, 94% for FL, 66% for MZL, and 39 % for SLL. Conclusions: Long term follow up confirms that PCR is an effective, robust and tolerable treatment regimen for indolent B-cell lymphomas with 34 of 36 patients with FL alive at 10 years with 27 remaining in remission. Clinical Trial Information NCT00496873 Clinical trial information: NCT00496873.
Effect of atopic skin stressors on NMFs and skin cytokines
Authors: K.A. Engebretsen, S. Kezic, I. Jakasa, A. Hedengran, A. Linneberg, L. Skov, J.D. Johansen, J.P. Thyssen
Journal: British Journal of Dermatology (2018)

Atopic Dermatitis (AD) is a common type of eczema. There is often a greater risk of getting AD by having a deficiency of NMFs (natural moisturising factors) that come from filaggrin in the skin. Filaggrin is a protein in your skin that plays a vital role in the skin barrier function and in releasing acids that help in water retention. While it is now known that AD is caused by the gene mutation of filaggrin, there has been little research done into environmental factors that can cause a deficiency of filaggrin in the body. A Danish study funded by the Lundbeck Foundation has attempted to discover what types of environmental skin stressors can impact on levels of NMF and cytokines. Cytokines are cell molecules that stimulate the movement of cells towards inflammation, infection and trauma. In the study, 40 healthy volunteers (18‐49) were exposed to hard, soft and chlorinated water, Sodium Lauryl Sulfate (SLS – a chemical found in foaming products such as shampoo), house mite dust, cat allergen, Staphylococcal enterotoxin B (SEB ‐ a protein commonly associated with food poisoning), cooling and histamine (a chemical created by the immune system). The volunteers were tape stripped (this means applying tape to the skin and then removing it and looking at the tape under a microscope) and the biological changes recorded after 24 and 48 hours for NMFs and after 24 hours for cytokines. At 24 hours, a significant decrease of NMFs was recorded for hard and soft waters, house dust mites and SEBs with an increase in cytokines compared with control tests. The study concluded that exposure to skin stressors causes NMF levels to decrease, with an additional increase in various types of cytokines, in healthy people. This data highlights that environmental data might play a role in AD pathophysiology.
Lymph node drainage patterns in resectable non-small cell lung cancer and its clinical significance.
Authors: Gang Lin, Zhun Wang, Xiaojiang Sun, Jinshi Liu, Yaping Xu
Journal: Journal of Clinical Oncology (2016)

e20065 Background: Our study aimed at analyzing the characteristics of regional lymph node metastasis in patients with resectable non-small cell lung cancer (NSCLC) and assessing its significance in surgical mediastinal lymph dissection and the target volume definition of postoperative radiotherapy. Methods: We retrospectively reviewed 810 patients with NSCLC, and the metastatic frequency of each regional lymph node station was analysed as well as the correlation between tumor location and regional lymph node metastases. Results: A total of 2315 groups of lymph nodes were removed. Pathology results showed that lymph node metastasis appeared in 550 groups. Regional lymph nodes metastases were significantly associated with age, histology, tumor size and tumor location (P = 0.013, 0.000, 0.009 and 0.000, respectively). The prior location of involved regional lymph nodes in different lobes of patients with NSCLC were as follows: The 2-4 station for right upper lobe tumors ; the 2-4 and 7 station for right middle lobe tumors and right lower lobe tumors; the 5-6 station for left upper lobe tumors;the 5-6 and 7 station for left lower lobe tumors. Conclusions: The younger patients with left lung adenocarcinomas and large tumor size tended to regional lymph node metastases. The trend of regional lymphatic drainage in lobes of lung occurred differently. We should pay more attention to regions regarding the higher frequencies of lymph node metastases, when determining the extent of lymph node dissection or delineating the target volume of postoperative radiotherapy for NSCLC patients.
Rate of false-negative findings in sentinel lymph node biopsy in patients with head and neck malignant melanoma.
Authors: Roman Rahimi-Nedjat, Keyvan Sagheb, Maike Hormes, Andrea Tuettenberg, Bilal Al-Nawas, Christian Walter
Journal: Journal of Clinical Oncology (2017)

e17566 Background: Sentinel Lymph Node Biopsy (SLNB) is the standard procedure for malignant melanoma with a thicknes above 1mm. However, the benefits of this procedure have recently been questioned because of a high number of false negative findings. The aim of our study was to investigate the number of early recurrence in patients with negative SLNB. Methods: All patients with malignant melanoma of the head and neck region who underwent SLNB between 2010 and 2016 in our department were included and data reviewed retrospectively. Recurrence in the same cervical lymph node region of the previously extirpated sentinel lymph node (SLN) within one year was defined as primary false-negative. Results: Allover 101 patients were investigated (mean age 62.48 years (±17.66; 73.3% ♂, 26.7% ♀). Most frequent location of the primary melanoma were the cheeks and ears (each 18.8%), followed by the hair bearing region (13.9%). Superficial Spreading Melanoma and Nodular Melanoma were the most frequently seen subtypes (each 23.8%), followed by Lentigo maligna Melanoma (19.8%). Median thickness of all patients was 2.5mm (min: 0.15 – max: 10.0 mm). In average 3 SLN were removed during operation (min: 1 – max 16). In 79.2% of the cases the SLN was negative. 13% showed one metastasis, 5.2% showed two and 1.6% three metastases. Positive findings in the SLN were significantly correlated with T-classification. Ulceration and tumor thickness showed significant tendencies in Χ 2 -Test and Mann-Whitney-Test. Out of the patients with negative SLN 13.1% had at least one metastasis in a cervical lymph node of the same region within one year. Mean duration until recurrence was 6.5 months. 75.0% of the metastases in our study were diagnosed within this period. 62.5% of the patients with secondary positive SLN had a tumor of intermediate thickness (between 1mm and 4mm). Conclusions: With 13.1 % secondary positive SLN this study shows that SLNB has a high rate of false-negative findings. However, SLNB has lower complication rates compared to traditional lymph node extirpation. This study shows that patients with negative SLN especially with intermediate tumor thickness should be controlled by ultrasound or computer tomography in short intervals.
Exploratory biomarker analysis in avelumab-treated patients with metastatic Merkel cell carcinoma progressed after chemotherapy.
Authors: Irina Shapiro, Hans Juergen Grote, Vittorio D'Urso, Anja von Heydebreck, Lisa Mahnke, Howard Kaufman, Paul Nghiem, Ti Cai
Journal: Journal of Clinical Oncology (2017)

9557 Background: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer. Tumor oncogenesis is linked to Merkel cell polyomavirus (MCPyV) integration and UV exposure. PD-L1 is often expressed in MCC tumors, suggesting that patients with MCC could benefit from anti-PD-L1 therapy. Avelumab is a fully human anti-PD-L1 IgG1 monoclonal antibody that has demonstrated clinical efficacy in patients (pts) with metastatic MCC (mMCC) in a Phase 2 trial with an objective response rate (ORR) of 31.8% in the primary analysis. Assessment of candidate predictive biomarkers may help to identify patients with a greater probability of response to avelumab and to improve understanding of MCC biology. Methods: Patients in a Phase 2 trial (NCT02155647) with mMCC and tumor progression on prior chemotherapy received avelumab at 10 mg/kg Q2W. PD-L1 expression, MCPyV status and CD8+ T-cell infiltration in pretreatment tumor samples were evaluated by immunohistochemistry (IHC). MCPyV status was also evaluated by real-time PCR. Results: Tumor PD-L1 expression was evaluable in 74 of 88 (84.1%) pts with mMCC treated with avelumab, of which 58 (65.9%) and 19 (21.6%) pts were positive at 1% and 5% cut-offs. ORR was 34.5% and 18.8% for PD-L1 positive and negative pts at 1% cutoff, and 52.6% and 23.6% for PD-L1 positive and negative pts at 5% cutoff. MCPyV status was positive in 60% (46/77) pts evaluable by IHC and 63% (45/71) pts evaluable by PCR; of 66 pts tested by both IHC and PCR, concordance was 90.9%. MCPyV+ and MCPyV– pts had similar frequencies of PD-L1+ tumors (80% and 73%) with an ORR of 26.1% and 35.5% respectively. Baseline CD8+ T-cell infiltration was assessed at tumor invasive margin and tumor center in 53 pts, ORR was 44.4% vs 19.2% and 32.1% vs 28% for pts with high or low CD8+ T-cell density at respective locations. Conclusions: In an international cohort of pts with mMCC, avelumab had clinical activity among biomarker subgroups analyzed, including PD-L1 expression, MCPyV status and density of CD8+ tumor-infiltrating T-cells. The current biomarkers were not predictive of response but further research into understanding how avelumab mediates anti-tumor activity in MCC may identify novel biomarkers. Clinical trial information: NCT02155647.
Evaluating intermittent dosing of aspirin for colorectal cancer prevention.
Authors: Katrina M. Alber, Harvey Murff, Reid Ness, Douglas Seidner, Xiangzhu Zhu, Martha Shrubsole, Mary Beth Tull, Kelly A. Benante, Adrian J. Segura, Kiril Kalinichenko, Lifang Hou, Borko Jovanovic, Gary Della'Zanna, Ellen Richmond, Seema Ahsan Khan, Qi Dai
Journal: Journal of Clinical Oncology (2018)

TPS1594 Background: Colorectal cancer (CRC) remains the 4th most common cancer in the United States. Thus the identification of effective and safe prevention methods remains important. While long-term use of COX-2 inhibitors, NSAIDs, and aspirin are associated with a reduced risk of CRC, the cardiovascular (CV) toxicity of COX-2 inhibitors and NSAIDs inhibits use in the prevention setting. Aspirin (ASA) does not confer risk of CV side effects and is a promising chemopreventive agent for CRC, but risks include gastrointestinal side effects and bleeding. Preclinical data suggest that intermittent dosing of aspirin would retain efficacy, with reduced toxicity [Mohammed, AACR 2018, NCI-N01-CN-250026]. Methods: This ongoing double-blind placebo-controlled randomized trial will enroll 90 subjects (men and women) to three arms: daily oral ASA 325 mg for 12 weeks (N = 40); intermittent aspirin 325 mg daily (4 cycles, alternating 3 weeks aspirin/placebo for a total of 12 weeks, N = 40); or daily placebo for 12 weeks (N = 10). The primary objective is to test for the equivalence of the two aspirin schedules, as demonstrated by similar changes in the ratio of cell proliferation to apoptosis in rectal biopsy samples (Ki67: Bax). Secondary endpoints include spectral markers of colon cancer risk and DNA methylation changes. Eligibility requirements include a history of colorectal adenoma (any grade), and no history of the following: invasive malignancy in the past 2 years; chronic renal or liver disease; unstable angina, hemorrhagic stroke or uncontrolled hypertension; anemia, peptic ulcer, gastrointestinal bleeding, active colitis, or inflammatory bowel disease. Participants must not have taken aspirin, other NSAIDs, or COX-2 inhibitors 3 weeks prior to the intervention; alcohol use < 2 drinks/day. They will undergo blood draws and rectal biopsies at entry, at 9 weeks, and at end of intervention. A 3-month follow-up visit is planned. Statistical analyses will be based on 32 evaluable subjects in each of the two aspirin arms (allowing for drop-outs); we will have 81% power to detect a change in the Ki67:Bax ratio of -3.0 to +3.0, based on the standard deviation of similar data from an ongoing trial. Enrollment began in January 2018. Funding: NCI #HHSN2612201200035I. Clinical trial information: NCT02965703.
Plasma caveolin-1 to predict disease reclassification in men with early stage prostate cancer in active surveillance.
Authors: Spyridon P Basourakos, John W. Davis, Brian Francis Chapin, John Francis Ward, Curtis Alvin Pettaway, Louis L. Pisters, Mary F. Achim, Xuemei Wang, Seungtaek Choi, Deborah A. Kuban, Patricia Troncoso, Christopher Logothetis, Timothy C. Thompson, Jeri Kim
Journal: Journal of Clinical Oncology (2016)

5052 Background: Given the morbidities of and limited tumor tissue from prostate biopsies (BXs), circulating biomarkers distinguishing indolent from aggressive disease and predicting disease reclassification (DR) could transform early prostate cancer (PC) management. We have shown that caveolin-1 (Cav-1), a component of caveolae and cellular membrane, is secreted by PC cells, and implicated in the transition from high grade prostatic epithelial neoplasia to prostate cancer and associated with biochemical recurrence after prostatectomy. We evaluated Cav-1’s potential to predict DR during active surveillance (AS). Methods: In a single-institution prospective study, between 2006 and 2014, 825 patients (pts) with early PC were stratified to AS group (GR) I (favorable risk: Gleason score [GS]/single core of 3+3/ < 3 mm or 3+4/ < 2 mm and PSA < 4 ng/mL), II (pt choice), or III (comorbidities preventing local therapy). Pts had entry BX within 6 months of diagnostic BX and repeat BXs every 1–2 years. Tumor volume (TV) or grade increases prompted DR. PSA was measured every 6 months. Baseline plasma Cav-1 was measured in 542 pts using established ELISA in GR I and II pts. Univariate and multivariate logistic regression analyses assessed associations between patient clinicopathologic characteristics and DR. Results: Of 542 pts, 190 (35.1%) met GR I criteria; 352 (64.9%) met GR II criteria. Median age was 64 years; clinical stage cT1c was found in 88.6%; median PSA was 4.1 ng/mL; and GS was 3+3 in 87.3%. After a median of 3.1 years’ follow-up, 163 (30.1%) had met DR. Mean and median Cav-1 levels were 2.2 (SD, 8.5) ng/mL and 0.2 (range, 0, 85.5) ng/mL, respectively. By univariate analysis, log-transformed Cav-1 was a significant predictor for DR (p= .01; OR = 1.33). No association between Cav-1 and PSA or Cav-1 and testosterone was found. On multivariate analysis, adjusting for age, PSA, TV, and GR assignment, log-transformed Cav-1 remained significantly associated with DR (p= .04; OR = 1.27). Longitudinal Cav-1 plasma levels and tissue expression are under study. Conclusions: In a prospective AS cohort, plasma Cav-1 predicted DR independent of other parameters. If validated, results may refine patient selection for AS. Clinical trial information: NCT00490763.
Gender and health care outcomes in patients with non-small cell lung cancer: A meta-analysis.
Authors: Junior S Torres-Roman, Claudio J. Flores, Alfredo Aguilar, Denisse Bretel, Christian Diego Rolfo, Luis E. Raez, Joseph A. Pinto, Luis Mas
Journal: Journal of Clinical Oncology (2017)

e18113 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. It is well known that there are differences in the outcome between genders; however the effects of the sex in the prognosis have not been previously properly defined. Our aim was to evaluate in a meta-analysis, differences in healthcare outcomes between women and men with NSCLC in terms of overall survival (OS) and progression-free survival (PFS). Methods: We searched for references of published studies of hospitalary databases indexed in PubMed/Medline. We retrieved 67 references (from 1989 to 2016), of which eleven references were eligible for data extraction. In total, 11 references were evaluable for OS. Meta-analysis for Hazard Ratios (HR) obtained from univariate and multivariate analysis were analyzed in different groups. The meta-analysis was done in the software Review Manager 5.3. Results: In total, 7 studies had information for OS univariate analysis, 7 studies for OS multivariate analysis, only, one for PFS univariate analysis and one for PFS multivariate analysis. The meta-analysis for OS univariate analysis resulted in a HR = 0.75 (P &lt; 0.00001; 95% CI: 0.71 to 0.79) for women compared to men, although there was a high statistical heterogeneity between cohorts (P &lt; 0.0001). In the meta-analysis for OS multivariate analysis was estimated a HR = 0.75 (P &lt; 0.00001; 95% CI: 0.73 to 0.78), with statistical heterogeneity between cohorts (P = 0.0005). Conclusions: Our study quantified a 25%-risk reduction of death for women with NSCLC compare with male men patients with the same diagnosis.