tbuckley/cabot-search huggingface dataset:
Impact of KRAS allele subtypes and concurrent genomic alterations on clinical outcomes to programmed death 1 axis blockade in non-small cell lung cancer.
Authors: Biagio Ricciuti, Gonzalo Recondo, Renato Umeton, Mizuki Nishino, Lynette M. Sholl, Mark M. Awad
Journal: Journal of Clinical Oncology (2019)

9082 Background: Immune checkpoint inhibitors (ICI) treatment can result in durable responses for KRAS-mutant (mut) non-small cell lung cancer (NSCLC). The impact of KRAS allele subtypes and concurrent genomic alterations on ICIs efficacy is unknown. Methods: We collected clinicopathologic and genomic data from patients (pts) with advanced NSCLC treated with programmed death (PD)-1 axis inhibition at the Dana-Farber Cancer Institute. We evaluated outcomes to ICIs according to KRAS mut alleles and concurrent STK11 and KEAP1 mut. Results: Of 617 ICI-treated NSCLCs, 181 (29.3%) had KRAS mut. Median TMB (mTMB) and median PD-L1 tumor proportion score (TPS) were similar between KRAS mut and KRAS wild type (wt) tumors. Among tumors with KRAS codon 12 mut, mTMB was higher in G12V (n = 37, 12.2 mut/Mb) compared to G12C (n = 84, 11.4 mut/Mb), G12D (n = 20, 9.4 mut/Mb) and G12A (n = 13, 10.1 mut/Mb), P = 0.05. Tumors with KRAS transversions (Tv) (n = 156) had higher mTMB compared to those with KRAS transitions (Ti) (n = 25) (10.9 vs 7.6 mut/Mb, P = 0.03). Median PD-L1 TPS was similar across KRAS mut alleles. Pts with KRAS G12V had longer median progression-free survival (mPFS) (5.5 vs 2.7 months, HR:0.62 [95%CI:0.40-0.96], P = 0.03) and overall survival (mOS) (17.5 vs 9.7 months, HR:0.62 [95%CI:0.36-0.99], P = 0.05), compared to non-G12V. Pts with KRAS Tv had longer mPFS and mOS compared to pts with Ti (mPFS: 3.4 vs 2.0 months, HR: 0.58 [95%CI:0.37-0.92], P = 0.02; mOS: 10.9 vs 5.4 months, HR:0.59 [95%CI:0.35-0.99], P = 0.048). Clinicopathologic features and STK11/KEAP1 mut were balanced across all KRAS mut alleles. Among KRAS mut pts, those with KEAP1 (n:52) and STK11 (n:50) concurrent mut had shorter mPFS (KEAP1 mut 1.8 vs. KEAP1 wt 4.1 months, HR: 0.55 [95%CI:0.38-0.80], P = 0.002; STK11 mut 1.8 vs STK11 wt 4.6 months, HR:0.46 [95%CI:0.32-0.67], P &lt; 0.0001) and mOS (KEAP1 mut 4.8 vs KEAP1 wt 15.1 months, HR: 0.51 [95%CI:0.34-0.76], P = 0.001; STK11 mut 4.8 vs STK11 wt 13.6 months, HR:0.51 [95%CI:0.34-0.76], P = 0.001). KEAP1 and STK11 mut did not impact outcome in KRAS wt pts. Conclusions: KRAS allele subtypes and concurrent genomic alterations impact ICI efficacy in NSCLC.
Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative trial in high risk localized prostate cancer (PC).
Authors: Laura Graham, Nicholas Reder, Roman Gulati, Petros Grivas, Jonathan L. Wright, Evan Y. Yu, Wendy Hou, Katie Nega, Todd Yezefski, Robert B. Montgomery, Elahe A. Mostaghel, William J. Ellis, Lawrence D. True, Daniel W. Lin, Peter Nelson, Michael Thomas Schweizer
Journal: Journal of Clinical Oncology (2019)

5081 Background: Studies have shown that localized PCs may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens, likely arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of combinatorial AR-targeted therapy, including indomethacin (Indo) to inhibit the steroidogenic enzyme AKR1C3, in men with high risk PC undergoing radical prostatectomy (RP). Methods: This was an open label, single-site, Phase II neoadjuvant trial in men with localized high to very-high risk PC, as defined by NCCN criteria. Patients received 12 weeks of neoadjuvant apalutamide (Apa), abiraterone (Abi) plus prednisone, degarelix, and Indo at their respective FDA-approved doses followed by RP. The primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included assessing for minimal residual disease (MRD) (i.e. ≤0.25 cm 3 tumor volume corrected for cellularity), measuring intraprostatic androgens and assessing molecular features associated with drug resistance. Twenty evaluable patients provided 91% power (one-sided alpha = 7.5%) to detect a difference in pCR rate of 5% (H0) vs. 25% (H1). Results: Twenty-two patients enrolled and 20 were evaluable for the primary endpoint (1 patient came off to pursue stereotactic radiosurgery; 1 was removed after developing grade 2 transaminitis). At baseline, the median PSA was 10.1 ng/mL (4.4-159.4), 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had a pCR, 6 (30%) had MRD, 18 (90%) had ypT3 disease and 7 (35%) had lymph node (LN) metastases. Treatment was generally well tolerated and adverse events were consistent with each individual drug’s known safety profile. Additional follow up data and correlative work will be presented at the meeting. Conclusions: In our cohort of men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy. Ongoing pharmacodynamic studies aimed at determining if Indo effectively inhibited AKR1C3 will provide important insights regarding the utility of targeting this steroidogenic enzyme. Clinical trial information: NCT02849990.
Squamous-cell carcinoma variant histology (SCC-VH) in muscle-invasive bladder cancer (MIBC): A comprehensive clinical, genomic, and therapeutic assessment from multiple datasets.
Authors: Marco Bandini, Filippo Pederzoli, Russell Madison, Alberto Briganti, Elizabeth R. Plimack, Jeffrey S. Ross, Guenter Niegisch, Evan Y. Yu, Aristotelis Bamias, Neeraj Agarwal, Srikala S. Sridhar, Jonathan E. Rosenberg, Joaquim Bellmunt, Matt D. Galsky, Andrea Gallina, Andrea Salonia, Francesco Montorsi, Siraj Mahamed Ali, Jon Chung, Andrea Necchi
Journal: Journal of Clinical Oncology (2019)

4535 Background: Pure or predominant SCC-VH is not uncommon in MIBC. Nevertheless, very few data are available about the efficacy of neoadjuvant chemotherapy (NAC). Here, we examined the outcomes after NAC, explored novel therapeutic targets, and propose new results in these patients (pts) by integrating multiple datasets. Methods: Within RISC and San Raffaele databases (1990-2018), we identified 2858 MIBC pts with urothelial cancer (UC, N = 2229) or VH (N = 629) who received RC +/- NAC. Kaplan-Meier and Cox regression analyses compared cancer-specific survival (CSS) between SCC and UC with NAC stratification. Logistic regression models tested the odds of clinical-to-pathological downstaging (cT &gt; pT). Foundation Medicine (FMI) dataset was queried for SCC-VH. 97 pts were assayed with hybrid-capture based comprehensive genomic profiling (CGP). Finally, we looked at the results from the PURE-01 study, that is now amended and enrolling pts with VH (NCT02736266). Results: Overall, 127 (4.4%) had predominant SCC-VH, 157 (5.5%) UC+SCC. Among the NAC-treated pts, SCC was the only VH (N = 44) significantly associated with worse CSS, (p &lt; 0.001) and higher mortality (HR 2.10, p = 0.003) vs. UC. After NAC adjustment, SCC-VH showed lower rate of downstaging (3.7 vs 9.3%, OR 0.4, p = 0.028) vs. UC. Similar negative trends were confirmed in pN0 pts, where SCC exhibited worse CSS (p = 0.006) and higher mortality (HR 5.15, p = 0.002). In the FMI cohort, the median tumor mutational burden (TMB) of SCC was 6.25 mut/mb (vs 6.9 mut/mb of 1984 UC), 27% of pts having &gt; 10 mut/mb and 14% &gt; 20 mut/mb. Clinically relevant alterations occurred in PIK3CA (42%), CCND1 (15%), PTEN (9.3%), FGFR3 (9.3%), and ERBB2 (6.2%). In the PURE-01 study, 13/84 (15.5%) SCC-VH pts received pembrolizumab before RC. PD-L1 combined positive score was ≥10 in 11/13 pts; results yielded 4 pT0 (30.8%), 10 pT≤1 (76.9%), and no deaths (median FUP: 10.4 mo). Conclusions: We present a comprehensive assessment of SCC-VH in MIBC. SCC represents the VH with the lowest activity of NAC. While CGP revealed multiple opportunities for targeted therapy, the efficacy of neoadjuvant pembrolizumab in SCC is encouraging.
Apatinib monotherapy for chemotherapy-refractory metastatic colorectal cancer: A multicenter, single-arm, prospective study.
Authors: Fen Wang, Shubin Wang, Xia Yuan, Jun Jia, Xiaoxia Bi, Zeqiang Zhou, Qiming Zhou, Changguo Luo, Minghui Deng, Liangjie Yi, Yong Li, Xia Li, Jianxin Lu, Wenzhi Su, Hanbin Chen, Yu Zhu
Journal: Journal of Clinical Oncology (2019)

3527 Background: Apatinib is an oral highly-selective tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor 2 (VEGFR-2). This exploratory study evaluated the efficacy and safety of apatinib monotherapy in patients with chemotherapy-refractory metastatic colorectal cancer. Methods: In this multicenter, single-arm, prospective study, 48 patients with metastatic colorectal cancer who had failed at least two lines standard chemotherapies including fluorouracil, oxaliplatin and irinotecan were recruited from 14 centers in Guangdong, China. Apatinib at a 500mg dose was administered daily continuously. Each cycle was 4 weeks (28 days). The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. Results: A total of 48 patients was enrolled in the study from September 3, 2015 to June9, 2017. Four patients achieved a partial response, and 22 achieved stable disease, representing a response rate of 8.3% and a disease control rate of 60.4%. Median follow-up time was 10.3 months. Median progression-free survival (PFS) and overall survival (OS) of evaluable patients (n=41) were 4.7 months (95% confidence interval [CI] 3.7-5.9) and 9.7 months (95% CI 5.9-13.6). The most common grade 3 or 4 adverse events (AE) were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%), proteinuria (8.3%) and mucositis oral (6.3%). Conclusions: Apatinib monotherapy shows promising efficacy and manageable toxicities in patients with chemotherapy-refractory metastatic colorectal cancer. Further phase 3 trial is warranted. Clinical trial information: ChiCTR1900020503.
Design, engineering, and characterization of a novel long-acting (Pegylated) single isomer human arginase for arginine depriving anticancer treatment.
Authors: Kuo-Ming Yu, Tammy Pui-Shi Pang, Murray Cutler, Johnson Yiu-Nam Lau, Thomas Wai-Hung Lo, Thomas Yun-Chung Leung
Journal: Journal of Clinical Oncology (2019)

3090 Background: Arginine deprivation therapy is an attractive strategy to treat arginine-auxotrophic cancers with deficient expression of argininosuccinate synthetase, argininosuccinate lyase or ornithine transcarbamylase. We have designed and engineered a novel human arginase with single site pegylation exerting excellent preclinical pharmacologic profile to serve as a new class of therapy. Methods: Human arginase has three cysteines (at position 45, 168, 303) and none of them is in or close to the active site. Two cysteines were mutated to serines, leaving the only cysteine at 45 for the simple and cost-effective synthesis of a single isoform of pegylated human arginase. Different forms of PEG moieties were evaluated for the selection of a drug candidate (PT01), followed by extensive characterization. Results: Converting Cys at 168 and 303 to serine impacted least on enzymatic activity (with cobalt cation). Pegylation with different sizes and shapes showed that 20 and 40 kDa (linear and branched) had similar PK/PD profile without damaging enzymatic activity. Therefore, arginase modified with a linear 20 kDa PEG was chosen as the candidate. A single 0.4 mg/kg IV dose of PT01 in rats induced 4 days of near complete plasma arginine depletion, while 6–7 days of depletion between 1.2 and 2 mg/kg. Plasma arginine levels were reversible. First-order clearance of both plasma PT01 concentration and activity suggested a terminal half-life of about 20 hours. In vitro assay showed very potent cytotoxicity at sub-nM level against various cell lines of breast, prostate, and pancreas in origins. In two mouse cancer models (hard-to-cure pancreas and castration-resistant prostate), weekly infusion at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose. Conclusions: A novel single isoform of pegylated human arginase was created, showing excellent enzymatic activity, PK/PD profiles, and cytotoxicity in vitro. Mouse xenograft models showed good tumor growth inhibition activity with tolerable toxicity as manifested on transient weight loss during therapy.
The mutational landscape of circulating cell-free DNA to identify neoadjuvant chemotherapy response in colorectal cancer patients.
Authors: Yanlong Liu, Xiaoli Wei, Xinying Shi, Ying Yang, Lili Fu, Beibei Mao, Henghui Zhang, Binbin Cui
Journal: Journal of Clinical Oncology (2019)

e15096 Background: The neoadjuvant chemotherapy plays an important role in the current treatment of colorectal cancer (CRC), even though parts of patients could not be benefit from it. This study was aimed to explore the specific mutational profile of plasma cell free DNA (cfDNA) in CRC patients with or without response to neoadjuvant chemotherapy. Methods: 16 eligible CRC patients were enrolled in this study from Harbin Medical University Cancer Hospital. These patients were divided into two groups: with response ( R, n = 8) and without response (NR, n = 8) to neoadjuvant chemotherapy. All patients received neoadjuvant chemotherapy and their baseline blood samples were collected. The cfDNA fragments were extracted for enrichment of a panel covering exon regions of 1,086 genes. Gene alterations were analyzed to investigate the relationship between genetic characterizations of cfDNA and response to neoadjuvant chemotherapy. Results: Principal component (PCA) analysis for copy number variation(CNV) of cfDNA differed significantly in two groups. In the R group, there were higher frequency CNV loss in ABL-1, ERBB3, SMO, IGF1R, AURKA, PDGFRA, IDH1, BRAF, PIK3CB, NRAS, NF1, MITF, PTCH1 genes, and CNV gain in MTRR, HSP90AA1, VHL, CREBBP, CHEK2, DDR2, MUTYH, NCOA1, XPC, FANCA genes. Regarding to the area under the ROC curve, CNV of these genes had a high value of 0.967, which implied that CNV of the candidate genes have predictive value for identifying response to neoadjuvant chemotherapy in CRC patients. Furthermore, the Copy Number Instability (CNI) value of R group was significantly higher than NR group(p = 0.0014). Conclusions: The candidate genes’ copy number variation and CNI value of baseline plasma cfDNA can identify the colorectal cancer patients with response or without response to neoadjuvant chemotherapy in this small cohort. The molecular profile of cfDNA in plasma may be a potential biomarker for predicting the response to neoadjuvant chemotherapy in colorectal cancer patients. These findings warrant further expanded prospective cohorts to validate.
Utility of the Lung Immune Prognostic Index (LIPI) in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab.
Authors: Juan Ruiz Bañobre, María C. Areses Manrique, Rosario García Campelo, Rafael Lopez, Francisco J. Afonso Afonso, Joaquín Casal Rubio, Sergio Vázquez Estévez, Cristina Azpitarte Raposeiras, Margarita Amenedo, Lucía Santomé, José Luis Fírvida Pérez, Joaquín Mosquera Martínez, Alexandra Cortegoso, Rocío Vilchez Simó, Gerardo Huidobro Vence, Natalia Fernández Núñez, Nazaret Quiroga Veiga, Jesús García Mata, Guillermo Alonso-Jáudenes Curbera, Urbano Anido Herranz
Journal: Journal of Clinical Oncology (2019)

e20645 Background: The lung immune prognostic index (LIPI) has been proposed as a new biomarker to select advanced non-small cell lung cancer (NSCLC) patients for anti-programmed cell death-1 or programmed death ligand 1 therapy. In this study, we investigate the prognostic and predictive utility of the LIPI in a multicentric nivolumab monotherapy-based cohort. Methods: 153 patients with available baseline LIPI were included. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The impact of the baseline LIPI on survival (PFS and OS), and DCR and ORR was assessed by Cox and logistic regression models respectively, adjusted for age, sex, ECOG-PS, smoking status, histology, TNM stage at diagnosis, presence of brain metastases and number of prior regimens. All p values were 2-sided, and those less than 0.05 were considered statistically significant. Results: 50.3% (n = 77) of the patients had a good (0 factors) LIPI, while 41.2% (n = 63) and 8.5% (n = 13) had intermediate (1 factor) and poor (2 factors) LIPI respectively. No significant differences were observed between the LIPI groups according to clinicopathologic characteristics. A high LIPI was significantly associated with poor OS in univariate (HR = 3.12, 95% CI 2.12 – 4.60; p &lt; 0.0001) and multivariate (HR = 3.10, 95% CI 2.09 – 4.58; p &lt; 0.0001) analyses. A high LIPI was associated with poor PFS (HR = 1.49, 95% CI 1.07 – 2.07; p = 0.02), but this correlation did not reach a statistical significance in multivariate analysis (HR = 1.37, 95% CI 0.98 – 1.92; p = 0.07). A higher LIPI was associated with a lower disease control rate in univariate (OR = 0.50, 95% CI 0.29 – 0.85; p = 0.01) and multivariate (OR = 0.55, 95% CI 0.31 – 0.98; p = 0.04) analyses. Conclusions: This study confirms the utility of the LIPI in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond.
Predictors of neoadjuvant chemotherapy efficacy in localized pancreatic head cancer: A 15-year experience at a high volume pancreatic cancer center.
Authors: Amr I. Al Abbas, Jacob Hodges, Patrick Varley, Connor Buchholz, Johanna E Bellon, Nathan Bahary, Aatur D. Singhi, Melissa Hogg, Herbert Zeh, Amer H. Zureikat
Journal: Journal of Clinical Oncology (2019)

e15724 Background: Surgery followed by adjuvant chemotherapy (SF) is the standard approach for localized pancreatic adenocarcinoma (PC). Although neoadjuvant chemotherapy (NC) is being increasingly used, its efficacy remains debatable. This study aims to identify baseline factors associated with benefit from NC as compared to SF for PC. Methods: Review of a prospectively maintained database of resected localized head PC undergoing NC or SF at a tertiary referral hospital from 2002 to 2018. Baseline factors investigated included clinical stage by EUS (7 th edition AJCC), CT vessel involvement, and serum CA19-9. Baseline CA19-9 levels were grouped into mild (37-200), moderate (200-900), and marked elevations (≥ 900). Patients with baseline serum CA19-9 &lt; 37 IU/dL were excluded from the analysis. Results: In total, 269 patients were evaluated: 165 (61%) received NC and 104 (39%) had SF. Mean patient age was 68.3 years and 50% were females. Of these, 42% had stage IIB, 44% had N1 disease, and 38% had vascular involvement. Compared to SF approach, NC was associated with improved median survival for CA19-9 of &lt; 200 IU/dL (30 vs 21 months, p = 0.08), 200-900 IU/dL (32 vs 17 months, p &lt; 0.01), and the ≥900 IU/dL (33 vs 12 months, p &lt; 0.01) groups. On Cox regression, NC was the only baseline factor predictive of improved survival in the groups with moderate (HR:0.35,[95% CI:0.20-0.62];p &lt; 0.01) and marked (HR:0.36,[95% CI:0.18-0.71];p &lt; 0.01) pretreatment CA19-9 elevation. Notably, NC was not predictive of improved survival in the cohort with mild CA19-9 elevation. Conclusions: This study identifies a cohort of patients that benefits from neoadjuvant chemotherapy over a surgery first approach for localized pancreatic head cancer. Elevation in baseline CA19-9 may serve as the strongest indicator for chemotherapy before resection.
Evaluation of a risk-based approach to follow-up care for breast cancer survivors: From oncology specialist to primary care provider (PCP).
Authors: Kathleen Keenan, Megan Dunne
Journal: Journal of Clinical Oncology (2019)

6529 Background: The number of cancer survivors in the Unites States is expected to exceed 18 million by the year 2020. Predicted care demands coupled with an anticipated shortage of oncologists have led to alternate follow up care models and providers. This nurse practitioner- (NP) led survivorship team was charged with developing a risk-based discharge plan for the &gt; 8,000 breast cancer survivors in our survivorship clinic at this NCI-designated cancer center. Methods: In collaboration with breast oncologists and surgeons, a risk-based strategy to identify and transition eligible survivors to their PCPs was developed. Low risk was determined by: stage, absent disease and significant late-effects, and time since diagnosis. Interventions: Evidence supporting the willingness, availability and expectations of PCPs to provide follow-up care to cancer survivors was reviewed. Criteria for eligibility were developed; patient and PCP educational documents were created. Continued breast cancer screening at our center was offered with results sent directly to PCP. Outreach educational programs were provided to local PCP groups to build relationships and provide breast specific follow up recommendations. To promote communication and collaboration between NP and PCP prior to and at the time of transition, clinic notes were shared after each survivorship visit. A comprehensive transition note including detailed follow-up recommendations was provided at the time of transition. Patients were assured of rapid return to the oncology provider in the event of recurrence or cancer related issue. Results: 5080 patients were offered transition, with 3642 accepting. Mitigating factors and facilitators to transition for both patients and PCP will be discussed and educational strategies to overcome barriers will be described. Conclusions: Transition of breast cancer survivors’ care to PCPs is successful approximately 56% of the time. Key factors include seamless communication among providers and early discussions with patients to set expectations and normalize the transition early in the care pathway.