tbuckley/cabot-search huggingface dataset:
Surgery and peptide receptor radionuclide therapy: An effective multimodal approach for metastatic neuroendocrine tumors.
Authors: Andreja Frilling, Ashley Clift, Adil Al-Nahhas, Richard P. Baum, Daniel Kaemmerer
Journal: Journal of Clinical Oncology (2019)

4113 Background: Neuroendocrine neoplasia (NEN) of the pancreas (PanNEN) or small bowel (SBNEN) frequently present with metastases at initial diagnosis, undermining the efficacy of surgical treatment. Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90 Y-DOTATOC and 177 Lu-DOTATATE, has been shown to achieve prolonged progression-free survival (PFS) and overall survival (OS) in a substantial number of non-surgical patients with advanced NEN. Our aim was to prospectively determine the efficacy of a combination of radical loco-regional surgery and 177Lu PRRT in patients with metastasised NEN. Methods: A set of inclusion criteria was defined (e.g. PanNEN or SBNEN, G1/G2 NEN, initial tumour diagnosis, treatment naïve patient, stage IV NEN, positivity on 68Ga DOTATATE or DOTATOC PET/CT, eligibility for surgery and PRRT). Patients underwent PRRT within 3 months following surgery. Follow-up included biochemistry and imaging. Outcome measures included 1-, 3-, and 5-year OS and PFS from initial diagnosis. Results: Forty-one patients met eligibility criteria and were included. There were 26 males (63.4%) and median age at surgery was 58.8 years (range 32.1-78.3). All patients with SBNEN underwent right hemicolectomy, terminal ileal resection and mesenteric lympadenectomy. In PanNEN patients either Whipple procedure or distal pancreatectomy and peripancreatic lymphadenectomy were performed. The median number of PRRT cycles was 4 (range 2-6). Post-treatment mortality was 0%. Surgical morbidity was 12% (all grade 1 according Clavien-Dindo) and transient grade 1 toxicity occurred post PRRT in 40%. There was no grade 3 toxicity. Median follow-up was 5.48 years (range 0.53 – 11.98). Median PFS and OS were 3.33 years and 9.07 years, respectively. Progression-free survival (with 95% CI) was at 1-, 3-, and 5-years 80% (68.7-92.6), 60.9% (45.9-75.9) and 43.3% (27.4-59.3), respectively. Overall survival (with 95% CI) at 1-, 3-, and 5-years was 97.6% (93-100), 97.6% (93-100), and 95% (87-100), respectively. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NEN.
Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma
Authors: Yuan Zhang, Lei Chen, Guo-Qing Hu, Ning Zhang, Xiao-Dong Zhu, Kun-Yu Yang, Feng Jin, Mei Shi, Yu-Pei Chen, Wei-Han Hu, Zhi-Bin Cheng, Si-Yang Wang, Ye Tian, Xi-Cheng Wang, Yan Sun, Jin-Gao Li, Wen-Fei Li, Yu-Hong Li, Ling-Long Tang, Yan-Ping Mao, Guan-Qun Zhou, Rui Sun, Xu Liu, Rui Guo, Guo-Xian Long, Shao-Qiang Liang, Ling Li, Jing Huang, Jin-Hua Long, Jian Zang, Qiao-Dan Liu, Li Zou, Qiong-Fei Su, Bao-Min Zheng, Yun Xiao, Ying Guo, Fei Han, Hao-Yuan Mo, Jia-Wei Lv, Xiao-Jing Du, Cheng Xu, Na Liu, Ying-Qin Li, Melvin L. K. Chua, Fang-Yun Xie, Ying Sun, Jun Ma
Journal: New England Journal of Medicine (2019)

Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.
5-factor prognostic model for survival of patients with metastatic urothelial carcinoma receiving three different post-platinum PD-L1 inhibitors.
Authors: Guru Sonpavde, Juliane Manitz, Chen Gao, Daniel Hennessy, Doris Makari, Guenter Niegisch, Jonathan E. Rosenberg, Dean F. Bajorin, Petros Grivas, Andrea B. Apolo, Robert Dreicer, Noah M. Hahn, Matt D. Galsky, Andrea Necchi, Sandy Srinivas, Thomas Powles, Ashok Kumar Gupta, Shaad Essa Abdullah, Gregory Russell Pond
Journal: Journal of Clinical Oncology (2019)

4552 Background: A prognostic model for overall survival (OS) of metastatic urothelial carcinoma (mUC) was previously reported in the setting of post-platinum atezolizumab (Pond GR, GU ASCO 2018). This model was limited by employing only atezolizumab treated patients (pts), small size of the validation dataset and unclear applicability to other PD-1/L1 inhibitors. Hence, we constructed a robust prognostic model utilizing the combined atezolizumab cohort as the discovery dataset and used 2 separate validation datasets comprised of post-platinum avelumab or durvalumab treated pts. Methods: The discovery dataset consisted of pt level data from 2 phase I/II trials (IMvigor210 and PCD4989g) evaluating atezolizumab (n = 405). Pts enrolled on 2 separate phase I/II trials, EMR 100070-001 that evaluated post-platinum avelumab (n = 242) and CD1108 that evaluated durvalumab (n = 189) comprised the validation datasets. Cox regression analyses evaluated the association of candidate prognostic factors with OS. Factors were dichotomized and laboratory values were normalized by logarithmic transformation. Stepwise selection was employed to propose an optimal model using the discovery dataset. Discrimination and calibration were assessed in the avelumab and durvalumab datasets following the validation procedure by Royston and Altman (2013). Results: The 5 factors included in the optimal prognostic model in the discovery dataset were ECOG-PS (1 vs. 0; HR 1.80; 95% CI [1.36-2.36]), presence/absence of liver metastasis (HR 1.55; 95% CI [1.20-2.00]), number of platelets (HR 2.22; 95% CI [1.54-3.18]), neutrophil-lymphocyte ratio (NLR; HR 1.94; 95% CI [1.57-2.40]) and lactate dehydrogenase (LDH; HR 1.60; 95% CI [1.28-1.99]). There was robust discrimination of survival between low, intermediate and high-risk groups based on 0-1, 2-3 and 4 factors. The concordance of survival was 0.692 in the discovery and 0.671 and 0.775 in the avelumab and durvalumab validation datasets, respectively. Acceptable or good calibration of expected 1-year survival rate was observed. Conclusions: A 5-factor prognostic model is prognostic for survival across 3 different PD-L1 inhibitors (atezolizumab, avelumab, durvalumab) in this large study totaling 836 pts overall in the setting of post-platinum therapy for mUC. This model may assist in prognostic stratification and interpreting nonrandomized trials of post-platinum PD1/L1 inhibitors.
A 3D micro-tumor model capturing tumor heterogeneity of a patient's primary tumor biopsy.
Authors: Katya Nikolov, Ellen Sampson, Christian Apfel
Journal: Journal of Clinical Oncology (2019)

e17076 Background: Cancer is a genetic disease. However, because of the randomness of mutations, less than 20% of patients have known driver mutations and it is estimated that in the United States, less than 5% of patients benefit from genome-driven targeted therapy. [1] Thus, treatment for millions of cancer patients is still today a hit or miss experiment. Therefore, we have developed a developed a genome-free and mechanism agnostic 3D micro-tumor platform (SAGE Direct Test™) to help oncologists and patients alike to directly identify the treatment that is most effective for an individual patient. Methods: The SAGE Direct Test™ works as follows with actionable results within 1 week: Disaggregation of the patient’s tumor tissue and recreation of 3D microtumors that resemble the tumor biology and heterogeneity of the patient’s primary tumor biopsy. Exposure of those 3D microtumors to a panel of potential treatment options. Measuring the metabolic or image-based response of such 3D microtumors, for example as EC 50 . Results: We created hundreds of 3D micro-tumors from biopsies of 7 ovarian cancer patients. Not surprisingly, when these microtumors were exposed to various cytotoxic chemotherapies such as cisplatin, paclitaxel or gemcitabine or targeted therapies such as erlotinib or crizotinib, the median EC 50 varied significantly from drug to drug. However, for any given drug, the EC 50 varied significantly from patient to patient, with an interquartile range spreading often by more than one order of magnitude. Values in the table are standardized means with their standard deviations. Conclusions: We have developed a 3D micro-tumor model that can measure the sensitivity of a patient’s cancer biopsy tissue within one week. Furthermore, we found that the sensitivities of those 3D microtumors differed significantly from patient to patient. These results have not yet established a correlation between this 3D micro-tumor model and patients’ tumor responses, which is one of the next steps towards establishing clinical utility for the millions of patients where genomic testing remains non-informative. [Table: see text]
Combined BRAF and MEK Inhibition in Patients with unresectable or metastatic cutaneous melanoma: A meta-analysis of randomized controlled trials.
Authors: Adam Biedny, Adam Chahine, Ahmed Abdalla, Shima Sidahmed, Babikir Kheiri, Zyad Kafri, Tarik H. Hadid
Journal: Journal of Clinical Oncology (2019)

e21030 Background: Malignant melanoma is a dangerous disease with increasing incidence. Over the past several years, medical advancements have allowed for markedly improved therapeutic options. In patients with BRAF V600E or V600K mutations, the use of various BRAF inhibitors in combination with MEK inhibitors have been approved for stage III unresectable and metastatic disease. Therefore, we aimed to evaluate the efficacy and safety of this combination in comparison to a single agent BRAF inhibitor. Methods: A comprehensive electronic database search was conducted for all randomized controlled trials (RCTs) comparing the clinical outcomes of combination BRAF inhibitor and MEK inhibitor versus BRAF inhibitor alone in patients with unresectable stage III or stage IV BRAF-mutated malignant melanoma. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), overall response, and various selected adverse events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included five RCTs with 2,113 total patients, with a mean age of 55.5 years and 56.1% male. The combination therapy of BRAF and MEK inhibitors showed superior results with regard to PFS (HR 0.57; 95% CI: 0.50-0.67; p &lt; 0.001), OS (HR 0.69; 95% CI: 0.61-0.78; p &lt; 0.001), and overall response (HR 1.32; 95% CI: 1.23-1.43; p &lt; 0.001) when compared to BRAF inhibitor alone. Additionally, patients treated with combination therapy had a lower incidence of cutaneous squamous cell carcinoma (Risk Ratio: 0.22; 95% CI: 0.10-0.47; p &lt; 0.001) and arthralgia (Risk Ratio 0.34; 95% CI: 0.15-0.74; p &lt; 0.001). Patients who received combination therapy, however, had a higher incidence of diarrhea (risk ratio 2.53; 95% CI: 1.05-6.09; p = 0.04) and pyrexia (risk ratio 4.98; 95% CI: 2.27-10.92; p &lt; 0.001). Conclusions: For patients with unresectable stage III malignant melanoma or metastatic malignant melanoma, combination therapy with BRAF inhibitor and MEK inhibitor was associated with superior PFS, OS, overall response, and lower incidence of cutaneous squamous cell carcinoma and arthralgia compared with BRAF inhibitor alone. The combination therapy, however, was associated with a higher incidence of diarrhea and pyrexia.
Breast Cancer Index and risk stratification in luminal subtypes: A trans-ATAC study.
Authors: Ivana Sestak, Yi Zhang, Catherine A. Schnabel, Jack M. Cuzick, Mitchell Dowsett
Journal: Journal of Clinical Oncology (2019)

534 Background: The Breast Cancer Index (BCI) is a gene-expression based signature that provides prognostic information for overall (0-10 years) and late (5-10 years) distant recurrence (DR) and prediction of extended endocrine benefit in hormone receptor positive (HR+) early stage breast cancer. The current analysis aims to further characterize, correlate and compare the prognostic performance of BCI in luminal subtypes based on immunohistochemical classification. Methods: 670 postmenopausal women with HR+, LN- disease from the TransATAC cohort were included in this analysis. Luminal A-like tumors (LumA) were identified as those with ER+ and/or PR+ and HER2 -, and Ki67 &lt; 20% by IHC. All other tumors were classified as Luminal B-like (LumB) for this analysis. Primary endpoint was DR. Cox regression models were used to examine BCI prognostic performance according to luminal subtype, adjusting for the clinicopathological model Clinical Treatment Score (CTS). Results: 452 (67.5%) patients were classified as LumA and 218 (32.5%) as LumB. BCI was highly prognostic in LumA cancers (adjusted HR = 1.57 (1.23-1.96), P &lt; 0.001, ΔLR-χ 2 = 14.09), but not in LumB tumors (adjusted HR = 1.20 (0.94-1.52, P = 0.14, ΔLR-χ 2 = 2.23). In LumA, 10-year DR risks in BCI intermediate and high risk groups were very similar (25.6% (16.4-38.6) and 25.3% (13.5-44.3), respectively) and significantly different from BCI low (3.9% (2.1-7.0); HR = 7.47 (3.50-15.96) and HR = 8.13 (3.27-20.23), respectively). In LumB, 10-year DR risks in BCI low and BCI intermediate risk groups (13.8% (6.8-26.9) and 14.6% (8.3-24.9), respectively) were very similar and significantly lower than for the BCI high (29.1% (20.0-41.1)). Lum subtyping was only prognostic in the BCI low risk group (LumA vs. LumB: HR = 4.27 (1.65-11.02)) but not in the other two BCI risk groups. Conclusions: BCI provided significant prognostic information in Lum A subtype. These results show that BCI intermediate and high risk had similar risk of DR in LumA tumors, while shared similarly low risk of DR as BCI-low in LumB tumors. Further evaluation is needed to elucidate the distinct mechanisms underlying each classification system.
Abandonment trajectories of conventionally fractionated adjuvant radiotherapy in breast cancer care.
Authors: Xiao Xu, Pamela R. Soulos, Jeph Herrin, Shi-Yi Wang, Craig Evan Pollack, Suzanne B. Evans, Cary Philip Gross, James B. Yu
Journal: Journal of Clinical Oncology (2019)

531 Background: Hypofractionated radiotherapy is the recommended approach for adjuvant breast cancer care. Yet physicians have been slow to abandon conventionally fractionated radiotherapy (CFRT). We examined distinct trajectories of abandoning CFRT among physician patient-sharing peer groups and the associated cost implications. Methods: Using 2011-2014 national Medicare claims, we constructed peer groups of physicians (radiation and medical oncologists, surgeons, and primary care physicians) who cared for women with breast cancer. Women ≥66 years of age who underwent lumpectomy plus adjuvant radiotherapy were included. Peer groups represented physicians who frequently shared patients with one another. For each peer group, we calculated risk-adjusted rate of CFRT use in 2011-2012 (T1) and 2013-2014 (T2) after accounting for patient risk factors. Based on these utilization rates and a latent growth curve analysis, we identified distinct trajectories of abandoning CFRT among peer groups and estimated their cost implications from the Medicare perspective. Results: The 215 physician peer groups (caring for 16,988 patients) exhibited four distinct trajectories of CFRT use: 1) persistent high use (mean adjusted utilization: T1 = 94.3%, T2 = 90.6%); 2) decreased high use (T1 = 81.3%, T2 = 65.3%); 3) decreased medium use (T1 = 60.1%, T2 = 44.0%); and 4) decreased low use (T1 = 31.6%, T2 = 23.6%). They accounted for 33.0%, 35.3%, 25.6% and 6.0% of the peer groups, respectively. Compared to “persistent high use” of CFRT, peer groups with “decreased high use” and “decreased medium use” of CFRT had a smaller proportion of patients receiving radiotherapy at free-standing (vs. hospital-based) facilities (adjusted odds ratio = 0.89, p = 0.01; and 0.78, p &lt; 0.01; respectively). Accelerating abandonment of CFRT in the three higher utilization trajectories to “decreased low use” for the 2011-2014 patient cohort could save Medicare $342.7 million (95% confidence interval: $232.2-$457.6 million). Conclusions: Physician peer groups had distinct trajectories in abandoning CFRT exhibiting different baseline levels and rates of change in utilization. Efforts to reduce overuse of CFRT could generate substantial savings.
Clonal hematopoiesis mutations in plasma cfDNA RAS/BRAF genotyping of metastatic colorectal cancer.
Authors: Beili Wang, Fei Huang, Minna Shen, Shengchao Wu, Qian Yu, Huiqin Jiang, Yiyi Yu, Yihui Yang, Ying Zhao, Yiwen Zhou, Baishen Pan, Tianshu Liu, Wei Guo
Journal: Journal of Clinical Oncology (2019)

e15083 Background: Clonal hematopoiesis (CH) leads to blood-derived somatic mutations in KRAS, NRAS and BRAF. Our aim is to identify the prevalence of CH-derived mutations in these three genes in metastatic colorectal cancer (mCRC) patients and reveal the practical clinical implication of these mutations on plasma genotyping. Methods: We analyzed KRAS, NRAS and BRAF genotypes in plasma and matched tumor tissues of 236 mCRC patients through next-generation sequencing (NGS) and polymerase chain reaction. Suspected CH mutations were defined as those only detected in plasma with variant allelic frequencies (AFs) of &lt;5% and were confirmed by paired peripheral blood cells (PBCs) using droplet digital PCR (ddPCR). The hemopoietic lineage harboring a CH-derived mutation was analyzed through flow cytometry. Results: We identified suspected CH mutations in twenty patients (8.4%, 20/236). Three of these patients (1.27%, 3/236) had a CH-derived KRAS mutation, which was confirmed present in paired PBCs. Two of them had a KRAS G12X and the third had a KRAS Q61H. We did not detect CH-derived NRAS or BRAF mutations in our cohort. All three patients harboring a CH-derived mutation previously received chemotherapy treatment. In a selected CH-derived KRAS G12X case, the mutation was enriched in lymphocytes and persisted in plasma cell-free DNA (cfDNA) over the course of 4 months of therapy. Conclusions: In summary, we confirmed the existence of CH-derived KRAS mutations in a small proportion of mCRC patients. This should be noted to prevent misclassification as tumor somatic mutations when performing cfDNA sequencing in the absence of genotyping matched PBCs.
Phase II study of durvalumab (MEDI4736) in cancer patients HIV-1-infected.
Authors: María González-Cao, Teresa Moran, Judith Dalmau, Javier Garcia-Corbacho, Reyes Bernabé, Oscar Juan, Javier De Castro, Remei Blanco, Andreas Meyerhans, Julia Blanco, Niki Karachaliou, Christian Brander, Julia Garcia-Prado, Jorge Carrillo, Mariano Provencio, Miguel Angel Molina Vila, Bartomeu Massuti, Bonaventura Clotet, Javier Martinez-Picado, Rafael Rosell
Journal: Journal of Clinical Oncology (2019)

2501 Background: Durvalumab (MEDI4736), a programmed cell death-ligand 1 (PD-L1) blocking antibody, is currently approved for treatment of several cancer types. As HIV-1-infected (HIV+) patients have been excluded from cancer clinical trials, there are no data on the safety of durvalumab in this population. Methods: DURVAST (NCT03094286) is a multicenter, open-label, phase 2 clinical trial evaluating the safety and feasibility of durvalumab treatment at the recommended dose of 1500 mg Q4W in HIV+ cancer patients with solid tumors. Secondary endpoints include analyses of antitumoral activity in terms of objective response rate and duration of response (DOR). An associated translational sub-study includes the assessment of antiviral activity and the interaction of chronic viral infection with anti-cancer response and drug tolerance. Results: Twenty HIV+ individuals with advanced solid tumors were enrolled (Table). All participants maintained their standard-of-care antiretroviral therapy. Basal plasma viremia was undetectable and CD4 + T-cell count was over 200/mm 3 . There were no durvalumab-related serious adverse events. Only 8 patients (40%) presented drug-related adverse events (all grade 1-2) including diarrhea (15%), rash (15%), nausea (15%) and asthenia (10%). Best response includes: partial response in 5 (25%) (4 NSCLC and 1 anal cancer), stable disease in 4 (20%) (3 NSCLC and 1 melanoma) and progression disease in 11 (55%) patients. At data cut-off, 8 patients (40%) remained on therapy for a median of 10.5 months (range: 6-19 m). Median DOR has not been reached (range 1m to 19 m+). Plasma viremia remained suppressed during the study suggesting no viral reactivation upon durvalumab treatment. Conclusions: DURVAST study demonstrates durvalumab safety in HIV+ cancer patients and suggests an excellent tolerance profile. Understanding how chronic viral infection could contribute to a better tolerance towards immune checkpoint inhibitors will open a new way for the development of safer anti-cancer immunotherapy strategies. Clinical trial information: NCT03094286. [Table: see text]
A highly efficient, low-cost, novel multicomponent nanosystem for rapid enumeration of circulating tumor cells.
Authors: Jayant Khandare, Burhanuddin Qayyumi, Kumar Prabhash, Rohit Chavan, Aland Gourishankar, Zamila Khatun, Manish Mair, Arjun Singh, Aravindan Vasudevan, Ajit Sagare, Vamshi Chidara, Atul Bharde, Pankaj Chaturvedi
Journal: Journal of Clinical Oncology (2019)

e14516 Background: ‘Liquid biopsy’ technologies are unaffordable and unavailable in developing countries despite having highest cancer burden and mortality rates. Current Circulating Tumor Cell (CTCs) technologies sustain clinical concerns of a) non-specificity b) low efficiency c) high blood volume requirement d) long turn-around time, and d) exorbitant cost (~$900-1400). We report, an extremely low cost, innovative nanosystem for rapid enumeration of CTS with higher specificity and efficiency. Methods: We designed a nanosystem mediated by conjugation of anti-EpCAM through multi-reactive glutathione spacer, carbon allotrope and amine terminated dendrimer. The platform was evaluated for enhanced aqueous dispersibility and increased interaction with CTCs for rapid isolation and enumeration in 100 Head and Neck Cancer (HNC) patients having primary tumor sub-sites-oral cavity, larynx, hypopharynx, oropharynx, nasopharynx, salivary gland, and thyroid. The captured cells were immuno-stained and the optimal fluorescence acquisition intensity was validated in accounting CTCs with CK18 protein expression. There was complete elimination of the false positive normal cells (NC) count to CTCs by our method. The analysis was performed with only 1.5 ml of collected blood samples. Results: The CTC distribution in cohort study ranged from 1 - 85 cells per 1.5 mL of blood. In more than 80% of patient’s CTCs, the quantitative estimation of anti-CK18 protein over-expression indicated ~10-fold higher intensity over to NCs. As compared to treatment naive, recurrent, and disease-free patients, the spread of CTC number across the clinical range appeared to be tight (close to mean value). The CTC enumeration sensitivity linearity was ~99.2%, and the complete enumeration process time was under 03 hours/1.5 ml of blood. Consequently, efficient, rapid and yet affordable CTC platform was designed and clinically validated. Conclusions: ‘OncoDiscover’ liquid biopsy technology for CTC enumeration is poised to revolutionize the liquid biopsy due to its high sensitivity and affordability (~ $120) and shall resolve a major unmet medical need in impoverished world.