tbuckley/cabot-search huggingface dataset:
Oesophageal cancer: Commonly familial, possibly heritable.
Authors: Niamh Peters, Sinead King, Emily O'Donovan, David James Gallagher, John V Reynolds
Journal: Journal of Clinical Oncology (2017)

23 Background: Oesophageal cancer (OC) accounts for 400 deaths in Ireland per year. Prognosis remains poor, and improved prevention is needed. Familial clustering has been described however, The Nordic Twin Study of Cancer does not support a strong hereditability. We investigated familial OC over a decade in Ireland. Methods: The independent records of two national referral services were reviewed: an oesophageal surgery database and a hereditary cancer genetics database. Demographic Factors including family history of OC were recorded from the surgical database. Families containing a single OC diagnosis were identified in the genetics database. Age at diagnosis and additional cancer diagnoses in the family were recorded. Results: 1238 patients with OC were seen at St. James’s Hospital from 2005 to 2015. Demographic characteristics are shown in Table. 641 patients (51%) had a family history of malignancy. Seventy eight (6.3%) reported a family history of OC, 6 (7.6%) of whom had two or more first degree relatives with OC and 10 (13%) had both a first degree and second degree relative with OC. More male relatives were diagnosed with OC than female (59% vs 41%).The majority (24%) with a family history were diagnosed at Stage III, the majority (29%) without a family history were diagnosed at Stage II. 1840 pedigrees from the genetic database were reviewed. No pedigree contained a Proband with OC.4.5%(n = 84) included at least one family member with OC. The median age at diagnosis was 64. Breast, colorectal and gastric were the most commonly associated cancers with median ages of 50,59 and 64 respectively. Conclusions: More than half of patients presenting with OC report a family history of cancer, with likely hereditary and environmental components. OC patients are rarely referred for genetic assessment, possibly due to treatment related morbidity and poor clinical outcome. [Table: see text]
Implications of HER family inhibition in targeted therapy of ovarian cancer
Authors: S. L. Bull, J. O. Schorge, M. J. Peyton, L. Xiang, D. S. Miller, J. D. Minna, J. S. Lea
Journal: Journal of Clinical Oncology (2006)

13120 Background: The human epidermal receptor (HER) family couples binding of extracellular ligands to intracellular tyrosine kinase (TK) signal transduction pathways, contributing to cellular proliferation. Overexpression of HER family members has been associated with poor prognosis in ovarian cancer. There is growing evidence to support that none of the individual HER members can be considered as the stand-alone target in ovarian cancer and that cooperation between them influences therapeutic response. To evaluate this receptor cooperation in ovarian cancer our goal was to determine HER family expression and to quantify inhibition of HER1 alone compared to inhibition of HER1/HER2 combined. Methods: HER1, HER2, HER3 and HER4 expression was determined by Western blot in 9 ovarian cancer cell lines. Ovarian cancer cell proliferation was determined after inhibition of HER1 using the monoclonal antibody cetuximab, the TK inhibitor gefitinib, or combination of the two. To quantify the combined inhibition of HER1/HER2, 3 cell lines were selected with variable HER1 and HER2 expression. Cell proliferation was then determined in these 3 cell lines after treatment with cetuximab combined with the monoclonal HER2 antibody, trastuzumab. IC50 values were calculated for all treatment arms and compared. A lung cancer cell line (HCC827), with a HER1 TK mutation and sensitivity to gefitinib and cetuximab, was used as a positive control. Results: HER1 was overexpressed in 3/9 ovarian cancer cell lines, HER2 in 1/9, HER3 in 2/9, and HER4 in 4/9. Minimal to no growth inhibition was seen in the 9 cell lines after blocking HER1 with cetuximab, gefitinib, or the combination of both. In the 3 cell lines selected for HER1 and HER2 expression, there was no growth inhibition achieved despite combining cetuximab with trastuzumab. However, this treatment combination increased resistance in 1 of the 3 cell lines (HCC60), noted to overexpress HER1, 2, and 4. Conclusions: Ovarian cancer has variable HER family expression. No correlation was found between HER1 and HER2 overexpression and response to their targeted inhibition. Our findings support the concept the entire HER family plays a role in ovarian cancer growth and suggest an equilibrium shift of HER heterodimerization may play an important role in maintaining cell signaling. No significant financial relationships to disclose.
Clinicopathologic correlation and effect of Oncotype DX Recurrence Score on treatment decisions at a community-based academic cancer center.
Authors: Pawan Kumar Karanam, Sameer Tolay, Chad Pedersen, Mohammed Al-Hamadani, Angela Smith, Leah L. Dietrich
Journal: Journal of Clinical Oncology (2015)

e11511 Background: Oncotype DX, a 21 gene recurrence score (RS) is used to predict the likelihood of benefit from systemic chemotherapy in women with node-negative, estrogen receptor (ER) positive breast cancer. NCCN guidelines recommend adjuvant endocrine therapy for RS < 18 (low) and addition of chemo for RS ≥ 31 (high). Role of chemo in intermediate RS (18-30) patients remains unclear. Methods: We retrospectively reviewed records of patients who had Oncotype DX test from 2004 through 2012. We assessed the correlation of RS to clinicopathologic variables and its effect on treatment decisions. Results: Of the 126 patients reviewed, 69 had low RS, 47 an intermediate RS and 10 had high RS. Univariate analysis (Table 1) showed no significant differences with relation to age, tumor size, lymph node status or NPI score. High and Intermediate RS groups had more grade 3 tumors than Low RS (P = .004). Low RS had higher percentage of ER+/PR+ than ER+/PR- tumors (P = .023). Intermediate and High RS were more likely to receive chemo (P < .0001). However, on multivariate analysis, only ER+/PR -status [OR 0.21 (95%CI 0.06-0.72)] and chemo [OR 9.58 (3.77-24.36)] significantly correlated with RS. Chemo decisions in Intermediate RS were based more often on clinical trial randomizations. Conclusions: There was significant correlation between grade, ER/PR status, chemo administration, and Recurrence Score. Decisons about chemo among intermediate RS patients were based on the clinical trial randomizations rather than clinicopathologic factors. Follow up was too short to elucidate any survival benefit. Recurrence Score Group p-value Low RS Int RS High RS Low vs Int Low vs Int vs High Total n (%) 69(100) 47(100) 10(100) Age (years) 0.334 0.202 ≤50 25(36.2) 13(27.7) 1(10) >50 44(63.8) 34(72.3) 9(90) Tumor size 0.710 0.820 ≤1 cm 14(20.3) 8(17) 1(10) 1.1-2 cm 36(52.2) 29(61.7) 6(60) 2.1-3 cm 15(21.7) 9(19.2) 3(30) >3 cm 4(5.8) 1(2.1) 0(0) Histologic grade 0.109 0.004 1 34(49.3) 19(40.4) 2(20) 2 33(47.8) 22(46.8) 4(40) 3 2(2.9) 6(12.8) 4(40) ER/PR status 0.189 0.023 ER+/PR+ 66(95.6) 42(89.4) 7(70) ER+/PR- 3(4.4) 5(10.6) 3(30) Chemotherapy 0.003 <0.0001 Yes 5(7.2) 13(27.7) 8(80) No 64(92.8) 34(72.3) 2(20)
Eligibility criteria and endpoints in metastatic renal cell carcinoma trials.
Authors: Sarah Wong, David I. Quinn, Georg A. Bjarnason, Scott A. North, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2017)

465 Background: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In Sept 2015, DATECAN published recommendations for time-to-event endpoints in mRCC trials. The success of their efforts to harmonize endpoints has not yet been assessed. Methods: We assessed eligibility criteria and endpoints from 18 Phase III mRCC trials starting from 2003 onwards. We also assessed 4 Phase III trials submitted after Sept. 2015 for compliance with DATECAN recommendations. Results: Among the 18 trials, consistent criteria were: absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, and bilirubin ≤1.5xULN. However, the following differed in requirements and measures used: see table.The 4 newer trials did not entirely follow DATECAN’s recommendations. Although their primary endpoint is progression free survival (PFS) as recommended, 3/4 trials do not define PFS, and the one that does includes death from any cause instead of DATECAN’s “death from kidney cancer.” Conclusions: Key eligibility criteria were somewhat inconsistent across phase III mRCC trials, and newer trials’ endpoints did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and enforcement of recommendations is needed to harmonize trial design and improve comparability.[Table: see text]
High prevalence of alcohol use disorders in patients with inflammatory skin diseases
Authors: K. Al‐Jefri, D. Newbury‐Birch, C.R. Muirhead, E. Gilvarry, V. Araújo‐Soares, N.J. Reynolds, E. Kaner, P.J. Hampton
Journal: British Journal of Dermatology (2017)

There is a known association between psoriasis and heavy alcohol consumption. The association between heavy alcohol consumption and other inflammatory skin diseases remains to be defined.To examine the prevalence of heavy drinking using the Alcohol Use Disorders Identification Test (AUDIT) in patients with inflammatory skin disease.We conducted an observational cross-sectional study in a single hospital outpatient department. We recruited 609 patients with either psoriasis, eczema, cutaneous lupus or other inflammatory disorders, and a reference population with skin lesions. Primary outcome was the proportion of patients in each group with an alcohol use disorder (AUD).The observed prevalence of AUD was 30·6% in patients with psoriasis, 33·3% in those with eczema, 12·3% in those with cutaneous lupus, 21·8% in those with other inflammatory disease and 14·3% in those with non-inflammatory disease. Odds ratios (OR) for AUD in patients in the inflammatory groups compared with those in the noninflammatory groups, adjusted for age and sex, were as follows: psoriasis 1·65 [95% confidence interval (CI) 0·86-3·17], eczema 2·00 (95% CI 1·03-3·85), lupus 1·03 (95% CI 0·39-2·71), other inflammatory disease 1·32 (95% CI 0·68-2·56). ORs were reduced if also adjusted for Dermatology Life Quality Index (DLQI). The prevalence of DLQI ≥ 11 was 31·1% for psoriasis, 43·7% for eczema, 17·5% for cutaneous lupus, 17·2% for other inflammatory disease and 2·8% for noninflammatory disease.Patients with eczema attending a hospital clinic have been shown to have high levels of AUD of a similar level to patients with psoriasis and higher than patients with noninflammatory skin diseases.
Multicenter phase II study using increasing dose of irinotecan (CPT11) combined with simplified LV5FU regimen in metastatic colorectal cancer (MCRC)
Authors: M. Ychou, S. Gourgou, F. Desseigne, C. Debrigode, L. Mineur, P. Chalbos, J. Duffour
Journal: Journal of Clinical Oncology (2004)

3601 Background: The combination of CPT11 at 180 mg/m2 combined with LV5FU2 regimen is one of the standard therapies in first line MCRC. We previously showed (Ychou et al., Cancer Chemother Pharmacol. 2002.) a safe dose effect activity of CPT11 in monotherapy increasing the dose from 350 to 500 mg/m2 every 3 weeks. This phase II study aims to evaluate the increasing dose of CPT11 combined with the simplified LV5FU regimen. Methods: First line MCRC patients received every two weeks simplified LV5FU regimen combined with CPT11 at 180 mg/m2 at C1, increased to 220 mg/m2 at C2 and to 260 mg/m2 at C3 and subsequent cycles in the absence of NCI-CTC gr3–4 toxicities other than alopecia or neutropenia. Results: 55 patients (pts) were included in 4 centers between 02/2001 and 06/2003. Data were available for 45 pts and 10 pts are ongoing. Patient characteristics : M/F : 25/20, median age: 60 y (42–74), PS (0/1/2) : 29/15/1, median number of metastatic sites : 2 (1–4). Safety data were available for 432 cycles (cy) : Neutropenia gr3–4 58 % pts (11 % cy) and G-CSF support in 86 % pts (26% cy), febrile neutropenia 4.2 % pts (0.4 % cy); diarrhea gr3–4 22 % pts (3 % cy). Median Relative Dose Intensity was for CPT-11 : 0.93 [0.72–1.00] and 5-FU: 0.92 [0.78–1.00]. 82 % of patients received 260 mg/m2 of CPT-11 at least for one cycle. 42 patients were evaluable for response reviewed by independent panel (one toxic death, one severe toxicity and one early withdrawal). We observed one CR and 20 PR, ORR: 50%, 95%CI[34–66] and disease control 81%, 95%CI[66–91]. Conclusions: We confirm the feasibility to increase the dose of CPT11 from 180 to 260 mg/m2 in the FOLFIRI regimen in more than 80% of pts, with a high disease control rate in non selected MCRC. This high dose CPT11 schedule needs to be compared to standard regimen. No significant financial relationships to disclose.
Tumor sidedness, adjuvant chemotherapy (AC), and other factors affecting survival in patients with stage II colon cancer (CC-II).
Authors: Shiva Kumar Reddy Mukkamalla, Donny V. Huynh, Ponnandai Sadasivan Somasundar, Ritesh Rathore
Journal: Journal of Clinical Oncology (2017)

768 Background: The role of AC in CC-II is not well defined due to lack of conclusive randomized trial data. This updated analysis using National Cancer Database (NCDB) addresses the overall survival (OS) benefit from AC in CC-II using more refined and case appropriate population cohort. Methods: NCDB was queried for patients diagnosed with CC-II from 2004-2008 with survival information through 2013. Only those patients with pathologically confirmed CC diagnosis were included. Patients undergoing any surgical procedure less than a partial colectomy were excluded. Pearson Chi-square test, Kaplan Meier survival curves and Cox proportional hazards model were used for statistical analysis. Results: A cohort of 36,630 patients was identified for analysis. Elderly patients received less frequent AC (p &lt; 0.0001) and AC was associated with an improved 5-year OS with no difference noted in outcomes from single or multi-agent regimens. AC was an independent predictor of OS regardless of age, gender, race, comorbidity index, insurance status, income level, year of diagnosis, tumor sidedness, tumor grade, adequacy of lymph node evaluation, pathologic tumor (pT) status, colectomy type, margin involvement or academic level of treating institution. In multivariate analysis, right-sided cancers had better survival outcomes compared to left-sided cancers (HR 0.91; p &lt; 0.0001). Conclusions: This study validates previous findings of improved OS from AC in CC-II while addressing some of the shortcomings of prior retrospective studies. Only patients with CC-II without any other primary cancer diagnoses were included. To our knowledge this is the most uptodate analysis of AC in CC-II which includes cases diagnosed up to 2008. Our study found similar improvement in 5-year OS irrespective of chemotherapy regimen. Interestingly, improved OS was seen in right sided tumors compared to left sided tumors, in contrary to that seen with metastatic colon cancer (Venook et al). [Table: see text]
The impact of multifocal perineural invasion on biochemical recurrence and timing of adjuvant androgen-deprivation therapy in high-risk prostate cancer following radical prostatectomy.
Authors: Pengfei Shen, Guangxi Sun, Hao Zeng, Xingming Zhang
Journal: Journal of Clinical Oncology (2017)

e595 Background: Perineural invasion (PNI) is a distinct pathologic entity and a recognized source of tumor spread. However, the role of PNI in high-risk prostate cancer (PCa) has not been explored. We investigated the impact of the severity of PNI on biochemical recurrence (BCR) and optimal timing of adjuvant androgen deprivation therapy (ADT) post radical prostatectomy (RP). Methods: Of 265 prostatectomies, median follow-up 45 months, were assessed for the presence of PNI and its intensity (unifocal PNI and multifocal PNI) in RP specimen. Kaplan-Merier curves were used to estimate BCR probabilities. Cox proportional hazard models were used to address predictors of BCR. Harrell’s C-index was conducted to further validate prognostic value of multi-PNI. Results: A total of 123 patients (46.4%) were PNI positive, among which, 91 (74%) and 32 (26%) had unifocal PNI (uni-PNI) and multifocal PNI (multi-PNI), respectively. Other than uni-PNI, the presence of multi-PNI was strongly associated with increasing incidence of BCR (HR = 3.87, 95% CI: 1.66-9.01, p = 0.002). Patients with uni-PNI seemed to have a similar BCR rate to those without PNI after adjuvant ADT. For men with multi-PNI, immediate ADT obviously appeared to be superior to delayed ADT in decreasing biochemical failure. Conclusions: Multi-PNI detected in high-risk RP specimens could be a prognosticator for early biochemical relapse post-surgery. Our findings suggest that patients with multi-PNI appear appropriate to choose adjuvant therapy as soon as possible after surgery.
Ablative therapy to induce local and systemic immune changes in patients with metastatic renal cell carcinoma.
Authors: Matthew T. Campbell, Surena F. Matin, Rebecca Slack, Jing Jing Sun, Derek Ng Tang, Hong Chen, Jorge M Blando, Li Zhang, Priya Rao, Padmanee Sharma
Journal: Journal of Clinical Oncology (2017)

505 Background: Ablative therapy including cryoablation or radiofrequency ablation is a therapeutic option for small renal cell carcinomas (RCC) and provides effective palliation for symptomatic metastatic lesions, with reports of associated abscopal phenomenon in small numbers of patients. Pre-clinical animal modeling has suggested potential synergy with the use of ablative therapy and immune checkpoint blockade with ipilimumab. Methods: We performed retrospective analysis of 17 patients who underwent an ablative procedure followed later by nephrectomy. These samples were analyzed by IHC and gene expression studies. We also prospectively evaluated pre and post treatment blood samples from a different cohort of 13 patients. These samples were evaluated for immune cell subsets and cytokine profiles. Results: IHC studies revealed an increased frequency of PD-1 + immune cells in post-ablative tumor samples as compared to control samples. Gene expression studies also revealed higher expression of immune gene signatures as compared to control samples. Blood samples detected changes in regulatory T cell subsets and interleukin-6 cytokine levels in the short term, which normalized by 1 month post-ablation, suggested an active downregulation of the initial immune response. Based on these data, we initiated a clinical pilot study to treat patients with anti-CTLA-4 (tremelimumab) with or without cryoablation in patients with metastatic RCC. The primary endpoint of the trial will be safety. Secondary endpoints include objective response rate, progression free survival, and immune monitoring. A total of 30 patients, 15 in each arm, will be accrued. Initial data from the clinical trial will be presented. Conclusions: Ablative therapy causes immune changes that can be detected both at the tissue and systemic level. We hope to capitalize on these changes by combining immune checkpoint blockade and ablation in an ongoing prospective clinical trial.
First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC).
Authors: Diletta Bianchini, Aurelius Gabriel Omlin, Carmel Jo Pezaro, Deborah Mukherji, David Lorente Estelles, Andrea Zivi, Roberta Ferraldeschi, Mateus Crespo, Aby Buchbinder, Gerhardt Attard, Howard I. Scher, Johann Sebastian De Bono, Daniel Costin Danila
Journal: Journal of Clinical Oncology (2013)

5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]