tbuckley/cabot-search huggingface dataset:
International comparison of <i>BRAF</i> testing in melanoma.
Authors: Marcos Tadeu dos Santos, Neil Atkey, Eloise Aita, Jordan Clark
Journal: Journal of Clinical Oncology (2016)

e21053 Background: According to current NCCN guidelines, melanoma patients with metastatic or unresectable disease should be tested for BRAF V600 mutations to evaluate therapy options. Test adoption was analyzed by comparing BRAF testing volumes for eligible melanoma patients in six countries. Methods: Using the most recent published melanoma incidence data from each country we applied the frequencies of Stages III and IV to estimate the number of eligible melanoma patients for BRAF V600 testing. Data from SEER-NIH were used for USA and Canada (13%) and from specific publications for UK (21%), France (21%), Spain (17%), Australia (12%) and Brazil (36%). Within each country, we mapped the labs offering clinical routine BRAF testing and collected real-world annual test volumes for 2015 to evaluate test adoption rates. Results: With the exception of Brazil, all countries are performing more BRAF V600 tests than expected for the number of eligible melanoma patients (Stages III and IV). We cannot infer that all eligible melanoma patients are being tested but we attribute the high volume of testing to 1) earlier adoption, despite the stage of the disease, 2) easy access to testing and 3) low reimbursement barriers. When test adoption is compared to total incidence of melanoma, we conclude that the USA, Spain and Brazil are more likely to limit testing to eligible patients. Conclusions: The high adoption rates for BRAF V600 testing in melanoma within the countries evaluated suggest faster adoption and improved utilization of companion dx testing for future BRAF inhibitor therapies. Melanoma Incidence (year) [A] Eligible Patients for BRAF V600 test - Stages III and IV [B] Volume of BRAF V600 tests performed (year) [C] Test Adoption [Incidence - C/A] Test Adoption [Eligible - B/A] USA 73870 9602 10105 14% 105% Canada 6800 884 3540 52% 400% UK 13497 2834 7520 56% 265% France 11176 2300 5026 45% 219% Spain 4869 828 1000 21% 121% Australia 12960 1543 5256 41% 341% Brazil 5670 2018 1010 18% 50%
Trial in progress: An open-label, multicenter, phase 3b study to assess the safety and efficacy of midostaurin in patients (pts) aged ≥ 18 y with newly diagnosed (ND) <i>FLT3</i>-mutated acute myeloid leukemia (AML) who are eligible for 7+3 or 5+2 chemotherapy (chemo).
Authors: Adolfo Fuentes, Moez Ben Ali, Joan Maier, Ythier Deniau, Anne Ruault, Laura Cuenot, Valerie Campello-Iddison
Journal: Journal of Clinical Oncology (2018)

TPS7079 Background: FLT3 mutations, found in ≈30% of pts with AML, are associated with a poor prognosis. Midostaurin is a multikinase inhibitor that targets FLT3 and other kinases involved in AML pathogenesis. In the phase 3, randomized, placebo-controlled RATIFY trial, midostaurin + chemo significantly improved OS and EFS in adults (aged 18-59 y) with ND FLT3-mutated AML. The chemo regimen in RATIFY was 7+3 induction (1-2 cycles of cytarabine [Ara-C] 200 mg/m2/d on d1-7 + daunorubicin 60 mg/m2/d on d1-3) and consolidation (≤4 cycles of Ara-C 3000 mg/m2/d every 12 h on d1, 3, 5). Midostaurin + chemo was approved in the United States and Europe for pts aged ≥18 y with ND FLT3-mutated AML. However, many institutions use different chemo regimens as the standard of care (SOC). The aim of this new study is to assess the safety and efficacy of midostaurin 50 mg bid in combination with different SOC chemo regimens and as single-agent maintenance. Methods: CPKC412A2408 (NCT03379727) is an open-label, single-arm, multicenter, phase 3b study in adults aged ≥18 y and fit for chemo with ND AML per WHO 2008 classification, ECOG performance status of ≤2, and a documented FLT3 internal tandem duplication or tyrosine kinase domain mutation (estimated enrollment, 300). Pts must start their first induction chemo cycle with 7+3 (Ara-C 100-200 mg/m2/d on d1-7 + daunorubicin 60-90 mg/m2/d or idarubicin 12 mg/m2/d on d1-3) or 5+2 (a reduced-dose regimen with these agents) per investigator’s discretion and enroll by d7 of the first induction cycle. Once pts start on 7+3 or 5+2, they may not switch. Pts will receive consolidation with Ara-C, with dose per investigator’s choice. Midostaurin 50 mg bid will be administered on d8-28 of each 28-d induction and consolidation cycle and daily for ≤12 cycles of maintenance. Pts will discontinue the study if not in complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction or consolidation or if they receive a stem cell transplant. The primary and secondary endpoints are safety and the proportion of pts achieving CR/CRi, respectively. Clinical trial information: NCT03379727.
Mutation profiling and treatment choosing of Chinese <i>ROS1</i> positive advanced lung cancer patients.
Authors: Jun Zhao, Qin Li, Gen Lin, Qun Liu, Rongrong Chen, Xin Yi, Xuefeng Xia, Shun Lu
Journal: Journal of Clinical Oncology (2018)

e21102 Background: ROS1 is one of the rare driver genes in lung cancer, especially in NSCLC. In this study, we performed mutation and treatment profiling in Chinese advanced lung cancer patients. Methods: A total of 2755 advanced lung cancer patients were enrolled in this study, all samples were analyzed by next-generation sequencing across 59 genes based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations. Results: Mutation profiling was possible for all patients, ROS1 mutations were detected in 39 patients (1.4%). In these ROS1+ patients, 28 patients were NSCLC (72%), including 1 Squamous Cell Carcinoma and 1 Spindle Cell Carcinoma of the Lung. ROS1 rearrangement occured in all these patients, predominantly fused with CD74 (51%) and EZR (21%), with SDC4, SLC34A2, AQP4, GOPC and TPM3 followed. 3 patients coexist with ROS1 G2032 mutation. None of these patients coexist with EGFR/ALK/RET/HER2/MET mutations. For treatments, 54% patients chose ROS-TKIs, another 25% patients chose chemotherapy. One patient with GOPC-ROS1 fusion accepted Crizotinib as first-line therapy for 19 months, and disease progressed due to ROS1 G2032 mutation, passed away after 3 months with Cabozantinib. Conclusions: ROS1 fusion mutation also has complex heterogeneity, ROS-TKIs has been the major therapy choice of Chinese ROS1+ advanced lung cancer patients.
The effect of an adolescent and young adult (AYA) consultation service on documentation of infertility risk at the Princess Margaret Cancer Center (PM).
Authors: Jeremy Howard Lewin, Laura Mitchell, Seline Tam, Natasha Puri, Justin Ming Zheng Ma, Derek Stephens, Amirrtha Srikanthan, Philippe L. Bedard, Albiruni R. Razak, Michael Crump, David Warr, Meredith Elana Giuliani, Abha A. Gupta
Journal: Journal of Clinical Oncology (2016)

10077 Background: Limited data exists regarding the documentation of therapy-associated infertility risk (IR) and options for fertility preservation (FP) during the initial oncology consultation. This study aimed to 1) investigate predictors of documentation of IR and FP options and 2) assess the effect of a dedicated AYA service on these rates. Methods: Patients at PM who underwent chemotherapy had records retrospectively reviewed over a period 21 months before and 8 months after implementation of an AYA service (launched May 2014), for documentation of IR/FP. Eligible patients included: age 18-40, AYA tumour sites (sarcoma, breast, leukaemia, lymphoma, testis), no prior gonadotoxins and available initial consultation with a PM oncologist. The AYA service provided 1) patient consultations 2) health care provider education regarding IR/FP and 3) development of fertility resources (pamphlets, institutional guidelines). The impact of the AYA program on IR/FP documentation rates was assessed using univariate and multiple logistic regression. Results: Of 173 eligible records, documentation rates of IR/FP were 66% and 66%, respectively. On univariate analysis, IR/FP documentation was less likely if patients had metastatic disease (P = 0.001, 0.001), by tumour type (P = 0.003, 0.001), less intensive gonadotoxins (P = 0.03, 0.06), older age (P = 0.14, 0.006) and more children (P = 0.001, 0.001). Males were more likely to have FP discussion (P = 0.02). On multivariate analysis, number of children (P = 0.004, 0.004), older age (P = 0.003, 0.004) and tumour type (P = 0.03, 0.05) were associated with lower rate of IR and FP documentation. Following implementation of the AYA service, IR/FP rates increased from 56% (CI 46-65%) to 85% (CI 74–92%, P < 0.0001) and 54% (CI 45 – 64%) to 86% (75 – 93%, P < 0.0001), respectively. The effect of availability of the AYA program on documentation was most noticeable in leukaemia, lymphoma and breast group sites (P < 0.0001). Conclusions: It is evident that a dedicated AYA consultation service at an adult institution had a significantly positive effect on rates of IR/FP documentation. Specific programming can improve service delivery to AYA with cancer.
Healthcare resource use and expenditures among patients with Merkel cell carcinoma by level of comorbidity.
Authors: Mairead Kearney, Katia Thokagevistk, Emmanuelle Boutmy, Michael Locker, Murtuza Bharmal
Journal: Journal of Clinical Oncology (2018)

e18932 Background: Merkel cell carcinoma (MCC) is a rare, neuroendocrine, cutaneous malignancy, which occurs more frequently in the elderly, exhibits aggressive clinical features, and is associated with a poor prognosis. Data on the economic burden of MCC and associated comorbidities are limited. The objective of this study was to describe healthcare resource utilization (HRU) and expenditures by level of comorbidity in newly diagnosed patients with MCC in the United States. Methods: Newly diagnosed patients with MCC were identified by ICD-9 codes 209.31-209.36 or 209.75 between July 2010 and December 2014 in MarketScan administrative claims databases. Patients were stratified by Deyo-Charlson Comorbidity Index (CCI) scores (0, 1, 2, ≥ 3). HRU and costs were calculated per patient per year (PPPY). All costs were adjusted to 2017 US dollars. Results: 2,355 patients met the selection criteria, of which 2,177 had the requisite continuous plan enrollment of ≥ 6 months before the index date and no enrollment gap ≥ 30 days during follow-up. The mean age at diagnosis was 68.8 years (SD, 14.9), and 60.3% were male. The overall mean Deyo-CCI score, as measured over the entire observation period, was 2.14 (SD, 2.26), with 81.6% of patients aged ≥ 65 years having a score of ≥ 1; of these, 51.9% had a Deyo-CCI score of ≥ 3. The most prevalent comorbid medical conditions during follow-up were diabetes (27.8%), chronic pulmonary disease (23.1%), cerebrovascular disease (19.2%), congestive heart failure (14.2%), and renal disease (14.0%). HRU and expenditures were found to increase with the severity of patients’ Deyo-CCI scores. The mean overall expenditures PPPY by Deyo-CCI score were: 0, $62,401 (SD, 92,420); 1, $73,537 (SD, 115,361); 2, $95,741; (SD, 180,415) and ≥ 3, $109,690 (SD, 200,280). Conclusions: This large administrative claims analysis suggests that patients with MCC have a substantial comorbidity burden, and that HRU and expenditures increase with patients’ worsening comorbidities. Recently approved innovative treatment options may potentially offset some of the economic burden incurred with the disease and its associated comorbidities.
The impact of polypharmacy and comorbidities on surgical morbidity and mortality in patients with gynecological malignancies: Results of a prospective study in 237 patients.
Authors: Guelhan Inci, Hannah Woopen, Rolf Richter, Radoslav Chekerov, Mustafa Zelal Muallem, Jalid Sehouli
Journal: Journal of Clinical Oncology (2017)

e18255 Background: Physicians need to risk-stratify their patients preoperatively to adjust the radicality and the indication of surgery. So far, there are only retrospective and limiting data available. Aim of this study is to evaluate the predictive clinical characteristics such as polypharmacy and Charlson-Comorbidity Index (CCI) for postoperative complications in patients undergoing gynecologic cancer surgery. Methods: This is a prospective cohort study of patients undergoing gynecologic cancer surgery at a tertiary care academic center from October 2015 through January 2017. Surgical complications were graded using validated Clavien-Dindo criteria. Using logistic regression, we identified demographic and predictive clinical characteristics for postoperative complications. Results: Out of the 237 enrolled patients 41(17.3%) experienced a grade≥3b complication. Within 30 days of surgery, 9 (3.8%) patients has died. Charlson Comorbidity index (CCI)&gt; 2(p&lt;0.015, OR 2.33, 95% CI 1.18-4.61), polypharmacy (p&lt;0.001, OR 3.40, 95% CI 1.63-7.10), ASA (p&lt;0.0001, OR 2.98, 95% CI 1.65-5.38), BMI&gt;25kg/m 2 (p&lt;0.001, OR 4.25, 95% CI 1.86-9.69), preoperative albumin&lt;3.5 g/dl (p&lt;0.009, OR 3.22, 95% CI 1.33-7.79) and potassium &lt; 3.6 mmol/L (p=0.007, OR 5.11, 95% CI 1.55-16.81) were predictive for complications grade≥3b. A multivariable model included duration of surgery (p=0.012, OR 1.26, 95% CI 1.05-1.52), ASA (p=0.01, OR 2.60, 95% CI 1.20-5.60), preoperative albumin&lt;3.5 g/dl (p=0.028, OR 3.37, 95% CI 1.14-10.00), BMI &gt;25kg/m 2 (p=0.009, OR 3.81, 95% CI 1.40-10.35) and potassium &lt; 3.6 mmol/L (p=0.02, OR 3.69, 95% CI 1.20-11.38) was predictive of 30-day Morbidity and Mortality. Age (p=0.49, OR 0.89, 95% CI 0.95-1.02), CCI &gt; 2(p=0.88, OR 1.06, 95% CI 0.42-2.69) and polypharmacy (p=0.65, OR 1.26, 95% CI 0.41-3.98) showed no association for postoperative complications. Conclusions: Only ASA, BMI, preoperative albumin and potassium are associated with severe postoperative complications in patients undergoing gynecologic cancer surgery. Subsequent studies should confirm this result to identify better frail cancer patients.
Association of chronic kidney disease and locally-advanced RCC.
Authors: Sumi Dey, Zachary Hamilton, Sabrina L Noyes, Ithaar Derweesh, Brian R. Lane
Journal: Journal of Clinical Oncology (2016)

e16078 Background: Chronic kidney disease (CKD) is classified according to cause, glomerular filtration rate (GFR), and proteinuria. In renal cell carcinoma (RCC) patients, reduced GFR has been related to tumor size/stage. Previous studies indicate proteinuria as an independent predictor of renal functional decline and mortality. We retrospectively evaluated proteinuria obtained prior to nephrectomy to evaluate its relationship to stage. Methods: Institutional registries from SH (n=1115) and UCSD (n=453) were queried for preoperative GFR and proteinuria status prior to radical (RN) or partial nephrectomy. Clinical stage was grouped as I, II, III and proteinuria was classified as A1 (<30 mg), A2 (30-300mg), and A3 (>300 mg). KDIGO classification was used for CKD progression risk (low, moderately-increased, high, very-high). Results: Among 1568 patients with stage I-III RCC, 35% had GFR<60 (n=548) and 13% had proteinuria (n=209) prior to surgery. Albuminuria group was A1 (86.7%), A2 (11.2%), and A3 (2.1%). Classification of patients according to GFR and albuminuria identified 55.2%, 23.4%, 12.4%, and 9.0% at low, moderately-increased, high, and very-high risk for CKD progression. Preoperative CKD was more common in locally-advanced RCC patients. Tumor stage and CKD association was observed with stage I, II, and III RCC patients having 20.5%, 29.1%, and 30.4% prevalence of high or very-high risk for CKD progression before treatment (p<0.05). CKD incidence following RN for higher stage RCC further increases risk for progression limiting their ability to receive therapies dependent on renal function. Conclusions: In this study, reduced GFR (<60) was present in 35% of patients. When proteinuria was considered, the proportion of patients at moderate or greater risk increased to 45%. A positive correlation between pre-treatment CKD and higher stage RCC was present. This likely relates to increased loss of functional parenchyma with increasing tumor size/stage and has important implications in patient management. KDIGO classification of pre-treatment CKD by clinical stage. Risk Group Stage I Stage II Stage III Very-High Risk 8.7% 11.8% 13.0% High Risk 11.8% 17.3% 17.4% Moderately –Increased Risk 22.9% 24.4% 47.8% Low Risk 56.6% 46.5% 21.7%
Evaluation of the TruSight Tumor 170 (TST170) assay and its value in clinical research
Authors: C. Heydt, R. Pappesch, K. Stecker, J. Neumann, R. Buettner, S. Merkelbach-Bruse
Journal: Annals of Oncology (2018)

Background: In recent years, parallel sequencing technologies have become integrated into daily clinical practice. Many institutions use amplicon-based approaches for the detection of somatic mutations. However, these assays do not routinely detect chromosomal aberrations or copy number changes (CNVs), which are still widely analysed by FISH and IHC, and struggle with de novo fusions. The development of new technologies to detect all therapeutically relevant genomic alterations in a single assay is an ongoing process. This study aimed to evaluate the TruSight Tumor 170 assay, a hybrid capture-based assay, for the simultaneous detection of somatic gene mutations, gene fusions and CNVs and its implementation into routine diagnostics. Methods: Until now 24 of 48 tumour samples with known genetic aberrations were evaluated including three control samples. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue. After DNA shearing, DNA and RNA libraries were prepared with the TruSight Tumor 170 assay (Illumina) according to the manufacturer's instructions. Sequencing was performed on the NextSeq (Illumina). For data analysis, variant calling was performed using the TruSight Tumor 170 app on BaseSpace Sequence Hub (Illumina), and for variant interpretation BaseSpace Variant Interpreter (Illumina) and the Molecular Health Guide Software were used. Results: DNA and RNA were successfully extracted. 22 of 24 DNA libraries were analysable with DNA concentrations between 9 – 120 ng DNA. All 24 RNA libraries were analysable with RNA concentrations between 1 – 85 ng. All previously known exonic mutations and 1 high-level MET amplification were detected. Intronic variants and low-level MET amplifications were not detected. 9 of 13 fusions and splice variant were confirmed with the TruSight Tumor 170 assay. The remaining 4 aberrations were false positive by the previous methods. Conclusions: The TruSight Tumor 170 assay works well even with very low DNA and RNA concentrations in comparison to other methods and can be used in a routine workflow. The number of samples will be increased to 48 samples to evaluate the assay further. Additionally, automated solutions for DNA/RNA extraction from same slide might be needed. Legal entity responsible for the study: Carina Heydt. Funding: Illumina. Disclosure: K. Stecker: Molecular Health GmbH. J. Neumann: Illumina. All other authors have declared no conflicts of interest.
Clonal concordance and genomic heterogeneity in single CTC copy number alterations vs. paired IMPACT metastatic tissue sequencing from mCRPC patient samples.
Authors: Howard I. Scher, Angel E Dago, Jerry Lee, Ramsay Sutton, Ryon P Graf, Nicole A. Schreiber, Melanie Hullings, Yipeng Wang, Mark Andrew Landers, David B. Solit, Michael F. Berger, Nikolaus Schultz, Ryan Dittamore
Journal: Journal of Clinical Oncology (2018)

5054 Background: High CTC phenotypic heterogeneity is associated with non-response to ARSi but not taxane chemotherapy assessed using a non-invasive rapid blood test. The MSK-IMPACT™ NGS assay is FDA approved for tumor tissue profiling to guide treatment selection. The frequency of directly actionable alterations in prostate cancer (PC) is ~35%. Recognizing many cancers harbor intra, inter and intracellular heterogeneity, we sought to evaluate concordance of sequencing single CTCs vs. paired biopsy analyzed by MSK-IMPACT, to assess CTC clonality in circulation vs. tumor, the relationship to CTC phenotypic heterogeneity and response. Methods: Metastatic tumor biopsies collected from 50 mCRPC patients (lymph nodes n = 26, bone n = 9, visceral n = 10 and other soft tissue n = 5) prior to new treatment were sequenced by MSK-IMPACT. Time matched blood samples (n = 50) were collected for CTC analysis (Epic Sciences). CTCs (n = 644, range 2-27, med = 13) underwent single cell low pass whole genome sequencing for copy number variation (CNV). Intra-patient CTC clonality was estimated based on similarity of DNA copy number segments. Phenotypic CTC heterogeneity was estimated by previously developed algorithms and compared to genomic clonal heterogeneity. Results: Large chromosomal CNV were detected in CTCs from 47/50 (94%) patients, 34/50 (67%) had multiple subclones with distinguishable CNV. Overall, a median of 3 distinct clones/pt (range 1-6) were observed across the cohort, with the number of clones not associated with the number of CTCs detected. Genomic clones observed in tissue were confirmed in CTCs from 32/50 (64%) pts, while 16/50 (32%) pts were discordant in CTCs, 2 pts were unevaluable. > 4 genomic clones were found in 13/50 pts, 12 of which had high phenotypic heterogeneity scores (top 50%). Conclusions: Single CTC sequencing is often concordant to metastatic tissue, but unique CTC clones highlight the prevalence of sub-clonal disease in mCRPC patients under-sampled by tissue biopsy. High genomic heterogeneity can be predicted by phenotypic CTC heterogeneity and may be useful to find patients unlikely to respond to targeted therapy.
The efficacy and safety of PD-1 inhibitors in combination with or without chemotherapy and/or bevacizumab as second line treatment or beyond in non-small cell lung cancer: Preliminary data from a real-world setting.
Authors: Fan Zhang, Di Huang, Yuzi Zhang, Guoqiang Wang, Shangli Cai, Yi Hu
Journal: Journal of Clinical Oncology (2018)

e21129 Background: PD-1 inhibitors monotherapy has been proved to be effective in non-small cell lung cancer (NSCLC) as second-line treatment and beyond, but only limited to a small proportion of patients. Recent studies have demonstrated that the ORR is higher when anti-PD-1 or anti-PD-L1 combined with chemotherapy and/or bevacizumab as first-line treatment in NSCLC. So in the present study, we retrospectively assessed whether anti-PD-1 combined with chemotherapy and/or bevacizumab improves efficacy compared with anti-PD-1 alone as second-line treatment or beyond in advanced NSCLC patients. Methods: 92 patients of stage IIIB or IV NSCLC treated with anti-PD-1 therapy in the Cancer Center of the Chinese People’s Liberation Army from September 2015 to September 2017 were screened for eligibility. First-line treatment or combined drugs beyond chemotherapy and bevacizumab were excluded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR) and safety profile. Results: In total, 55 patients were included in the analysis of the study, including 33 patients with anti-PD-1 monotherapy and 22 patients with anti-PD-1 plus chemotherapy and/or bevacizumab. The PFS was longer in combination therapy group than monotherapy group (median, 7.5 vs 3.3 months, HR 0.35, 95% CI 0.17-0.73, P < 0.0001). 7 (31.8%) of 22 patients in the combination group achieved a response compared with 3 (10.0%) of 30 patients in the monotherapy group (P = 0.075). 21 of 22 (95.5%) patients in the combination group achieved a disease control compared with 14 of 30 (46.7%) patients in the monotherapy group (P = 0.000). The incidence of grade 3 or worse treatment-related adverse event was similar between groups (2 [6.1%] of 33 in monotherapy group, 5 [22.7%] of 22 in combination group, P = 0.10). Conclusions: The addition of chemotherapy and/or bevacizumab to anti-PD-1 therapy could be an effective and tolerable second line or beyond treatment option for patients with advanced NSCLC. These findings need to be further explored by randomized controlled studies.