tbuckley/cabot-search huggingface dataset:
Optimizing the sequence of biological agents in advanced colorectal cancer: A decision analysis.
Authors: Maria C. Riesco Martinez, Scott R. Berry, Yoo-Joung Ko, Kelvin Chan
Journal: Journal of Clinical Oncology (2012)

e14171 Background: Patients (pts) with wild-type (WT) K-ras metastatic colorectal cancer(mCRC) may benefit from the following five drugs/classes: fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (B) and EGFR inhibitors (EGFRI). However, pending the results of ongoing randomized trials, the optimal sequencing of these agents is unclear. Methods: A Markov model was constructed for a hypothetical cohort of pts with WT K-ras unresectable mCRC to examine the outcomes of 3 different treatment strategies over a time horizon of 5 years. Strategy A: 1st line B+FP+O/I, 2nd line FP+I/O, 3rd line EGFRI monotherapy. Strategy B: 1st line B+FP+O/I, 2nd line FP+I/O, 3rd line EGFRI + I. Strategy C: 1st line EGFRI+FP+O/I, 2nd line B+ FP+I/O, 3rd line best supportive care. Efficacy and probability data were obtained from published clinical trials identified through a systematic review using MEDLINE, EMBASE and the Cochrane Central registry of clinical trials. The primary endpoint was mean overall survival (OS). Results: The results are shown in the table below. One-way sensitivity analyses revealed that strategy C may be preferred to B when less than 30% of pts were eligible to receive 3rd line treatment (base case was 34%), or when the relative benefit of 3rd line EGFRI+I to EGFRI alone had a hazard ratio (HR) of more than 0.57 (base case HR = 0.54). First order micro-simulation (n=100,000) suggested that 77% and 82% of the simulations revealed the differences between strategies B and C to be less than 1 month and 3 months respectively. Only 6% of the simulations suggested strategy B was superior to others by more than 3 months, while only 12% suggested strategy C was superior to others by more than 3 months. Conclusions: All 3 strategies appeared to result in similar OS for pts with unresectable mCRC. Objective evidence regarding the proportion of patients eligible for 3rd line EGFRI treatment in clinical practice would be useful given the implications for a preferred strategy to maximize OS. [Table: see text]
Outcomes of elderly patients treated for oral cavity squamous cell carcinoma.
Authors: Jennifer Lobo Shah, Michael Kaplan, A. Dimitrios Colevas, Quynh-Thu Le, Wendy Hara
Journal: Journal of Clinical Oncology (2015)

6076 Background: Implementing standard treatment recommendations for oral cavity cancer in the elderly population can be challenging due to the comorbidities seen in this population. We sought to compare outcomes in patients of age 70 years or older compared to their counterparts. Methods: We retrospectively reviewed 551 consecutive patients treated at the Stanford Cancer Institute from 1998-2013 for oral cavity squamous cell carcinoma with surgical resection followed by adjuvant therapy if indicated. Patients treated for recurrent disease and metastatic disease were not included. Of this cohort, 188 patients were elderly, defined as age 70 years or above, and 363 patients were younger than age 70. Survival estimates were determined using the Kaplan-Meier method, and recurrence rates were determined using cumulative incidence estimates including competing-risk analyses. Results: At 2 years after diagnosis, overall survival was 55% in the elderly group compared to 75% in those younger than age 70 (p < 0.0001). Loco-regional recurrence at 2 years was 29% in the elderly group compared to 34% in the younger group (p = 0.09). Freedom from progression was 32% in the elderly group compared to 36% in the younger group (p = 0.11). Within the elderly group, 69 patients underwent neck dissection as a component of their initial surgical resection. Overall survival at 2 years was 50% for elderly patients who underwent neck dissection compared to 58% for elderly patients who did not (p = 0.09). Conclusions: Consistent with life expectancy, elderly patients age 70 years or older treated for oral cavity cancer had worse overall survival compared to younger patients. Loco-regional recurrence and freedom from progression, however, were lower in the elderly population. Less aggressive management may be acceptable in this population.
Final results of a prospective, observational study of the effectiveness of darbepoetin alfa administered every three weeks for the treatment of chemotherapy-induced anaemia in elderly patients
Authors: G. Esquerdo, M. Doménech, J. C. Bermejo, P. López, C. Pedro, K. Villadiego, M. Constenla, P. Sánchez-Rovira, J. A. Gasquet, C. A. Rodríguez
Journal: Journal of Clinical Oncology (2009)

e20654 Background: Cancer incidence is increasing in elderly but specific treatment data in this population is not often available. The objectives of this study were to evaluate the effectiveness and safety of darbepoetin alfa (DA) administered once every 3 weeks (Q3W) for the treatment of chemotherapy-induced anaemia (CIA) in elderly within routine clinical practice. Methods: Prospective, observational, single-arm, multicentre study performed in 28 centres across Spain. Eligible patients (pts):≥65 years, anaemic (haemoglobin [Hb] 11 g/dl), with non-myeloid malignancies, and scheduled to receive ≥9 weeks (wks) of chemotherapy. Pts were treated with a fixed dose of DA 500 μg Q3W and treatment stopped if Hb levels exceeded 13g/dl. Primary endpoint was hematopoietic response (Hb increase ≥2g/dl or Hb ≥12g/dl without transfusions in the previous 28 days). Secondary endpoints included percentage of pts achieving target Hb (&gt;11g/dl from wk 5 till end of treatment without red blood cell transfusion within 28 days), changes in the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale and the incidence of adverse reactions. Results: Data were prospectively collected from 153 pts: women (56.86%), mean (SD) age 73.43 (5.77) years, ECOG Performance Status 0–1 (65.36%) with solid tumors (66.67%) and lymphoproliferative malignancies (33.33%) and stage III/IV (63.40%). Most pts (90.20%) had baseline Hb levels between 9–11g/dL. DA was administered for a median of 9.0 wks (range: 1–22.57). The Kaplan-Meier percentage (KM; 95% CI) of pts who achieved hematopoietic response was 69.70% (56.06–83.34) and 72.22% (57.5–86.94) for pts who achieved target Hb (&gt;11g/dL). FACT-F median score at baseline was 29.00 and 33.00 at the end of the study. Only one (0.7%) non-serious adverse reaction (cutaneous eruption) was reported. Conclusions: These results suggest that DA given at 500 μg Q3W to elderly pts with non-myeloid malignancies is an effective and well-tolerated treatment for CIA. [Table: see text]
Surgery for early non-small cell lung cancer with preoperative erlotinib (SELECT): A correlative biomarker study.
Authors: Adrian G. Sacher, Humberto Lara-Guerra, Thomas K. Waddell, Lucia Kim, Zhuo Chen, Alexandra Salvarrey, Gail Darling, Kazuhiro Yasufuku, Shaf Keshavjee, Marc de Perrot, Frances A. Shepherd, Geoffrey Liu, Ming Sound Tsao, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2013)

7516 Background: Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild-type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers. Methods: Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Pharmacodynamic changes were assessed through comparison of pre- and post-treatment tumour samples (including Sequenom MassARRAY analysis) and measurement of circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR SNP, EGFR ECD). Secondary endpoints included pathological response, toxicity and progression-free survival. Results: Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (14) with smaller numbers of squamous carcinoma (7) and large cell carcinoma (1). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR exon 19 deletion was detected in one adenocarcinoma case; the patient experienced a minor radiographic response to treatment. Genotyping, functional protein assays and ligand analysis are ongoing. Conclusions: Erlotinib appears to demonstrate some activity in patients with squamous histology. While EGFR mutations have been infrequently demonstrated in squamous NSCLC, the potential exists for other biomarkers predictive of benefit. Clinical trial information: NCT00462995.
The impact of MRE11 in nuclear to cytoplasmic ratio on outcomes in muscle invasive bladder cancer an analysis of NRG/RTOG 8802, 8903, 9506, 9706, 9906, and 0233.
Authors: Anthony Martin Magliocco, Jennifer Moughan, Jeff Simko, Jason A. Efstathiou, Phillip J Gray, Michael P Hagan, Donald S Kaufman, William J. Tester, Anthony L. Zietman, Susan M McCarthy, Alan C Hartford, Ashish Bharat Patel, Seth A. Rosenthal, David G McGowan, Richard H Greenberg, Michael A Schwartz, Mark E Augspurger, John A. Keech, Kathryn A Winter, William U. Shipley
Journal: Journal of Clinical Oncology (2017)

343 Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was &gt;1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.
Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes
Authors: Michael S. Lee, David G. Menter, Scott Kopetz
Journal: Journal of the National Comprehensive Cancer Network (2017)

Although clinical management of colon cancer generally has not accounted for the primary tumor site, left-sided and right-sided colon cancers harbor different clinical and biologic characteristics. Right-sided colon cancers are more likely to have genome-wide hypermethylation via the CpG island methylator phenotype (CIMP), hypermutated state via microsatellite instability, and BRAF mutation. There are also differential exposures to potential carcinogenic toxins and microbiota in the right and left colon. Gene expression analyses further shed light on distinct biologic subtypes of colorectal cancers (CRCs), with 4 consensus molecular subtypes (CMSs) identified. Importantly, these subtypes are differentially distributed between right- and left-sided CRCs, with greater proportions of the “microsatellite unstable/immune” CMS1 and the “metabolic” CMS3 subtypes found in right-sided colon cancers. This review summarizes important biologic distinctions between right- and left-sided CRCs that likely impact prognosis and may predict for differential responses to biologic therapy. Given the inferior prognosis of stage III–IV right-sided CRCs and emerging data suggesting that anti–epidermal growth factor receptor antibody therapy is associated with worse survival in right-sided stage IV CRCs compared with left-sided cancers, these biologic differences between right- and left-sided CRCs provide critical context and may provide opportunities to personalize therapy.
Punctuated evolution of copy-number alterations to define two molecular subtypes of muscle-invasive urothelial carcinoma.
Authors: Bishoy Faltas, Davide Prandi, Scott T. Tagawa, David M. Nanus, Ana M. Molina, Himisha Beltran, Francesca Demichelis, Mark A. Rubin
Journal: Journal of Clinical Oncology (2017)

299 Background: Somatic copy-number alterations (SCNAs) are distinct molecular events occurring in muscle-invasive urothelial carcinoma (UC). Defining the biologic role and the timing of SCNAs in UC’s evolution is critical for precision therapy. Methods: To examine whether distinct SCNAs define specific subtypes of UC and characterize the evolutionary dynamics of SCNA acquisition, we conducted whole-exome sequencing (WES) of a discovery cohort of 44 advanced UC tumors and matching germline samples, including 13 pairs of matched primary and metastatic tumors prospectively collected before and after chemotherapy. We queried WES data from 285 UCs from The Cancer Genome Atlas (TCGA) as a validation cohort. We performed a novel in-depth allele-specific copy-number analysis in 2503 cancer genes using the CLONET computational framework, which accounts for tumor ploidy and cellularity to infer the clonal hierarchy of SCNAs. Results: Analysis of SCNAs from tumor pairs within each patient revealed punctuated evolution of SCNAs occurring early in UC’s development followed by minor changes (clonal stasis) throughout the tumor’s lifetime. Two distinct clusters of UCs with strikingly different SCNA profiles in the discovery cohort emerged. Cluster A was defined by diploid copy number background and focal deletions in the 9p21 region (CDKN2A, CDKN2B and MTAP). Cluster B was defined by genome-wide duplications and several enriched amplifications including 1q21.1 (SETDB1 and MLLT11), (P = 0.0002) and 6p22.3 (E2F3), (P = 0.001). TP53 mutations (P = 0.0001) were enriched in the cluster B, consistent with the role of functional p53 as a “guardian of the genome” preventing chromosomal instability. SCNAs clusters A and B were confirmed in the TCGA validation cohort. Cluster A was enriched with tumors belonging to TCGA bladder cancer cluster III (“basal/squamous-like”) (P = 0.02). Conclusions: Using novel allele-specific SCNAs analysis, we define two distinct clusters of UC presenting a framework for understanding this aspect of UC’s biology. In contrast to somatic mutations, SCNAs are clonally static during each tumor’s evolution. This data has important implications for precision medicine for UC.
Targeted modified IL-2 (NHS-IL2, MSB0010445) combined with stereotactic body radiation in advanced melanoma patients after progression on ipilimumab: Assessment of safety, clinical, and biologic activity in a phase 2a study.
Authors: Howard L Kaufman, Janice M. Mehnert, Jean-Marie Cuillerot, Anja von Heydebreck, Patrick Alexander Ott, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2014)

TPS9107 Background: Advanced melanoma patients (pts) can benefit from IL-2 therapy, but treatment is often limited by severe toxicities. The immunocytokine NHS-IL2 is a fusion protein composed of genetically modified IL-2 that preferentially binds to the high-affinity IL-2 receptor, and of a human IgG2 antibody targeting DNA exposed in necrotic tumor regions (NHS76). In preclinical studies, NHS-IL2 showed antitumor activity; in phase 1 trials it was biologically active and well tolerated, both as a monotherapy and in a sequential combination with radiotherapy (Gillessen et al. Eur J Cancer 2013; van den Heuvel et al. submitted). This phase 2a, open-label, parallel-group dose-escalation trial investigates safety, clinical and biologic activity of NHS-IL2 following stereotactic body radiation(SBRT) in pts with advanced melanoma (NCT01973608). Methods: The primary study objective is to determine the maximum tolerated dose of NHS-IL2 combined with SBRT. Exploratory study objectives are safety, biologic and clinical activity of the combination, and immunogenicity and pharmacokinetics of NHS-IL2. Pts with advanced unresectable or metastatic melanoma that has progressed after ipilimumab as immediately preceding treatment are eligible. Main exclusion criteria: active brain metastases and concurrent systemic immunosuppressive therapy. Up to 86 pts will be enrolled to receive ≤3 SBRT (up to 20 Gy on max. 3 lesions or up to 16 Gy if irradiated lesion is located in the thorax), followed by NHS-IL2 iv every 3 weeks in 3 arms: fixed doses of 0.3 mg/kg and 1.0 mg/kg; and dose escalation at 1.8–3.6 mg/kg (standard 3+3 design). If safety allows, up to 14 pts per arm will be enrolled to assess biologic activity, defined by the changes in infiltration of CD8+ and regulatory T cells into the tumor before and during therapy. Depending on the biologic activity, trial arms will be expanded or pooled to determine objective response in 40 pts treated with an active dose. Combination treatment will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. As of Jan 31, 2014, 2 pts are enrolled. Clinical trial information: NCT01973608.
Biological difference of right versus left colon cancer: An analysis of the National Cancer Data Base and Surveillance, Epidemiology and End Results.
Authors: Sukamal Saha, Lindsay Berbiglia, Mohammed Shaik, Jill Gernand, Supriya Kumar Saha, Michael Hicks, Madan L. Arora, David Wiese
Journal: Journal of Clinical Oncology (2015)

e14624 Background: Although all colon cancers (CCa) are staged and treated similarly, it is somewhat unknown whether the biological behavior of right (R) CCa differs from left (L) CCa. Hence a comparative analysis was done to identify differences between R and L CCa from the National Cancer Data Base (NCDB) and Surveillance, Epidemiology and End Results (SEER) data. Methods: Retrospective review of NCDB and SEER’s data of CCa patients (pts) from 1998-2010 was performed. Kaplan Meier method was used for overall 5-year survival (5yrOS). Cox proportional regression analysis calculated adjusted hazard ratios (aHR) controlling for age, sex, race, grade, lymph node (LN) yield and TNM stage. Results: There were 258,623 CCa pts after surgery from NCDB and 67,702 from SEER. RCCa had higher age, tumor size, grade, no. of LN examined and positive LN when compared to LCCa (Table). Stages I and II were more common in R and III and IV were more common in LCCa, 5yrOS was worse for R compared to LCCa. aHR was significantly higher for R versus LCCa. (Table) Conclusions: Despite more earlier stage disease in R than in LCCa, 5yrOS was worse for RCCa. RCCa pts had 17-20% increased chance of death over LCCa pts. Although the causes of poorer prognosis are unknown, further prospective study with newer biologic markers may explain such behavior. Characteristics of right and left colon cancer and survival comparison between right and left colon cancer. NCDB SEER Right (143,979) Left (114,644) p-value Right (36,985) Left (30,717) p-value Age 71.5 67.4 <0.001 70.5 65.1 <0.001 Tumor Size (cm) 4.8 4.3 <0.001 5.4 4.5 <0.001 No. LN examined 16.7 13.9 <0.001 19.0 16.4 <0.001 No. LN positive 2.8 2.4 <0.001 2.8 2.6 0.006 Stage I&II 56.1% 52.4% <0.001 52.1% 47.1% <0.001 Stage III 21.1% 22.1% <0.001 31.6% 34.6% <0.001 Stage IV 22.7% 25.5% <0.001 15.4% 17.4% <0.001 NCDB SEER 5yrOS Right Left p-value Right Left p-value Stage I&II 67.0% 69.3% <0.001 70.4% 72.8% <0.001 Stage III 45.8% 54.7% <0.001 52.7% 62.8% <0.001 Stage IV 8.2% 13.4% <0.001 9.8% 16.9% <0.001 aHR 1.17 1.00 <0.001 1.20 1.00 <0.001
Determinants of treatment in patients with stage IV renal cell carcinoma.
Authors: Christopher S. Hollenbeak, Eric W. Schaefer, Justin Doan, Jay D. Raman
Journal: Journal of Clinical Oncology (2017)

486 Background: Although there have been significant advances in the detection and treatment of renal cell carcinoma (RCC), many elderly patients—particularly those with stage IV disease—likely receive no treatment. The purpose of this research was to study treatment patterns for elderly patients with stage IV RCC and determine patient and disease characteristics associated with receiving no treatment. Methods: Data from the Surveillance Epidemiology and End Results (SEER) and Medicare linked data set were analyzed. We identified 949 stage IV RCC patients over age 65 years diagnosed between 2007 and 2011. Surgery was identified using Medicare Part A and B claims, and use of systemic therapy was identified from Part D claims in addition to Part A and B claims. Treatment approach, including no treatment, was modeled using multinomial logistic regression controlling for several patient and disease characteristics, allowing us to identify significant risk factors for no treatment. We also performed landmark analyses at 3 and 6 months to account for early death as a potential cause for no treatment. Results: Of the 949 patients with stage IV RCC, 26.2% received surgery and 34.1% received systemic therapy within 6 months of diagnosis. Of 324 patients who received systemic therapy, most received sunitinib (57.1%), temsirolimus (21.3%), or sorafenib (12.3%). Over half of patients (51.2%) had no evidence of receiving surgery or systemic therapy. Of the 618 patients who survived at least 3 months, 38.3% received no treatment within 3 months, and among the 447 patients who survived at least 6 months, 26.6% received no treatment within 6 months. Older patients and those with a higher Charlson Comorbidity Index had lower odds of being treated with surgery, systemic therapy, or both; married patients had higher odds of being treated. These results were largely sustained in 3- and 6-month landmark analyses. Conclusions: Many elderly patients with stage IV RCC did not receive surgery or systemic therapy despite surviving at least 6 months from diagnosis. Several factors appear to be associated with this phenomenon. Further investigation should determine reasons why physicians and/or patients are reluctant to use systemic therapy in patients.