tbuckley/cabot-search huggingface dataset:
Concordance of KRAS, NRAS, BRAF, PIK3CA mutation status in the primary tumor (PT) and metachronous metastases in patients (pts) with colorectal cancer (CRC).
Authors: Mikhail Fedyanin, Anna Stroganova, Anastasia Senderovich, Svetlana Dranko, Alexey Tryakin, Ilya Pokataev, Elizaveta Polyanskaya, Sergey Gordeev, Arsen Rasulov, Alex Polyakov, Igor Sagaydak, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2016)

e15026 Background: The concordance of KRAS mutation status between the PT of CRC and synchronous metastases is 95%. However, there were reports showing that KRAS mutation status in metastases may change during chemotherapy (CT). The aim of this study was to evaluate the concordance KRAS, NRAS, BRAF, PIK3CA mutation status between the PT and metachronous metastasesin pts with CRC. Methods: The inclusion criteria were: metachronous metastases (appearance ≥ 12 mo. from the date of surgery for the PT) and ≥ 2 metastasectomy. Only 19 from 1457 (1.3%) pts met the inclusion criteria. PT was located in the colon in 37% pts. The median time between the resection of the PT and metastasectomy was 19.7 mon. (12-63). Most of pts (74%) received CT before metastasectomy. None of the pts received anti-EGFR Mabs. We performed DNA melting analysis with TaqMan probes with following Sanger sequencing for detection of mutation hot-spots in exon 2 and 3 KRAS and NRAS, exon 15 BRAF, exon 9 and 20 PIK3CA. Statistical analyses were performed using SPSS v.22, Inc., Chicago, IL. Results: Mutations in KRAS, NRAS, PIK3CA and BRAF genes in PT were detected in 57.9%, 5.2%, 26.3% and 0%, respectively. Mutations in the tumor material obtained at the first metastasectomy were found in 68.4%, 0%, 21% and 0% pts, respectively. In tumor obtained in subsequent metastasectomy, mutations were detected in 52.6%, 5.2%, 10.5% and 0% pts, respectively. Discordance in any gene mutation status between PT and metastases were found in 42% pts: in KRAS status - 26.3%, NRAS - 5.2% and PIK3CA - 21% pts. The average time between the resection of the PT and metastasectomy did not differ between pts with or without changes in gene status: 18.2 mon. vs. 21.3 mon., p = 0.7. Nonsignificant prevalence in changes of mutation status revealed in pts with rectal cancer: 41.7% vs 14.2%, p = 0.3. CT between resection of the PT and metastasectomy was not associated with changes in gene mutation status (p = 1.0). Conclusions: We detected clinical significant differences in the mutational status of KRAS between the PT and metachronous metastases in pts with CRC. We recommend to re-test of KRAS mutation status in case of metachronous ( ≥ 12 mon.) metastatic disease
Final analysis of erlotinib monotherapy for elderly patients with non-small-cell lung cancer harboring activating <i>EGFR</i> mutations.
Authors: Norimichi Akiyama, Yusuke Inoue, Naoki Inui, Kazuhiro Asada, Masato Karayama, Hiroyuki Matsuda, Koshi Yokomura, Naoki Koshimizu, Shiro Imokawa, Takashi Yamada, Toshihiro Shirai, Norio Kasamatsu, Takafumi Suda
Journal: Journal of Clinical Oncology (2016)

e20566 Background: The number of elderly patients with non-small-cell lung cancer (NSCLC) is increasing in advanced countries. EGFR mutation is common in elderly patients as well as in younger patients. We previously reported the efficacy and safety of erlotinib restricted for elderly EGFR-mutant NSCLC. Here we report the updated analysis regarding survival outcomes and safety profiles. Methods: Patients aged ≥ 75 years with NSCLC harboring EGFR mutations (exon19 deletions or L858R) were recruited between March 2013 and November 2014. All patients received erlotinib 150 mg daily until disease progression or intolerable toxicity in the first- or second-line settings. The primary endpoint was the overall response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty-two patients were enrolled. The median age was 80 years (range, 75-87) and 23 patients (72%) were female. All but one patient had good performance status of 0 or 1, but half of patients had comorbidities. Twenty-seven patients (84.4%) had stage IV disease, and seven had brain metastasis at the time of enrollment. An exon 19 deletion and an L858R mutation were detected in 12 (37.5%) and 20 patients (62.5%), respectively. The ORR was 56.3 % (95% confidence interval [CI], 39.4–72.0%), and the disease control rate was 90.6 % (95% CI, 75.2–97.6%). The median PFS and OS were 12.1 (95% CI, 6.4–15.5) and 25.3 months (95% CI, 10.9–not reached), respectively. Progression of brain metastasis was observed in a patient and new central nervous system involvement did not occur in any patient. The most common adverse event of any grade was skin disorders, followed by diarrhea and appetite loss. The grade ≥ 3 adverse events were observed in nine patients. Treatment-related death due to pneumonitis occurred in one patient. Conclusions: Erlotinib was effective and tolerated in elderly patients with EGFR-mutated NSCLC. Clinical trial information: UMIN0000010525.
Impact of patient navigation program in cervical cancer in Uruguay.
Authors: Diego Touya, Sandra San Miguel, Andrea Schiavone, Ana Laura Revello, Rafael Alonso, Alexandra Bukowski, Jessica St. Louis, Rocio Valiero, Natalia Pérez, Keyla Lopez, Lindsay Krush, Itoro E Inoyo, Paul E. Goss
Journal: Journal of Clinical Oncology (2018)

e13554 Background: CC is a significant public health problem in Uruguay because despite having a comprehensive national prevention plan, the disease continues to impact the most vulnerable women in Uruguayan society. Patient navigation has been shown to be effective in promoting cancer screening, timely diagnosis, and prompting cancer treatment among underserved communities. The first patient navigation program (PNP) implemented in Uruguay sought to reduce “loss to follow-up (LTFU) rates” among women who had received an abnormal PAP result during 2014-2015 at the Jardines del Hipódromo Health Center and had not returned for followed up with their care. Methods: Uruguay PNP is a prospective interventional study. Women with a pathological PAP result and LTFU were identified for this study. Trained patient navigators facilitated the national guidelines and identified barriers for follow up and care. Results: 178 women were identified with a pathological PAP, 73 met the inclusion criteria and 57 were enrolled in the PNP (78%). 43 women completed the PNP (75%). A total of 7 patients required a leep or surgical cone. The PNP successfully identified the socio-economic and cultural barriers that prevented women from following up with their appropriate care. Preliminary results indicate the main barriers as low socio-economic status, lack of awareness and knowledge, and time/lack of time. Of the study population, 50% had a family income less than $450 USD, only 31% knew the link between HPV and CC, and 31% of participants listed time as a barrier. Identifying the barriers is fundamental to implement national policies in order to improve CC screening. 100% of the patients felt satisfied with the Uruguay PNP, particularly appreciated feeling heard and included in their health decision making, An unexpected and successful result from the study includes the return of the patients and their families to the health system for their basic health care needs. Conclusions: The Uruguay PNP successfully met its 3 proposed goals: contact patients with abnormal PAP and follow up with their care; facilitating the process of timely diagnosis and treatment and identifying barriers to care; and including the patients’ family as part of the process integrating them into the health system.
Lung cancer screening rates: Data from the lung cancer screening registry.
Authors: Danh Pham, Shruti Bhandari, Malgorzata Oechsli, Christina M Pinkston, Goetz H. Kloecker
Journal: Journal of Clinical Oncology (2018)

6504 Background: Lung cancer is the leading cause of cancer related mortality in the United States. Since 2013, the United States Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with low-dose computed tomography (LDCT) for those aged 55-80 years for those who have smoked at least 30 pack years who currently smoke or have quit within the past 15 years. Current literature has provided only estimates of lung cancer screening since implementation. Our study aims to present the number of screening LDCTs being performed across the United States. Methods: Using data from the Lung Cancer Screening Registry (LCSR) provided by the American College of Radiology (ACR) in 2016, we collected the total number of LDCT from all 1,796 accredited radiographic screening sites. We used the 2015 National Health Interview Survey (NHIS) to estimate screening eligible smokers per USPSTF criteria and compared them with the 2016 LCSR reported screens. Analyses excluded respondents with missing data and history of lung cancer. Results: In 2016, 1.9% of 7.6 million eligible smokers were screened. These rates varied by region from 1.0% in the West to 3.5% in the Northeast (Table). The majority of eligible smokers were populated in the South and had the most accredited screening sites, but were still amongst the lowest in screening rate. Approximately 85% of the screened current smokers were offered smoking cessation. Conclusions: Annual LDCT screening remains inadequate following USPSTF recommendations despite the time since implementation and potential to prevent thousands of lung cancer deaths each year. It remains unclear why the lung cancer screening rate is dramatically lower than other cancer screening modalities such as mammography and colonoscopy. Further initiatives are needed including awareness programs and mandating lung cancer screening as a national quality measure. LDCT screens performed in 2016 compared to eligible smokers per USPSTF criteria. U.S. Census Region No. of Accredited Centers Estimated Eligible Smokers LDCT Screens Rate (%) Northeast 404 1,152,141 40,105 3.5 Midwest 497 2,020,045 38,931 1.9 South 663 3,072,095 47,966 1.6 West 232 1,368,694 14,080 1.0 Total 1796 7,612,975 141,260 1.9
Allogeneic NK cells generated from cord blood as universal treatment for cervical cancer enabled by HLA independent killing mechanisms.
Authors: John Veluchamy, A.Marijne Heeren, Jan Spanholtz, Jaap D.H van Eendenburg, Danielle Heideman, Henk M.W. Verheul, Gemma Kenter, Hans J. Van Der Vliet, Ekaterina S. Jordanova, Tanja D. de Gruijl
Journal: Journal of Clinical Oncology (2016)

e14526 Background: Cetuximab monotherapy is not effective in epidermal growth factor receptor (EGFR) positive cervical cancer patients. NK cells synergize with cetuximab through antibody dependent cellular cytotoxicity (ADCC) to lyse cervical cancer cells. As NK cells of cancer patients are dysfunctional and low in number, adoptive NK cell infusion could overcome those limitations. Allogeneic NK cell products, like cord blood derived NK cells (oNKord), have shown safety in clinical trials serving as promising treatment option.Methods: Activated peripheral blood NK cells (PBNK) were cultured with ten various cervical cancer cell lines, coated or non-coated with cetuximab. Their cytotoxic effect was compared with oNKord cells using flow cytometry based NK cell cytotoxicity assays. Results: While cetuximab monotherapy was ineffective, activated PBNK were capable of lysing cervical cancer cells, in vitro (p < 0.05), and this cytotoxic effect was further increased (p < 0.01) on cetuximab coated tumor targets (n = 5). PBNK and oNKord cytotoxicity was positively regulated by NK activating receptors NKG2D and DNAM-1 (p < 0.05), as supported by blocking experiments. Significantly (p < 0.01) higher cytotoxicity was induced by oNKord compared to activated PBNK (7/10). Moreover, oNKord cytotoxicity was higher compared to PBNK + cetuximab in CSCC7 (23 ± 2% vs 36 ± 5%), CC8 (36 ± 8% vs 51 ± 9%), HeLa (19 ± 5% vs 30 ± 4%) and equal to the cytotoxic efficacy of PBNK + cetuximab in other cell lines. Importantly, correlation analysis of PBNK and oNKord cytotoxicity showed independency related to HLA-E and G levels. PBNK showed a strong inhibition of cytolytic activity (p = 0.05) with increasing HLA-ABC expression levels, whereas oNKord cytotoxicity was entirely independent (p = 0.72) of HLA-ABC expression.Conclusions: Superior anti-tumor effects and the ability to overcome target cell resistance, makes adoptive transfer of oNKord an effective and novel immunotherapeutic strategy for cervical cancer. A first in human proof of concept trial to treat cervical cancer patients with oNKord is planned to start end 2016.
Laparoscopy-assisted versus open D2 distal gastrectomy for advanced gastric cancer: Results from a randomized phase II multicenter clinical trial (COACT 1001).
Authors: Young Woo Kim, Young-Kyu Park, Hong Man Yoon, Ji Yeon Park, Keun Won Ryu, Young-Joon Lee, Oh Jeong, Ki Young Yoon, Jun Ho Lee, Sang Eog Lee, Wansik Yu, Sang-Ho Jeong, Taebong Kim, Sohee Kim, Byung-Ho Nam
Journal: Journal of Clinical Oncology (2016)

4028 Background: For advanced gastric cancer (AGC), D2 gastrectomy is the standard treatment worldwide, and this procedure shows improved survival. One systematic review and several retrospective studies showed that overall survival rate and disease-free survival following laparoscopic D2 gastrectomy for AGC was not significantly different from ODG. In addition, we showed that the compliance rate of D2 lymph node dissection in LADG was not different from that in ODG in gastric cancer patients. Laparoscopic D2 gastrectomies are technically challenging, and their oncologic safety has not been proven by a prospective randomized controlled trial. This study was a multicenter, prospective, randomized phase II study to evaluate the feasibility of LADG with D2 lymph node dissection compared with ODG for AGC treatment. Methods: Patients with cT2-T4a and cN0-2 (AJCC 7thstaging system) distal gastric cancer were randomly but not blindingly assigned to LADG or ODG groups using fixed block sizes with a 1:1 allocation ratio. The primary endpoint was the noncompliance rate of the lymph node dissection, which was used to evaluate feasibility. Secondary endpoints included 3-year disease-free survival, 5-year overall survival, complications, and surgical stress response. Results: Between Jun 2010 and Oct 2011,204 patients were enrolled and underwent either LADG (n = 105) or ODG (n = 99). Of those, 196 patients (100 in LADG and 96 in ODG) were included in the intention-to-treat analysis. There were no significant differences in the overall noncompliance rate of lymph node dissection between LADG and ODG groups (47.0% and 43.2%, respectively; p = 0.648). In the subgroup analysis, the noncompliance rate in the LADG group was significantly higher than in the ODG group for clinical stage III disease (52.0% vs. 25.0%, p = 0.043). Three-year disease-free survival was not different in between the groups (LADG, 80.1%; ODG, 81.9%; p = 0.448). Postoperative complication rate and surgical stress response were not different between the groups. Conclusions: LADG was feasible for AGC treatment based on the noncompliance rate of D2 lymph node dissection. Clinical trial information: NCT01088204.
Randomized phase II trial of a DNA vaccine encoding prostatic acid phosphatase (PAP) versus GM-CSF adjuvant in patients with biochemically recurrent prostate cancer.
Authors: Glenn Liu, Lawrence Fong, Emmanuel S. Antonarakis, Jens C. Eickhoff, Laura E. Johnson, Douglas G. McNeel
Journal: Journal of Clinical Oncology (2016)

TPS3114 Background: We have previously reported the results from a phase I trial using a PAP-encoding DNA vaccine (pTVG-HP) in men with PSA-recurrent, non-metastatic, non-castrate, prostate cancer (clinical stage D0/M0). In that trial, patients received six intradermal immunizations, with GM-CSF co-administered as an adjuvant, over 12 weeks. No significant adverse events were detected, and CD4+ and CD8+ T cell immune responses to the PAP target antigen were elicited. The development of persistent Th1-type immunity was associated with favorable changes in PSA doubling time. A second trial, conducted in men with PSA-recurrent, non-metastatic, castrate-resistant prostate cancer (D0.5/M0) evaluated this vaccine administered over a 2-year period. In that trial there were no significant adverse events, the development of persistent Th1-biased PAP-specific immunity was detected, and many patients experienced a prolongation of PSA doubling time. Based on these results, we are currently conducting a multi-center trial using pTVG-HP plus GM-CSF adjuvant, versus GM-CSF adjuvant only, in patients with stage D0/M0 prostate cancer. Methods: Patients with non-castrate, non-metastatic prostate cancer (negative CT and bone scans), with rising PSA and a doubling time of < 12 months, are being randomly assigned to receive pTVG-HP + GM-CSF versus GM-CSF adjuvant. Treatments are being delivered intradermally every 2 weeks x 6, and then quarterly for up to 24 months. The primary endpoint is 2-year metastasis-free survival. Secondary endpoints include median progression-free survival, and determining whether immunization affects PSA doubling time. Laboratory endpoints include determining whether PAP-specific T-cell immunity is associated with progression-free survival. The trial was expanded in 2014 to include a total of 106 patients allowing for further exploratory biomarker analyses and to increase the statistical power, now enabling a > 90% power to detect an anticipated difference of 40% versus 70% in 2-year metastasis-free survival at the one-sided 5% significance level. Clinical trial information: NCT01341652.
Lenalidomide (LEN) pharmacokinetics (PKs) in multiple myeloma (MM) patients (pts) with various renal functions.
Authors: Yanshuo Cao, Eric Xueyu Chen, Lisa W Le, Olga Levina, Harminder Paul, Sumeet Kakar, Anthea Lau, Hongzhuan Chen, Christine Chen
Journal: Journal of Clinical Oncology (2018)

8039 Background: LEN is a backbone drug used in the treatment of MM. Because over 80% LEN is excreted unchanged in urine, dose modifications for RD are recommended, based on PK evaluation following single dose LEN in non-malignant renal failure. In this analysis, MM pts with varying degrees of RD after single and multiple dosing of LEN were evaluated for PK to validate these dosing recommendations. Methods: Previously untreated MM pts received LEN in combination with dexamethasone according to creatinine clearance (CrCL) as recommended by the current LEN label. CrCL was calculated based on 24-hour urine collection. Serial venous blood samples were obtained on Days 1 and 17 and analyzed for LEN. PK parameters were calculated using non-compartmental methods. Results: A total of 25 pts were enrolled, 9 pts with normal renal function (CrCl ≥ 60 ml/min), 8 with moderate RD (30 ≤ CrCl < 60 ml/min), and 8 with severe RD (CrCL < 30 ml/min or on dialysis). Median age: 59 years (range: 39-69); male/female: 16/9. After a single dose, LEN half-life increased with RD (4.1 vs 6.7 vs 11.1 hours, p < 0.01). Plasma LEN concentrations were lowest in moderate RD, resulting in significantly lower maximum concentration (Cmax) and area under concentration-time curve (AUC). LEN clearance decreased with more advanced RD, and correlated with calculated CrCL, with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula providing the best correlation compared to the Modification of Diet in Renal Disease (MDRD) formula and the Cockcroft-Gault formula. There was no LEN accumulation between Day 1 and Day 17 in pts with normal renal function or moderate RD. Cmax and AUC were significantly lower on Day 17 for pts with severe RD (413.8 ng/ml vs 71.1 ng/ml, p < 0.0001, and 4946 ng×hr/ml vs 538 ng×hr/ml, p = 0.002). Conclusions: MM pts with moderate RD are significantly under-dosed with the current LEN dosing recommendation. LEN PKs after multiple doses are similar for pts with normal or moderate RD, but those with severe RD may benefit from therapeutic drug monitoring and dose adjustment. The CKD-EPI formula should be used to calculate CrCL and LEN dose determination. The current LEN dose recommendation should be revised for pts with moderate RD. Clinical trial information: NCT01270932.
Utility of circulating tumor DNA (ctDNA) in the management of patients with gastrointestinal stromal tumor (GIST): Analysis of 152 patients.
Authors: Junaid Arshad, Ali Roberts, Rebecca J Nagy, Breelyn A. Wilky, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2018)

11539 Background: GIST is the most common sarcoma of the GI tract. Management of GIST is determined by KIT, PDGFR, or other genomic alterations. Tissue diagnosis has been the mainstay of the biomarker assessment but next generation sequencing (NGS) - based analysis of ctDNA is a novel, effective and non-invasive alternative. Methods: DNA sequencing of the circulating tumor DNA (ctDNA) was perfomed on blood samples from 152 patients. Samples were collected, shipped at room temperature and centrifuged to isolate plasma. DNA was extracted, concentrated, and quantified. Results: Of 152 unique patients, 72 (47%) females and 80 (52%) males with a median age of 59. 41 ( 27%) patients did not test positive for either KIT or PDGFRA while 111 (73%) had either KIT or PDGFRA mutation. 6 patients were positive for both KIT and PDGFRA mutations. Of these 6, 1 had KIT amp plus PDGFRA amp, then only a KIT point mutation 6 months later. 2 had KIT plus PDGFRA point mutations. Most of the imatinib resistance mutations were missense mutations and were found in males (p = .005). There were 3 (2%) patients positive for PDGFRA D842V with resistance to imatinib. Mutations other than KIT or PDGFRA included EGFR 8(7%), ERBB2 8 (7%), NF1 7 (6%), PIK3CA 7(6%), ARID1A 6(5%), FGFR2 6(5%), KRAS 6(5%), BRCA2 5 4%), MET 5(4%), PTEN 5(4%), MYC 4(3%), NTRK1 4(3%). Overall, the average number of mutations at first test: 3 ( range 1-11). The average highest MAF: 4.74% (RANGE 0-52.98%), MEDIAN 0.72%. Of the the 25 patients with clinical annotation 15 (10%) had treatment impacted, 20 (13%) identified resistance mutations, and and 30 (20%) of patients were found to harbor additional mutations. Conclusions: Digital DNA sequencing from ctDNA provides a reliable picture of the genomic profile in GIST. However, there is limited information related to resistance, prognosis or predictive role along with the effect of chemotherapy. Further validation and evaluation of clinical utility is warranted.