tbuckley/cabot-search huggingface dataset:
New docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer.
Authors: Michel Demeule, Borhane Annabi, Jean-Christophe Currie, Alain Larocque, Cyndia Charfi, Richard Béliveau
Journal: Journal of Clinical Oncology (2019)

e12556 Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease which still lacks defined molecular biomarkers. In the last decade, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the Sortilin (SORT1) receptor has been reported in TNBC patients. Given SORT1 functions in protein internalization, sorting and trafficking, we developed a new peptide-anticancer drug conjugation platform to target SORT1-positive breast cancer by linking Docetaxel to a peptide (KA-peptide) that specifically targets SORT1. Methods: MDA-MB-231 cells were used as a TNBC cell model for in vitro and in vivo xenograft (CD1 nude mice) assays. Cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. Results: In MDA-MB-231, the Docetaxel-KA-peptide conjugate (DoceKA) exerted potent anti-proliferative and anti-migratory activities in vitro. DoceKA triggered faster and higher cell death mechanisms than did free Docetaxel alone. The apoptotic and anti-migratory effects were reversed by the SORT1 ligands Neurotensin and Progranulin, and upon siRNA-mediated silencing of SORT1. DoceKA altered microtubules polymerization and triggered the down-regulation of IL-6, Survivin, Bcl-xL and mutant p53 pro-survival biomarkers. In vivo, DoceKA exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Conclusions: Collectively, we demonstrate that DoceKA is specifically internalized through a receptor-mediated mechanism. Such property allows for targeting SORT1-positive breast cancers, and makes DoceKA a promising novel therapy for the treatment of TNBC.
Impact of precision medicine on clinical care: A single institution retrospective study.
Authors: Rajvi Patel, Ryann Quinn, Xinhua Zhu
Journal: Journal of Clinical Oncology (2019)

e14601 Background: In Oncology, precision medicine (PM) looks at molecular characteristics of tumors instead of traditional histology to determine treatment strategies. Examples are EGFR, ALK, BRAF, ROS1 and PD-L1 in non-small cell lung cancer, HER2 in breast and gastric cancer, K-RAS, N-RAS in colon cancer, and MMR/MSI in all solid tumors. Genomic testing is commonly done for patients with advanced cancer resistant to standard treatment. FoundationOne-CDx (F1CDx) is expensive but only FDA approved test for somatic genomic profiling of tumors. It is necessary to review an expensive test and its impact on clinical care. At our institution, we have patients who have had F1CDx testing. Our aim was to determine proportion of tumors that have actionable mutation (AM) for which there are currently FDA or non-FDA approved targeted treatment(s) (TT) available, proportion of pts who received TT, and barriers to receiving TT. Methods: Retrospective study of 1000 patients treated at our institution who had F1CDx testing done between September 2012 and July 2018. Variables collected included primary tumor type, F1CDx results, treatments received, and any barriers. Descriptive statistics including frequencies and proportions were utilized. Results: Of 1000 pts, 652 had tumors harboring AM. Of the 652 pts: 42 went on a clinical trial, 165 received standard next line chemotherapy, 135 received TT (38 pts received currently non-FDA approved TT), 144 either went on hospice or died prior to receiving treatment, 142 were lost to follow up, 21 were treated with surgery only, and 3 had issues with insurance approval of TT. Conclusions: Of the 65% of pts with tumors harboring AM, only 20% received TT. 25% of pts received standard next line chemotherapy. Going on hospice and being lost to follow up largely accounted for patients not receiving TT. Therefore, treating physicians should strongly consider pts’ performance status and co-morbidities prior to sending expensive genomic testing as it may have limited impact on clinical outcome. Our next steps to further investigate will be to look at objective response rate, progression free survival, and overall survival in pts who received non-FDA approved TT.
Use, attitudes, and perceptions of tumor genomic testing: Survey of TAPUR physicians.
Authors: Suanna S. Bruinooge, Amylou C. Dueck, Stacy W. Gray, Nicole L. Butler, Carol B. White, Mary Lou Smith, Pam K. Mangat, Allison W. Kurian, Elda Railey, Sarah T. Hawley, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2019)

6531 Background: This survey of Targeted Agent and Profiling Utilization Registry (TAPUR) Study physicians examined use, attitudes, and perception of tumor genomic testing (TGT), defined as any DNA test performed on tumor specimen/plasma. TAPUR is a multibasket study of marketed agents targeting tumor genomics. Methods: 333 physicians at 54 TAPUR sites were surveyed (2016-2017). Survey domains included use of TGT, barriers to ordering TGT, and genomic confidence. Surveys included 3 scenarios for TGT ordering 1) pretreated advanced cancer patients (pts) without options, 2) newly diagnosed, untreated, metastatic pts and 3) early stage/potentially curable pts with standard options. Data were analyzed with descriptive statistics. Results: 112 physicians responded (33%). The table displays demographics and genomic confidence. Respondents reported a median of 25% of their pts had TGT in past 12 months for trials/routine care (range 0-85%). Barriers to testing included access to tumor specimen (86%), insurance coverage (67%), concerns that results will not be actionable (55%), and test issues (wait time, unsure which test/lab to use, test accuracy) (54%). TGT was ordered most often for scenario 1 (96%) and 2 pts (70%). Few respondents (32%) would order testing in scenario 3. Of those who reported testing for scenarios 1 &amp; 2, most told pts that results could inform treatment/prognosis/trials (97%) or may be uninformative (84%). In all scenarios, pt expectations of TGT results were discussed prior to testing. A minority reported frequently telling pts in advance that results could inform heritable cancer susceptibility (37%). Conclusions: Confidence in using TGT was high. TGT was performed most for pts with advanced cancer and few options. Availability of specimens was largest barrier reported, indicating the importance of blood-based tests. Few respondents discussed implications of germline findings in advance, despite growing evidence of germline findings in somatic testing. [Table: see text]
Adjuvant axitinib dose modification in renal cell carcinoma (RCC): Analysis of the ATLAS study.
Authors: David I. Quinn, Tae Gyun Kwon, Masatoshi Eto, Dingwei Ye, Hideaki Miyake, Seong Il Seo, Seok-Soo Byun, Jae-Lyun Lee, Viraj A. Master, Chi-Fai Ng, Rolf Gerhard Linke, Brad Rosbrook, Mahgull Nazar Thakur, Enrique Grande, Marine Gross-Goupil, Chao-Hsiang Chang
Journal: Journal of Clinical Oncology (2019)

4573 Background: The ATLAS trial compared axitinib vs placebo in patients (pts) with locoregional RCC at risk of recurrence after nephrectomy. ATLAS was stopped due to futility at a pre-planned interim analysis; results showed no difference in disease-free survival (DFS) between the treatment arms. We explored whether pts treated longer with axitinib achieved better outcomes and the impact of axitinib dose reduction or increase on DFS – the trial required dose reduction for toxicity and allowed dose escalation in the event of no or minimal toxicity. Methods: Pts in ATLAS received a maximum of 3 y of study treatment. A landmark analysis was conducted comparing pts treated with axitinib ≤1 y vs &gt; 1 y. Pts who recurred or censored prior to 1 y were excluded. An analysis of daily dose characteristics was undertaken to compare patients whose dose was reduced and whose dose was increased to those with a stable dose of axitinib. Cox proportional hazard model was used for DFS analysis. Toxicity analysis using a 90-day landmark was also conducted. Results: Overall, 264 axitinib-treated pts were included in this analysis. Of these 42 pts were treated for ≤1 y and 222 pts for &gt; 1 y. Pts remaining on axitinib &gt; 1 y vs ≤1 y did not have different DFS (hazard ratio [HR] = 0.572, 95% confidence interval [CI]: 0.247–1.327, P= 0.1874). Pts with dose reduction had longer DFS than those with a stable dose (HR = 0.458, CI: 0.305–0.687, P= 0.0001). Pts with dose increase did not have DFS different to stable dose pts (HR = 1.936, CI: 0.937–3.997, P= 0.0685). No difference in DFS in pts experiencing grade ≥2 adverse events (AEs) vs grade &lt; 2 AEs within 90 d of start of treatment was observed (HR = 0.885, CI: 0.419–1.869, P= 0.7488). Pts experiencing grade ≥3 AEs within 90 d of start of treatment had shorter DFS compared to those that did not (HR = 1.643, CI: 0.963–2.801, P= 0.0653). Conclusions: DFS did not vary based on duration of axitinib treatment, however, pts with dose reductions had longer DFS vs pts with stable dose or dose increases. This difference suggests that there is a relation between axitinib exposure and DFS as seen with sunitinib in the advanced setting and pazopanib in the PROTECT study.
Randomized phase II CLIO study on olaparib monotherapy versus chemotherapy in platinum-resistant ovarian cancer.
Authors: Adriaan Vanderstichele, Els Van Nieuwenhuysen, Sileny Han, Nicole Concin, Toon Van Gorp, Patrick Berteloot, Patrick Neven, Pieter Busschaert, Diether Lambrechts, Ignace Vergote
Journal: Journal of Clinical Oncology (2019)

5507 Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m 2 q 4 wks; Topotecan 1.25 mg/m 2 day 1—5 q 3 wks; Paclitaxel 80 mg/m 2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m 2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.
Risk of colon adenoma in patients with breast cancer.
Authors: Yinghong Wang, Hamzah Abu-Sbeih, Faisal Ali, Phillip S. Ge, Carlos Hernando Barcenas, Phillip Lum, Wei Qiao, Robert Bresalier, Manoop S. Bhutani, Raju S. Gottumukkala
Journal: Journal of Clinical Oncology (2019)

1541 Background: In our clinical practice at a tertiary cancer center, we have observed increased adenoma detection rate (ADR) in patients with breast cancer. Here, we describe ADR in patients with breast cancer to define the appropriate timing to initiate colonoscopy screening in these patients. Methods: We conducted a retrospective study of patients with breast cancer who underwent a colonoscopy after their diagnosis of breast cancer between 2000 and 2017. A control group ( n = 3295) comprised patients without any type of cancer who underwent their first screening colonoscopy between 2008 and 2017 was used in the logistic regression. Results: Of the 62,820 patients who had a diagnosis of breast cancer, 3304 were included. The mean age was 59 years. Regarding ADR, 1803 patients (55%) had adenomas. High-grade dysplasia was evident in 28% of polyps and invasive adenocarcinoma in 172 (5%). The median time from breast cancer diagnosis to adenoma detection was 3 years (IQR 1-6). The ADR was 21% in patients younger than 40 years ( n=63), 39% in patients between 40 and 50 years ( n=314), 54% in patients between 50 and 60 years ( n=1420), and 60% in patients older than 60 years ( n=1507). ADR in patients younger than 50 years of age who do not have a family history of colorectal cancer or a body mass index (BMI) higher than 30 kg/m 2 was 26%. A subsequent colonoscopy was performed in 831 patients who had colonic adenoma in the initial colonoscopy. The ADR was 40% in patients who had a repeat colonoscopy within 3 years, 50% within 3-5 years, and 53% &gt; 5 years. Multivariate logistic regression analyses revealed an increased risk of colon adenoma with older age, male sex, higher BMI, and personal history of breast cancer ( P&lt;0.05). Conclusions: In patients with breast cancer, ADR was higher than that of patients without history of cancer. Notably, breast cancer was an independent risk factor for colon adenoma. In patients who are younger than 40 years of age, screening colonoscopy should be considered within five years of breast cancer diagnosis. Multivariate logistic regression: risk factors of adenoma. [Table: see text]
Microsatellite instability and mutations in BRAF and KRAS in small bowel adenocarcinoma.
Authors: Vasiliki Michalaki, Andreas Polydorou, Theodosios Theodosopoulos, George Frangulidis, Nikolaos Dafnios, Matrona Frangou Plemmenou, Christos Papadimitriou
Journal: Journal of Clinical Oncology (2019)

e15037 Background: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) The aim of this study was to perform a comprehensive immunohistochemical.analysis of KRAS, NRAS, V600E BRAF mutations and microsatellite instability using a cohort of surgically resected cases in our institution. Methods: A total of 17 patients (10 males and 7 females; mean age, 56.2 years old; range, 45-75 years old) received chemotherapy due to non-curative tumor resection, unresectable tumor or post-operative recurrence. Twelve patents received fluoropirimidine and oxaliplatin based first line chemotherapy. Molecular targeted agents were administered to 15 patients, for whom it was their first- or second-line therapy. Results: KRAS mutations were found in 7 cases (41%), out of which 5 (29%) were in exons 12/13. BRAFV600E mutation was observed in 1/17 pt. Microsatellite instability was identified in 3/17pt (MSI; 18%), mainly related to a loss of expression of MLH1 protein. Univariate analysis revealed a PS of 0 (P=0.0226) and treatment with platinum-based chemotherapy (P=0.0047) were significant factors for an improved prognosis. Among the 12 patients who received oxaliplatin-based chemotherapy as a first-line chemotherapy, a PS of 0 (P=0.0255) and treatment with anti-EGFR agents (P=0.0127) were significant positive prognostic factors. Toxicities due to the molecular targeted agents were not experienced. The median overall survival time was 14.3 months (range, 3-52 months), the median DFS was 14.2 months and the median OS was 32 months. Conclusions: To date, there is no standard chemotherapy regimen for advanced SBAs and little is known about their molecular characteristics. The results of the present study indicate that oxaliplatin based chemotherapy containing molecular targeted agents is a well-tolerated and effective treatment option for SBA. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine.
Long-Term Evaluation and Clinical Spectrum of the Pubertal Abnormalities of Two Siblings Harboring NR0B1 Inactivating Mutation
Authors: Sorahia Domenice, Vinicius N. Brito, Priscila Cukier, Ivo J. P. Arnold, Mirian Y. Nishi, Ana C. Latronico, Berenice B. Mendonca
Journal: Endocrine Reviews (2012)
NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database.
Authors: Abhishek Tripathi, Edwin Lin, Roberto Nussenzveig, Mark Yandell, Sumanta K. Pal, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2019)

e16591 Background: Immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 pathway have shown modest activity in patients with advanced PC. Additional immunosuppressive mechanisms in the PC tumor microenvironment need to be investigated. Increased CD73 (encoded by NT5E) expression results in generation of immunosuppressive adenosine in the tumor microenvironment and has been associated with metastasis and poor survival in PC. Utilizing the TCGA dataset, we investigated the association of NT5E expression with the immune landscape of PC. Methods: RNA-seq data for 331 PC tumor samples and 51 normal adjacent tissue (NAT) samples was downloaded and log2 transformed. Patients were split into low, intermediate, and high expression groups based on NT5E expression (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean) in tumor and NAT. A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged tumor expression of 18 previously validated genes (Ayers et al, 2017). Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes (Charoentong et al, 2017). Immune cell abundance scores and TIS were compared between NT5E expression groups using the Mann-Whitney U test and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression in NAT was not associated with the TIS or expression of immune cell marker genes. In contrast, NT5E expression in tumor tissue correlated positively with TIS (P &lt; 0.001). Compared to tumors with low NT5E expression, those in high NT5E expression group had higher expression of central memory CD4 + , effector memory CD8 + , type 1 helper, NK and regulatory T (Treg) cell markers. Conclusions: In our analysis, NT5E expression correlated with markers of inflamed tumor phenotype in PC. Although NT5E expression was associated with higher CD8 + and CD4 + T cells, concurrent increase in Tregs could inhibit the infiltrating lymphocytes and promote tumor growth. Our findings indicate a possible role for the adenosine pathway as a mediator of immunosuppression in PC and a potential therapeutic target. AT and EL: Equal contribution
EGF (epidermal growth factor) receptor expression in blood: Prognostic biomarker in overall survival (OS) of patients with non-metastatic triple negative (TN) breast carcinoma.
Authors: Rogerio Agenor De Araujo, Felipe Andrés Cordero da Luz, Pedro Augusto do Amaral, Eduarda da Costa Marinho, Camila Piqui Nascimento, Etelvina Rocha Mosca, Patricia Ferreira Ribeiro Delfino, Rafael Mathias Antonioli, Thais Rezende Mendes, Breno Jeha Araújo, Marcelo José Barbosa Silva, Morun Bernardino Neto
Journal: Journal of Clinical Oncology (2019)

e14518 Background: EGF acts on tumor progression and its receptor can be measured by immunohistochemistry, or in the blood by immunoenzymatic method. This study quantified the expression of blood EGF receptors (bEGFR) in the molecular subtypes of breast carcinoma and their impact on OS. Methods: Prospective study with 125 patients (pts) and 89 healthy women (controls). All of them signed the free and detailed consent form. The blood collection was performed before the surgery (stages I–10pts; II–59pts) and before neoadjuvant chemotherapy (stage III-41pts) or palliative (stage IV–15pts). All the patients have made the protocol of a public service treatment. Measurement of bEGFR expression was done by the ELISA method. The statistical significance was set at p &lt; 0.05. Results: In a follow-up of 29.9 months (8-44m) 23 deaths occurred at 15.8 months (8-34.5m); 58pt had bEGFR &lt; 40ng/mL (E40-) and 67pt ≥40ng/mL (E40 +). TNs (28pt) had lower OS than Luminal (A = 29pts; B = 44pts) and HER2 (24pts) (p = 0.0020). But in TN E40- the significant difference in OS disappeared (TN versus Luminal A: p = 0.0785; TN versus Luminal B: p = 0.1995; TN versus HER2: p = 0.3017); which did not occur in TN E40 + (TN versus Luminal A: p = 0.0009; TN versus Luminal B: p = 0.0241; TN versus HER2: p = 0.0014). In OS of non-metastatic 24 TN (3pts stages 0/I; 13pts II; 8pts III) there was significant difference according to bEGFR expression (E40+ with lower OS than E40-, HR:5.49; 95%CI:1.26–15.07;p = 0.0159). In binary logistic regression, bEGFR was considered to be a significant predictor of death in TN non-metastatic, p = 0.008 (bEGFR of 30ng/mL = death probability of 6.7% until bEGFR of 80ng/mL = probability of death of 99.8%). There were no significant differences in bEGFR between patients and controls, among grades of histological differentiation, or in those with ki67 &gt; 14%. There was no difference in OS according to bEGFR in stages I, III or IV, except in stage II (E40+ with lower OS than E40-, HR:4.248;95% CI:1.229–14.68; p = 0.0460). Conclusions: Increased expression of bEGFR in non-metastatic TNs is a predictor of lower OS, with statistical significance.