tbuckley/cabot-search huggingface dataset:
Tracking endocrine resistance in estrogen-receptor positive breast cancer in ctDNA.
Authors: Magdalena Meissner, Rachel Butler, Angela Claire Casbard, Margherita Carucci, Tracie-Ann Madden, Sacha Jon Howell, Robert Hugh Jones
Journal: Journal of Clinical Oncology (2019)

e14550 Background: Endocrine therapy is the standard of care treatment for patients with estrogen-receptor positive advanced breast cancer, owing to improved tolerability and comparable efficacy to that of cytotoxic chemotherapy. Half of such cancers will progress through first line therapy (primary endocrine resistance) and half will progress after an initial period of disease control (secondary or acquired endocrine resistance). A significant challenge is to test for and identify biomarkers which can guide the likely success of endocrine therapy as a single agent or in combination with small molecule inhibitors.This is particularly challenging where metastatic deposits reside at sites where biopsy is difficult. Potential biomarkers indicative of resistance to endocrine therapy have been identified and can be detected in circulating tumour DNA (ctDNA). CtDNA is shed from tumours and is detectable in a cancer patient’s bloodstream. Information on mutational profiles can guide an oncologist in the selection of targeted therapy in addition to hormonal therapy. Methods: We have analysed formalin-fixed paraffin-embedded(FFPE) tumour samples and longitudinal liquid biopsies from 19 patients who were treated with fulvestrant in combination with a novel inhibitor of the PIK3CA/AKT pathway with next-generation sequencing using a targeted 44-gene panel. Mutations identified using this technique were tracked during the course of treatment using droplet-digital PCR(ddPCR). Results: 57 samples were tested using a 44-gene panel; 19 FFPE tumour samples and matched ctDNA samples were obtained prior therapy and ctDNA samples at disease progression. Mutations detected in PIK3CA, AKT1, ESR1and TP53 genes were trackable in longitudinal ctDNA samples using ddPCR. The association between ctDNA dynamics and outcome will be presented. Conclusions: Multiple mutations that enable the early detection of treatment failure and resistance can be tracked in ctDNA. Investigating the clinical utility of ctDNA is paramount.
Outcomes following lobectomy and pneumonectomy in stage IIIA non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiation.
Authors: Anuhya Kommalapati, Sri Harsha Tella, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2019)

e20042 Background: INT 0139 study showed that patients who received surgery after neoadjuvant chemoradiation did not have an overall survival (OS) benefit as compared to chemoradiation alone. Moreover, patients who underwent right sided pneumonectomy had non-significantly worse overall survival than chemoradiation alone. Methods: We sought to compare the survival outcomes in patients who received surgery after neoadjuvant chemoradiation based on the surgery type and the laterality of the disease using National Cancer Data Base (2004-15). Kaplan-Meier estimates were used to compare OS between the groups. Results: A total of 2881 and 499 patients had lobectomy and pneumonectomy after neoadjuvant chemoradiation, respectively. We found no difference in median OS in the patients who had left vs right lobectomy (Table). However, 30-, 90-day morality was higher in right lobectomy patients (p = 0.03). Similar trend was seen in the 30-, 90-day mortality and median OS in right and left pneumonectomies (Table). Total number of patients that got right pneumonectomy after neo-adjuvant chemoradiation before and after INT 0139 study (2009) did not change (49% vs 45%, p = 0.33). Conclusions: The short-term mortality was higher in right sided stage IIIA NSCLC patients in our cohort who received surgery irrespective of type of surgery. Interestingly, we did not notice any decrease in pneumonectomy rates since 2009. [Table: see text]
Abstract 19753: Impact of Stent Diameter on Stent Patency After Self-expanding Drug-eluting Stent Implantation in Superficial Femoral Artery Lesions
Authors: Kojiro Miki, Koji Yanaka, Nagataka Yoshihara, Kenji Kawai, Takahiro Imanaka, Hirokuni Akahori, Tohru Masuyama, Masaharu Ishihara
Journal: Circulation (2017)

Introduction: The optimal sizing of self-expanding drug-eluting stents (DES) in the treatment for superficial femoral artery (SFA) lesions is unclear. Hypothesis: This study sought to investigate w...
Physician benefit-risk preferences for non-metastatic castration-resistant prostate cancer treatment (nmCRPC).
Authors: Sandy Srinivas, Ateesha F. Mohamed, Sreevalsa Appukkuttan, Marc Botteman, Xinyi Ng, Namita Joshi, Erica Horodniceanu, Reg Waldeck, Stacey J. Simmons
Journal: Journal of Clinical Oncology (2019)

e16610 Background: Second-generation androgen receptor inhibitors (SGARIs) are now available for the management of nmCRPC based on improvements in metastasis-free survival. We used a discrete choice experiment (DCE) to explore how U.S. oncologists and urologists may balance different SGARIs’ risks (i.e., adverse events [AEs]) against survival, when treating an otherwise asymptomatic patient population. Methods: We invited oncologists and urologists treating nmCRPC patients via online panels to participate. The survey included 14 treatment choice questions, each comparing 2 hypothetical medication profiles, which varied in terms of 5 safety and 2 efficacy attributes. These attributes were selected via qualitative interviews and pre-testing with physicians, patients, and caregivers. We described safety attributes (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency and efficacy attributes (overall survival [OS] and time to pain progression) in terms of duration of effect. We used a main-effects random parameters logit model to estimate preference weights and importance scores for each attribute. Results: 74 oncologists and 75 urologists completed the survey. Among safety attributes, physicians were most concerned with cognitive problems, fractures, and fatigue. Physicians placed 36% more importance on reducing cognitive problems from severe to none compared to improving OS by 12 months instead of 3 months. On average, physicians were willing to trade off 7.1 months of OS for a reduction in fatigue severity from severe to mild/moderate and 0.8 months of OS for a reduction in fatigue from mild/moderate to none. Physicians were willing to trade off approximately 4.2 and 5.0 months of OS for reduction in fracture risk from 8% to 5%, and 5% to 0%, respectively. Conclusions: As shown in this DCE, physicians making treatment decisions for largely asymptomatic nmCRPC patients, were willing to trade substantial amounts of survival to avoid AEs. These results emphasize the importance of carefully balancing the risk-benefit profiles of SGARI therapy when treating this patient population, to ultimately optimize the overall quality of the patients’ survival.
Extra-mammary Paget’s disease (EMPD) of the skin: A comprehensive genomic profiling (CGP) study.
Authors: Julie Tse, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Ngo, Douglas I. Lin, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Dean Pavlick, Siraj Mahamed Ali, Alexa Betzig Schrock, Jon Chung, Prasanth Reddy, Kimberly McGregor, Brian Alexander, Vincent A. Miller, Andrea Necchi, Gennady Bratslavsky, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

9591 Background: EMPD is an intraepidermal adenocarcinoma which frequently progresses into invasive/metastatic disease. Methods: 29 EMPD underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: All patients had locally recurrent and/or metastatic disease. The 20 (69%) male and 9 (31%) female patients had a median age of 70 years (range 45 to 101 years). The primary EMPD site, known in 90% of cases and involved the scrotum (6 cases), groin (6 cases), vulva (5 cases), anus (3 cases), perineum (2 cases), abdomen (2 cases), penis (1 case) and buttock (1 case). was used for sequencing in 15 (52%) cases and a metastatic site 14 (48%) cases. The GA/tumor frequency was 5.0. The most frequent currently untargetable GA involved TP53 (48%), CDKN2A (38%), CDKN2B (31%), KMT2C (28%), and MYC (14%). The most frequent potentially targetable GA were identified in ERBB2 (35%), ERBB3 (17%) and PTEN (14%) and rarely in PDGFRA, CDK4/6, NF1/2, and ROS1 (fusion) all at 3%. The ERBB2 GA included short variant (SV) activating mutations (21%), amplifications (10%) and multiple ERBB2 GA in 3%. This finding is in contrast with mammary Paget’s disease which classically features &gt; 90% of cases with ERBB2 amplification. No EMPD cases were either MSI-High or stained positively for PD-L1 expression. The median and mean TMB were 5.2 mut/Mb and 6.3 mut/Mb, respectively; 4 (14%) had TMB ≥ 10 mut/Mb and 1 (3%) had TMB ≥ 20 mut/Mb. Conclusions: EMPD is a rare source of relapsed/metastatic adenocarcinoma which features GA that are distinct from the more common disease originating on the nipple of the breast including a lower ERBB2 GA frequency and lower relative frequency of ERBB2 amplification versus SV mutations. A variety of MTOR pathway, cell cycle and kinase targets are also identified when EMPD undergoes CGP. However, the low TMB and absence of both MSI-High status and PD-L1 expression in EMPD cohort indicates a likely lack of benefit for immunotherapies for patients suffering from this rare form of malignancy.
Association of human endogenous retrovirus (hERV) expression with clinical efficacy of PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Jean-Christophe Pignon, Opeyemi Jegede, Sachet A Shukla, David A. Braun, Christine Horak, Megan Wind-Rotolo, Yuko Ishii, Paul J. Catalano, Gordon J. Freeman, Rebecca B Jennings, Aguirre De Cubas, Kimryn Rathmell, Toni K. Choueiri, Michael B. Atkins, David F. McDermott, Sabina Signoretti
Journal: Journal of Clinical Oncology (2019)

4568 Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase II study of pts with mccRCC (Checkmate 010). Methods: Reverse transcribed RNA extracted from 99 FFPE pretreatment tumors were analyzed by RT-qPCR to assess levels of pan- ERVE4, pan- ERV3.2, hERV4700 GAG or ENV, and the reference genes 18S and HPRT1. Normalized hERV levels were transformed as categorical value (high or low) using population quartiles as cutoffs. For each cutoff, samples with non-quantifiable hERV levels for which the limit of quantification was above the tested cutoff could not be categorized and were excluded from analysis. Log rank test was used to test the association of hERV levels with PFS/irPFS (RECISTv1.1/irRECIST) at each cutoff using Holm-Bonferroni correction for Type I error control; adjusted P-values are reported. Fisher’s exact test was then used to explore the association with ORR/irORR (RECISTv1.1/irRECIST). Results: Among the hERV studied, only hERV4700 ENV was significantly associated with PFS/irPFS. At the 25 th percentile cutoff, 45 pts had high levels of hERV4700 ENV and 24 pts had low levels of hERV4700 ENV. Median PFS and irPFS were significantly longer in the high- hERV4700 ENV group [7.0 (95% CI: 2.2 - 10.2) and 8.5 (95% CI: 4.2 - 14.1) months, respectively] versus the low- hERV4700 ENV group [2.6 (95% CI: 1.4 - 5.4) and 2.9 (95% CI: 1.4 - 5.7) months, respectively] ( P = 0.010 for PFS and P = 0.028 for irPFS). At the same cutoff, ORR and irORR rates were significantly higher in the high- hERV4700 ENV group [35.6 (95% CI: 21.9 - 51.2) % for both ORR/irORR] versus the low- hERV4700 ENV group [12.5 (95% CI: 2.7 - 32.4) and 8.3 (95% CI: 1.0 - 27.0) %, respectively] ( P = 0.036 for ORR and P = 0.012 for irORR). Conclusions: hERV4700 ENV levels may predict outcome on nivolumab in mccRCC. Validation of our results and correlation of hERV levels with immune markers in a controlled phase III trial (CheckMate 025) is ongoing.
Compliant substratum modulates vinculin expression in focal adhesion plaques in skeletal cells
Authors: Chenchen Zhou, Qingxuan Wang, Demao Zhang, Linyi Cai, Wei Du, Jing Xie
Journal: International Journal of Oral Science (2019)

The biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. In the skeleton system, bone shows the potential to adapt its architecture and contexture to environmental rigidity via the bone remodelling process, which involves chondrocytes, osteoblasts, osteoclasts, osteocytes and even peripheral bone marrow-derived stem/stromal cells (BMSCs). In the current study, we generated stiff (~1 014 ± 56) kPa, Young's modulus) and soft (~46 ± 11) kPa silicon-based elastomer polydimethylsiloxane (PDMS) substrates by mixing curing agent into oligomeric base at 1:5 and 1:45 ratios, respectively, and investigated the influence of substrate stiffness on the cell behaviours by characterizing cell spreading area, cell cytoskeleton and cell adhesion capacity. The results showed that the cell spreading areas of chondrocytes, osteoblasts, osteoclasts, osteocytes and BMSCs were all reduced in the soft substrate relative to those in the stiff substrate. F-actin staining confirmed that the cytoskeleton was also changed in the soft group compared to that in the stiff group. Vinculin in focal adhesion plaques was significantly decreased in response to soft substrate compared to stiff substrate. This study establishes the potential correlation between microenvironmental mechanics and the skeletal system, and the results regarding changes in cell spreading area, cytoskeleton and cell adhesion further indicate the important role of biomechanics in the cell-matrix interaction.
Six cycles of adjuvant anthracycline-taxane-based chemotherapy compared with eight cycles for women with breast cancer.
Authors: Michael Lee, Sheridan Wilson, David James Porter
Journal: Journal of Clinical Oncology (2019)

e12045 Background: 3rd generation adjuvant chemotherapy regimens for breast cancer include FEC every three weeks (Q3W) x 3 cycles and Docetaxel (D) Q3W or weekly paclitaxel (P1W) x 9 weeks (FEC-D/P1W) and AC Q3W x 4 followed by P1W x 12 weeks or D x 4 cycles (AC-P1W). These regimens were developed independently and have not been directly compared. Real world effect of weekly paclitaxel schedule is unknown. Methods: Women with stage 1-3 breast cancer who received 3rd generation adjuvant chemotherapy (with 1 year of adjuvant trastuzumab if HER2+) between 2010-2015 inclusive were identified in the New Zealand Breast Cancer Database. Taxane regimens Q3W D and P1W were grouped for analysis. We compared 5 year overall survival (OS) between shorter FEC-D/P1W (total 6 cycles) and longer AC-P1W or Docetaxel Q3W x 4 cycles (total 8 cycles). Patients who received other taxane schedules or non-standard duration of chemotherapy were excluded. Results: 772 women received the FEC-D/P1W regimen and 488 were treated with AC-P1W. The FEC-D/P1W had more grade II/III disease (96.4% v 93.8%), BMI ≥30 (44.7% v 34.5%), HER2 positive (37.8% v 23.6%) and higher chemotherapy completion rate (95.1% v 83.8%). The AC-P1W cohort had higher nodal positive cases (97.1% v 80.6%). Univariate analysis showed no statistical significance for age, BMI, ethnicity, histological subtype and surgery type but tumour grade, stage and hormone status were significant. We constructed a cohort (n = 926) matched for these factors. After median follow up 27 months, 5yr OS for case matched cohort is 87.4% for FEC-D/P1W v 86.4% for AC-D/P1W (p = 0.825) with HR 0.96 (95%CI 0.67-1.38) in favour of FEC-D/P1W. Conclusions: These results suggest one can de-escalate chemotherapy by using a 6 cycle anthracycline/taxane regimen offering an opportunity to reduce the burden of chemotherapy without compromising survival.
Does mismatch repair (MMR) deficiency have prognostic significance in low-risk endometrioid endometrial cancers?
Authors: Soyoun Rachel Kim, Annick Pina, Arianne Albert, Jessica N. McAlpine, Robert Wolber, Cyril Blake Gilks, Mark S Carey, Janice S Kwon
Journal: Journal of Clinical Oncology (2019)

e17122 Background: Mismatch repair (MMR) deficiency is observed in 25-30% of all endometrial cancers. This can be detected by the absence of MMR protein staining on immunohistochemistry (IHC), and is used in many jurisdictions as a screen for an inherited mutation in one of the MMR genes (Lynch Syndrome). Only 10% of women with MMR deficiency (MMRd) have Lynch syndrome, but MMRd may still have prognostic significance. The objective of this study was to compare clinical outcomes between MMR deficient and proficient low-risk endometrioid endometrial cancers (stage IA, grade 1/2). Methods: This was a retrospective population-based cohort study of all low-risk endometrial cancers from Vancouver Coastal Health authority region from 2011 to 2016 that were assessed for MMR deficiency (MMRd). Primary outcome measures were recurrence rates expressed per person-years (py), progression free survival (PFS) and overall survival (OS) calculated using Kaplan-Meier method and log-rank tests. Cox proportional hazards model estimated the association between MMRd and recurrence and death after adjustment for covariates, expressed as hazard ratios (HR). Results: There were 475 low-risk patients, including 131 MMRd (27.6%) and 345 MMRp (proficient) patients. Women with MMRd tumors had higher recurrence rates (3.53p100py vs 1.21p100py) and worse PFS (p = 0.0082) compared to women with MMRp tumors. After adjustment for age, LVSI status, adjuvant therapy, and post-operative grade, MMRd status remained associated with a higher risk of recurrence (HR 2.99, 95% CI 1.27-7.04). There was no significant difference in OS between MMR groups (HR 1.38, 95% CI 0.57-3.33). Conclusions: In low-risk stage IA grade 1 or 2 endometrioid endometrial cancers, MMR deficiency is associated with a higher recurrence rate than in MMR proficient cases, after adjustment for covariates, implying that MMR deficiency reflects a different biology in endometrial cancer.
Adaptive Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in combination with GC4419 in pancreatic cancer.
Authors: Jon Holmlund, Melissa Brookes, Lauren Elizabeth Colbert, Shalini Moningi, Manoop S. Bhutani, Matthew H. G. Katz, Gauri Rajani Varadhachary, Peter F. Thall, Joseph M. Herman, Cullen M. Taniguchi
Journal: Journal of Clinical Oncology (2019)

TPS4164 Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5-7 Gy/fraction x 5 are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation is necessary to improve SBRT efficacy. GC4419, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. GC4419 is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, ASCO 2018). GC4419 improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H2O2, and more tolerant to elevated O2•-, than normal cells, and GC4419 demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding GC4419 to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with localized, unresectable PC without frank duodenal invasion, who have received 3+ cycles of induction chemotherapy, are to be randomized 1:1 to placebo or GC4419, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death ;stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10=100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with GC4419 or placebo. Exploratory endpoints include change in tumor radiographic resectability, correlative studies (ctDNA, exosomal DNA, tumor exome/transcriptome sequencing, immune profiling). Supported by Galera Therapeutics, Inc. Clinical trial information: NCT03340974.
Genetic profiling of synchronous multiple primary lung carcinomas presenting as ground-glass opacities.
Authors: Fenglei Yu, Jingqun Tang, Wenliang Liu, Xiang Wang, Chen Chen, Muyun Peng, Mingming Yuan, Min Zhang, Rongrong Chen, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e20034 Background: An increased incidence of synchronous multifocal pulmonary ground-glass opacities (GGOs) has been found in recent decades as a result of the advances in lung cancer screening techniques. However, little was known about the molecular mechanisms of their carcinogenesis, which may have important diagnostic, prognostic and therapeutic implications. Methods: 10 patients (pts) with clinically designated synchronous multiple primary lung cancers (sMPLC) who underwent surgical resection at our hospital were included in this study (Table). The imaging findings of all lesions were GGOs. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), enabling the simultaneous detection of mutations in 1021 cancer-associated genes. Tumor mutation burden (TMB) was calculated as the number of non-synonymous SNVs and Indels per Mb in the coding region. Results: The genetic profiles of 21 tumor lesions were analyzed. No common mutations were detected between different tumors from 70% of pts (7/10). These pts had different actionable mutations, which indicate disparate even contradictory therapeutic implications. 20% of pts (2/10) shared one driver mutation of EGFR or KRAS. Only one patient had a highly consistent mutation profiles between different GGOs. Two nodules of the patient shared 55% (6/11) of mutations, including EGFR L858R, supporting the possibility of aerogenic metastasis. The median TMB difference between nodules from one individual was 2 muts/Mb. The highest TMB difference was 16 muts/Mb, which might influence the decision of immunotherapy. Conclusions: NGS reveals independent clonality of multiple GGO lesions in most sMPLC pts, which may have contradictory therapeutic implications. In addition, it could be an auxiliary tool to differentiate intrapulmonary metastasis from multiple primary lung cancers. Therefore, broader molecular profiling is strongly advised for sMPLC pts. [Table: see text]