tbuckley/cabot-search huggingface dataset:
Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms of resistance to chemotherapy in triple-negative breast cancer patients.
Authors: Adriana Aguilar-Mahecha, Josiane Lafleur, Carole Seguin, Catalin Liviu Dragos Mihalcioiu, Josee-Anne Roy, Christine Desbiens, Andre Robidoux, Zuanel Diaz, Manuela Pelmus, Gerald Batist, Mark Basik
Journal: Journal of Clinical Oncology (2012)

TPS1139 Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.
A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors.
Authors: Yousef Zakharia, Theodore S. Johnson, Howard Colman, Nicholas N. Vahanian, Charles J. Link, Eugene Kennedy, Ramses F. Sadek, Feng Ming Kong, John Vender, David Munn, Olivier Rixe
Journal: Journal of Clinical Oncology (2014)

TPS2107 Background: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory endogenous enzyme that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in a large proportion of solid tumors, including 50% to 90% of glioblastomas (GBMs). High IDO expression is correlated with poor prognosis in GBM. IDO inhibitors such as indoximod (1-Methyl-D-tryptophan / D-1MT) can improve anti-tumor T cell responses which slows tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. The purpose of this ongoing phase I study is to determine maximal tolerated dose (MTD) of indoximod in combination with TMZ in GBM. This will be followed by an expansion phase II cohort, testing the activity of the indoximod-TMZ combination in several relevant situations, including the addition of bevacizumab or stereotactic radiosurgery in clinically-indicated cases. Methods: After progression to standard front line-therapy, patients with GBM are currently being enrolled in a phase I dose escalation study of indoximod (600, 1000 or 1200 mg twice daily given orally) with a standard fixed dose of TMZ. Then, in the phase II portion, patients will be separated into 3 cohorts: Cohort 2a: indoximod with TMZ, cohort 2b: indoximod with TMZ and bevacizumab (for patients who are currently on bevacizumab), cohort 2c: indoximod with TMZ and stereotactic radiosurgery. Statistical analysis: The study uses a 3+3 dose escalation design, until reaching the MTD or the maximal absorbed dose. Sample size in phase II is based on the primary endpoint of 6 months progression free survival (PFS). Correlative studies: This study will assess primary tumor samples for methylguanine-DNA methyltransferase, IDO expression, intra-tumoral T cells (CD4:CD8 ratio); patient serum for biomarkers of IDO activity (kynurenine and tryptophan) and indoximod pharmacokinetics. Clinical trial information: NCT02052648.
A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis comparing <i>nab</i>-paclitaxel plus carboplatin (nab-PC) with solvent-based paclitaxel plus carboplatin (sb-PC) in first-line advanced non-small cell lung cancer (NSCLC).
Authors: Corey J. Langer, Vera Hirsh, Yin Wan, Fang-Ju Lin, Scott Whiting, Teng Jin Ong, Marc Botteman
Journal: Journal of Clinical Oncology (2014)

e19004 Background: To compare the quality-adjusted survival of nab-PC vs sb-PC in first-line advanced NSCLC, the Q-TWiST methodology was applied to a Phase 3 randomized clinical trial which showed a significantly higher ORR, the primary endpoint, and non-inferior PFS and OS for nab-PC (Socinski et al, 2012). Methods: OS was partitioned into time: before disease progression without grade ≥ 3 toxicity (TWiST); with grade ≥ 3 toxicity (TOX); and after progression (REL). Mean Q-TWiST was calculated by multiplying the time spent in each state by utilities to estimate the quality-adjusted OS. In the base case, the health state utilities were assigned TWiST=1; TOX=0.5; REL=0.5. In threshold analyses, TOX and REL utilities were varied from 0 to 1. Comparisons between treatments were made for the intent-to-treat (ITT) population and subgroups by age, region, histology, and stage. Nonparametric bootstrap 95% CIs were derived to assess the statistical significance of differences in Q-TWiST. A relative gain in Q-TWiST (vs mean OS of control group) of ≥10% was defined as clinically important (Revicki et al, 2006). Results: The ITT population included 1052 patients (pts). In the base case, pts receiving nab-PC vs sb-PC gained a non-significant 0.45 month Q-TWiST (10.4 [n = 521] vs 10.0 [n = 531] months; 95% CI, −0.4 - 1.4). In North American pts, nab-PC yielded a statistically significant Q-TWiST gain of 2.5 months (10.2 [n = 81] vs 7.6 [n = 84] months; 95% CI, 0.6 - 4.3), with a relative Q-TWiST gain of 23.3% (range in threshold analysis 18.4% - 28.4%). nab-PC pts aged ≥ 60 years also had statistically significant Q-TWiST gains of 1.4 months (11.1 [n = 265] vs 9.8 [n = 281] months; 95% CI, 0.2 - 2.6), with a relative gain of 10.8% (range in threshold analysis 6.4% - 15.1%). In nearly all other subgroups, Q-TWiST differences also favored nab-PC but were not significant. Conclusions: Relative to sb-PC, nab-PC provides a clinically important and statistically significant improvement in quality-adjusted survival in advanced NSCLC pts ≥ 60 years or from North America. Clinical trial information: NCT00540514.
Immunohistochemical (IHC) prediction of lapatinib efficacy in HER2-positive advanced breast cancer patients.
Authors: Renata Duchnowska, Piotr Jan Wysocki, Konstanty Korski, Bogumila Czartoryska-Arlukowicz, Anna Niwinska, Marlena Orlikowska, Barbara Radecka, Maciej Studziński, Regina Demlova, Barbara Ziolkowska, Monika Merdalska, Lukasz Hajac, Paulina Myśliwiec, Dorota Zuziak, Sylwia Debska, Istvan Lang, Malgorzata Foszczynska-Kloda, Anna Kowalczyk, Wojciech Biernat, Jacek Jassem
Journal: Journal of Clinical Oncology (2014)

639 Background: Molecular mechanisms of resistance to lapatinib are not well understood. We analyzed retrospectively expression of six potentially useful biomarkers and correlated their status with clinical efficacy of lapatinib. Methods: Study group included 199 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine after progression of trastuzumab-based therapy. Expression of MAP-K, pAMPK alpha2, HIF-2 alpha, p-P70S6K alpha, cyclin E and PTEN in tumor samples of primary tumor was investigated by IHC using tissue microarray technology and industrial kits. Staining H-score was calculated for all markers as percent of stained tumor cells x average staining intensity graded from 0 to 3, resulting in a score value between 0 and 300. The most discriminative cut-off values (Cox regression) were subjected to multivariate analysis considering other predictive variables. Results: Median duration of lapatinib therapy was 6 months (range 0-52). In 82% of patients lapatinib therapy was discontinued due to disease progression. Using best discriminative values, expression of p-P70S6K alpha (P=0.014) and cyclin E (P=0.05) was predictive for progression free survival (PFS), the primary endpoint, and their predictive value was confirmed in the multivariate analysis (HR 0.44; 95%CI 0.24-0.80; P=0.007 and HR 1.87; 95% CI 1.09-3.21; P=0.024, respectively). PFS was also associated with the presence of brain metastasis (HR 1.79; 95% CI 1.28=2.49; P=0.001). Overall survival (OS) was associated with expression of cyclin E (p=0.015), p-P70S6K alpha (P=0.021), PTEN (P=0.034) and pAMPK alpha2 (P=0.020), of which cyclin E and MAP-K were confirmed in multivariate analysis (HR 3.66; 95%CI 1-55-8.81; P=0.003 and HR 1.59; 95%CI 1.12-2.27; P=0.010, respectively). Another independent determinant of OS was the presence of brain metastasis (HR 1.69; 95% CI 1.17-2.40; P=0.005). Conclusions: Clinical efficacy of lapatinib is associated with activity of downstream signaling pathways – PI3K/AKT/mTOR and MAPK, that seem to play opposite roles. Further investigation may indicate potential role of combining lapatinib with MAP pathway inhibitors.
Does microsatellite instability predict the effect of adjuvant chemotherapy in stage III colorectal cancer? A meta-analysis
Authors: G. Des Guetz, B. Uzzan, P. Nicolas, K. Chouahnia, G. Perret, L. Zelek, J. Morere
Journal: Journal of Clinical Oncology (2009)

4121 Background: Microsatellite instability (MSI) is a prognostic factor in colorectal cancer. Whether it predicts the effect of adjuvant chemotherapy (CT) on overall survival (OS) and relapse-free survival (RFS) is controversial. Methods: Studies were identified by an electronic search using online PubMed, with simultaneous keywords (colorectal neoplasm, microsatellite instability, chemotherapy, prognosis). Abstracts from ASCO and AACR proceedings were reviewed. Articles were obtained from cross-checking of references and from a previous prognostic meta-analysis (MA) (Popat, 2005). We used EasyMA software, available online. A Hazard Ratio (HR) &lt; 1 for MSI-high (MSI-H) status compared with microsatellite stable (MSS) meant a better survival. Results: Our MA found 21 studies (4 abstracts). Statistical calculations were performed in 11 studies (5087 patients including 2879 receiving 5FU-based CT; mean age: 63 years; 1489 stage II, 2648 stage III (64%)). MSI-H was found in 644 patients (15% of total), MSS in 3624. Seven studies (2 randomized) assessed 2 cohorts receiving or not adjuvant CT, 4 studies only included patients receiving CT. Global HR OS (9 studies) was 0.79 (95% confidence interval or CI: 0.64–0.98; p = 0.03). Global HR RFS (8 studies) was 0.67 (95% CI: 0.54–0.83; p &lt; 0.001). A MA on stage III patients (4 studies, 719 patients, 137 MSI-H) found a higher survival among MSI-H than MSS patients receiving CT (HR OS: 0.71, 95% CI 0.49–1.03; HR RFS 0.56, 95% CI 0.42–0.75). Interaction between MSI status and CT status was statistically significant on OS and RFS (4 studies). A MA among MSI-H patients (7 studies) found no survival difference between patients under CT or not: HR OS: 0.70 (95% CI 0.44–1.09), HR RFS: 0.96 (95% CI: 0.62–1.49). Conclusions: Adjuvant CT significantly improved survival in MSI-H compared with MSS patients. MSI-H stage III patients receiving CT survived more than MSS. MSI-H status did not predict response to CT compared with no treatment. No significant financial relationships to disclose.
Genomic profiling of nephrectomy and metastatic sites in patients with advanced clear cell renal cell carcinoma (RCC).
Authors: Guillermo de Velasco, Russell Madison, Siraj Mahamed Ali, Sabina Signoretti, Stephanie Anne Mullane, Jeffrey S. Ross, Vincent A. Miller, Philip J. Stephens, Alexa Betzig Schrock, Lauren Young, Sumanta K. Pal, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

513 Background: Novel biomarkers are required to accurately assess response in renal cancer. Genomic alterations (GAs) in samples from primary (nephrectomy) (N) as compared distant metastases (M) in clear cell RCC (ccRCC) may have clinical implications as well as mutations in circulating tumour DNA (ctDNA). Methods: 237 primary ccRCC nephrectomy specimens and 156 samples from distant metastases were assayed by hybrid capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify GAs suggesting benefit from targeted therapy. Tumor mutation burden (TMB) was assessed as the number of somatic coding point mutations per megabase of targeted territory. Aditionally, 17 patient-specific assays were developed to quantify ctDNA allele fraction (AF) in plasma of mRCC patients. Results: 1263 GAs and 34 clinically relevant GA (CRGAs) were identified. Most common GA identified were VHL (74%/72%), PBRM1 (40%/51%), SETD2 (28%/26%) in N and m respectively (Table). Additionally, most common CRGA identified were TP53 (8%/15%), PTEN (10%/10%), TSC1 (6%/6%), and TERT(5%/9%) in N and m respectively. No difference in TMB was seen between primary and metastatic samples. By site of metastases, soft tissue, and adrenal gland had the highest TMB and lymph node the lowest. In the 17 patients with available ctDNA, 15/17 (88.2%) have a maximum somatic AF &lt; 1% (median 0.33% [0% - 22%]) suggesting generally low tumor content. Interestingly, ctDNA in 3 patients were successfully sequenced including a patient with an EML4-ALKfusion treated with alectinib. Conclusions: This data supports that both primary and metastatic RCC share the majority of common GA. Quantitation of ctDNA is a promising biomarker for response. [Table: see text]
Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), with cetuximab (C) as reference.
Authors: Christoph Mancao, Lilla Di Scala, Paul Delmar, Stéphane Temam, Jean-Charles Soria, James F. Spicer, Mark McGurk, Jean-Pierre Delord, Jerome Sarini, Niels Halama, Stefan Evers, Alexandre Passioukov
Journal: Journal of Clinical Oncology (2013)

3035 Background: GA201 is a novel humanized anti-epidermal growth factor receptor (EGFR) mAb with a dual MoA: glycoengineered to enhance ADCC on top of inhibition of EGFR signaling. In an open-label, multi-center trial of pts with HNSCC, an exploratory biomarker analysis of sequential tumor biopsies was performed to investigate the single/duplex marker correlation structure. Methods: Pts received 2 doses of 700 or 1,400 mg GA201 or C (day 1, 8). Tumor biopsies were taken at baseline (BL) and pre-surgery (day 15). Immunohistochemistry immune-cell counts (single/duplex markers), EGFR-pathway markers and intra-tumoral cytokines (LUMINEX) were assessed. Advanced exploratory statistical methods were used to analyse inter-relationship between BL and on treatment markers, and with response (as determined by FDG-PET). Results: All immune markers (single and duplex) presented highly heterogeneous median values at BL, but cluster analysis emphasized their strong inter-correlation. These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201. Intra-tumoral cytokines like CXCL12 showed good correlation with BL CD3, 16 and 68 infiltration. Principle component analysis also confirmed a good association between most BL immune markers and was able to differentiate strongest PET responders in the 700 mg GA201 cohort. Conclusions: Multivariate statistical methods were used to demonstrate strong interdependencies between immune-effector markers and to highlight their promising associations with response to GA201 treatment, likely due to ADCC processes in the tumors. Clinical trial information: NCT01046266.
Surgical resection of primary tumors (SRPT) in asymptomatic patients with stage IV colorectal cancer (CRC): A Canadian province experience.
Authors: Shahid Ahmed, Anthony L.A. Fields, Leis Anne, Selliah Kanthan, Adnan Zaidi, Bruce Reeder, Riaz Alvi, Punam Pahwa
Journal: Journal of Clinical Oncology (2014)

3527 Background: Surgical resection of primary tumors (SRPT) in asymptomatic stage IV colorectal cancer (CRC) patients remains controversial. Reported survival benefit in literature has been attributed to selection of younger healthier patients with good performance status (PS). We have shown that SRPT improves survival independent of age, PS, and comorbid illness (JCO 30: 2013;456). This study was conducted to validate prognostic role of SRPT in asymptomatic patients with stage IV CRC. Methods: A cohort of newly diagnosed asymptomatic patients with stage IV CRC during 1992-2005, in Saskatchewan, was evaluated. Kaplan-Meier method was used to determine survival. Log-Rank test was done to compare survival. Cox proportional hazard model was performed to determine prognostic importance of SPRT. Results: There were834 patients with median age of 70 years (22-93) and male to female ratio of 58:42 were identified. Twenty six percent had Eastern Cooperative Oncology Group (ECOG) PS of >1 and 62% had a comorbid illness. There were 521 (63%) patients who underwent SRPT and 43.3% received chemotherapy. Median overall survival (OS) of patients who received chemotherapy was 16 (95% CI: 13.8-18.2) months. Patients who underwent SRPT had median OS of 19.7 (16.9-22.6) months vs. 8.4 (6.9-10.0) months without surgery (p<0.0001). Patients who received second generation therapy and underwent SRPT had median OS of 29.4 months (24.2-34.5) vs. 16.0 (13.2-18.9) months if they received older regimen. On multivariate analysis 5FU-based chemotherapy (HR 0.43; 95% CI: 0.36-0.53), SRPT (0.47; 0.39-0.57), metastesectomy (0.48; 0.38-0.62), and second line chemotherapy (0.72; 0.58-0.92) were correlated with superior survival whereas, elevated bilirubin (1.48; 1.11-1.62), low albumin (1.48; 1.25-1.75), ECOG PS >1 (1.36; 1.15-1.62), high grade tumor (1.34; 1.06-1.58), leukocytosis (1.30; 1.06-1.58), anemia (1.28;1.09-1.49), and age ≥ 65 years (1.20; 1.02-1.42) were correlated with poor survival. Test for interaction between ≥ 1 metastatic sites and SRPT was significant (p=0.03) suggesting larger benefit of SRPT in stage IVA disease. Conclusions: This first large population based cohort study confirmss that SRPT, improves survival independent of chemotherapy, age, functional status and comorbid illness, in asymptomatic patients with stage IV CRC .
Prognostic factors for patients with advanced thoracic esophageal squamous cell carcinoma receiving preoperative cisplatin plus 5-fluorouracil (JCOG9907).
Authors: Tomoya Yokota, Nobutoshi Ando, Hiroyasu Igaki, Masayuki Shinoda, Ken Kato, Yuko Kitagawa, Junki Mizusawa, Hiroshi Katayama, Kenichi Nakamura
Journal: Journal of Clinical Oncology (2014)

4045 Background: Preoperative chemotherapy with cisplatin plus 5-fluorouracil followed by esophagectomy with 2-3 field lymph node dissection is one of the standard treatments for patients with clinical stage II/III squamous cell carcinoma (SCC) of the esophagus. This study investigated the prognostic factors for patients who received preoperative chemotherapy. Methods: Of 164 patients assigned to receive preoperative chemotherapy in JCOG9907 study, multivariate analyses were performed in 159 patients for evaluating preoperative prognostic factors and in 154 patients for postoperative prognostic factors. Results: Multivariate analyses using preoperative factors showed that clinical T3 (vs.cT1-2) (HR 3.602, p=0.0007) and serum albumin (Alb)<4.0g/dl (vs.>=4.0g/dl) (HR 2.293, p=0.0005) were associated with a poor prognosis. A prognostic index using these preoperative factors was constructed dividing patients into good (cT1-2 and Alb>=4.0: 3yOS 92.3%), moderate (cT1-2 and Alb<4.0 or cT3 and Alb>=4.0: 66.3%), and poor (cT3 and Alb<4.0: 37.2%) risk groups. Three independent prognostic factors were identified by multivariate analysis using postoperative factors: pathological curability pB [either R1, R0 with stage IV, or the nodal dissection area smaller than the extent of nodal metastasis] or pC [R2] (vs. pA [R0]) (HR 2.199, p=0.0027), pathological N1-4 (vs. pN0) (HR 3.397, p=0.0012) and histological therapeutic effect (Grade>=2) (HR 0.301, p=0.0104). A prognostic index using postoperative factors was constructed dividing patients into good (no or one risk factor), moderate (two risk factors) or poor (three risk factors) risk groups. 3yOS for good, moderate and poor risk groups were 87.7%, 56.0%, and 31.6%, respectively. Conclusions: cT, Alb and postoperative pathological findings are independent prognostic factors for advanced thoracic esophageal SCC patients who received preoperative chemotherapy. Information from this analysis can be used to aid clinical decision-making and help individual patient risk stratification.