tbuckley/cabot-search huggingface dataset:
Effects of molecular tumor board and different NGS panels implementation for the treatment of patients with cancer.
Authors: Christian Diego Rolfo, Paolo Manca, Roberto Salgado, Peter Van Dam, Amelie Dendooven, Andreia Machado Coelho, Ferri Pep, Annemie Rutten, Willem Lybaert, Joanna Vermeij, Thomas Gevaert, Sofie Metsu, Steven J Van Laere, Marc Peeters, Patrick Pauwels
Journal: Journal of Clinical Oncology (2018)

e18511 Background: Molecular Tumor Boards (MTBs) for patient selection and assessment of treatment options were created for adequate precision medicine delivering. We evaluated the implementation of both the MTB of the region of Antwerp/Belgium and different next generation sequencing (NGS) panels – comprising panels performed on liquid biopsy specimens – in treatments selection. Methods: Patients progressing to standard treatments who underwent NGS of tumor tissue, cell-free circulating tumor DNA (ctDNA) or both were included. The MTB expressed either a positive or negative opinion for the inclusion of the patient in a clinical trial, in an expanded access or as part of a compassionate use program. The alterations found were matched with OncoKB levels (MSKCC) of evidence for alteration-specific treatments. Results: The MTB evaluated 173 cases with at least one NGS panel available. Overall, the MTB proposed alteration-specific targeted therapy to 72 out of 173 patients (41.6%). 49 patients (28.3%) were indicated to enter a clinical trial. In 28 patients with matched lbNGS and ttNGS, lbNGS and ttNGS detected, respectively, 48 and 16 point mutations. In this cohort the MTB could allocate 7 patients (25%) to a clinical trial even in the absence of a OncoKB recommendation level ≥ 3b and proposed an alternative treatment to 4 patients (14.3%) with a ≥ 3b recommendation. Discussion: Previously, the use of NGS panels were reported to improve patients outcomes. This is not confirmed by the SHIVA trial. Previous studies reported only on the added value of use of an MTB without comparison to a commonly used standard of variant-classification such as OncoKb. To our knowledge, we are the first to compare MTB decisions with a set of evidence-based recommendations, thus making it possible to measure the impact of MTB decisions as a change of treatment. The remarkably higher sensitivity of lbNGS raises the question on whether ttNGS can be considered reliable in such settings. Conclusions: Our MTB allows patients with refractory cancer to be included in clinical trials and improves the precision of clinical decisions compared to a standardized set of mutation-driven recommendations.
Patterns of metastases, treatment (tx), and outcomes in bone predominant (BP) metastatic urothelial carcinoma (mUC).
Authors: Ariel Ann Nelson, Aman Opneja, Behtash Ghazi Nezami, Lee Evan Ponsky, Matthew David Wright, Patrick Mergler, Ravi Kumar Kyasaram, Cheryl Eitman, Krupen Patel, Gregory MacLennan, Matthew M. Cooney, Petros Grivas, Pedro C. Barata, Jorge A. Garcia, Pingfu Fu, Christopher J. Hoimes
Journal: Journal of Clinical Oncology (2018)

e16523 Background: The clinical phenotype of BP mUC includes patients (pts) with at least as many bone lesions as non-bone lesions. UC molecular subtypes that may correlate with BP phenotype and prognosis have been defined. Better understanding and treatment of the BP phenotype is needed. To characterize this BP population, we determined the patterns of spread, tx responses, overall survival (OS), and opioid use amongst BP and non-bone predominant (NBP) pts. Methods: We searched our electronic medical record (EMR) and tumor board registry to identify pts with mUC who received treatment at our institution. Demographic, clinicopathologic, treatment, response, progression-free survival (PFS), OS, and opioid daily dosage data were recorded. Imaging was reviewed to identify NBP or BP disease based on imaging criteria. Results: We identified 67 pts (58% men), median age 66, 33% of those were BP. Overall, 37% of pts had de novo metastatic disease; of those, 40% were BP. All de novo metastatic BP pts had bone metastases (mets), 30% had lymph node (LN) mets, none had lung mets. NBP pts had de novo mets to lung (80%), LN (47%) and bone (40%). BP pts who progressed to mUC, progressed in the bone (75%) and LN (33%) vs NBP pts who had progression primarily to LN (60%) and few to bone (13%). 39% of pts received palliative radiation, 54% were BP and all those received radiation to bone vs 58% of NBP pts. Despite similar use of platinum and taxane based tx in the BP vs NBP cohorts (86% vs 78% and 32% vs 31% of pts, respectively) there was a significant increase in daily opioid use in the BP group from first to last oncology visit (p=0.032). Median OS from date of UC diagnosis was 23.7 months with a significant difference between BP and NBP cohorts (15.2 vs 28 months, p=0.026). PFS from date of 1st line treatment for the entire cohort was 3.4 months and was not significantly different between BP and NBP cohorts (p=0.389). Conclusions: BP mUC pts have a distinct pattern of metastatic progression, higher opioid daily dosages, and shorter OS from time of diagnosis compared to NBP pts. Clinical trials focusing on interventions for palliative and efficacy endpoints in the BP subtype are needed. Further molecular analyses on pathologic specimens are planned.
Neoadjuvant radiotherapy vs. surgery alone for stage II/III mid-low rectal cancer with or without high risk factors: A multicenter randomized trial.
Authors: Ziqiang Wang, Xiangbing Deng, Ping Liu, Xin Wang, Dan Jiang, Mingtian Wei, Yuanchuan Zhang, Qingbin Wu, Wanbin He, Xuyang Yang, Tinghan Yang, Meng Wang, Bing Wu, Yanjun Liu, Wenjian Meng, Meng Qiu, Hua Zhuang, Yunfeng Li, Feng Xu, Zongguang Zhou
Journal: Journal of Clinical Oncology (2017)

3537 Background: Neoadjuvant (chemo)radiotherapy (NRT) is the standard treatment for locally advanced rectal cancer (RC),which reducing local recurrence (LR) without survival benefit. There are also reports claiming similar local control achieved by surgery alone in selected patients, that raising the issue of omitting NRT in low risk patients. The aim of this study was to clarify the benefit of NRT in stage II/III RC with or without high risk factors. Methods: Eligible participants with mid-low cT3-4aN± RC were included and classified as high risk patients and low risk patients according to the clinical staging. High risk was defined as T3 tumor with extramural spread &gt; 5mm, T4a or lymph node &gt; 8mm. High and low risk patients were both randomized into two groups: high risk radiotherapy (HRR) or high risk surgery (HRS), low risk radiotherapy (LRR) or low risk surgery (LRS) separately. Patients in HRR and LRR received short term NRT (5*5Gy) + TME, while patients in HRS and LRS underwent surgery alone. The primary endpoint was 3-y LR. The secondary endpoints were OS, DFS, quality of surgery and safety. Results: From Jun. 2011 to Dec. 2015,401 consecutive patients were analyzed (LRS 99, LRR 97, HRS 102, HRR 103). As for primary endpoint, 3-y LR was obviously lower in low risk patients (3% vs. 9%, p = 0.026), but comparable in LRR vs. LRS (3% vs. 2%, p = 0.32) and HRR vs. HRS (11% vs. 7%, p = 0.42). Concerning secondary endpoints, low risk patients were favorable in 3-y OS (p &lt; 0.001), DFS (p &lt; 0.001), and distant metastasis (p = 0.001), compared to the high risk. And 3-y OS in HRR was higher than that in HRS (82% vs. 70%, p = 0.032). NRT caused 1.5% grade 3/4°radiation-related complications with a higher rate of late leakage (4.5% vs 0.0%, p = 0.004). Besides, positive CRM was higher in HRS (HRS 14.7% vs. HRR 4.9%, p = 0.017). Conclusions: Depth of extramural spread and lymph node status are favorable predictors for LR and survival. NRT may improve OS for high-risk RC. Low-risk RC has very low LR, suggesting against routine use of NRT. Relatively high LR and better OS in high risk patients justify use of NRT or NCR. Short-term radiation is safe for Asian patients, given caution be paid to more late leakage. Clinical trial information: NCT01437514.
A phase I study of the PI3K inhibitor buplarlisib (B) with concurrent chemoradiotherapy (CRT) in patients with high risk locally advanced squamous cell cancer of the head and neck (LASCCHN).
Authors: Jochen H. Lorch, Roy B. Tishler, Nicole Grace Chau, Glenn J. Hanna, Guilherme Rabinowits, Jonathan Daniel Schoenfeld, Danielle Nina Margalit, Anne M. O'Neill, Donald Annino, Laura A Goguen, Ravi Uppaluri, Ethan James Harris, Alec Kacew, Julian Huang, Laura Ma, Patricia Mchugh, Robert I. Haddad
Journal: Journal of Clinical Oncology (2018)

6071 Background: Prognosis in smokers with LASCCHN remains poor. Activating mutations of PI3K are linked to poor outcome and PI3K activation in response to RT is implicated in resistance to CRT. Methods: In this phase I study, the oral pan-PI3K inhibitor B combined with CRT was tested in pts with stage III/IV LASCCHN and ≥10 pack-year history of tobacco use treated with curative intent. Pts received B during a 2-week run-in phase and during CRT consisting of 70Gy/35fx of radiotherapy plus weekly cisplatin. Results: Twenty-three pts (19 m, 4 f) were enrolled. Four had stage III, 19 (83%) had stage IV disease. 18 were former smokers, 5 smoked currently. Primary tumor locations: Oral cavity (6, 26%), oropharynx (11, 48%), larynx (3, 13%), other 3 (13%). HPV was pos in 14 cases. Among 7 pts enrolled on dose level 1 (DL1) (B 40mg daily, CDDP 30mg/m2/IMRT), 1 pt experienced gr 4 rash. Among 6 patients on DL2 (B 40mg daily, CDDP 35 mg/m2/IMRT), DLTs were observed in 4 cases (gr 3 neutropenia, LFT abn, mucositis, rash). Ten additional pts were enrolled at the RP2D (DL1). Additional gr 3 AEs included anorexia, anemia, dysphagia and confusion. One pt experienced grade 4 hyperamylasemia. With a median follow-up of 12 months (range 3-24), 2 pts (2/9%) had recurrence, one of whom died .Five pts had a response to buparlisib alone during the run-in phase assessed clinically or radiographically. To date, targeted NexGen sequencing was available in 8 pts. 4/5 cases with response to B alone had sequencing results and demonstrated mutations in FANCD2/EP300; FANCA/FGFR3; FANCI/FLT1 and PIC3CA/EP300. The patient who died had PIC3CA/STL11 mutations. Conclusions: B was tolerable in combination with CRT and appears to have promising activity. Genetic analysis is ongoing and may be helpful to identify patients suitable for this approach. Clinical trial information: NCT02113878.
Impact of earlier adjuvant chemotherapy after surgery on prognosis in patients with operable gastric cancer: A propensity score matched analysis.
Authors: Mi-Jung Kim, Keun Won Ryu, Bang Wool Eom, Hong Man Yoon, Rak Yeong Son, Hark Kyun Kim, Myeong-Cherl Kook, Young Woo Kim, Young Iee Park
Journal: Journal of Clinical Oncology (2016)

4057 Background: Adjuvant chemotherapy improves survival after curative D2 gastrectomy in patients with operable gastric cancer. However, the optimal timing of initiation of adjuvant chemotherapy after surgery is not clearly defined. Methods: Patients with operable gastric cancer who had undergone adjuvant chemotherapy after D2 gastrectomy for stage II and III gastric cancer from January 2009 to December 2012 at National Cancer Center, South Korea were included. Patients were classified into the two groups ( ≤ 6 weeks vs. > 6 weeks) according to the time to initiation of adjuvant chemotherapy after surgery. Propensity score matching (PSM) was performed to adjust the difference of baseline clinicopathologic characteristics between the two groups. Survival outcomes were compared between groups after PSM. Results: Of 484 enrolled patients, 367 patients started adjuvant chemotherapy within 6 weeks after surgery (early group), and 117 patients started adjuvant chemotherapy more than 6 weeks after surgery (late group). After PSM, 232 patients were included (116 in the early group vs. 116 in the late group). In pre-PSM analysis, baseline characteristics were significantly different for age, surgical complication, the type of chemotherapy regimen and the degree of chemotherapy completion between the early and late groups. With median follow up of 60 months (range, 37.3 – 85.5), the 5-year overall survival (OS) rate was 71.4% in the early group and 74.5% in the late group (P = 0.864). The 5-year disease-free survival (DFS) was 66.6% vs. 69.8%, respectively (P = 0.801). After PSM, baseline characteristics were well balanced between groups, but there was no significant difference for survival outcomes between groups: for 5-year OS rate, 76.4% vs. 75.1% (P = 0.741), for 5-year DFS rate, 70.2% vs. 70.4% (P = 0.550). Conclusions: This study suggests that adjuvant chemotherapy is equally effective regardless of the initiation of adjuvant chemotherapy within 6 weeks after surgery. Clinicians should consider allowing adequate time for patient recovery after D2 gastrectomy.
Change in tumor lysis syndrome risk after lead-in treatment in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax for chronic lymphocytic leukemia.
Authors: Kerry Anne Rogers, Ying Huang, Amy S. Ruppert, Todd Civils, Subhashish Das, Christin Fedor, W. Thomas Whitlow, Farrukh T Awan, Kami J. Maddocks, Jennifer Ann Woyach, Jeffrey Alan Jones, John C. Byrd
Journal: Journal of Clinical Oncology (2018)

7528 Background: Venetoclax (VEN) is highly effective for the treatment of chronic lymphocytic leukemia (CLL). Tumor lysis syndrome (TLS) during VEN initiation is a major risk and management, including hospitalization for high risk patients, increases treatment burden and limits use. Strategies to decrease TLS risk are of interest. We reviewed our phase 1b/2 study of combination obinutuzumab (OBIN), ibrutinib (IBR), and VEN to understand how lead-in OBIN and IBR change TLS risk. Methods: All study patients who completed 3 cycles (C) of treatment were included. Agents were started sequentially over C1-3 with OBIN C1 (C1 D1: 100mg, C1 D2: 900mg, C1 D8,D15: 1,000mg, C2-8 D1: 1,000mg), IBR C2 (C2-14 D1-28: 420mg), and VEN C3. Risk for TLS was assessed according to the VEN US label at baseline and prior to C3. We recorded absolute lymphocyte count (ALC) and lymph node (LN) sum of the product of longest diameters (SPD) and tested for changes in TLS risk between C1 and C3 using the Wilcoxon signed-rank test. Results: 61 patients were included: 36 relapsed or refractory and 25 treatment naïve. ALC and LN (C1-3) and TLS risk (baseline, C3) are in Table 1. ALC significantly decreased from C1 to C3 (p < 0.0001) with a median change of -93.2% (range -99.6-194.5%). LN similarly decreased (p < 0.0001). OBIN attenuated IBR lymphocytosis with a median ALC change C2 to C3 of 2.1 (range -0.3-46.7). Twelve (20%) patients reduced TLS risk from high to medium, 26 (43%) from medium to low, and 23 (38%) had no change. There were no incidents of clinical or laboratory TLS. Conclusions: Lead-in OBIN and IBR decreased TLS risk in the majority of high (12/19, 63%) or medium (26/34, 76%) risk patients when reassessed prior to VEN. This strategy may improve the safety of VEN initiation, allow some initially high risk patients to avoid hospitalization, and expand settings where VEN is used. Clinical trial information: NCT02427451.CLL burden and TLS risk (n = 61). ALC in k/uL, median (range) - C1 69.7 (0.2-445.6) C2 1.1 (0.2-10.2) C3 3.7 (0.3-48.3) Palpable LN SPD in cm, median (range) - C1 12.3 (0-235) C2 0.5 (0-158) C3 0 (0-47) Baseline TLS risk, n (%) - High 19 (31) Medium 34 (56) Low 8 (13) C3 TLS Risk, n (%) - High 7(11) Medium 20 (33) Low 34 (56)
Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML).
Authors: Courtney Denton Dinardo, Anthony Selwyn Stein, Eytan M. Stein, Amir Tahmasb Fathi, Andre C. Schuh, Pau Montesinos Fernández, Olatoyosi Odenike, Hagop M. Kantarjian, Richard M. Stone, Robert Collins, Giovanni Martinelli, Montserrat Arnan, Bin Wu, Daniel O. Koralek, Jason Van Oostendorp, Jing Gong, Kyle J. MacBeth, Paresh Vyas
Journal: Journal of Clinical Oncology (2018)

7042 Background: Ivosidenib (IVO; AG-120) and enasidenib (ENA; AG-221) are oral inhibitors of mIDH1 and mIDH2 proteins. In vitro, mIDH inhibitor + AZA combinations enhance cell differentiation and apoptosis. We report results of an ongoing phase 1b/2 study of mIDH inhibitors + AZA in patients (pts) with newly diagnosed (ND) AML (NCT02677922). Methods: Adult pts with mIDH ND-AML ineligible for intensive treatment (Tx) receive continuous IVO (mIDH1) 500 mg or ENA (mIDH2) 100 or 200 mg QD, plus SC AZA 75 mg/m2 x 7d, in repeated 28d cycles. Response is defined by IWG 2003 AML criteria. Results: At data cutoff (Sep 1, 2017) 17 pts had received IVO 500 mg (n = 11) or ENA 100 mg (3) or 200 mg (3) + AZA in the phase 1b portion of the study; 11 were ongoing. IVO: Median age was 76 yrs. Median number of Tx cycles was 3 (range 1-13).Three pts discontinued Tx, 2 due to progressive disease (PD).AEs in ≥4 pts (any grade) were nausea (n = 8), constipation (6), fatigue (5) and diarrhea (4). Grade 3-4 hematological AEs (Table) occurred at similar frequency to what has been reported for AZA alone. Serious AEs in > 1 pt were pneumonia, febrile neutropenia (n = 2 each). Eight of 11 pts responded, including 4 complete remissions (CRs). ENA:Median age was 68 yrs. Median number of Tx cycles was 9 (1-13). Three pts discontinued Tx, 2 due to PD. Most common AEs (any grade) were nausea and hyperbilirubinemia (n = 4 each). Serious AEs in > 1 pt were pyrexia, bilirubin increase, pneumonia (n = 2 each). Four of 6 pts responded, including 2 CRs. Conclusions: mIDH inhibitor + AZA regimens were generally well tolerated in pts with ND-AML. Most AEs were grade 1-2 GI events and ENA-related indirect bilirubin elevations due to off-target UGT1A1 inhibition. Response rates are encouraging. Phase 1b enrollment completed in late 2017; updated data for all 23 IVO and 6 ENA pts will be presented, as well as longitudinal changes in mIDH variant allele frequencies. Enrollment continues in the phase 2 portion of this study (ENA + AZA) and the phase 3 AGILE study of IVO + AZA (NCT03173248). Clinical trial information: NCT02677922.Grade 3-4 hematological AEs. IVO 500 mg + AZA (n = 11) ENA 100 mg + AZA (n = 3) ENA 200 mg + AZA (n = 3) n Thrombocytopenia 1 0 1 Anemia 2 0 1 Febrile neutropenia 2 0 1 Neutropenia 1 0 2 Lymphocyte decrease 0 0 1 WBC decrease 0 0 1
Trends in ovarian cancer incidence and relative survival in the U.S. by race/ethnicity and histologic subtypes: A SEER analysis 2000-2012.
Authors: Hyo K. Park, Julie Ruterbusch, Michele L. Cote
Journal: Journal of Clinical Oncology (2016)

e17051 Background: Incidence rates have been decreasing and survival of ovarian cancer has improved over the past three decades in the United States (U.S.); however, incidence and survival rates for non-serous histologic subtypes in racial/ethnic minorities remain relatively unknown. We examined the trends in incidence and survival rates for epithelial ovarian cancer by histologic subtypes and race/ethnic groups in the U.S. Methods: Ovarian cancer incidence and mortality data were obtained fromSurveillance, Epidemiology, and End Results (SEER) database from 2000 to 2012. Age-adjusted incidence and annual percentage changes (APC) were calculated by histology and race/ethnicity subgroups, and also stratified by age at diagnosis. Five-year relative survival rates were calculated by stage and race/ethnicity for each histologic subtypes for women diagnosed with ovarian cancer between 2000 and 2008. Results: A small but significant decrease in adjusted incidence rates of epithelial ovarian cancer was seen for non-Hispanic white (NHW) and Hispanic women over 13 years (APC -1.6, -1.2, respectively) while incidence rates in non-Hispanic black (NHB) and Asian women remained relatively stable. Rates decreased among all subtypes, except a significant increase in incidence rate was observed in Asian women with clear cell carcinoma (APC 2.1). In addition, the decreasing incidence rates were seen across all age-strata. The five-year relative survival rates for all histologic subtypes combined were significantly lower in NHB women with localized (84% vs 90%) and distant (19% vs. 29%) disease compared to NHW. Trends towards poorer five-year relative survival in NHB compared to NHW women were observed across all histology subtypes and stages, but not all were statistically significant. Hispanic and Asian women had similar five-year relative survival compared to NHW women. Conclusions: Overall incidence rates of epithelial ovarian cancer decreased from 2000 to 2012 but trends varied by histologic and race/ethnic subgroups.Poor relative survival in NHB women compared to NHW counterparts were observed across all histologic subtypes and were more pronounced for distant disease.
Lasofoxifene efficacy in a mammary intraductal (MIND) xenograft model of ERα+ breast cancer.
Authors: Muriel Laine, Marianne Greene, Ya-fang Chang, Linda Phung, Richard Hiipakka, Barry Komm, Geoffrey Greene
Journal: Journal of Clinical Oncology (2018)

e13054 Background: Postmenopausal ERα+ breast cancer patients are routinely treated with tamoxifen or an aromatase inhibitor as first line endocrine therapy. However, a number of patients that progress to metastatic disease become resistant to endocrine therapy, which correlates with the acquisition of activating somatic mutations in the estrogen receptor protein. The two most common ERα mutations are Y537S and D538G, both of which confer ERα constitutive activity. Lasofoxifene is a SERM originally developed to treat vulvovaginal atrophy and osteoporosis. In this study, we analyzed the efficacy of lasofoxifene in the treatment of MCF7 tumor explant models that were engineered with CRISPR/Cas9 to express Y537S and D538G ERα. Methods: To better mimic the natural environment of infiltrating ductal ERα+ breast cancers, NSG mice were injected, via the nipple in the inguinal mammary glands, with three MCF7 cell variants: MCF7 WT, MCF7 Y537S and MCF7 D538G. Prior to injection, cells were labeled with a luciferase reporter to monitor tumor growth in vivo using a Xenogen IVIS imager. Mice were treated with three different doses of lasofoxifene (1, 5, and 10mg/kg; 5days/wk SQ), vehicle, or the SERD, fulvestrant, (5 mg SQ once per week = 250 mg/kg). Results: After 70 days of treatment, tumor growth as measured by tumor weight, of MCF7 WT and MCF7 D538G explants was significantly inhibited versus vehicle by 10 mg/kg lasofoxifene. For the MCF7 Y537S explants, lasofoxifene significantly inhibited the growth of tumors at all doses. Fulvestrant also significantly inhibited MCF7 Y537S explants, but to a lesser extent. Compared to fulvestrant, lasofoxifene was significantly more effective at 5 and 10 mg/kg for the MCF7 Y537S tumors. Conclusions: These data suggest that lasofoxifene has potential as an adjuvant therapy for metastatic breast cancers, with particular use preference in those that express constitutively active D538G and Y537S mutant ERα.
Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial
Authors: Alvaro Romera, Sergiy Peredpaya, Yaroslav Shparyk, Igor Bondarenko, Giovanni Mendonça Bariani, Kathia Cristina Abdalla, Enrique Roca, Fábio Franke, Felipe Melo Cruz, Anita Ramesh, Vikas Ostwal, Pradeep Shah, Sajeed Abdul Rahuman, Alexandra Paravisini, Camino Huerga, Ana Del Campo García, Susana Millán
Journal: The Lancet. Gastroenterology & hepatology (2018)