tbuckley/cabot-search huggingface dataset:
Prognostic stromal and immune response expression patterns in early-stage colorectal cancer predicted by genes intrinsically expressed by tumor epithelial cells.
Authors: Pratyaksha Wirapati, Xueping Qu, Ling Huw, Emre Etlioglu, Sabine Tejpar, Omar Kabbarah
Journal: Journal of Clinical Oncology (2019)

3601 Background: High stromal content (CMS4) and immune infiltration (CMS1) are important features of the tumor micro-environment (TME) in early stage colorectal cancer, with poor and good RFS prognosis, respectively. However, it remains unclear how these TME features are influenced by intrinsic tumor epithelial expression profiles. We examined how the former can be predicted by the latter, and assessed their respective prognostic contributions. Methods: Eighteen public gene-expression datasets (n=3511) were used for discovery, and an adjuvant trial dataset (PETACC3 n=688) was used for validation. Whole-transcriptome hierarchical clustering was applied to identify intrinsic versus extrinsic co-expression modules, corroborated by single-cell profiling data. The epithelial gene subset were used to predict previously assigned CMS labels, producing new CRC classifier that we refer to as epithelial-CMS (eCMS). Results: Despite lacking stromal and immune response genes, eCMS predicted CMS with an accuracy of 82% [CI 78-85%] in the test dataset. Not only were the RFS prognostic values retained (eCMS1 vs non-eCMS1: HR=0.59 [CI 0.35–0.95, p=0.029], and eCMS4 vs non-e-CMS4: HR=1.82 [CI 1.38–2.41, p=0.0003]), but they were also significantly improved when compared to the original CMS classification (CMS1 vs non-CMS1: HR=0.76 [CI 0.49–1.16, p=0.2] and CMS4 vs non-CMS4: HR=1.43 [CI 1.07–1.91, p=0.017]. In a multivariable regression comparison, eCMS was superior to CMS (p=0.001 vs p=0.36). Each eCMS group was associated with specific combinations of up- and down-regulation of CRC-relevant pathways, such as CDX2, map-kinase, mucin secretion, DNA damage repair and cell proliferation. Conclusions: Stromal and immune infiltration patterns in the TME are strongly associated with tumor epithelial expression profiles, as captured by eCMS. This finding sheds new light on the interplay between intrinsic molecular features of CRCs and their TME, and illuminates new paths for potential combination therapies.
The clinical prognostic factors in advanced lung adenocarcinoma patients with different EGFR mutation subtype.
Authors: Yudong Wang, Jianzhu Yan, Jing Zuo, Zhisong Fan, Long Wang, Xiaoli Xu, Fengling Liu, Suju Wei, Da Jiang
Journal: Journal of Clinical Oncology (2019)

e20680 Background: The prognostic factors of advanced NSCLC patients with EGFR mutation subtypes remains controversial. This study aimed to investgate the association of clinical prognostic factors with EGFR-TKI efficacy in advanced lung adenocacinoma patients with different EGFR mutation subtypes. Methods: The clinical characteristics, treatment and survival data of advanced lung adenocarcinoma patients with EGFR sensitive mutations who were treated with Icotinib (Betta Pharmaceuticals, China) from January 2011 to December 2017 in our medical center were reviewed. The prognositic factors of patients between with EGFR exon 19 deletion (19-Del) and exon 21 Leu858Arg mutation (L858R) were retrospectively analyzed by using the Kaplan-Meier method, the chi-square test, and multivariate Cox hazards model. Results: A total of 187 patients were enrolled in the study, including 104 patients with EGFR19-Del and 83 patients with EGFR21-L858R. The results showed that no significant difference in mPFS between the two groups (19-Del vs. L858R: 15.0 months, 95% CI 17.2-32.8months vs. 13.0 months 95% CI 11.7-14.3 months, p = 0.347), while the mOS of patients with 19-Del (35months, 95% CI 28.6-41.4 months) was significantly better than that of patients with EGFR21-L858R (25 months, 95%CI 17.2-32.8 months, p = 0.020). For PFS, liver metastasis was an independent prognostic factor in EGFR19-DEL patients (HR 5.009, 95%CI 1.296-19.354, p = 0.019), while gender (HR 5.881, 95%CI 2.105-16.431, p = 0.001), smoking status (HR 6.972, 95%CI 2.851-17.049, p = 0.001), lymph node metastasis (HR 2.676, 95%CI 1.002-7.148, p = 0.050) were independent prognostic factors in patients with L858R. As for OS, age (HR 1.080, 95%CI 1.017-1.147, p = 0.012), brain metastases (HR 23.166, 95%CI 3.946-136.009, p = 0.001), liver metastases (HR 14.088, 95%CI 1.782-111.385, p = 0.012), renal or adrenal metastasis (HR 10.558, 95%CI 1.480-75.326, p = 0.019), TKI initial efficacy (HR 6.638, 95%CI 2.743-16.067, p = 0.001) were independent prognostic factors in patients with 19-del, however, the initial efficacy of TKI (HR 6.089, 95% CI 2.669-13.893, p = 0.001) was an independent prognostic factor in patients with L858R. Conclusions: The mOS of patients with EGFR 19-Del treated with Icotinib was significantly better than that of patients with L858R, while the mPFS of both were similar. Moreover, there are significant differences in prognostic factors of advanced lung adenocarcinoma patients between with 19-Del and L858R subtypes, which may be helpful for the clinical treatment strategy of EGFR-TKI.
A prospective validation cohort study of a prediction model on non-sentinel lymph node involvement in early breast cancer.
Authors: Xingfei Yu, Linyan Zhou, Chen Yang, Yang Yu, Daobao Chen, Jian Huang, Hongjian Yang, Chen Wang
Journal: Journal of Clinical Oncology (2019)

559 Background: Early breast cancer (cT 1-2 N 0 ) with one or two sentinel lymph node (SLN) involved may avoid axillary lymph node dissection (ALND) if follow by radiotherapy supported by Z0011 and AMAROS trials. However, only less than one-third of those patients have positive non-sentinel lymph node (nSLN) and can truly benefit from radiotherapy or ALND in those two trials. It is necessary to identify the risk of nSLN metastasis before local treatment decision. We previously developed a predictive model for nSLN involvement using circulating CK19 mRNA level combined with contrast-enhanced ultrasound (CEUS) score (ASCO2017 poster 239, NCT02992067) in a training set. To evaluate the predict effect of this model, we designed a further study using the model prospectively in a validation set (NCT03280134). Methods: We identified early breast cancer cases in Zhejiang Cancer Hospital from July 2017 to June 2018. The level of circulating CK19 mRNA tested by qRT-PCR and CEUS scores were collected before surgery in each case. Patients with 1~2 SLN involved were enrolled and continued for ALND. The estimated percentage of nSLN-involved were calculated both by our model formula and the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram. The predictive accuracy and false negative rates (FNR) were evaluated and the area under curve (AUC) was compared between two predictive models. Results: Totally, 235 patients diagnosed as early breast cancer with 1~2 SLN involved were enrolled and 35.36% of them were nSLN involved after ALND. The total accuracy and FNR by our model for nSLN-involved prediction was 94.89% and 6.02%, respectively. The AUC was 0.952 (95%CI, 0.922~0.982), significantly higher than that in MSKCC model 0.880 (95%CI, 0.833~0.927). Furthermore, only CK19 mRNA level (HR = 40.091, 95%CI, 13.663~117.635) and CEUS score (HR = 2.009, 95%CI 1.158~3.485) are significantly related to nSLN involvement in both univariate and multivariate analysis, adjusted by age, menopause statue, tumor size, histological grade, estrogen receptor, progesterone receptor and human epidermalgrowth factor receptor-2 expression. Conclusions: Our model using CK19 mRNA and CEUS score showed potential predictive value of nSLN before surgery in early breast cancer patients. Further validation in larger multicenter cohort is warranted before changing clinical practice.
Help end NHS fees for overseas doctors, campaigners tell medical institutions
Authors: Abi Rimmer
Journal: BMJ (2019)

NHS doctors from outside the European Union can be forced to pay £400 (€453; $507) a year to use the health service despite paying tax and national insurance, a campaign group has said.

EveryDoctor, a non-profit campaigning organisation run by doctors, has written to a range of professional organisations including medical royal colleges, the BMA, and the General Medical Council to ask them to join their campaign to end these fees for doctors.1 Opposition to the fees is already part of …
Video-based patient education on carcinoid syndrome: Positive knowledge and behavior shift for patients.
Authors: Anne Roc, Wendy Turell, Grace Goldstein, Edward M. Wolin
Journal: Journal of Clinical Oncology (2019)

e15697 Background: Carcinoid syndrome (CS) negatively affects quality of life (QOL), compromising physical, daily, and emotional functioning. Reticence to discuss symptoms, particularly debilitating diarrhea, perpetuates negative QOL, as does confusion of CS symptoms with other conditions and dietary challenges. To address these needs, we created video-based patient education activities with the Carcinoid Cancer Foundation (CCF) to empower patients with information and resources on CS facts, diagnosis, medical management, eating well and self-care. Methods: Two 1-hour patient education activities were broadcast live online and on-demand in 2017 and 2018 at CancerCoachLive.com , carcinoid.org, and Facebook Live for 6+ months. Features included panel discussions, slides, live polling and Q&amp;A, and video vignettes of real patient experiences. Knowledge-focused test questions were administered at 3 time points (pre-activity, immediate post-activity, and 8-week [follow-up] post). Behavioral and communication-focused questions were also asked at follow up. Data from these questions, live poll responses, and learner-submitted questions pre-event and during live Q&amp;A were analyzed to determine engagement, lessons learned and continuing patient needs. Results: In total, 1,893 patients took part in the activities, and attracted 39,821 Facebook engagements (“views”). Respondents (n = 116-119) reported: 57%, improved communication with their healthcare providers (HCPs) regarding CS; 44%, improved feeling of being “in-control” of health care decision; 31%, improved care behaviors for their health. Improved communication with their HCPs were specific to: their disease and symptoms, treatments, and diet. Changes in behaviors included: dietary changes, more “involved” in care decisions, asking questions of HCPs, and proactively learning about CS. Knowledge improvements were observed on 7 of 8 questions on CS facts, diet, and treatment (5 of 7 statistically significant; average effect size = 1.16; n averaged 382 pre and 96 post). Conclusions: Patient education on CS can yield immediate and sustained gains in knowledge and behavior, which may improve diagnosis, treatment, and improve patient QOL.
Objective response and prolonged stable disease in refractory adrenocortical carcinoma treated with cabozantinib: An international case series and protocols of phase II clinical trials.
Authors: Matthias Kroiss, Felix Megerle, Julia Wendler, Camilo Jimenez, Marcus Quinkler, Uwe Malzahn, Maria-Elisabeth Goebeler, Martin Fassnacht, Mouhammed Amir Habra
Journal: Journal of Clinical Oncology (2019)

e16118 Background: Median overall survival (OS) in advanced adrenocortical (ACC) is only 12-15 months. Previous clinical trials with oral multi-kinase inhibitors (MKI) were negative likely due to inadvertent drug interaction with mitotane. Objective: To investigate the potential of cabozantinib (CABO) monotherapy in ACC patients. Methods: Retrospective cohort study at three referral centers for ACC (U.S. and Germany). Results: Fifteen patients (13 female) with progressive disease after mitotane (14/15 patients) and three (median; range 0-8) further systemic therapies were treated with 60 mg (20-140) CABO. Mitotane had been discontinued in all patients, in 11/15 patients mitotane was stopped &gt; 270 days before CABO treatment or plasma concentration documented to be &lt; 2 mg/L. Adverse events (AE) of grade 1/2 and 3 were observed in 12 and 2 patients, respectively and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 4 and progressive disease in 8 patients. Progression-free survival (PFS) of &gt; 4 months (PFS4) was observed in 7 patients. Median PFS and OS was 12 and 41 weeks, respectively. Two single center phase II trials of CABO in advanced ACC in the U.S. (NCT03370718) and Germany (NCT03612232) will accrue 18 and 37 patients, respectively. Mitotane discontinuation and plasma concentrations &lt; 2 mg/L are key inclusion criteria. The primary endpoint is PFS4. Conclusions: Cabozantinib monotherapy appears to be safe and active as a monotherapy in advanced ACC. Two parallel phase II trials will investigate CABO prospectively while controlling for drug interaction with mitotane.
Evolutionary action score of TP53 analysis in pathologically high-risk HPV-negative head and neck cancer from a phase II clinical trial: NRG Oncology RTOG 0234.
Authors: Chieko Michikawa, Pedro A. Torres-Saavedra, Natalie L. Silver, Paul M. Harari, Merrill S. Kies, David Ira Rosenthal, Quynh-Thu Le, Richard C. Jordan, Dzifa Yawa Duose, Saradhi Mallampati, Sanchit Trivedi, Rajyalakshmi Luthra, Ignacio Ivan Wistuba, Olivier Lichtarge, Robert Leonard Foote, Upendra Parvathaneni, David N. Hayes, Curtis R. Pickering, Jeffrey Myers
Journal: Journal of Clinical Oncology (2019)

6010 Background: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations and speciation stratifies head and neck squamous cell carcinoma (HNSCC) patients bearing TP53 missense mutations as high-risk (high, EAp53≥75), associated with poor outcomes, or low-risk (low), with similar outcomes as TP53 wild-type (wt), and has been validated as a reliable prognostic marker. This study is designed to further validate prior findings that EAp53 is a prognostic marker for locally advanced HNSCC patients, and assess its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods: Eighty one resection specimens from patients treated surgically for stage III or IV human papillomavirus-negative (HPV(-)) HNSCC with high-risk pathologic features, who received either Arm 1) radiotherapy(RT)+cetuximab(CTX)+cisplatin or Arm 2) RT+CTX+docetaxel, as adjuvant treatment in a phase II randomized clinical trial (RTOG 0234) underwent TP53 targeted sequencing, and EAp53 scoring. The EAp53 scores were correlated with clinical outcomes. Due to limited sample sizes, patients were combined into 2 EAp53 groups: wt/low and high/other. Results: At median follow-up of 10 years, there was a significant interaction between treatment and EAp53 group for overall survival (OS) (p = 0.008), disease-free survival (DFS) (p = 0.05) and distant metastasis (DM) (p = 0.004). Within arm 2, high/other showed worse OS [HR 4.69 (1.52-14.50)], DFS [HR 2.69 (1.16-6.21)], and had higher DM [HR 11.71 (1.50-91.68)] than wt/low. Within arm 1, there was no significant difference by EAp53 in OS, DFS and DM. Within the wt/low group, arm 2 had better OS [HR 0.11 (0.03-0.36)], DFS [HR 0.24 (0.09-0.61)], and DM [HR 0.04 (0.01-0.31)] than arm 1 but this was not found in high/other. Conclusions: High/other EAp53 scores were associated with worse survival for patients in arm 2. Arm 2 is associated with better survival than arm 1 for patients with wt/low EAp53. This benefit appears to be largely driven by a reduction in DM. Further validation is required to determine whether EAp53 can be used for personalized post-operative treatment decisions in HPV(-) HNSCC.
Efficacy and safety of lanreotide 120 mg in the treatment of clinical symptoms associated with inoperable malignant intestinal obstruction (IMIO): Results from a phase II multicenter study.
Authors: Lionel Duck, Gauthier Demolin, Lionel A. D'Hondt, Catherine Dopchie, Koenraad Hendrickx, Beatrice Lannoye, Fabienne Bastin, Dominique Lossignol, Oussama Ibrahim Hamdan, Willem Lybaert, Vincent Vandenhaute, Torkia Grira, Vincent De Ruyter, Karen Paula Geboes
Journal: Journal of Clinical Oncology (2019)

4118 Background: Intestinal obstruction is a severe complication in patients (pts) with digestive or gynecological cancers. For inoperable pts, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms such as nausea, vomiting and pain. Methods: This was a single arm, prospective study (NCT02275338). Pts with IMIO received one deep subcutaneous injection of LAN 120mg at day 0 (D0). Evaluations were performed on D7, 14 and 28. The primary endpoint was the proportion of responders before or at D7. Response was defined as ≤2 vomiting episodes/day (for pts without NGT at baseline) or no vomiting recurrence (after NGT removal), during at least 3 consecutive days at any time point between the D0 and D7. In line with the literature, a proportion of 30% responders was used as reference for defining statistical significance. Responders at D28 were offered a second LAN 120 mg injection. Results: 52 pts with advanced GI or ovarian malignancies were included in 15 Belgian sites. 17 pts without NGT and 35 with NGT. 21 pts received a second dose of LAN. Median age was 68.0 (59.5; 76.0) years. On D7 the proportion of responders in the ITT population was 24/52 (46.2%), significantly greater than the reference proportion of 30% (one-sided binomial test: p = 0.006). Pts without NGT responded better (15/17, 88.2%) than pts with NGT (9/35, 25.7%). Pts without ascites responded better (57.7% vs 34.6%). Pts with NGT showed a steady trend for clinical improvement leading to sustainable responses of 45.7% on D14. Median time to response was 9 days for the overall population; 3 days for patients without NGT vs 14 days for patients with NGT (p &lt; 0.001). The most frequently reported AEs were GI disorders (in 34 pts). The most common events were diarrhoea and abdominal pain. Conclusions: Our study is the first using long acting LAN 120mg in patients with IMIO and suggests an effect in controlling clinical symptoms in pts with and without NGT at baseline. LAN 120 mg safety profile was similar to that reported for the other indications. Clinical trial information: NCT02275338.
Genomic alterations after EGFR blockade in patients with RAS wild-type metastatic colorectal cancer: Combined tissue and blood-based analysis from SCRUM-Japan GI-SCREEN and GOZILA.
Authors: Yoshiaki Nakamura, Riu Yamashita, Wataru Okamoto, Yukiya Narita, Yoshito Komatsu, Yoshinori Kagawa, Naoki Takahashi, Taito Esaki, Takeshi Kato, Yu Sunakawa, Tadamichi Denda, Tomohiro Nishina, Atsuo Takashima, Takaaki Kobayashi, Manabu Shiozawa, Eiji Oki, Taroh Satoh, Yuta Adachi, Justin Odegaard, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2019)

3528 Background: Anti-EGFR therapy (tx) in RAS wild-type (wt) metastatic colorectal cancer (mCRC) induces resistance through acquired genomic alterations. We aimed to define such alterations in Nationwide Cancer Genome Screening Project tissue and blood specimens, using next generation sequencing (NGS). Methods: Tumor specimens in patients (pts) with RAS wt mCRC were obtained from SCRUM-Japan GI-SCREEN (tissue) and GOZILA (circulating tumor DNA [ctDNA] from blood). Genomic alterations were compared using the Oncomine Comprehensive Assay (SCRUM) and Guardant360 (GOZILA), before anti-EGFR tx and after progression. Results: 373 total actionable alterations were identified in 71 pts with available matched tissue and ctDNA; 255 (68%) were acquired after anti-EGFR tx progression. Frequently seen acquired oncogenic alterations included KRAS mutations (27%) and amplifications (amps) of EGFR (41%), CDK6 (24%), BRAF (20%), MYC (17%), MET (14%), PIK3CA (11%), FGFR1 (11%), and KRAS (10%). Fusions of RET, ALK, and FGFR3 were newly acquired in 1-4%. Acquired alterations co-arose in multiple pathways, including the cell cycle, PI3K-AKT, and MAPK, although 29% of pts had none. Acquired mutations were less frequently clonal versus primary mutations (p&lt;0.0001), but clonal acquired mutations were seen in several oncogenes, including EGFR, KRAS, and PIK3CA. A subset of acquired KRAS, MET, CCND2, and EGFR amps had high (&gt;7) adjusted plasma copy numbers (ApCN). Acquired ERBB2 amps were identified in 3 pts (4%) with a median ApCN of 4, one of whom (ApCN=4.2), treated with dual HER2 blockade, progressed after 2 cycles. Conclusions: Our integrated analysis revealed that anti-EGFR tx of pts with RAS WT mCRC led to acquired genomic alterations in multiple oncogenic pathways. Although most acquired alterations were subclonal, a subset of oncogenic alterations had relatively high clonality and ApCN, suggesting potential targets for overcoming acquired resistance to anti-EGFR tx. Early progression in a pt with an ApCN of 4.2 suggests low-level/subclonal acquired alterations may not be effective treatment targets.
Reproductive health in cancer.
Authors: Erika K Radeke, Ju-Whei Lee, Ashlesha Patel, Howard A. Zaren, Michael Jordan Fisch, Lynne I. Wagner
Journal: Journal of Clinical Oncology (2019)

TPS6649 Background: Reproductive health needs of females ages 15 to 55 with cancer are poorly understood and overlooked, despite their importance to patients. Uncertainties regarding fertility and pregnancy are intricate and challenging for a patient and a cancer care team. The goals of reproductive health care may come in conflict with the primary objective of cancer care. However, with appropriate counseling and preventive measures, this conflict can be absolved to unify objectives. The primary objective of this trial is to evaluate the success of the implementation of reproductive health programming among reproductive aged females with cancer. To expand knowledge on this subject, the NCI approved the ECOG-ACRIN EROS trial: Engendering Reproductive Health within Cancer Survivorship, with two ancillary studies: Endocrine Disruption in Cancer Care and Sexuality in the first 5 years after Cancer Diagnosis. Methods: The primary study is a multicenter, cluster randomized control trial, with NCI Community Oncology Research Programs randomized to either the non-intervention arm (usual standard practice related to reproductive health) or the intervention arm (using study-specific training and tools). The accrual goal is 668 patients based on the expectation that the intervention can increase the adoption of appropriate reproductive health management within 3 months from the baseline visit from 50% to 80%, with the first 200 to consent to the endocrine disruption substudy. All patients participate in the sexuality part. Pre-menopausal female patients ages 15 to 55 with an initial diagnosis of any type of cancer who have not initiated treatment of any type are eligible to participate. Patients are asked to complete 2 questionnaires at 8 timepoints regarding their reproductive health interests. Providers are also asked to complete questionnaires regarding their healthcare practice in general as well as specific to patients enrolled in this study. The reproductive health management rate at each time point will be summarized, by arm, with frequency and percentage along with its 95% confidence interval. The comparison between the two arms, using a GEE model, can evaluate the intervention effect. EROS was activated in September 2015. To date, 264 patients have been enrolled to the main study and half of these patients are participating in the endocrine disruption correlative. Outcomes pertaining to management and treatment implementation and modification are the cornerstones of this study. It should inform organizations in cancer care to improve guidelines and to include a reproductive health assessment for all young females with cancer. Clinical trial information: NCT01806129.