tbuckley/cabot-search huggingface dataset:
An optimized homologous recombination deficiency (HRD) algorithm ASGAD for predicting PARP inhibitor response in ovarian cancer patient.
Authors: Yang Jiao, Dong Ju Chen, Bo Liu, Pei Meng, Lei Sun, Yu Hang Cai, Tai Ping Shi
Journal: Journal of Clinical Oncology (2019)

e17077 Background: Homologous recombination deficiency (HRD) results less efficient and error-prone DNA double strand break (DSB) repair, thus causes genomic in stability and impacts on cancer susceptibility to Poly‐(ADP‐Ribose)‐Polymerase (PARP) inhibitors. Evaluating HRD level in gynecologic cancer patients is becoming far more important and influential, so far, there is no standard method to be used in clinical. Methods: Here, we optimized an HRD score algorithm, termed as ASGAD, which combines three classic factors, including loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI), large-scale state transition score (LST), along with tumor ploidy to predict PARP inhibitor response in ovarian cancer patient. Results: Traditional global optimization strategy for purity and ploidy calculation is usually sensitive to initial values and may lead to incorrect convergences. Here we designed a two-step optimization manner to avoid this problem. Firstly, a density-based clustering algorithm was applied on BAF and CN, and the genotype was assigned to the most legible cluster. Then the rectified BAF and CN was calculated and used to find the maximum likelihood genotype of each segment. The segmentation processed was also improved by applying a series of statistical test to merge similar adjacent segments. The accuracy of allele-specific copy-number detection is significantly improved vie this algorithm, deriving stable and reliable HRD scores especially on aneuploid and hyperploid tumor cases. In this study, we assessed ASGAD algorithm in almost 150 ovarian cancer patient samples, who had treated with platinum effectively. BRCA1/2 deficient was defined as either one deleterious mutation in BRCA1/2, with LOH in the wild type copy or two deleterious mutations in the same gene. The results showed that the 19/23 BRCA1/2 deficient samples are also HRD-high, giving the sensitivity of 82.61%. Besides, we identify 58 HRD-high samples with intact BRCA1/2, who might benefit from PARP inhibitors, by the ASGAD algorithm. Interestingly, we analyzed 4 HRD-high samples by using whole-exome sequencing (WES), and found other HR genes mutations in these samples, including PARP4, FANCM, MSH2, MSH6, ATR, POLD1. Conclusions: The expanded use of PARP inhibitors in HRD tumors using the ASGAD algorithm requires more validation.
Anticancer activity in patients with advanced ovarian and biliary tract cancers treated with NUC-1031 and a platinum agent.
Authors: Sarah Patricia Blagden, Jennifer Bré, Peter Mullen, Chathunissa Gnanaranjan, Essam Ahmed Ghazaly, Mairead Geraldine McNamara, Juan W. Valle
Journal: Journal of Clinical Oncology (2019)

3030 Background: The inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. This, in combination with platinum-induced DNA-damage, is key to promoting anti-cancer activity in a variety of tumors, including ovarian, biliary tract, lung, breast and bladder. NUC-1031, a phosphoramidate transformation of gemcitabine is designed to overcome resistance mechanisms that limit the efficacy of this nucleoside analog. NUC-1031 has shown broad clinical activity across multiple solid tumors as both a single agent and in combination with platinum agents. We show potential synergism between NUC-1031 and a platinum agent in advanced ovarian (OC) and biliary tract (BTC) cancers. Methods: PRO-002 was a phase Ib study; 25 patients (pts) with recurrent OC who had exhausted all other therapy options received NUC-1031 + carboplatin. 17 pts were considered platinum resistant (10) or platinum refractory (7). ABC-08 is a phase Ib study, 14 pts with advanced BTC treated in the first-line setting with NUC-1031 + cisplatin. Results: In PRO-002, strong efficacy signals were observed in non-platinum-responsive patients. Of the 17 response-evaluable platinum-resistant or refractory pts, 5 partial responses (PRs) and 11 stable diseases (SDs) were achieved, resulting in an ORR of 29% and a DCR of 94%. NUC-1031 + carboplatin was well-tolerated with no unexpected AEs; DLTs were myelosuppression and fatigue. Encouraging response rates were also observed in ABC-08 compared to historical standard of care (ABC-02). One CR (7%), 6 PRs (43%) and 1 SD (7%) were observed, resulting in an ORR of 50%. NUC-1031 + cisplatin was well-tolerated, with no unexpected AEs or DLTs. Complementary in vitro evidence suggests that the beneficial interaction occurs whereby platinum treatment sensitizes cells to NUC-1031. Conclusions: Increasing evidence suggests that NUC-1031 in combination with a platinum agent may have synergistic properties, leading to enhanced anti-cancer activity. In both OC and BTC, durable tumor shrinkage was observed. This was particularly encouraging in a platinum resistant/refractory OC population. Future studies utilizing both NUC-1031 plus a platinum agent will further elucidate the potential of this therapeutic combination.
Social values and cancer funding priorities: Empirical evidence for cancer policy.
Authors: Avram Denburg
Journal: Journal of Clinical Oncology (2019)

e18352 Background: Achieving value in health care requires knowledge of public values and priorities. To better understand public values for resource allocation on cancer care, we conducted a population-based stated preference survey with a nested randomized controlled moral reasoning intervention. Our objective was to generate evidence to inform economic evaluation and policymaking on cancer care priority-setting and payment reform in developed health systems. Methods: We conducted a population-based stated preference survey of societal views on the prioritization of health resources between children and adults, administered to a nationally representative sample (n = 1,556) of Canadian adults. Allocative preferences were elicited across a range of hypothetical treatment scenarios and scored on a visual analogue scale. Participants were randomized to a moral reasoning intervention (n = 773) or a control group (n = 783). Those randomized to the intervention group were exposed to a moral reasoning exercise prior to each choice task. The exercise presented participants with a list of ethical principles relevant to health care resource allocation and tasked them to select the top principles guiding their choice. The main outcomes were the difference in mean preference scores by group, scenario, and participant demographics. Results: Multiple regression analyses demonstrated a consistent aggregate preference by participants to allocate scarce health system resources to children. Exposure to the moral reasoning exercise weakened but did not eliminate allocative preference for children, as compared to control (difference 0.72, SE 0.14, p &lt; 0.0001). Younger respondent age (-0.71, SE 0.14, p &lt; 0.0001) and parenthood (-0.40, SE 0.11, p &lt; 0.0002) were associated with greater preference for children. The top three principles guiding participants’ allocative decisions were treat equally (54.3-63.9%), relieve suffering (39.6-66.1%), and rescue those at risk of dying (37-40.8%). Conclusions: Our results demonstrate a significant preference by participants to allocate health care resources to children, but one attenuated by exposure to a range of ethical principles to guide decision-making. It also evinced strong support for humanitarian principles to guide health care resource allocation. Definitions of value in health care based primarily on the magnitude of clinical benefit and cost-effectiveness may exclude moral considerations that the public values.
Efficacy and prognostic factors of systemic therapies for metastatic adenoid cystic carcinoma.
Authors: Cyril Roussel-Simonin, Francois Riet, Geneviève Hervé, Chloe Bertolus, Philippe Maingon, Jean-Philippe Spano, Aurelien Gobert
Journal: Journal of Clinical Oncology (2019)

e17587 Background: Metastatic cystic adenoid carcinoma (mCCA) is a rare entity of cancer associated with a poor prognostic. Only limited efficacy data based on case-reports and retrospective analysis are available and there is currently no standard for treatment. The aim of our study is to evaluate the efficacy and prognostic factors in recently diagnosed mCCA. Methods: We retrospectively collected demographic and efficacy data from patients treated for mCCA between September 2012 and January 2019 at the Pitié-Salpêtrière Hospital. Univariate analysis of prognostic factors was performed using the Cox model. Survival was estimated using the Kaplan-Meier method and long rank analysis. Results: Fifteen patients were included: 8 women and 7 men with a median age at diagnosis of 57 years (range 32-71). The primitive sites were accessory salivary glands in 9 patients, major salivary glands in 3 patients, lung, cervix and lacrimal glands in each of the 3 other patients. Histology of the primary tumor was available for 7 patients with 4 cribriform and 3 solid types respectively, an intermediate grade in 5 patients, a high in 2 patients, and a median of Ki67 at 35% (range 8.5-40%). Thirteen patients received a first line therapy, including 10 with platinum – LV5FU2, 2 with cisplatine anthracycline and cyclophosphamide association (CAP) and 1 with sunitinib. A stable disease was found in 7 patients (54%), a partial response in 4 patients (31%) and 2 patients had progression at first evaluation. The median 1 st line PFS was 5.8 months (range 2.0-12.7). With a median time of follow-up at 12.9 months (range 4.0-61.3), 5 patients (33%) were dead, 8 patients (53%) were still receiving systemic therapy and 4 patients (27%) received 4 lines. A patient with partial response after 6 CAP cycles,received a liposomal anthracycline combined with carboplatin for 8 cycles with a response time of 12.7 months. In univariate analysis, no statistically significant prognostic factors were found. Conclusions: In our retrospective study, 1 st line of systemic therapy is efficient in mACC with a 31% response rate. Furthermore, here we report the first patient treated with liposomal anthracycline associated with duration of response for 12.7 months. These preliminary results should be confirmed before becoming a new option for treatment in mACC.
Geographic and demographic disparities in neuroendocrine tumors (NETs): A population-based study.
Authors: Rohit Gosain, Somedeb Ball, Navpreet Kaur Rana, Adrienne Groman, Elizabeth Gage-Bouchard, Arvind Dasari, Sarbajit Mukherjee
Journal: Journal of Clinical Oncology (2019)

e15694 Background: The incidence and prevalence of Neuroendocrine Tumors (NETs) are rapidly rising. There are very few studies investigating the role of sociodemographic factors on NETs. The aim of our study was to identify the disparities in the NET population. Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database, and studied NETs patient population from 1973 to 2015. Univariate and multivariate analyses were performed to evaluate patients’ disease-specific survival (DSS) and overall survival (OS). Different socio-demographic factors including location of residence: urban area (UA) versus rural area (RA), gender, race, insurance status and marital status were included in the analysis. Results: A total of 53,522[ RA: N = 9,053; UA: N = 43,981] patients were included in the analysis. The incidence of NETs was found to be rising in both RA and UA but more rapidly in UA. RA was associated with more advanced stage at presentation in comparison to UA (p &lt; 0.001). Cause-specific mortality remained higher in RA than UA throughout the study period. In the multivariate model, RA had a trend towards poorer DSS (HR:1.03, p = 0.399) and a worse OS compared to UA (HR = 1.06, p = 0.0003). Blacks had a poorer OS compared to non-Hispanic Whites (HR = 1.16, p &lt; 0.001). Multivariate analysis showed significantly worse DSS and OS in uninsured, single and male patients compared to insured, married and female patients respectively. Conclusions: Our study identified sociodemographic disparities on NET outcomes. Access to healthcare could be a potential contributing factor although differences in environmental exposure, health behavior and tumor biology could also be responsible. Further population-based studies are required to address these disparities.
Arabic and Assyrian immigrants’ knowledge of hepatitis and liver cancer in Sydney, Australia. Findings of a community consultation process.
Authors: Monica Cristina Robotin, Gisselle Gallego, Zeinab Mansour, Ximena Masgoret, Jack Wallace, Jacob George
Journal: Journal of Clinical Oncology (2019)

e18167 Background: In Australia over 50% of hepatocellular cancers (HCC) are diagnosed in immigrants born in viral hepatitis endemic areas. Therefore, increasing community awareness of viral hepatitis as a preventable and treatable cause of liver cancer is critical in designing community-based cancer prevention programs. Although 7% of Australians living with chronic hepatitis B (CHB) were born in Africa or the Middle East, limited information exists about these communities’ knowledge and beliefs around hepatitis and cancer. To assist the design of effective strategies for screening and treatment, we conducted a community consultation process among Arabic and Assyrian-speaking communities in Sydney, Australia. Methods: The consultation involved semi-structured interviews with key opinion leaders in the Arabic and Assyrian communities and focus group discussions (FGD) conducted in Arabic, Assyrian and English with community members. Interviews and discussion were digitally recorded, translated and transcribed. Framework analysis was employed for data analysis. Results: Twelve face to face semi-structured interviews were conducted with Arabic and Assyrian community leaders. Sixty-six participants, aged from 22 to 71 years took part in seven FGDs. Findings were highly confluent and highlighted a limited knowledge and understanding of hepatitis and of links to liver cancer. Hepatitis and cancer are stigmatising diseases and kept within the family. To mitigate the distress brought about by cancer, euphemisms and protective language are used and a cancer diagnosis is not disclosed to family members. Communities’ ability to engage with the health system is limited. Fear and past medical interactions influence decision about accessing care and education levels, health literacy and English proficiency are significant barriers to navigating the health system. The internet, doctors, television and radio are the communities’ main sources of health information. Conclusions: Reluctance to talk openly about hepatitis and cancer and widespread ‘cancer fatalism’ need to be considered in clinical interactions. Health information messages need to be tailored to patients’ cultural beliefs, couched in accessible terms and delivered through a range of communication channels.
Outcomes associated with rapid genetic testing for BRCA1 and BRCA2 at time of breast cancer diagnosis.
Authors: Kelly A. Metcalfe, Aletta Poll, Andrea Eisen, Jordan Lerner-Ellis, Steven Narod
Journal: Journal of Clinical Oncology (2019)

1577 Background: Bilateral mastectomy improves survival for women with BRCA-associated breast cancer. Most women do not know their BRCA status at the time of BC diagnosis when making surgical decisions. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is also unclear if there are psychosocial implications associated with genetic testing at the time of breast cancer diagnosis. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling and genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 1010 women consented to participate and 60 (5.9%) were identified with a BRCA mutation. 15% of those identified with a BRCA mutation did not meet provincial eligibility criteria for genetic testing, and 20% were eligible prior to a breast cancer diagnosis but had not received testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p &lt; .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 67.3% reported that their surgery choice changed. 73.7% of BRCA carriers had a bilateral mastectomy, compared to 20.2% of BRCA negative (p &lt; 0.001). Most women used genetic testing results for surgical decision making (96.1% of BRCA positive and 86.4% for negative). Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.
Prognostic models for prediction of overall survival after first-line platinum-based chemotherapy for primary metastatic nasopharyngeal carcinoma.
Authors: Wang-Zhong Li, Guo-Ying Liu, Hu Liang, Shu-Hui Lv, Xing Lv, Xiang Guo, Wei-Xiong Xia, Xiang Yanqun
Journal: Journal of Clinical Oncology (2019)

e17501 Background: Platinum-based chemotherapy remains the main treatment strategy for patients with primary metastatic nasopharyngeal carcinoma (mNPC). However, survival outcomes are heterogeneous. The present study sought to develop clinical predictive models for overall survival (OS) in mNPC. Methods: Institutional database was queried for patients with mNPC who received first-line platinum-based chemotherapy between 2008 and 2015. Eligible patients (n = 460) were split into a training (2008-2013, n = 296) and an internal validation cohort (2014-2015, n = 164) according to the period of diagnosis. Potential prognostic factors for OS were evaluated using univariate and multivariate analyses. The performance of prognostic models was assessed by discrimination and calibration. The clinical usefulness of prognostic models was evaluated by decision curve analysis. Results: We established two nomogram-based prognostic models to predict OS probability, the first (baseline model) based on baseline factors, the second (composite model) incorporating posttreatment plasma Epstein-Barr virus DNA (EBV DNA) and objective response (OR) to first-line chemotherapy. The incorporation of posttreatment plasma EBV DNA and OR to the model improved the predictive accuracy. The C-index of composite model for predicting OS was 0.767 (P &lt; .001), which was statistically higher than the C-index values for baseline model (0.686). The results were confirmed in the internal validation cohort. Conclusions: We developed and validated two prognostic models that can be used before and after completion of first-line chemotherapy, respectively. The proposed models can be used for prognosis prediction and better selection of patient into clinical trials.
Cetuximab maintenance therapy in unresectable metastatic colorectal cancer patients with wild-type RAS and BRAF: A single-center retrospective study.
Authors: Tao Jiang, Xiaoyan Lin, Hao Chen, Jianwei Zhen, Bin Du, Qing Liu, Dongta Zhong, Baoyu Yang, Xinli Wang
Journal: Journal of Clinical Oncology (2019)

e15004 Background: Cetuximab plus FOLFIRI (leucovorin, fluorouracil and irinotecan) is preferred first line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC) patients. However, the side effects often require dose-reductions or discontinuation calling for maintenance strategies to reduce toxicity and preserve efficacy. Therefore, we evaluated efficacy and safety of cetuximab maintenance therapy after first-line treatment in unresectable mCRC patients with RBWT. Methods: This single center, retrospective study enrolled patients (aged 18-71 years) with untreated mCRC with RBWT, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, with at least one measurable lesion according to response evaluation criteria in solid tumor (RECIST). All patients received first line cetuximab plus FOLFIRI every two weeks for 9-12 cycles, after which, patients with treatment response chose to either enter observation (stop treatment) or maintenance 1 (cetuximab plus irinotecan) group. After 6-12 cycles of maintenance 1, patients with treatment response entered maintenance 2 (cetuximab only). If patients progressed on maintenance 2, reintroduction of cetuximab plus FOLFIRI was suggested. Primary endpoint was failure-free survival (FFS); while secondary endpoints included disease control rate (DCR), objective remission rate (ORR) and progression free survival (PFS). Safety events were also evaluated. Results: Among 62 enrolled patients, 56 patients completed first-line treatment (DCR: 90.3%, ORR: 62.9%) and 30 patients entered maintenance 1 [median PFS1 (mPFS) =6.1 months, 95%CI: 6.0-6.2, DCR=60%, ORR=30%]. Of these, 18 entered maintenance 2 [mPFS2=6.6 months, 95%CI: 5.1-8.1, DCR=27.8%, ORR=5.6%]. The mFFS was significantly longer in maintenance 1 (12.8 months, 95%CI: 10.8-14.8) compared to observation group (3.0 months; hazard ratio [HR]: 0.21, 95%CI: 2.6-3.4, P&lt;0.001). Overall mFFS was 19.0 (95%CI: 11.0-27.0) in maintenance and 9.5 months in observation group (HR: 0.195, 95%CI: 7.4-11.6; P&lt;0.001). Rash acneiform, mucositis and asthenia were the common adverse events observed during maintenance treatment. Conclusions: Maintenance treatment with cetuximab after first line therapy significantly improved FFS, with acceptable safety profile in untreated mCRC RBWT patients.