tbuckley/cabot-search huggingface dataset:
OncoKB: Annotation of the oncogenic effect and treatment implications of somatic mutations in cancer.
Authors: Debyani Chakravarty, Sarah M Phillips, JianJiong Gao, Ritika Kundra, Hongxin Zhang, Julia E. Rudolph, Rona D. Yaeger, Tara Soumerai, Moriah H Nissan, Sarat Chandarlapaty, Tiffany A. Traina, Paul K. Paik, Alan Loh Ho, Feras Hantash, Andrew Grupe, Ederlinda Paraiso, Marc Ladanyi, David B. Solit, Paul Sabbatini, Nikolaus Schultz
Journal: Journal of Clinical Oncology (2016)

11583 Background: Sequencing of tumor DNA is becoming part of routine clinical care, with the goal of matching patients to approved treatments or clinical trials based on specific mutations. However, interpretation of the clinical implications of identified variants remains a challenge for the treating oncologist, and currently there is no comprehensive database integrated within clinical care that reliably annotates actionable mutations. To address this, we developed OncoKB, a knowledgebase for the oncogenic effects and treatment implications of cancer gene alterations. Methods: With a network of clinical and research fellows, as well as faculty members at Memorial Sloan Kettering Cancer Center (MSK), we have curated detailed information about common cancer genes and their alterations, using diverse sources such as FDA-, NCCN- and other guidelines, ClinicalTrials.gov and the scientific literature. For each variant, the biological effect, prevalence and prognostic information, as well as treatment implications and available clinical trials were collected in a tumor type-specific way. Treatment information was classified by level of evidence, ranging from standard of care to investigational or hypothetical treatments. Results: To date, information on 2,941 unique variants in 417 genes implicated in cancer has been captured in OncoKB (Table 1). Specific alterations in 13 genes are linked to standard and approved therapies, and 32 genes have alterations with emerging evidence for drug sensitivity with the potential to guide patient enrollment for clinical trials. Conclusions: Based on MSK best practices, OncoKB offers oncologists detailed information about individual mutations found in cancer and enables them to make treatment decisions. The information is used in MSK clinical sequencing reports and in OncoVantageTM reports by Quest Diagnostics. Annotated variants, their biological effect and associated level of evidence will be publicly available at oncokb.org and via the cBioPortal for Cancer Genomics. OncoKB Metrics, 2/2/16. Genes Variants Standard Of Care 11 56 Strong Clinical Evidence 32 428 Hypothetical Therapeutic Implications 106 529 Biological Information Only 375 1764
Mutation count, a potential surrogate for tumor mutation load, of circulating tumor DNA (ctDNA) using targeted panel sequencing correlates with clinical outcomes in late stage lung adenocarcinoma and small cell lung cancer.
Authors: Stephanie Yaung, Liu Xi, Corinna Woestmann, Sylvie McNamara, Bernd Hinzmann, Sebastian Fröhler, Nalin Tikoo, Christine Ju, Aarthi Balasubramanyam, Patrik Vitazka, Amrita Pati, Alexander F. Lovejoy, Daniel M. Klass, Hans-Peter Adams, Michael Thomas, Felix Herth, Thomas Muley, Birgit Wehnl, John F. Palma, Xiaoju Max Ma
Journal: Journal of Clinical Oncology (2018)

12045 Background: Studies show that mutation count can be used as a biomarker to predict whether or not a patient may respond to immunotherapy or chemoradiation therapy. However, mutation count is usually determined by whole exome sequencing or large targeted panel sequencing of tumor tissue DNA. Tissue biopsy is often inaccessible for many late stage lung cancer patients. Methods: We assessed mutation count using the AVENIO ctDNA Surveillance Kit, a targeted next-generation sequencing panel of 198 kilobases, on pre-treatment plasma samples from a prospective, observational study, where 43 late stage lung adenocarcinoma and 72 late stage small cell lung cancers (SCLC) treated with first-line chemo or chemoradiation therapies were initially assessed. Synonymous and prevalent driver mutations were filtered out from the detected somatic mutations prior to calculating a mutation count per megabase. Subjects were classified as high mutation count if the filtered somatic mutation count was above the bottom tertile of their cancer type. Results: We detected somatic variants in all 43 lung adenocarcinoma and 72 SCLC subjects with a median mutation count of 9 and 14, respectively. Lung adenocarcinoma subjects with low mutation count showed better survival in terms of overall survival (OS) (18.3 vs 7.8 mo, HR 0.41, p = 0.026) and progression free survival (PFS) (6.2 vs 4.3 mo, HR 0.51, p = 0.042). SCLC subjects with low mutation count had shorter OS (9.3 vs 14.1 mo, HR 1.75, p = 0.034) and a similar trend in PFS. Conclusions: We were able to derive a ctDNA-based mutation count from a panel the size of one-fifth of a megabase and identified an association between low mutation count and better prognosis in subjects with late stage lung adenocarcinoma treated with chemo or chemoradiation therapy. In late stage SCLC, however, high mutation count correlated with better prognosis. Our findings suggest differences in lung cancer histology are key to understanding measurements of mutation count and their potential to predict outcome on chemotherapy. Studies to further validate these results are ongoing.
Predicting outcomes of advanced non-small cell lung cancer patients treated with PD-1/PDL-1 inhibitors: Independent international validation of the iSEND model.
Authors: Wungki Park, Laura Mezquita, Naoyuki Okabe, Deukwoo Kwon, Diana Saravia, Young Kwang Chae, Amrita Desai, David Planchard, Caroline Caramella, Raja Mudad, Mohammad Jahanzeb, Hiroyuki Suzuki, Benjamin Besse, Gilberto Lopes
Journal: Journal of Clinical Oncology (2018)

3015 Background: There is an unmet need for affordable and readily available biomarkers to predict outcomes to PD-1/PD-L1 inhibitors (PD-1/L1i) in advanced non-small cell lung cancer patients (aNSCLC pts). We previously developed a multivariate risk prediction model called the iSEND in a cohort of 159 patients with aNSCLC pts (n = 159) treated with nivolumab in second-line or above setting (2L+). Here, we report the independent multicentric validation. Methods: The iSEND model includes simple clinical and laboratory characteristics: Sex, ECOG performance status, and baseline and post-treatment change after 1st cycle of NLR (Neutrophil-to-Lymphocyte Ratios), intended to reflect reactive increase of the myeloid-lymphoid balance. For independent validation, we used a retrospective cohort of 230 aNSCLC pts from the authors’ institutions in the United States, France and Japan who received 2L+ PD-L/L1i. The outcomes for the iSEND Good, Intermediate, and Poor groups were compared. The performance was assessed using receiver operating characteristic (ROC) curves. Results: The median follow-up was 15.2 months (M) (95% Confidence Interval [CI]: 12.4-17.9). The median OS for iSEND Good, Intermediate, and Poor was 15.9 M (CI: 2.8-29.0), 12.4 M (CI: 9.6-15.1), and 4.0 M (CI: 3.0-5.0), respectively. And log-rank test was significant (p = 0.001). The median Progression Free Survival (PFS) was 2.6 M (CI: 2.0-3.1), 2.9 M (CI: 1.6-4.2), and 1.6 M (CI: 1.3-1.8), respectively. (Log-rank: p = 0.002) Time-dependent area under curves (AUC) of the iSEND model for OS at 6, 12, 18, 24, and 36 M were 0.63 (CI: 0.56-0.71), 0.61 (CI: 0.54-0.69), 0.59 (CI: 0.50-0.68), 0.60 (CI: 0.47-0.73), and 0.70 (CI: 58-0.82). The iSEND Poor group had significant correlation with progressive disease compared to the iSEND Good group (HR: 2.7, CI: 1.2-6.1, p = 0.013). Conclusions: This study validates the iSEND model in an independent international cohort confirming that it predicts outcomes of aNSCLC pts treated with 2L+ PD-1/L1i. Exploring its validity in a prospective cohort as well as in aNSCLC pts treated with effective myeloid modulating combination strategy is strongly supported and underway.
Clinical profile of triple negative breast cancer in Indian women: Long term follow-up study.
Authors: Tara Rajendran, Krishna Prasad
Journal: Journal of Clinical Oncology (2018)

e13109 Background: Triple negative breast cancer (TNBC) is defined as the lack of expression of estrogen, progesteron and HER2 receptors. Out of all the breast cancer diagnosed annually nearly 17 percent has triple negative phenotype. Methods: We included all the 711 patients who received neoadjuvant and adjuvant chemotherapy at Kasturba Medical College hospital, India for stage I–IV breast cancer from 2002 to 2018 and for whom complete receptor information were available. Results: This is a multicentre retrospective study with long term follow up of around 16 years. 711 carcinoma breast patients diagnosed through 2002 till 2018. There were 100 patients with triple negative breast cancer with median follow–up time of 11.2 years. Median age was 34 years. 50% patients with left breast involvement. 48% with right breast and 2% with bilateral involvement. Metastasis present 10% of the TNBCs. 7% to the lung and 3% to bone. Majority of the patients belonged to stage 2a and 2b followed by 3a. 85% received adjuvant chemotherapy and 15% received neoadjuvant chemotherapy. Modified radical mastectomy was done in 80% of the patients. Wide local excision 5%. Lumpectomy done in 15%.45% received radiotherapy. 50% did not receive and rest 5% denied radiation therapy. 5% had relapse. On our long term follow up we studied that 77% patients are alive with non evidence of disease and 6% alive with disease. 2% lost follow up. 5% still on treatment. Conclusions: Triple negative carcinoma breast is aggressive than any of the other phenotypes. Early detection and prompt treatment leads to disease free survival. In our centre the long term follow ups showed very good survival outcome.
BTC1.07 Brain metastases: immune characterization and the impact over prognosis
Authors: M Dionísio
Journal: Neuro-Oncology (2018)

Brain metastases (BrMets) are one of the most frequent and devastating neurological complications related to systemic cancer, thus representing a significant cause of morbidity and mortality. They are the commonest intracranial tumours, surpassing primary brain tumours. Most brain metastases originate from lung cancer (36–64%), breast cancer (15–25%) and melanoma (5–20%), and account for 67%-80% of all cancers.Few studies of human CNS metastases are available because only a small percentage of affected patients undergo surgery. The activation of immune cells by targeting check point inhibitors showed promising results e several primary tumors but the use in brain metastases special type of metastization considering the brain nich and its particular sanctuary characteristics is to be better underst and In vivo studies: we used a retrospective cohort of 30 patients diagnosed with breast cancer and brain metastases, who underwent excision of BCBM in Hospital de Santa Maria - CHLN and adjuvant treatment as clinical indicated. The cohort includes complete demographic, clinicopathologic, and clinical outcome data extracted from medical records to explore the classical survival endpoints. The expression of estrogen receptor alpha (ERα), progesterone receptor (PR) and HER2 was determined by immunohistochemistry (IHC) in the metastatic tissue and with the primary tumours. The expression of CD4+, CD8+(TIL′s-Tumour Inflitrating Lymphocites), PD-L1, glial fibrillary acid protein (GFAP) was also be performed by IHC in the brain metastases. 2. In vitro experiments: The breast cancer brain tropic cell line (MDA-MB-231 BR Her 2+ and Her2-) was cultured to determine the expression of ERα, PR, HER2, PD-1, PD-L1 and by RT-qPCR. In our Cohort, reflecting the expected prevalence of breast cancer subtypes prevalence, Nor the PDL 1 nor GFAP or TiĹs status were biomarkers of prognosis although the in vitro studies for brain tropic cells point to distinct significant expressions according to tropism/subtype. Breast cancer doesn′t seem to assume an immunogenic behavior when brain metastases are well-established though the process to tropism may assume a step where immunogenecity cross talk between cells and stroma may be different considering brain nich.
Tumor mutation burden (TMB) and immune-related adverse events (irAEs) compared to antibiotic (abx) use to predict for response to immune checkpoint inhibitors in esophagogastric cancer (EGC).
Authors: Megan Greally, Walid K Chatila, Matthew Margolis, Jaclyn Frances Hechtman, Yaelle Tuvy, Ritika Kundra, Marc Ladanyi, David Paul Kelsen, David H. Ilson, Michael F. Berger, Laura H. Tang, David B. Solit, Nikolaus Schultz, Yelena Yuriy Janjigian, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2018)

4056 Background: Immune checkpoint inhibitors (nivolumab and pembrolizumab) have clear activity in EGC. However, benefit is modest in an unselected population. TMB may be of value as a quantitive marker to identify patients (pts) with durable benefit from immunotherapy (Cancer Discov 2018 Jan;8(1):49-58). We present updated data from an expanded cohort, including irAEs and abx use as determinants of pt outcomes. Methods: All pts treated with anti-CTLA-4, PD-1 or PD-L1 Abs were identified. Outcomes were correlated with TMB by MSK-IMPACT NGS panel of up to 468 genes and clinical variables, including irAEs and abx use. The third quartile of TMB was used as the cut-off. Progression-free (PFS) and overall survival (OS) were calculated from the start of immunotherapy. Results: Of 120 pts (110 adenoCs, 10 SCC), 90% had received ≥2 prior chemo regimens, 6 received ≥2 IO regimens. 66 (55%), 17 (14%) and 37 (31%) pts respectively received anti-PD-1, anti PD-L1 and anti-CTLA-4 plus anti-PD-1/PD-L1 Abs. The median PFS and OS were 1.8 and 5.9 mos; 2-yr OS 19%; objective response rate of 13% (n = 15, 7 PRs, 8 CRs). In IMPACT tested tumors, excluding low purity samples (n = 62), a TMB cut-off of ≥7.4 mut/Mb stratified TMB-low vs -high pts (46 vs 16), with a trend toward improved OS in the TMB-high group (27.1 vs 8.4 mos, p = 0.063). 7 of 7 dMMR pts were TMB-high. In 41 pts (34%) treated with abx during immunotherapy (and 1 month prior), there was a significant improvement in PFS (3.3 vs 1.6 mos, p = 0.04) vs those who were not; with no difference in OS (7.3 vs 4.7 mos, p = 0.23). irAEs occurred in 36 pts (30%) and were associated with improved OS (18.2 vs 3.7 mos, p < 0.0001), irrespective of AE grade. OS (12.7 vs 4.2 mos, p = 0.034) was improved even in pts where irAEs occurred ≤8 weeks from start of immunotherapy. The median PFS and OS in 36 pts (30%) who received chemo following progression were 4.3 and 7.7 mos. Conclusions: A TMB of 7.4 may serve as a cut-off to identify EGC pts more likely to benefit from immunotherapy. Abx use did not negatively impact outcomes and occurrence of irAEs was associated with improved OS. Outcomes for post-immunotherapy chemo appear promising in these heavily treated pts.
Enrichment of melanoma-associated T cells in 6-thioguanine-resistant T cells from the peripheral blood of a melanoma patient following successful treatment with immune checkpoint blockade.
Authors: Mark R. Albertini, Cindy L Zuleger, Michael A Newton, Xiuyu Ma, Irene M Ong
Journal: Journal of Clinical Oncology (2018)

e21607 Background: Somatic mutations in vivo preferentially arise in proliferating (activated) cells. Ex vivo selection of T cells resistant to 6-thioguanine identifies T cells with in vivo hypoxanthine-guanine phosphoribosyltransferase gene mutations (MT). We previously reported that MT from melanoma patients are enriched for proliferating T cells that persist in blood and infiltrate the tumor. We hypothesize that T cells identified in vivo at sites of tumor (i.e. melanoma-associated T cells) will persist in MT following successful treatment with immune checkpoint blockade. Methods: Persistence of melanoma-associated T cells in uncultured (T0) peripheral blood mononuclear cells (PBMC) and in PBMC expanded with (MT) or without (wild-type (WT)) 6-thioguanine selection was examined in a metastatic melanoma patient who achieved a durable antitumor response following 2 intratumoral α-gal glycolipid injections (IT-AG) followed by Ipilimumab (Ipi) every 3 weeks for 4 doses given 4 weeks later at a time of disease progression. TCR beta chain (TRB) repertoire was examined in melanoma-associated T cells from a tumor sample obtained ~20 months prior to IT-AG (T-T0) and also in T0, WT, and MT from PBMC obtained before and 4-weeks after IT-AG as well as 1-, 4-, and 13-months post-Ipi via 5’ RACE and Illumina MiSeq sequencing. Results: The patient achieved a durable antitumor response, and several expanded or activated T cell clones persisted in this patient in T0, WT, and MT. Identical TRB were observed between MT and WT and T0, and expansions and contractions of T cell clones were noted over time. TRB identified in T-T0 persisted in the blood with identical TRBs identified in T0, WT, and MT. Detection rates of TRB shared between T-T0 and MT, WT, or T0 (any timepoints) were 11.0 % (72/656), 1.5 % (206/13,639), and 1.3 % (381/29,807), respectively (p = 10-7 by Monte Carlo computations for the MT vs WT and MT vs T0 comparisons). Conclusions: MT are enriched for melanoma-associated T cells following successful treatment of a melanoma patient with immune checkpoint blockade and merit further study as a biomarker of response to immunotherapy.
Phase 2 of intra-arterial hepatic (IAH) bevacizumab with systemic chemotherapy (CT) in second line treatment of liver metastases of colorectal cancer (LMCRC).
Authors: Michel Ducreux, Olivier Glehen, Gabrielle Tergemina-Clain, Denis Michel Smith, Benjamin Lacas, Valerie Boige, Guillaume Passot, David Malka, Jean-Pierre Pignon, Eric Dupont-Bierre, Rosine Guimbaud
Journal: Journal of Clinical Oncology (2016)

e15003 Background: IAHCT is more and more recognized in the management of LMCRC. Regarding its anti-angiogenic effect bevacizumab (B) could be considered as a good candidate for IAH treatment. This phase II evaluate IAH administration of B in second line treatment of LMCRC combined with systemic treatment. We report here the results of the planned interim analysis on toxicity plus those on efficacy as the trial closed prematurely. Methods: Inclusion criteria: patients (pts) with LMCRC after failure to a 1st line of IV CT ; ECOG performance status (PS) 0 or 1; at least one liver lesion evaluable by RECIST; extra-hepatic disease acceptable when limited to one or two lung metastases or lymph nodes potentially accessible to a curative treatment. They had to receive IAH treatment with B, 7.5 mg/kg every 3 weeks, and systemic CT with capecitabine (2 g/m²/day (d) 14 d, followed by 7 d rest) + irinotecan (200 mg/m² every 21d) or oxaliplatin (130 mg/m² every 21 d) depending on the 1st line received. Results: Between June 2013 and February 2015, 10 pts from 5 centers were included: 6 men, 4 women (median age 61 years); ECOG PS0 (n = 7) and PS1 (n = 3); limited extra-hepatic disease in 4 pts. Median duration of 1st line treatment was 6 months. IAH catheter was implanted surgically in one pt and radiologically in 9. Pts had an average of 6 cycles of IAH B, 3 received oxaliplatin and 7 irinotecan concomitantly. There was one grade (G) 3 allergic reaction to IAH B, one G3 abdominal pain, one G3 mucositis, one G3 nausea and one G3 vomiting events. Related to the use of B, 2 G3 thromboembolic events and 3 G3 hypertension were observed. In the 9 evaluable pts, 2 had partial response (22%), 5 stable disease (56%) and 2 progressive disease (22%). The median progression-free and overall survival were 5.2 months 95%CI [1.6 – 6.2] and 13.5 months [4.8 – Not reached], respectively. Conclusions: IAH administration of bevacizumab in patients with LMCRC seems to be feasible with no major side effect. The efficacy reported did not suggest a major effect of this treatment that should rather be used in combination with IAH chemotherapy such as oxaliplatin. We thank the PHRC for its financial support. Clinical trial information: NCT01677884.
Efficacy and cost-effectiveness of clofarabine with high-dose cytarabine for treatment of relapsed/refractory acute myeloid leukemia (R/R AML).
Authors: Sara Nunnery, Dorothy Wang, Marisela Tan, Richard Fong, Mimi Ming Lo, Rebecca L. Olin
Journal: Journal of Clinical Oncology (2018)

e19009 Background: There is no standard reinduction regimen for adults with R/R AML. Clofarabine with high-dose cytarabine (Clo-HiDAC) is commonly used, but limited data exists to support its efficacy. Its cost-effectiveness over other non-clofarabine based regimens is also controversial. Methods: We performed a single-center, retrospective cohort study evaluating 71 adult patients with R/R AML treated with Clo-HiDAC (cytarabine dose ≥ 1 g/m2 x5 days) between July 2012 and June 2017. The primary outcome was complete remission (CR). Secondary outcomes included overall response rate (ORR; defined as CR + CR with incomplete neutrophil and/or platelet recovery), event free survival (EFS) and overall survival (OS). We analyzed the cost-effectiveness of this regimen based on wholesale drug acquisition costs. Results: Median age in this cohort was 54 years (range 21-75). Median number of prior lines of therapy was 1 (range 1-5), and 24% had prior allogeneic transplant. The CR rate was 30% and ORR was 42%. In responders, median duration of response was 18.8 months. For the overall cohort, median EFS was 1.4 months, and median OS was 12.2 months. There was no difference in CR, ORR, EFS, or OS by age ( < 55 vs ≥55 years), primary refractory vs relapsed disease, prior lines of therapy (1 vs > 1) or prior allogeneic transplant. Using wholesale drug acquisition costs, the cost per patient of Clo-HiDAC is $25,083 using generic clofarabine and $57,724 using brand name clofarabine. We compared the efficacy (based on literature review), cost per patient and cost per CR of common AML reinduction regimens and found Clo-HiDAC not to be cost-effective (Table). Conclusions: Our analysis found rates of CR and ORR (30% and 42% respectively) to be comparable to prior report. The poor cost effectiveness of Clo-HiDAC may limit its utility to patients who cannot receive anthracycline. Future work will include a retrospective review of patients receiving anthracycline-based reinduction. Regimen CR Rate Cost Cost/CR Clo-HiDAC (generic) 30% $25,083 $83,610 Clo-HiDAC (brand) 30% $57,724 $192,413 MEC 18-65%* $924 $1,422 – $5,133 FLAG-Ida 63%* $2,679 $4,252 CLAG-M 53%* $3,094 $5,838 *Based on literature review