tbuckley/cabot-search huggingface dataset:
Defining undertreatment and overtreatment in older patients with cancer: A scoping review of the literature.
Authors: Clark DuMontier, Kah Poh Loh, Paul A Bain, Rebecca A Silliman, Gregory A. Abel, Benjamin Djulbegovic, Jane A. Driver, William Dale
Journal: Journal of Clinical Oncology (2019)

e23020 Background: The terms “undertreatment” and “overtreatment” are often used to describe the management of older adults with cancer. The aim of this scoping review was to explore the explicit and implicit definitions associated with the use of these terms. Methods: We searched PubMed (NCBI), Embase (Elsevier), and CINAHL (EBSCO) for titles and abstracts that included the terms "undertreatment" or "overtreatment" (overtreat OR undertreat OR over treat OR under treat) of older adults with cancer. We included all types of articles, cancers, and treatments. We excluded studies that only included patients younger than 60 years old or studies without a defined focus on older adults. CD and KL independently reviewed a subset of included articles to assess for inter-reviewer reliability. Results: We identified 224 primary and secondary research articles that used the terms “undertreatment” (192), “overtreatment” (72), or both (45) regarding the management of older adults with cancer. Only 14 (6.3%) articles provided an explicit definition; for the remaining articles, we derived the implicit definitions from the terms’ surrounding context. There was substantial agreement between CD and KL in their interpretation of definitions of these terms (kappa 0.81). “Undertreatment” was commonly used to imply less than “standard” therapy (130 articles, 67.7%), or less than “standard” therapy that contributed to worse outcomes (62, 32.3%). Many articles did not account for the underrepresentation of older adults in trials leading to “standard” therapy, and 24 primary studies performed no or limited adjustment for geriatric domains (e.g., function) in their analyses that suggested worse survival in older adults treated with substandard therapy. “Overtreatment” was commonly used to imply cancer treatment in an older adult whose cancer would not have caused symptoms in his/her remaining lifetime (31, 43.1%), or aggressive treatment in whom the harms of treatment outweigh its benefits (41, 56.9%). Conclusions: Nearly all articles used the terms “undertreatment” and/or “overtreatment” without an explicit definition, and we identified variability and limitations in the meanings implied by these terms.
Points-to-consider on the return of results in epigenetic research
Authors: Stephanie O. M. Dyke, Katie M. Saulnier, Charles Dupras, Amy P. Webster, Karen Maschke, Mark Rothstein, Reiner Siebert, Jörn Walter, Stephan Beck, Tomi Pastinen, Yann Joly
Journal: Genome Medicine (2019)

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies, will be of growing importance. Members of the International Human Epigenome Consortium (IHEC) Bioethics Workgroup considered the potential ethical, legal, and social issues (ELSI) involved in returning epigenetic research results and incidental findings in order to produce a set of 'Points-to-consider' (P-t-C) for the epigenetics research community. These P-t-C draw on existing guidance on the return of genetic research results, while also integrating the IHEC Bioethics Workgroup's ELSI research on and discussion of the issues associated with epigenetic data as well as the experience of a return of results pilot study by the Personal Genome Project UK (PGP-UK). Major challenges include how to determine the clinical validity and actionability of epigenetic results, and considerations related to environmental exposures and epigenetic marks, including circumstances warranting the sharing of results with family members and third parties. Interdisciplinary collaboration and good public communication regarding epigenetic risk will be important to advance the return of results framework for epigenetic science.
Histological growth pattern as a potential marker of oligometastatic disease in patients operated for colorectal liver metastases.
Authors: Ali Bohlok, Robin Dezes, Valerio Lucidi, Fikri Bouazza, Desislava Germanova, Jean Luc Van Laethem, Alain Hendlisz, Pieter Demetter, Denis Larsimont, Vincent Donckier, Peter B. Vermeulen
Journal: Journal of Clinical Oncology (2019)

e15093 Background: The identification of oligometastatic profile in patients with resectable colorectal liver metastases (CRLM) would represent a major progress to improve selection for surgery. Currently, in the absence of biomarkers, the most reliable method to identify oligometastatic (OLM) and non-oligometastatic (NOLM) tumors relies on the oncological outcome after metastases-targeted surgery. The histological growth pattern (HGP) of CRLM, defined as desmoplastic (dHGP) or replacement (rHGP), has recently been shown to have prognostic value. We analyzed HGP in a series of patients operated for CRLM, characterized as OLM in case of prolonged postoperative recurrence-free survival (RFS) or NOLM in case of rapid postoperative relapse. Methods: In 357 patients operated for CRLM, we identified OLM patients as those with RFS≥5 years (N = 64), and NOLM patients as those with RFS &lt; 1 year (N = 77). Clinicopathologic and surgical parameters were analyzed. In each CRLM, HGP was assessed in archival H&amp;E stained tissue sections, according to international consensus guidelines. Proportions of rHGP and dHGP were determined in each metastasis. In case of multiple metastases, the mean HGP was calculated in each patient. Patients were categorized as pure (&gt; 95% rHGP or dHGP) or dominant phenotypes (&gt; 50% rHGP or dHGP, of the entire tumor-liver interface). Results: Preoperative characteristics of primary tumor and CRLM, and surgical data were identical in OLM and NOLM groups. In a first set of analyses, HGP was determined in 39 OLM and 52 NOLM patients. Pure dHGP was observed in 54.3% of OLM and 17.3% of NOLM patients (p = 0.001). Pure rHGP was similarly distributed among OLM and NOLM groups. Sixty-nine% of the OLM patients displayed a dHGP-dominant phenotype, whereas 57.7% of the NOLM patients presented with a rHGP-dominant phenotype (p = 0.02). Conclusions: These results confirm the potential prognostic value of HGP in patients operated for CRLM. dHGP, associated with angiogenesis and inflammation, could represent a (surrogate) marker for oligometastatic progression, whereas rHGP appears strongly associated with rapid postoperative relapse.
Prospective validation of a serum miRNA panel for early detection of gastric cancer.
Authors: Lihan Zhou, Jimmy So, Ritika Kapoor, Feng Zhu, Ruiyang Zou, Calvin J Koh, Sun Young Rha, Hyun Cheol Chung, Joanne Yoong, Celestial T Yap, Jaideepraj Rao, Chung-King Chia, Stephen Tsao, Asim Shabbir, Kong-Peng Lam, Mikael Hartman, Wei Peng Yong, Heng-Phon Too, Khay Guan Yeoh
Journal: Journal of Clinical Oncology (2019)

4065 Background: High mortality from gastric cancer is related to the late manifestation of its symptoms. A blood-based non-invasive biomarker with the ability to detect all stages of gastric cancer could significantly improve patient outcomes. We aimed to develop a novel serum miRNA assay for diagnosis of gastric cancer. Methods: We conducted a multi-center study involving 892 gastric cancer and control subjects from Singapore and Korea to develop a multi-target miRNA assay. Using RT-qPCR, we quantified the expressions of 578 serum miRNAs and constructed a 12-miR biomarker panel through multi-variant data analysis. The results were generated with the use of a logistic-regression algorithm, with the value of 40 or more considered to be positive. We subsequently validated this multi-miR assay in a large prospective cohort involving 4566 subjects and compared its performance with traditional markers such as H.Pylori and Pepsinogen. All participants underwent gastroscopy independent of the assay results. Results: Of the 4566 subjects that underwent gastroscopy and histopathological examination in the prospective cohort, 125 were diagnosed with gastric cancer. The 12-miR assay achieved an Area-Under-Curve (AUC) of 0.84, significantly outperforming (p-value &lt; 0.01) that of H.Pylori (AUC of 0.64) and Pepsinogen (AUC of 0.62). The sensitivity of the miRNA assay in detecting early (stage 0-2) and late (stage 3-4) stage gastric cancer was 82.6% (95% CI, 68.6% to 92.2%) and 88.4% (95% CI, 78.4% to 94.9%) respectively at a specificity of 70.0% (95% CI, 67.8% to 71.9%). In comparison, H.Pylori showed a sensitivity of 80.4% at a specificity of 44.3% whereas the Pepsinogen showed sensitivity of 9.52% at a specificity of 95.3%. Using the miRNA assay as a pre-screening tool could potentially reduce number of endoscopy needed by 62% in detecting one case of gastric cancer. Conclusions: Our serum miRNA panel is a useful, non-invasive screening test for gastric cancer. It is cost-effective as it can reduce unnecessary diagnostic endoscopy.
Palbociclib (P) in advanced acral lentiginous melanoma (ALM) with CDK4 pathway gene aberrations.
Authors: Lili Mao, Yabing Cao, Xinan Sheng, Xue Bai, Zhihong Chi, Chuanliang Cui, Xuan Wang, Bixia Tang, Bin Lian, Xieqiao Yan, Siming Li, Li Zhou, Xiaoting Wei, Caili Li, Zhong Hui Qi, Lu Si, Jun Guo
Journal: Journal of Clinical Oncology (2019)

9528 Background: Genetic Aberrations in the CDK4 Pathway occur in 82% of the ALM pts (Clin Cancer Res,2017, 23(22):6946-6957), which is predominant subtype in China. This study is to evaluate the anti-tumor activity of palbociclib, a CDK4/6 inhibitor, in advanced ALM pts with CDK pathway gene aberrations. Methods: In this phase II trial, patients with advanced ALM with CDK pathway gene aberrations (CDK4 or/and CCND1 amplification or/and CDKN2A loss) were treated with palbociclib 125 mg po, d1-21 of 28 day cycles. According to the study design, this trial will be closed if less than 2 patients yield objective response (OR) or stable disease (SD) at a preset 8-week landmark analysis. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Fifteen pts were enrolled from April to Nov 2018. All pts are included in the data analysis for demographics, safety, ORR, PFS and OS. Median age was 54 y (range, 25-74y), 6(40%) were males,5( 33.3%) had the primary sites of subungual, 4(26.7%) were of stage III. Median numbers of prior therapies: 2 (range: 0-5). Three (20.0%) pts achieved tumor shrinkage at 8 wks, including 1 confirmed partial responses (PR). Two pts had treatment ongoing at the data cutoff (January 2019). Median PFS was 2.5m (range, 1.5-8.8m), estimated mean OS was 8.1m (range, 6.7-9.4m). Four pts deceased due to disease progression. The most common treatment related adverse events (TRAEs) were leukopenia/neutropenia (87%; G3, 33%), thrombocytopenia (27%; G3, 7%), anemia (40%; G3, 7%). Conclusions: Monotherapy with palbociclib demonstrated preliminary activities in advanced melanoma pts with CDK pathway gene aberrations. Therefore, the study met its primary endpoint. Palbociclib had an acceptable safety profile as previous studies. Combination of CDK4/6 inhibitor with other agents is under consideration. Clinical trial information: NCT03454919.
Cardiometabolic risk factors and survival after cancer in the women’s health initiative.
Authors: Michael S. Simon, Theresa Hastert, Juhua Luo, Rowan T. Chlebowski, Julie J. Ruterbusch, Jennifer Lynn Beebe-Dimmer
Journal: Journal of Clinical Oncology (2019)

1556 Background: Features associated with metabolic syndrome have been connected to both risk and poorer outcomes for certain cancers. Methods: We used data on 12,107 women enrolled in the Women’s Health Initiative diagnosed prospectively with either local or regional stage cancer to evaluate the association between cardiometabolic risk factors identified at study entry, (elevated waist circumference (WC), hypertension, high cholesterol, and presence of type 2 diabetes), with death from either cancer, cardiovascular disease (CVD), or other causes. Cancer sites included those previously linked in the published literature to metabolic syndrome and cancer risk: breast, colorectal, endometrial, non-Hodgkin’s lymphoma, kidney, pancreatic, ovarian, stomach and liver. Multiple imputation methods were used to account for missing data (6.9%). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for other significant predictors of survival. Results: After a median follow-up of 10.0 years, there were 3,612 total deaths with 1,547 (43 %) due to cancer. Most participants (60.3%) had at least 2 cardiometabolic risk factors, and 5.8% had 3 or 4. Having 3-4 risk factors, was associated with significantly higher mortality due to cancer (HR: 1.39, 95% CI: 1.12, 1.71), CVD (HR: 2.62, 95% CI: 1.91, 3.59), and other causes (HR: 1.97, 95% CI: 1.57-2.47) compared with no risk factors. High WC was associated with higher mortality due to cancer and other causes, and history of diabetes, and hypertension were associated with higher mortality due to CVD, and other causes. Conclusions: Among women diagnosed with early or regional stage cancer, the presence of 3-4 cardiometabolic risk factors which is consistent with a diagnosis of metabolic syndrome, are significantly associated with death due to cancer, CVD, and other causes. Attention to primary prevention focused on weight control, physical activity and diet after cancer diagnosis and treatment, can have an important positive influence on survivorship after cancer.
EACH: A randomised phase II study evaluating the safety and anti-tumour activity of the combination of avelumab and cetuximab relative to avelumab monotherapy in recurrent/metastatic head and neck squamous cell cancer.
Authors: Martin David Forster, Joseph J. Sacco, Anthony Hee Kong, Graham Wheeler, Sharon Forsyth, Reshma Bhat, Kameka Blair, Helen Lowe, Victoria J Spanswick, Leah Ensell, John A. Hartley, Laura White
Journal: Journal of Clinical Oncology (2019)

TPS6091 Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) have low response rates to licensed second line therapies, including PD-1 inhibitors nivolumab and pembrolizumab, and represent an area of unmet clinical need. The chimeric IgG1 epithelial growth factor receptor (EGFR) monoclonal antibody cetuximab potentiates the activity of radiotherapy in locally advanced HNSCC and chemotherapy in R/M HNSCC and is also licensed with modest activity as a single agent. Cetuximab initiates Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), resulting in an anti-tumour immune response and the potential to augment the activity of PD-1/PD-L1 inhibition. EACH aims to examine the safety and efficacy of the potentially synergistic interaction between cetuximab and avelumab, a fully human IgG1 anti-PD-L1 monoclonal antibody in R/M HNSCC. Methods: EACH is a randomised phase II trial preceded by a safety run-in phase. Eligible patients have histologically or cytologically confirmed measurable recurrent or metastatic squamous cell carcinoma of any site in the safety run-in phase, and HNSCC in phase II, that is considered incurable by local therapies. The safety run-in has a single arm de-escalating design, aiming to establish the safety of cetuximab with avelumab and determine the optimal dose of cetuximab within this combination. The safety run-in has a dosing schedule of avelumab (10 mg/kg) + cetuximab (500 mg/m 2 ) intravenously every 2 weeks, with de-escalation of cetuximab to 400 mg/m 2 and 300 mg/m 2 if necessary. The safety run-in phase commenced recruitment in July 2018 and is ongoing. The phase II component will randomize 114 HNSCC patients between either avelumab + cetuximab at the dose determined by the safety run-in phase or avelumab (10 mg/kg) alone. Treatment will be in 4-week cycles for up to one year. The primary endpoint in the safety run-in phase is the occurrence of dose limiting toxicities, and in phase II is Disease Control Rate at 24 weeks, using iRECIST. Blood and fresh tissue will be collected for exploratory translational studies, which will focus on the identification of potential novel predictive biomarkers for response. Clinical trial information: NCT03494322.
Phase II clinical trial using anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) for HER2-negative (0-2+) metastatic breast cancer.
Authors: Lawrence G. Lum, Archana Thakur, Zaid S. Al-Kadhimi, Abhinav Deol, Michael S. Simon, Dana Schalk, Qin Liu, Lawrence E. Flaherty
Journal: Journal of Clinical Oncology (2019)

1080 Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD &gt; 4 months. For patients who completed 3 or 4 infusions (17-83 x 10 9 BATs), 8 of 31 patients had TTP &gt; 4 months. One patient completed 2 infusions (17 x 10 9 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.
Aspirin as adjuvant treatment for colorectal cancer: Rationale and progress of the Add-Aspirin trial.
Authors: Ruth E Langley, Richard H. Wilson, Fay Helen Cafferty, Nalinie Joharatnam, Janet Shirley Graham, Daniel Swinson, Timothy Iveson, Farhat Vanessa Nasim Din, Robert J.C. Steele, Verity Henson, Anne Crossley, C S. Pramesh, Axel Walther, Richard Adams, Lesley K. Dawson, Roshan Agarwal, Komel Khabra, Mahesh K B Parmar
Journal: Journal of Clinical Oncology (2019)

TPS3624 Background: There is now a body of evidence indicating a potential role for aspirin in colorectal cancer (CRC) prevention. In cardiovascular trials, effects on incidence of cancer metastases and short-term mortality suggest further possible roles in the treatment setting, supported by observational studies of aspirin use after cancer diagnosis. In the prevention setting, aspirin use has been limited by toxicity concerns, particularly of serious bleeding. In the adjuvant setting, benefits associated with reducing recurrence and subsequent treatment may outweigh these risks. The Add-Aspirin trial will investigate this, and will also consider possible mechanisms of action for aspirin effects, including the impact of PIK3CA mutations, where there are currently several theories and conflicting data. Methods: Add-Aspirin (ISRCTN74358648) is an international, phase III, double-blind, randomised, placebo-controlled trial recruiting patients who have undergone surgery and relevant adjuvant treatment for stage II or III CRC, as well as those with completely resected CRC liver metastases. Parallel randomised cohorts will address the question in breast, gastro-oesophageal and prostate cancer. Participants take aspirin 100mg daily for an 8-week run-in, to assess adherence and toxicity, and those suitable to proceed are randomised (1:1:1) to aspirin 100mg, aspirin 300mg or placebo daily for at least 5 years. A number of measures – including blood pressure control and PPI use where relevant - are in place to reduce bleeding risk. The primary outcome is disease-free survival (target hazard ratio = 0.8, n = 2600 in 5 years) with a long term analysis of survival planned across the tumour groups. Translational work includes a sub-study monitoring urinary thromboxane B2 as a marker of platelet activation in a subgroup (n = 500) to investigate mechanisms of action. Add-Aspirin opened in 2015 and recruited 1505 CRC patients during the first 3 years from 137 UK centres. 1282 (85%) proceeded to randomisation. A pre-planned feasibility analysis of run-in data (n = 2253 across all 4 tumour groups) provided reassuring data on safety, tolerability and adherence, and recruitment continues with centres in India and Republic of Ireland recently joining. Clinical trial information: 74358648.