tbuckley/cabot-search huggingface dataset:
Comparative molecular analyses of pancreatic cancer (PC): <i>KRAS</i> wild type vs. <i>KRAS</i> mutant tumors and primary tumors vs. distant metastases.
Authors: Mohamed E. Salem, John Marshall, Rebecca Feldman, Michael J. Pishvaian, Wafik S. El-Deiry, Jimmy J. Hwang, Emil Lou, Hongkun Wang, Zoran Gatalica, Sandeep K. Reddy, Anthony Frank Shields, Philip Agop Philip
Journal: Journal of Clinical Oncology (2016)

4121 Background: Targeted therapy has a minimal role in PC, partly because PC has not yet been well molecularly characterized. Little is known about the molecular characteristics of the subset of PC that doesn’t carry KRAS mutations. Better knowledge would enhance our ability to develop targeted therapies. Methods: PC tumors submitted to Caris Life Sciences for IHC (protein expression), ISH (gene amplification), and NGS sequencing between 2009 and 2015 were studied. Chi-square tests determined differences. Results: A total of 2426 PC tumors were examined. KRAS mutations (85%) were the most frequent genetic alteration. Other commonly mutated genes were TP53 (63%), SMAD4 (13%), BRCA2 (12%), ATM/APC/NTRK1 (5% each), BRCA1 (4%) and cMET/PIK3CA (3% each). BRAF mutations were seen in 6% of the RAS WT tumors. When compared with KRAS MT, KRAS WT tumors had a greater frequency of BRCA1 (9% vs. 3%, p = 0.05), CTNNB1 (5% vs. 0.2%; p < 0.01), GNAS (4% vs. 1.5%, p = 0.02), and FGFR2 (1.2% vs. 0.1%, p < 0.01) mutations, whereas SMAD4 and TP53 mutations were higher in KRAS MT tumors (15% vs. 5%, p = 0.02; 68% vs. 28%, p < 0.01, respectively). KRAS MT tumors had higher expression (66% vs. 49%, p < 0.01) and amplification (2.5% vs. 0%, p = 0.04) of cMET, and higher expression of EGFR (90% vs. 82%, p = 0.04), whereas KRAS WT tumors had higher HER2 expression (2% vs. 0.4%, p < 0.01) and amplification (6% vs. 0.7%, p < 0.01). Comparing 1o (n = 1099) with Met (n = 1327) PC, 1o tumors had a higher frequency of “low” ERCC1 (81% vs. 63%, p < 0.01) and “low” RRM1 (87% vs. 77%, p < 0.01), and higher PD1+ TILs (45% vs. 34%, p < 0.01). Conversely, cMET (62% vs. 51%, p = 0.006), PDL1 (10% vs. 5%, p = 0.01), and TOPO1 (65 vs. 33, p < 0.01) were overexpressed at higher rates in Met PC. Lung Mets, had a higher expression of HER2 (2.3% vs. 0.5%; < 0.01), and PD1 TILs (50% vs. 33%; p = 0.03) than liver Mets, whereas, the PIK3CA mutation rate was higher in liver Mets (4% vs. 0%; p = 0.03). Conclusions: Genomic differences between KRAS WT vs. MT tumors suggest different carcinogenic pathways and tumor biology. 1o tumors may carry genetic alterations that are distinct from distant Mets. Mutations in druggable genes (e.g., HER-2, PIK3CA, BRCA2) may provide therapeutic opportunities.
Circulation cell-free tumor DNA and extra-tumor heterogeneity in post-mortem examination.
Authors: Hayato Koba, Kazuo Kasahara, Yuichi Tambo, Hideharu Kimura
Journal: Journal of Clinical Oncology (2018)

e24045 Background: The cell-free DNA (cfDNA) exists in very small amount and fragmented in the bloodstream. It is well known that cfDNA contains tumor-derived DNA(tDNA) in malignant patients Therefore, cfDNA has been clinically applied to oncogene testing as a liquid biopsy We hypothesised that cfDNA has a potency to alternate the whole state and heterogeneity of lung cancer. The purpose of this study is 1) to evaluate the cfDNA as a marker to evaluate inter-tumor heterogeneity in each patient, and 2) to evaluate the characteristics of tDNA found in cfDNA. Methods: The patients with primary lung cancer who died due to cancer progression and autopsies were obtained from September 2011 April to 2017 were entered in the study. It was also necessary that there is cfDNA sample one month before the death. Informed consent was obtained from substitute. The gene alterations detected from each lesion including metastases using next generation sequencing (NGS) were compared with those derived from cfDNA of own patient. Results: The seven patients were entered in this study. Seven primary lesion and XX metastatic tumor were analyzed. The mean number detectable gene alterations from per patient is 253 (range 99-1918) from tDNA samples and 218 (range 56-362) from cfDNA sample, respectively. Although not all gene alterations detected from tDNA samples derived from all lesions were found out in cfDNA sample, the truncal gene alterations that involved in carcinogenesis could be detected in cfDNA. The gene alterations detected in at least two tumor samples were detected in cfDNA more frequently, than those in one sample. Furthermore, gene abnormalities in with high allele frequencies in tumor DNA tended to be easily found abnormal with cfDNA. Conclusions: In conclusion, cfDNA have a great potency because it includes the essential gene alterations which were characterized as the broad range among the tumor extent and the deep variant frequency in certain lesion.
Impact of OPTIMOX-aflibercept as first-line therapy on time to health-related quality of life deterioration in patients with unresectable metastatic colorectal cancer: results of the GERCOR VELVET phase II single arm study.
Authors: Julie Henriques, Amelie Anota, Benoist Chibaudel, Jean Baptiste Bachet, Thierry André, Dominique Auby, Jérôme Desramé, Nabil Baba Hamed, Cedric Lecaille, Christophe Louvet, Christophe Tournigand, Valerie Lebrun-Ly, Jérôme Dauba, Marie-Line Garcia, Olivier Dubreuil, Malika Attia, Aimery De Gramont, Franck Bonnetain
Journal: Journal of Clinical Oncology (2016)

e15009 Background: Recent studies showed improvement of patients outcomes with addition of aflibercept to FOLFIRI as second-line therapy for metastatic colorectal cancer (mCRC). The addition of aflibercept to an oxaliplatin-based first-line treatment strategy for patients with unresectable mCRC was evaluated in the VELVET study (Chibaudel B et al, J Clin Oncol 33, 2015 (suppl; abstr 3567)). This study focuses on the Health-related quality of life (HRQoL) analysis as secondary endpoint. Methods: EORTC QLQ-C30 was used to assess HRQoL at baseline, during treatment and one month after treatment. Pre-specified targeted dimensions were global health, emotional and physical functioning, fatigue and pain. Baseline scores were compared between patients with and without follow-up scores. Longitudinal HRQoL analyses were done using the time until definitive HRQoL score deterioration (TUDD) approach with a 5-point Minimal Clinically Important Difference including or not death as an event. Sensitivity analysis was performed including no follow-up as event. TUDD was estimated with the Kaplan-Meier method and univariate Cox models used to estimate Hazard ratios (HR) with its 99% confidence interval (CI) based on a Bonferroni adjustment. Results: Among the 49 patients included from 2013 to 2014, 47 patients (96%) filled the baseline HRQoL questionnaire. Ten patients who did not have follow-up measure had a lower baseline HRQoL level than other patients. Median TUDD or death varying from 5.6 months (99%CI 2.0-10.3) for physical functioning to 8.9 months (99%CI 3.9-14.1) for emotional functioning. Sensitivity analysis showed that all medians for targeted dimensions were lower than 5 months. Abnormal monocyte level was associated with shorter TUDD of emotional functioning or death (HR = 3.7 (99%CI 1.1-12.0)). Conclusions: Patients without follow-up scores seemed to present a lower baseline HRQoL level. Besides, the early onset of TUDD events suggests that deterioration in HRQoL could be an indicator for a progression in coming. These two points should be investigated in future clinical trials. Clinical trial information: NCT01802684.
Screening and stepped care targeting psychological distress in patients with metastatic colorectal cancer: The TES cluster randomized trial.
Authors: Claudia Schuurhuizen, Annemarie Braamse, Aartjan Beekman, Pim Cuijpers, Mecheline Van Der Linden, Adriaan Hoogendoorn, Inge R. Konings, Henk M.W. Verheul, Joost Dekker
Journal: Journal of Clinical Oncology (2018)

3560 Background: Psychological distress occurs frequently in patients with cancer. Effective management requires targeted selection of patients (T), followed by enhanced care (E), and the application of stepped care for psychological distress (S). This study aimed to evaluate the effectiveness of a screening and stepped care program (the TES program) compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC) starting with first line systemic treatment. Methods: In this cluster randomized trial, 16 hospitals were assigned to either the TES program or care as usual (CAU). Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer/Problem List (at baseline, 10 and 18 weeks). Stepped care was offered to those with distress, as well as to patients expressing the need for psychosocial care. Stepped care consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental health care. The primary outcome was change in psychological distress over time (HADS); secondary outcomes were quality of life (QOL), satisfaction with care and recognition and referral of distressed patients by clinicians. Measures were assessed at baseline, after 3, 10, 24 and 48 weeks of follow-up. Linear mixed models were used to evaluate the outcome. Results: A total of 349 patients were included; 184 to the TES program and 165 to CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress; 26.1% of patients entered the stepped care program (14.7% only used watchful waiting, and 11.4% used at least one of the following steps).There was no difference in the course of psychological distress over time between treatment groups (p > 0.05). The TES group reported higher satisfaction with the received treatment over time and better cognitive QOL (all p-values < 0.05). Conclusions: Screening and subsequent treatment for psychological distress does not improve psychological distress. Our results suggest that enhanced discussion of psychosocial concerns may improve aspects of patient's well-being. Clinical trial information: NTR4034.
Phenotypic and genomic characterization of CTCs as a biomarker for prediction of Veliparib therapy benefit in mCRPC.
Authors: Ryan Dittamore, Yipeng Wang, Stephanie Daignault-Newton, Walter Michael Stadler, Adam Jendrisak, Felix Y Feng, Angel E Dago, Jerry Lee, Ryon P Graf, Mark Andrew Landers, Arul Chinnaiyan, Maha Hussain
Journal: Journal of Clinical Oncology (2018)

5012 Background: Response to PARPi in mCRPC patients (pts) particularly those with DNA damage response mutations (DDRm) was observed in the TOPARP trials (utilizing Olaparib) which enrolled heavily pre-treated, high CTC pts. However, the NCI 9012 study, randomizing 1st line mCRPC pts to Abiraterone (A) or A + Veliparib (V), did not demonstrate an advantage for V in any pre-specified subgroup, with DDRm pts having better outcomes on both arms. Here we explore the use of CTCs to ascertain phenotypic Genomic Instability (pGI) as a proposed selection biomarker for PARPi. Methods: 212 blood samples from 84 pts (n = 39 A & n = 42 A+V, 3 uneval) prior to and during therapy were processed utilizing the Epic Sciences CTC platform. 32 pts had a concomitant fresh biopsy sequenced by MI-ONCOSEQ. CTC pGI was determined using previously described algorithms (Scher et al. ASCO 2016) which predicts genomic instability with morphological features and protein expression. A subset of CTCs (n = 466) underwent single cell sequencing for genomic scarring/DDRm and results were compared to tissue DDRm. CTC biomarkers were correlated with pt outcomes. Results: 80.2% (65/81) of baseline (BL) blood samples had enumerable CTCs. 48% (39/81) of these had ≥ 1 CTCs with pGI detected (pGI+). pGI+ pts had improved PSA response in the A+V arm, 83% (20/24) compared to 33% (5/15) in A (p = 0.002). Higher BL CTC counts were detected in tissue DDRm vs. DDR wild type (wt) pts (med 3.8 CTC/mL vs. 2.7 CTC/mL). pGI+ CTCs were detected in 42% (5/12) DDRm pts and 35% (7/20) DDRwt pts. Discordant results between CTC genomic scarring and tissue DDRm were observed. 3 pts with tissue DDRm only had CTCs with low genomic scarring. Conversely, 3 DDRwt pts had CTCs with high genomic scarring. pGI+ CTCs decreased in pGI+ pts from baseline to on-therapy with A+ V, 82% (9/11) pts (mean of 40 pGI+ CTC/mL) had reductions to < 1 pGI CTC/mL , whereas on A, only 20% (1/5) pts. (mean of 6 pGI+ CTC/mL) had a reduction to < 1 pGI CTC/mL (p = 0.036). Conclusions: A CTC biomarker, pGI, is correlated to differential PSA responses associated with A + V. Single cell CTC sequencing highlights the heterogeneity of genomic scarring in patients with and without DDRm and may be more sensitive than tissue based markers. Clinical trial information: NCT01576172.
Persistence of AKT1 low quiescent cancer cells after neoadjuvant chemotherapy in triple negative breast cancer patients.
Authors: Sheheryar Kairas Kabraji, Xavier Sole, Ying Huang, Clyde Bango, Michaela Bowden, Aditya Bardia, Dennis Sgroi, Massimo Loda, Sridhar Ramaswamy
Journal: Journal of Clinical Oncology (2017)

11579 Background: The mechanisms that allow triple negative breast cancer (TNBC) tumors to survive neoadjuvant chemotherapy (NACT) are incompletely understood. Evidence suggests that proliferative heterogeneity may contribute to primary chemotherapy resistance in patients with localized triple negative breast cancer. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1 low quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy resistant subpopulation initially identified in experimental cancer models. Here, we asked whether AKT1 low QCCs actually exist in primary tumors from patients with TNBC and persist after treatment with NACT. Methods: We identified QCCs in primary and metastatic human breast tumors using automated, quantitative, immunofluorescence microscopy coupled with computational and statistical analysis. We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with neoadjuvant chemotherapy at Massachusetts General Hospital (n = 25). Using automated quantitative immunofluorescence microscopy, QCCs were identified as AKT low / H3K9me2 low / HES1 high cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented as 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. Results: We found that QCCs exist as non-random and heterogeneously distributed clusters within primary tumors. In addition, these QCC clusters are enriched after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors as well as nodal and distant metastases in patients with triple negative breast cancer. Conclusions: Together, these data qualify QCCs as a non-genetic mechanism of chemotherapy resistance in triple negative breast cancer patients that warrants further study.
Successful development of a first in class tissue-based morphometric approach to re-define prostate cancer Gleason grading and improve risk discrimination at the time of diagnosis.
Authors: Michael Donovan, Faisal M Khan, Richard Scott, Gerardo Fernandez
Journal: Journal of Clinical Oncology (2016)

e16610 Background: We have previously shown the importance of utilizing the intact tissue section and quantitative multiplex immunofluorescence (MIF) for developing accurate prognostic risk models in prostate cancer. Our earlier biopsy-based surgical outcome model utilized the clinical biopsy Gleason score with H&E and MIF images. We now have utilized next-gen MIF image analysis to deconstruct the histologic attributes of the current Gleason grading system. This resulted in the generation of highly complex IF morphometric features that improve upon traditional histologic assessment Methods: We utilized a prior MIF image training cohort of 628 patients with a median 8 years follow-up post-radical prostatectomy. The analytic group constituted 2400 MIF images from biopsy tissue probed with CK-18 (epithelial cells), CK 5/6 (basal cells), androgen receptor (AR), Ki67, AMACR and DAPI (nuclear marker). Novel image analysis features that reflect biopsy tumor grade and biology were included to discriminate Gleason score (GS) 6 + organ confined disease, < / = pT2 (Favorable Pathology) vs.any pattern 4 and or non-organ confined ( > / = pT3a) (UFP). AUC was used to assess predictive performance. Results: We have been able to replicate our original models with new image features that more accurately reflect Gleason grading in a quantitative, non-subjective manner. These new models do not contain any H&E features nor is the clinical Gleason utilized. The AUC of the new training models ranged from 0.75-0.78 (original FP model had an AUC = 0.78), sensitivty, 70% and specificity 70-74%. In addition to pre-surgical PSA, the MIF image features selected by the model included gland ring structures which characterize the architecture of the prostate cancer gland combined with Androgen Receptor and Ki67 distribution and levels throughout the stroma and epithelium, respectively. Conclusions: The ability to more accurately characterize the Gleason grading system and refine risk classification has the potential to impact on future treatment decisions.
AFM26 is a novel, highly potent BCMA/CD16A-directed bispecific antibody for high affinity NK-cell engagement in multiple myeloma.
Authors: Thorsten Gantke, Uwe Reusch, Christian Kellner, Kristina Ellwanger, Ivica Fucek, Michael Weichel, Anne Kerber, Matthias Peipp, Martin Treder
Journal: Journal of Clinical Oncology (2017)

8045 Background: Despite recent advances in the treatment of multiple myeloma (MM), novel therapies are needed to achieve long-lasting remissions in a greater number of patients. Natural killer (NK) cells play a key role in the immune response to MM and have been implicated in the clinical efficacy of current standard of care interventions, including IMiDs, proteasome inhibitors, recently approved immunotherapies and autologous stem cell transplantation (ASCT). Numerous strategies are being developed to enhance the natural NK-cell cytotoxicity against myeloma cells, which is frequently dysregulated in MM. Approaches include modulation of activity, through cytokine stimulation or immune checkpoint targeting, and adoptive transfer of culture expanded NK-cells in ASCT-eligible MM. While highly attractive, these approaches are non-targeted, as they rely on the natural cytotoxicity of NK-cells, and may benefit from antigen-specific retargeting and effector activation. AFM26 is a novel tetravalent, bispecific antibody designed to specifically enhance NK-cell anti-MM activity by redirecting NK-cell lysis to BCMA, an antigen expressed on MM cells. Methods: NK-cell engagement and cytotoxicity of AFM26 towards MM cell lines and freshly isolated tumor cells from MM patients was characterized in vitro and compared with classical antibody formats. Results: AFM26 engages NK-cells with superior avidity ( K D : 1-2nM) through bivalent interaction with CD16A (FcγRIIIa) and demonstrates extended cell surface retention that is not affected by high level IgG, as is particularly relevant in MM. Importantly, AFM26 does not induce NK-cell depletion but selectively induces potent and efficacious lysis of MM cells in vitro. Conclusions: In summary, AFM26 is a promising candidate to enhance NK-cell activity and confer tumor-specificity to NK-cells in MM. Differentiation of AFM26 from classical antibody formats and its potential for combination with cellular NK-cell therapies is highlighted.
Results of patients with thoracic cancers older than 70 years included in clinical trials: A center experience.
Authors: Alex Martinez Marti, Guadalupe Cabrera, Carolina Ortiz, Marta Vilaro, Josep M Miquel, Susana Cedres Perez, Alejandro Navarro, Nuria Pardo Aranda, Pablo Martinez, Adelaida Piera, LLuisa Carbonell, Iris De la Fuente, Silvia Garcia, Irene Sansano, Enriqueta Felip
Journal: Journal of Clinical Oncology (2016)

e20582 Background: Median age at diagnosis of lung cancer is 70 years (y) and approximately 45% of patients (pts) are 70y or older. No consensus guidelines for the management of these older pts exists. Older pts with thoracic malignancies are under represented in clinical trials and treatment decisions for old pts are mostly determined by extrapolation from trials with younger pts. Methods: The aim of this retrospective study was to describe characteristics from pts older than 70y ( ≥ 70y) included in clinical trials and to compare findings with those observed in younger pts (< 70y). The ≥ 70y group (n = 110) was compared with a similar randomly selected < 70y group (n = 111) from the same period. Objectives were to compare Overall Survival (OS), Progression Free Survival (PFS) from the time of inclusion to death or last follow up; Response rate was based on RECIST v-1.1 and adverse events (AEs) were extracted from the individual clinical trials. Results: The 2012-14 VHIO experience included 410 pts with thoracic malignancies recruited in clinical trials. A total of 110 pts included in clinical trials were ≥ 70y (26%).Among ≥ 70y group median age was 74y. Distribution in phase I, II or III clinical trials was 23.6%, 34.5.5% and 41.8% respectively. Most patients had stage IV disease (74.5%). Histology was non-squamous carcinoma in 42.73%, squamous carcinoma in 31.82%, small cell carcinoma in 19.09% and malignant pleural mesothelioma in 6.36%. A 47.28% of the pts had received ≥ 1 line of treatment in metastatic setting (p = 0.922). Best treatment response was 36.6%, 40.9% and 18.1% as partial response, stable disease and progressive disease respectively (p = 0.421). OS in the ≥ 70y group was 11.8 vs 11months (m) in < 70y (HR 1.03 CI 95% 0.75-1.43, p = 0.845). PFS in the ≥ 70y group was 6.3 vs 5.8m in < 70y (HR 0.92 CI 95% 0.68-1.27, p = 0.625). SAEs were presented 21.8% in ≥ 70y compared with 14.4% in < 70y (p = 0.210). Conclusions: Age over 70 years represents a quarter of our pts included in clinical trials. No difference in OS neither PFS are found between older and younger pts. Older age should not be an exclusion criteria to recruit pts with thoracic malignancies in clinical trials.